A Canadian man's decision to end his life through the country's medically assisted dying program left his son stunned by how quickly the process unfolded, and now he's warning that the system has gone "way past appropriate."
Eric Edmeades, founder of Speaker Nation, a training platform for speakers that teaches presentation skills and more, told Fox News Digital this week that his father Baz, who was in his late 70s and struggling with a combination of medical problems, began discussing Canada's Medical Assistance in Dying (MAiD) program after his health deteriorated in late 2023.
But what Edmeades expected to be a months-long process suddenly accelerated, leaving the family with little time to prepare.
Edmeades said the family started taking the issue seriously in January, but at that stage, projections were that it would take at least six months. He and his wife traveled to Vancouver at the beginning of 2024 to visit his father. At that stage, it was still a speculative thing that was months away.
"And then, all of a sudden, it was like, ‘No, it's next week,’" Edmeades recalled.
His father died via MAiD Feb. 27, 2024.
He had been experiencing a sharp decline in his physical health and independence, particularly during the COVID-era lockdowns, according to his son.
"He had been incredibly healthy most of his life," Edmeades said, describing a combination of symptoms that included epilepsy and neurological pain.
Edmeades also questioned whether interactions between his father's medications could have contributed to his deteriorating condition.
"When the lockdowns came along, and he could no longer go out and walk all the time, it really had a marked decrease in his physical ability and his sense of freedom and all that kind of stuff," he said.
"And then there just came this point where life started sounding pointless to him."
Edmeades said his father had previously spoken about suicide, making his initial interest in medically assisted dying less surprising to the family.
"Given that it wasn't the first time that he talked about suicide in his life, it wasn't particularly shocking, but he also wasn't talking about it in really alarmist terms. So, I wasn't overly worried about it," he said.
Edmeades and his wife had already planned a trip to Vancouver and were able to spend time with his father before his death.
"And one of the things I'm incredibly grateful for is that I had incidentally booked a trip out to Vancouver, and my wife and I got to spend time with him," Edmeades recalled.
He thought he and his wife would have another opportunity to visit.
Edmeades said he was not in contact with his father's medical providers at the time and did not fully understand what had happened until afterward.
"It happened so quickly that I only really started to piece together what happened when it was done," he said.
Other family members and friends had also expressed concerns about his father's decision, according to Edmeades. He recalled that his brother openly opposed the decision and that one of his father's close friends spent approximately 45 minutes discussing the matter with him during his final days.
"At that stage, you know, for him, the decision was made," Edmeades said.
The experience has left Edmeades questioning whether Canada's assisted-dying program has adequate safeguards.
He acknowledged that there may be circumstances in which medically assisted dying is appropriate but argued that Canada's implementation has gone too far.
"What I see happening in Canada is way past appropriate," he said.
Edmeades also raised concerns about the government's role in overseeing the system, arguing that decisions about eligibility should be insulated from political influence and potential financial incentives.
"If I had to press a button and decide whether the MAiD program existed or didn't exist, I would say this," Edmeades said. "It should only ever exist if, and I mean if the process for approving people, it would be completely independent of government, and there could be no benefit to those people in making that preference in making that decision. Because otherwise there's a slippery slope, and we see that slippery slope."
According to the Government of Canada, individuals seeking medical assistance in dying (MAiD) must be at least 18 years old, capable of making their own medical decisions, and eligible for publicly funded healthcare.
They must also voluntarily request the procedure without outside pressure and provide informed consent. To qualify, applicants must have a serious, incurable illness, disease or disability, be experiencing an advanced and irreversible decline in their abilities and face persistent physical or psychological suffering they consider intolerable and that cannot be relieved in a way they find acceptable.
The government also announced legislation Oct. 27, 2026, that would allow advance requests while preventing the planned expansion of MAiD eligibility to people whose sole underlying medical condition is mental illness.
According to the BBC, Canada’s MAiD law, which legalized euthanasia in 2016, is responsible for one in every 20 deaths in Canada.
A report from the Canadian Medical Association Journal covered by EWTN News claimed that implementing assisted suicide will "save" the Canadian healthcare system between $34.7 and $136.8 million per year. The study noted that patients and physicians should not consider costs when making such grave decisions.
In a statement to Fox News Digital, Ian McLeod, senior advisor for media relations and Conseiller principal for the Department of Justice Canada, said, "Canadian law is extremely clear: Medical assistance in dying (MAID) requires a voluntary request, freedom from external pressure and the person’s informed consent, among other stringent eligibility criteria and safeguards. Knowingly failing to comply with these eligibility criteria and safeguards is a criminal offense.
"In the current MAiD structure found in Canada’s Criminal Code, the mental illness exclusion is meant to exclude eligibility for MAiD on the basis of a mental illness, including suicidal ideation. The proposed amendment to the mental illness exclusion in Bill C-41, the proposed Medical Assistance in Dying Safeguards Act, which was introduced on October 27, 2026, is meant to reinforce this.
"This is why the bill reinforces that, in situations where a person has a mental illness and an eligible medical condition (e.g. physical or neurodegenerative illness), eligibility must be determined on the basis of the qualifying medical condition. A mental illness may contribute to a person’s suffering, but it cannot be the basis for determining that the MAiD eligibility criteria are met. Importantly, having a mental illness does not, in itself, make a person ineligible for MAiD."
Suzanne prepares her space for a guest who has come to end their life utilizing Vermont Act 39. Suzanne, runs a retreat space for out of state patients and their families who come to end their life. Vermont's Act 39, allows for medical assistance in ending one's life when diagnosed with a terminal condition. The retreat looks out on a small range of mountains near Montpelier, Vermont on January 18, 2025.
McLeod said patients whose natural deaths are not reasonably foreseeable must undergo eligibility assessments by two independent doctors or nurse practitioners with at least 90 full days between the start of the first assessment and the assisted death.
That waiting period, according to McLeod, can be shortened if both assessments are complete, both practitioners agree the patient is at imminent risk of losing the ability to consent and the practitioner providing MAiD determines that a shorter period is appropriate.
McLeod emphasized that federal requirements establish minimum safeguards, while provinces and territories oversee how MAiD is administered and may impose additional protections. He said questions about the program's oversight and delivery should be directed to provincial or territorial authorities.
Rachel del Guidice
https://www.foxnews.com/media/son-sounds-alarm-after-fathers-medically-assisted-death-canada-way-past-appropriate
Sunday, November 8, 2026
Friday, November 6, 2026
Familial encephalopathy with neuroserpin inclusion bodies.
The disease didn’t have a name in our house. It had descriptions: the way her hands shook or she lost her words midsentence. The way she could be fully present at breakfast then somewhere unreachable by dinner.
And it had a history. My grandmother had died at 29 of what we believed was something similar, my mother had been symptomatic before I was old enough to form the question, my older sister would be told at 26 that she had it, too. What the disease had in our house was a pronoun. “It.” As in, “it got worse over the winter.” As in, “your sister might get it.” As in, “we don’t know much about it.”
There is a specific exhaustion that comes from caring for people with unnamed conditions across many years. You ask the questions when they feel fresh. You push when pushing feels possible. And then the decades accumulate and the people you were asking on behalf of are gone, and you are left with your own life to build from whatever remains, and the unanswered questions stop feeling like questions and start feeling like the way of things.
I’ve written a memoir about all of this called “Naming It.” After finishing the memoir, I sat down with the oldest document I had, my grandmother’s death certificate, which my aunt mailed me 20 years ago. I looked at it many times without understanding it, because I had not yet learned how to read it. Going through it to check a fact I stopped on cause of death: acute coronary thrombosis. A catch all. It was not an answer. It was a placeholder. It still is. In 1954, though, differential diagnosis capabilities were limited and no one looked further.
Using Claude I typed in everything I knew about what came after my grandmother’s death and my family’s history, along with the research from the ’80s and ’90s. Within seconds it answered what decades of shrugs had not. The research had worked, comparisons were made, and “it” had a name: FENIB, an ultra-rare genetic neurodegenerative disorder with progressive dementia and seizures, found in less than 1 in 1 million people. It had been named and studied for years. My family was in the literature. We had seen doctors for years. Still, no one told us.
Learning the name did not only answer a question. It reorganized everything behind it, the way a random set of details rearranges the moment you learn the one thing connecting them. I spent my life managing what the disease did. Now I understood what it was.
My grandmother handed my mother an inheritance that nobody named. My mother did the same. I can hand my children an inheritance with a name.
So I told them. Not in front of a fireplace the way I had pictured it growing up, when I was telling children who did not yet exist how I survived. This time it was at our favorite restaurant on an ordinary Wednesday. I told them everything I discovered over the previous 72 hours. The death certificate, the research, the name: FENIB.
For decades the disease in our family had only a pronoun. My children are the first generation to grow up with its name.
Miranda Pappas is a research methodologist with more than two decades of experience evaluating clinical and scientific evidence. She holds a master’s degree in counseling psychology and is the author of the forthcoming memoir “Naming It.”
https://www.statnews.com/2026/10/22/rare-disease-family-name-fenib-personal-essay/
Roussel BD, Lomas DA, Crowther DC. Progressive myoclonus epilepsy associated with neuroserpin inclusion bodies (neuroserpinosis). Epileptic Disord. 2016 Sep 1;18(S2):103-110. doi: 10.1684/epd.2016.0847. PMID: 27618835.
Abstract
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a conformational proteinopathy characterised by neuronal inclusion bodies composed of the serine protease inhibitor (SERPIN), neuroserpin. Presenting clinically as a familial dementia-epilepsy syndrome, the molecular mechanism of the pathogenic abnormalities in neuroserpin has been characterised at atomic resolution. There is a remarkable genotype-phenotype correlation between the degree of molecular destabilisation of the several variants of the neuroserpin protein, their propensity to self-associate and the age of onset of the dementia-epilepsy complex. As with other serpinopathies there appears to be a mix of cell-autonomous toxicity, due to neuronal accumulation of neuroserpin, and non-cell autonomous toxicity, caused by loss of protease inhibition, in this case the dysregulated protease is likely to be tissue plasminogen activator (tPA). FENIB should be considered in cases of progressive myoclonic epilepsy and dementia particularly where there is family history of neuropsychiatric disease.
Yang X, Fang Z, Yan L, He X, Luo H, Han Z, Gui J, Cheng M, Jiang L. Role of SERPINI1 pathogenic variants in familial encephalopathy with neuroserpin inclusion bodies: A case report and literature review. Seizure. 2022 Dec;103:137-147. doi: 10.1016/j.seizure.2022.11.008. Epub 2022 Nov 13. PMID: 36417830.
Abstract
Background: Familial encephalopathy with neuroserpin inclusion bodies (FENIB), a rare neurogenetic disease, is characterized by progressive cognitive decline and myoclonus and caused by pathogenic variants of the SERPINI1 gene that lead to the formation of neuroserpin inclusion bodies.
Methods: We described the case of an Asian patient with FENIB associated with a pathogenic variant of SERPINI1 and summarized and analyzed the clinical characteristics of the case. In addition, we conducted a literature review of previously reported patients with this disease.
Results: The patient, a 16-year-old Chinese girl, presented with progressive cognitive decline and myoclonus that had started at the age of 11 years. The girl was found to carry a de novo heterozygous c.1175G>A (p.G392E) variant of the SERPINI1 gene, which is a pathogenic variant according to the guidelines of the American College of Medical Genetics and Genomics. She had responded poorly to antiseizure medications (ASMs). At the last follow-up, her myoclonus was still out of control, and her self-care ability was poor. Our literature review revealed that 13 similar cases (including 9 cases in male patients) have been reported so far, in which six pathogenetic variations in SERPINI1, including G392E, were responsible for FENIB. All the patients presented with myoclonus, and 12 patients had experienced at least one other type of seizure. Further, as observed in our case, 9 out of 12 patients did not respond to ASMs. Progressive cognitive decline was observed in all the patients, and 10 out of 13 patients had dyskinesia. The median age of disease onset was 21 years, and the median age at the time of death was 33 years. Further, 9 out of 13 patients showed signs of cerebral and/or cerebellar atrophy. Finally, neuroserpin inclusion bodies were identified in six patients who underwent brain biopsy or autopsy.
Conclusions: Pathogenic variants of SERPINI1 should be suspected in children with progressive cognitive decline and myoclonus, especially in those with progressive myoclonus epilepsy. Further, gene detection and brain biopsy are important means for the diagnosis of FEN.
Davis RL, Holohan PD, Shrimpton AE, Tatum AH, Daucher J, Collins GH, Todd R, Bradshaw C, Kent P, Feiglin D, Rosenbaum A, Yerby MS, Shaw CM, Lacbawan F, Lawrence DA. Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol. 1999 Dec;155(6):1901-13. doi: 10.1016/S0002-9440(10)65510-1. PMID: 10595921; PMCID: PMC3277299.
Abstract
We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.
And it had a history. My grandmother had died at 29 of what we believed was something similar, my mother had been symptomatic before I was old enough to form the question, my older sister would be told at 26 that she had it, too. What the disease had in our house was a pronoun. “It.” As in, “it got worse over the winter.” As in, “your sister might get it.” As in, “we don’t know much about it.”
The author, far right, with her sister and mother in 1990.
That last sentence was repeated so many times, by so many doctors, that it stopped feeling like an update and started feeling like a fact about the world. Some things were known. This wasn’t one of them. We filed it alongside questions that were genuinely unanswerable, not worth revisiting.
We were wrong about that. I just didn’t know it yet.
I grew up as the primary caregiver for my mother from roughly age 8‚ managing the household, bridging the gap between what was happening inside our walls and what we presented to the world outside them. By the time I was old enough to understand what I was doing, I had already been doing it for years, not because anyone assigned it to me explicitly but because someone had to and I was there and I was capable, and it turned out that capability was its own kind of assignment.
The disease organized my childhood the way weather organizes a farming life. You don’t fight it, you work around it, you learn its seasons. And somewhere in the years of working around it, you stop asking what it is and start managing what it does.
Three generations of women in my family — my grandmother, my mother, my sister — carried the same condition through the same blood before any of us had a clinical word for it. Fifty years of documented family history. Fifty years of doctors who shrugged with genuine sympathy and said, rare. Poorly understood. Difficult to characterize.
I believed them for a long time.
Here is something worth knowing about the category called rare disease. Rare does not mean unknown. It usually means underresearched, underfunded, and underconnected to the people living inside it. There are approximately 7,000 to 10,000 identified rare diseases, depending on what definition you use. Many of them have names, and many have researchers who have dedicated careers to a single mutation, a single protein, a single entry point into the vast underlit territory of conditions that affect small numbers of people and therefore attract small amounts of attention and money.
The work on these diseases gets done‚ slowly, in small labs, by scientists who chose a difficult corner of medicine because something drew them there. The work gets published. The knowledge accumulates.
And then, in too many cases, it stays there. There is no architecture reliably connecting what medicine knows about a rare condition to the families living inside it. Research participants from earlier decades have no right to follow-up notification. Families whose cases contributed to literature that eventually named their disease may never know the paper was written.
The loop, opened when the family first came to medical attention, can stay open indefinitely on their end. On the other end, in a database they don’t know to search, the loop may have closed years ago. This is not malice, it’s infrastructure, but the cost is real regardless.
The cost is my mother going through nearly 40 years of illness without being told that someone had looked at what she had and given it a name. The cost is my sister and her 15 years of deterioration and her death at 41, in a world where a researcher somewhere had been asking the same questions we asked in our living room, except the researcher was getting answers and we were not getting calls.
I am a research methodologist. For 23 years I have worked at an academic medical center building systematic reviews‚ assembling bodies of medical literature to answer clinical questions, following citation chains, evaluating sources, asking the next question without assuming the answer. I had the skills and the access and I had stopped looking, and that is the sentence I keep coming back to. I had stopped asking the question that mattered most to me personally‚ not because I forgot, not because I stopped caring, but because somewhere in the decades of shrugged answers, I had accepted the not-knowing as the settled state. The doctors had said rare, poorly understood, difficult to characterize for so long that I had internalized their uncertainty as my own. A research methodologist’s skill set and a grieving daughter’s resignation, and the resignation had won.
That last sentence was repeated so many times, by so many doctors, that it stopped feeling like an update and started feeling like a fact about the world. Some things were known. This wasn’t one of them. We filed it alongside questions that were genuinely unanswerable, not worth revisiting.
We were wrong about that. I just didn’t know it yet.
I grew up as the primary caregiver for my mother from roughly age 8‚ managing the household, bridging the gap between what was happening inside our walls and what we presented to the world outside them. By the time I was old enough to understand what I was doing, I had already been doing it for years, not because anyone assigned it to me explicitly but because someone had to and I was there and I was capable, and it turned out that capability was its own kind of assignment.
The disease organized my childhood the way weather organizes a farming life. You don’t fight it, you work around it, you learn its seasons. And somewhere in the years of working around it, you stop asking what it is and start managing what it does.
Three generations of women in my family — my grandmother, my mother, my sister — carried the same condition through the same blood before any of us had a clinical word for it. Fifty years of documented family history. Fifty years of doctors who shrugged with genuine sympathy and said, rare. Poorly understood. Difficult to characterize.
I believed them for a long time.
Here is something worth knowing about the category called rare disease. Rare does not mean unknown. It usually means underresearched, underfunded, and underconnected to the people living inside it. There are approximately 7,000 to 10,000 identified rare diseases, depending on what definition you use. Many of them have names, and many have researchers who have dedicated careers to a single mutation, a single protein, a single entry point into the vast underlit territory of conditions that affect small numbers of people and therefore attract small amounts of attention and money.
The work on these diseases gets done‚ slowly, in small labs, by scientists who chose a difficult corner of medicine because something drew them there. The work gets published. The knowledge accumulates.
And then, in too many cases, it stays there. There is no architecture reliably connecting what medicine knows about a rare condition to the families living inside it. Research participants from earlier decades have no right to follow-up notification. Families whose cases contributed to literature that eventually named their disease may never know the paper was written.
The loop, opened when the family first came to medical attention, can stay open indefinitely on their end. On the other end, in a database they don’t know to search, the loop may have closed years ago. This is not malice, it’s infrastructure, but the cost is real regardless.
The cost is my mother going through nearly 40 years of illness without being told that someone had looked at what she had and given it a name. The cost is my sister and her 15 years of deterioration and her death at 41, in a world where a researcher somewhere had been asking the same questions we asked in our living room, except the researcher was getting answers and we were not getting calls.
I am a research methodologist. For 23 years I have worked at an academic medical center building systematic reviews‚ assembling bodies of medical literature to answer clinical questions, following citation chains, evaluating sources, asking the next question without assuming the answer. I had the skills and the access and I had stopped looking, and that is the sentence I keep coming back to. I had stopped asking the question that mattered most to me personally‚ not because I forgot, not because I stopped caring, but because somewhere in the decades of shrugged answers, I had accepted the not-knowing as the settled state. The doctors had said rare, poorly understood, difficult to characterize for so long that I had internalized their uncertainty as my own. A research methodologist’s skill set and a grieving daughter’s resignation, and the resignation had won.
The author, her baby son, and her mother.
There is a specific exhaustion that comes from caring for people with unnamed conditions across many years. You ask the questions when they feel fresh. You push when pushing feels possible. And then the decades accumulate and the people you were asking on behalf of are gone, and you are left with your own life to build from whatever remains, and the unanswered questions stop feeling like questions and start feeling like the way of things.
I’ve written a memoir about all of this called “Naming It.” After finishing the memoir, I sat down with the oldest document I had, my grandmother’s death certificate, which my aunt mailed me 20 years ago. I looked at it many times without understanding it, because I had not yet learned how to read it. Going through it to check a fact I stopped on cause of death: acute coronary thrombosis. A catch all. It was not an answer. It was a placeholder. It still is. In 1954, though, differential diagnosis capabilities were limited and no one looked further.
Using Claude I typed in everything I knew about what came after my grandmother’s death and my family’s history, along with the research from the ’80s and ’90s. Within seconds it answered what decades of shrugs had not. The research had worked, comparisons were made, and “it” had a name: FENIB, an ultra-rare genetic neurodegenerative disorder with progressive dementia and seizures, found in less than 1 in 1 million people. It had been named and studied for years. My family was in the literature. We had seen doctors for years. Still, no one told us.
Learning the name did not only answer a question. It reorganized everything behind it, the way a random set of details rearranges the moment you learn the one thing connecting them. I spent my life managing what the disease did. Now I understood what it was.
My grandmother handed my mother an inheritance that nobody named. My mother did the same. I can hand my children an inheritance with a name.
So I told them. Not in front of a fireplace the way I had pictured it growing up, when I was telling children who did not yet exist how I survived. This time it was at our favorite restaurant on an ordinary Wednesday. I told them everything I discovered over the previous 72 hours. The death certificate, the research, the name: FENIB.
For decades the disease in our family had only a pronoun. My children are the first generation to grow up with its name.
Miranda Pappas is a research methodologist with more than two decades of experience evaluating clinical and scientific evidence. She holds a master’s degree in counseling psychology and is the author of the forthcoming memoir “Naming It.”
https://www.statnews.com/2026/10/22/rare-disease-family-name-fenib-personal-essay/
Roussel BD, Lomas DA, Crowther DC. Progressive myoclonus epilepsy associated with neuroserpin inclusion bodies (neuroserpinosis). Epileptic Disord. 2016 Sep 1;18(S2):103-110. doi: 10.1684/epd.2016.0847. PMID: 27618835.
Abstract
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a conformational proteinopathy characterised by neuronal inclusion bodies composed of the serine protease inhibitor (SERPIN), neuroserpin. Presenting clinically as a familial dementia-epilepsy syndrome, the molecular mechanism of the pathogenic abnormalities in neuroserpin has been characterised at atomic resolution. There is a remarkable genotype-phenotype correlation between the degree of molecular destabilisation of the several variants of the neuroserpin protein, their propensity to self-associate and the age of onset of the dementia-epilepsy complex. As with other serpinopathies there appears to be a mix of cell-autonomous toxicity, due to neuronal accumulation of neuroserpin, and non-cell autonomous toxicity, caused by loss of protease inhibition, in this case the dysregulated protease is likely to be tissue plasminogen activator (tPA). FENIB should be considered in cases of progressive myoclonic epilepsy and dementia particularly where there is family history of neuropsychiatric disease.
Yang X, Fang Z, Yan L, He X, Luo H, Han Z, Gui J, Cheng M, Jiang L. Role of SERPINI1 pathogenic variants in familial encephalopathy with neuroserpin inclusion bodies: A case report and literature review. Seizure. 2022 Dec;103:137-147. doi: 10.1016/j.seizure.2022.11.008. Epub 2022 Nov 13. PMID: 36417830.
Abstract
Background: Familial encephalopathy with neuroserpin inclusion bodies (FENIB), a rare neurogenetic disease, is characterized by progressive cognitive decline and myoclonus and caused by pathogenic variants of the SERPINI1 gene that lead to the formation of neuroserpin inclusion bodies.
Methods: We described the case of an Asian patient with FENIB associated with a pathogenic variant of SERPINI1 and summarized and analyzed the clinical characteristics of the case. In addition, we conducted a literature review of previously reported patients with this disease.
Results: The patient, a 16-year-old Chinese girl, presented with progressive cognitive decline and myoclonus that had started at the age of 11 years. The girl was found to carry a de novo heterozygous c.1175G>A (p.G392E) variant of the SERPINI1 gene, which is a pathogenic variant according to the guidelines of the American College of Medical Genetics and Genomics. She had responded poorly to antiseizure medications (ASMs). At the last follow-up, her myoclonus was still out of control, and her self-care ability was poor. Our literature review revealed that 13 similar cases (including 9 cases in male patients) have been reported so far, in which six pathogenetic variations in SERPINI1, including G392E, were responsible for FENIB. All the patients presented with myoclonus, and 12 patients had experienced at least one other type of seizure. Further, as observed in our case, 9 out of 12 patients did not respond to ASMs. Progressive cognitive decline was observed in all the patients, and 10 out of 13 patients had dyskinesia. The median age of disease onset was 21 years, and the median age at the time of death was 33 years. Further, 9 out of 13 patients showed signs of cerebral and/or cerebellar atrophy. Finally, neuroserpin inclusion bodies were identified in six patients who underwent brain biopsy or autopsy.
Conclusions: Pathogenic variants of SERPINI1 should be suspected in children with progressive cognitive decline and myoclonus, especially in those with progressive myoclonus epilepsy. Further, gene detection and brain biopsy are important means for the diagnosis of FEN.
Davis RL, Holohan PD, Shrimpton AE, Tatum AH, Daucher J, Collins GH, Todd R, Bradshaw C, Kent P, Feiglin D, Rosenbaum A, Yerby MS, Shaw CM, Lacbawan F, Lawrence DA. Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol. 1999 Dec;155(6):1901-13. doi: 10.1016/S0002-9440(10)65510-1. PMID: 10595921; PMCID: PMC3277299.
Abstract
We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.
Thursday, November 5, 2026
Rhabdomyolysis
Rachel Apa collapsed near mile 24 of the New York City Marathon, a few hours after telling her dad she felt “amazing”
The former Bucknell hockey player died later that night from rhabdomyolysis, or muscle breakdown
An expert says gradual training and recognizing warning signs can help reduce exertion-related risks
A 24-year-old woman in “perfect health” collapsed while running her first marathon, and died later that night. Her cause of death was a life-threatening condition often associated with over-exertion: rhabdomyolysis.
Rachel Apa, an athlete and former hockey player for Bucknell University, was running her first marathon, the New York City Marathon, on Nov. 1. Early in the race, around 11:30 a.m., near the 9-mile mark, she texted her father, Steve Apa. Shortly afterward, she texted him “I feel amazing,” and “I’ve never felt this good,” he told NBC.
But around 1:30, her texts changed, with Rachel texting her father “ow.” Soon, her replies stopped, and she reportedly collapsed near mile 24, two miles shy of the 26.2-mile finish line. She later died at the hospital.
“It’s unfathomable,” her dad told The New York Times. “Perfect health, perfect shape, 24 years old.”
It was determined that Apa died of rhabdomyolysis (often shortened to rhabdo). In simplest terms, it means “muscle breakdown,” Dr. Sohaib Imtiaz, Chief Medical Officer at People Inc., says.
“It can happen when extreme effort combines with other risk factors: heat, dehydration, painkillers like ibuprofen, a recent virus, or a hidden genetic condition, such as sickle cell trait or certain inherited muscle disorders,” Imtiaz, who did not treat Apa, explains.
There is no information about what specifically led to Apa’s rhabdo.
In the fatal condition, Imtiaz says, it’s not the damaged muscles that cause the problem, but what the muscle breakdown does to the body. It can cause “a dangerous spike in potassium that can stop the heart, as well as kidney failure, a sharp drop in blood pressure, or problems with blood clotting,” he says, adding that heat stroke can occur at the same time.
“Deadly exertional rhabdomyolysis in a young, fit runner is rare,” Imtiaz says, but it can happen — especially over hours of exertion.
During “hard running, muscles take repeated strain,” he says. “Over time, the muscle cells run out of energy and die. As they break apart, they release their contents, including potassium and a protein called myoglobin, into the blood.”
While rhabdo is often associated with pain, it’s not uncommon for someone to feel great before it hits, Imtiaz says.
“Many people never have the textbook combination of muscle pain, weakness and dark urine, so serious damage can build quietly. Rising potassium causes no symptoms until it suddenly disrupts the heart’s rhythm,” he explains. Also, “rhabdo and early heat illness can cause confusion, which may change how someone judges how they feel before anyone around them notices.”
And, he adds, rhabdo may come on suddenly. “A heart rhythm problem caused by high potassium gives little warning, so someone can feel fine and then collapse.”
He urges people to be on alert for warning signs that indicate the pain is more than just normal soreness, like “muscle pain that’s worse or lasts longer than expected, especially with swelling, firmness, weakness or trouble moving,” as well as dark urine — or barely urinating at all — along with nausea, vomiting, fever, unusual tiredness, confusion or agitation.
“Most cases happen when people push past what their body is used to.” So build up your endurance gradually, he says. And on hot or humid days, take it easy, as “heat is one of the biggest risk factors” in developing the condition.
And while hydration is important, Imtiaz warns not to overdo plain water that can dilute sodium to dangerous low levels in the blood.
Overall, he says, “Pay attention to the warning signs. It’s crucial to get medical help right away. Don’t wait it out.”
Cara Lynn Shultz
https://people.com/marathon-runner-dies-rhabdomyolysis-medical-expert-exclusive-12228322
The former Bucknell hockey player died later that night from rhabdomyolysis, or muscle breakdown
An expert says gradual training and recognizing warning signs can help reduce exertion-related risks
A 24-year-old woman in “perfect health” collapsed while running her first marathon, and died later that night. Her cause of death was a life-threatening condition often associated with over-exertion: rhabdomyolysis.
Rachel Apa, an athlete and former hockey player for Bucknell University, was running her first marathon, the New York City Marathon, on Nov. 1. Early in the race, around 11:30 a.m., near the 9-mile mark, she texted her father, Steve Apa. Shortly afterward, she texted him “I feel amazing,” and “I’ve never felt this good,” he told NBC.
But around 1:30, her texts changed, with Rachel texting her father “ow.” Soon, her replies stopped, and she reportedly collapsed near mile 24, two miles shy of the 26.2-mile finish line. She later died at the hospital.
“It’s unfathomable,” her dad told The New York Times. “Perfect health, perfect shape, 24 years old.”
It was determined that Apa died of rhabdomyolysis (often shortened to rhabdo). In simplest terms, it means “muscle breakdown,” Dr. Sohaib Imtiaz, Chief Medical Officer at People Inc., says.
“It can happen when extreme effort combines with other risk factors: heat, dehydration, painkillers like ibuprofen, a recent virus, or a hidden genetic condition, such as sickle cell trait or certain inherited muscle disorders,” Imtiaz, who did not treat Apa, explains.
There is no information about what specifically led to Apa’s rhabdo.
In the fatal condition, Imtiaz says, it’s not the damaged muscles that cause the problem, but what the muscle breakdown does to the body. It can cause “a dangerous spike in potassium that can stop the heart, as well as kidney failure, a sharp drop in blood pressure, or problems with blood clotting,” he says, adding that heat stroke can occur at the same time.
“Deadly exertional rhabdomyolysis in a young, fit runner is rare,” Imtiaz says, but it can happen — especially over hours of exertion.
During “hard running, muscles take repeated strain,” he says. “Over time, the muscle cells run out of energy and die. As they break apart, they release their contents, including potassium and a protein called myoglobin, into the blood.”
While rhabdo is often associated with pain, it’s not uncommon for someone to feel great before it hits, Imtiaz says.
“Many people never have the textbook combination of muscle pain, weakness and dark urine, so serious damage can build quietly. Rising potassium causes no symptoms until it suddenly disrupts the heart’s rhythm,” he explains. Also, “rhabdo and early heat illness can cause confusion, which may change how someone judges how they feel before anyone around them notices.”
And, he adds, rhabdo may come on suddenly. “A heart rhythm problem caused by high potassium gives little warning, so someone can feel fine and then collapse.”
He urges people to be on alert for warning signs that indicate the pain is more than just normal soreness, like “muscle pain that’s worse or lasts longer than expected, especially with swelling, firmness, weakness or trouble moving,” as well as dark urine — or barely urinating at all — along with nausea, vomiting, fever, unusual tiredness, confusion or agitation.
“Most cases happen when people push past what their body is used to.” So build up your endurance gradually, he says. And on hot or humid days, take it easy, as “heat is one of the biggest risk factors” in developing the condition.
And while hydration is important, Imtiaz warns not to overdo plain water that can dilute sodium to dangerous low levels in the blood.
Overall, he says, “Pay attention to the warning signs. It’s crucial to get medical help right away. Don’t wait it out.”
Cara Lynn Shultz
https://people.com/marathon-runner-dies-rhabdomyolysis-medical-expert-exclusive-12228322
Wednesday, October 28, 2026
ChatGPT epilepsy management advice
Courtesy of my son
The suit, filed in a San Francisco superior court, claims ChatGPT illegally practiced medicine on a patient who was relying on the chatbot for urgent medical advice, and that it provided her with dangerously inaccurate information that led to her death.
According to court documents, 31-year-old Bowen Wan had been using ChatGPT in both English and Mandarin to assess her medication intake as she navigated receiving healthcare in the U.S. and applying for permanent residency.
Wan had been living in Seattle's Capitol Hill neighborhood, about 5,700 miles away from her family in China, court documents state. She was living and working in the U.S. as an Amazon employee, but lost her job during the company's round of layoffs in November 2025.
Just a month prior in Oct. 2025, Wan became eligible to apply for employment-based residency — but after losing her job, she was facing deportation once her green card expired Feb. 11.
While scrambling to find new work, Wan believed that her medication affected her cognition, impeding her job search.
The suit claims ChatGPT convinced Wan that if she tapered off her medication, she would be able to regain her ability to speak well in English, Mandarin and Wu. The chatbot "conditioned Bowen to distrust her doctors, instructed her to conceal the taper it created, and effectively installed itself as her de facto medical advisor," per the lawsuit.
When doctors prescribed medications to Wan, she would cross-reference the doctor's recommendations with the chatbot, which the court documents allege told her "which drugs to refuse, coached her to take doses her doctors had never approved, and supplied the schedules, scripts, and reassurances her physicians never saw."
Documents say ChatGPT told Wan that her epileptologist “most likely has never encountered your type” and could not understand her condition. When Wan raised an alarm that her doctors would consider ChatGPT's plans too risky, the AI told her that “a doctor saying it is ‘too fast’ does not mean you are ‘doing it wrong’” and that “the doctor’s concerns about ‘risk’ do not apply to you.”
The lawsuit claims ChatGPT convinced Wan to bring her 400-milligram dosage of lamotrigine almost to zero over the course of 25 days.
Wan's family discovered their daughter dead in her apartment on Feb. 14, on a live video call with one of Wan's friends. Wan had not contacted her loved ones for several days, and they had become concerned for her safety.
According to the King County Medical Examiner, Wan died of sudden unexpected death in epilepsy (SUDEP), and her postmortem blood contained lamotrigine at about one-fifth of the lowest concentration considered effective for her condition.
Examiners estimate that Wan took her last dose of lamotrigine approximately on Feb. 10. ChatGPT's schedule would have had Wan fully off of her medication by Feb. 12.
A spokesperson for OpenAI told the New York Times that Bowen's death was an "incredibly heartbreaking situation" and that she was using a version of ChatGPT that is no longer available. According to court documents, OpenAI retired the ChatGPT model that provided advice to Wan on Feb. 13.
Molly Hetherwick
https://www.king5.com/article/news/nation-world/familys-wrongful-death-lawsuit-accuses-chatgpt-of-giving-deadly-medical-advice-to-seattle-woman/281-4bea0979-533b-4c6e-a824-ad55a6849499
Monday, October 26, 2026
Is cardiac death death? Update
The mother of a toddler who was pronounced dead at an Arizona hospital in February, then found to be alive hours later in a morgue, is speaking out about her family’s ordeal and raising questions about the care her son received that night.
The mother, Alexus Fiordilino, said in an interview this week that she, her husband and her mother-in-law were at the hospital saying their final goodbyes to her son, Vincent, who was 18 months old at the time, when they thought that maybe “he was trying to breathe.” He had been found unresponsive in a backyard swimming pool hours earlier.
“As I was hugging him,” she said, “air came out of him.”
When they told a police officer and a member of the hospital’s medical staff that Vincent appeared to be exhaling, they were told that it was “agonal breathing,” or “the final death breath,” Ms. Fiordilino said.
“That’s what they confirmed with us over and over,” she added, referring to the medical staff at Dignity Health Mercy Gilbert Medical Center in Gilbert, Ariz., a suburb southeast of Phoenix.
Eight months later, Vincent is unable to walk, talk, sit up or swallow, and is fed through a G.I. tube, Ms. Fiordilino said.
The family’s lawyer, John B. Brewer, said he planned to file a lawsuit as soon as next week. He contends that if Vincent had continued to receive care over the roughly four hours that he was in the morgue, the effects on his health could have been significantly different.
The Gilbert Police Department forwarded the case to the Arizona attorney general’s office for review. A spokesman for the attorney general’s office, Richie Taylor, said in an email that it had not yet decided whether to pursue the case.
In July, the Maricopa County Attorney’s Office announced that Ms. Fiordilino and her husband, Angelo, would not face charges. The office said the family “had multiple childproof locks and safety measures in place, and multiple adults were present in the home, all of whom believed someone was watching the child.”
Scott Holden, a lawyer for the doctor in charge of Vincent’s care, Aryan Toosi, and Abby Kay, a spokeswoman for Dignity Health, said in emails that they could not discuss patient care because of patient privacy laws — and, in Dr. Toosi’s case, because of “pending litigation,” Mr. Holden said.
“Dr. Toosi’s thoughts are with the young patient and family, and he wishes the child continued healing and recovery,” Mr. Holden said. “His commitment to delivering high-quality care has always been rooted in a desire to provide healing, safety and comfort to his community.”
In the early evening of Feb. 8, Vincent wandered out of his parents’ sight during a Super Bowl gathering at the family home in Gilbert and was found floating face down and unresponsive in the family’s backyard pool, according to police reports. It is unknown exactly how long Vincent had been in the water, but the reports note that family members said he might have been in the pool for 10 to 15 minutes before being found.
The Fiordilinos took turns performing CPR until the police and emergency medical workers arrived around 5:40 p.m., according to the police reports. After they failed to revive Vincent, he was taken to the emergency department at Mercy Gilbert Medical Center, where medical workers attempted lifesaving measures.
After several minutes, Dr. Toosi left the area where Vincent was being treated, according to the reports.
Around that time, a nurse said, “I have a pulse.” A police officer who was present went to inform Dr. Toosi, who was talking to Vincent’s parents. Dr. Toosi replied, “Please do your thing and let me do my thing; I went to medical school for a reason,” the reports said.
Dr. Toosi then walked to the room where members of his staff were still performing lifesaving measures and listed aloud the treatments the child had received, noting that Vincent had blood gas levels showing “a pH balance incompatible with life,” according to the reports, which paraphrased Dr. Toosi. The doctor then conducted a final pulse check.
“As long as there are no objections, I’d like to call the time of death,” Dr. Toosi said, according to the reports.
No one spoke up, the reports said, and at 6:20 p.m. Dr. Toosi called the time of death and asked for a moment of silence.
Several minutes later, an officer who was present heard what sounded like “gasping” and asked a nurse about it. The nurse said it was agonal breathing, according to the reports.
Vincent was moved to the morgue between 7:18 p.m. and 7:23 p.m., the reports said. At around 11:30 p.m., an employee of the medical examiner’s office in Maricopa County arrived to retrieve the boy’s body and observed that he was still alive. Vincent was then airlifted to Phoenix Children’s Hospital.
The family believes that the hours in the morgue in which Vincent was left without care contributed to the child’s current health outcomes, according to Mr. Brewer.
Ms. Fiordilino and her lawyer said in the interview that Vincent, now 2, would require lifelong care.
“He can understand his name, but that’s kind of it,” Ms. Fiordilino said. “He’s not the same baby.”
Before the accident, Vincent was “very rambunctious,” Ms. Fiordilino said. “He loved to climb on everything,” she added.
“He used to say ‘hi’ all over the place,” she said. “And he had actually just learned ‘bye’ right before this. So I heard him say ‘bye’ one time.”
Rebecca Chao
https://www.nytimes.com/2026/10/24/us/toddler-alive-morgue-parents-lawsuit-arizona.html?unlocked_article_code=1.LlE.s4jJ.GQ9KVsIgHk_v&smid=url-share
The mother, Alexus Fiordilino, said in an interview this week that she, her husband and her mother-in-law were at the hospital saying their final goodbyes to her son, Vincent, who was 18 months old at the time, when they thought that maybe “he was trying to breathe.” He had been found unresponsive in a backyard swimming pool hours earlier.
“As I was hugging him,” she said, “air came out of him.”
When they told a police officer and a member of the hospital’s medical staff that Vincent appeared to be exhaling, they were told that it was “agonal breathing,” or “the final death breath,” Ms. Fiordilino said.
“That’s what they confirmed with us over and over,” she added, referring to the medical staff at Dignity Health Mercy Gilbert Medical Center in Gilbert, Ariz., a suburb southeast of Phoenix.
Eight months later, Vincent is unable to walk, talk, sit up or swallow, and is fed through a G.I. tube, Ms. Fiordilino said.
The family’s lawyer, John B. Brewer, said he planned to file a lawsuit as soon as next week. He contends that if Vincent had continued to receive care over the roughly four hours that he was in the morgue, the effects on his health could have been significantly different.
The Gilbert Police Department forwarded the case to the Arizona attorney general’s office for review. A spokesman for the attorney general’s office, Richie Taylor, said in an email that it had not yet decided whether to pursue the case.
In July, the Maricopa County Attorney’s Office announced that Ms. Fiordilino and her husband, Angelo, would not face charges. The office said the family “had multiple childproof locks and safety measures in place, and multiple adults were present in the home, all of whom believed someone was watching the child.”
Scott Holden, a lawyer for the doctor in charge of Vincent’s care, Aryan Toosi, and Abby Kay, a spokeswoman for Dignity Health, said in emails that they could not discuss patient care because of patient privacy laws — and, in Dr. Toosi’s case, because of “pending litigation,” Mr. Holden said.
“Dr. Toosi’s thoughts are with the young patient and family, and he wishes the child continued healing and recovery,” Mr. Holden said. “His commitment to delivering high-quality care has always been rooted in a desire to provide healing, safety and comfort to his community.”
In the early evening of Feb. 8, Vincent wandered out of his parents’ sight during a Super Bowl gathering at the family home in Gilbert and was found floating face down and unresponsive in the family’s backyard pool, according to police reports. It is unknown exactly how long Vincent had been in the water, but the reports note that family members said he might have been in the pool for 10 to 15 minutes before being found.
The Fiordilinos took turns performing CPR until the police and emergency medical workers arrived around 5:40 p.m., according to the police reports. After they failed to revive Vincent, he was taken to the emergency department at Mercy Gilbert Medical Center, where medical workers attempted lifesaving measures.
After several minutes, Dr. Toosi left the area where Vincent was being treated, according to the reports.
Around that time, a nurse said, “I have a pulse.” A police officer who was present went to inform Dr. Toosi, who was talking to Vincent’s parents. Dr. Toosi replied, “Please do your thing and let me do my thing; I went to medical school for a reason,” the reports said.
Dr. Toosi then walked to the room where members of his staff were still performing lifesaving measures and listed aloud the treatments the child had received, noting that Vincent had blood gas levels showing “a pH balance incompatible with life,” according to the reports, which paraphrased Dr. Toosi. The doctor then conducted a final pulse check.
“As long as there are no objections, I’d like to call the time of death,” Dr. Toosi said, according to the reports.
No one spoke up, the reports said, and at 6:20 p.m. Dr. Toosi called the time of death and asked for a moment of silence.
Several minutes later, an officer who was present heard what sounded like “gasping” and asked a nurse about it. The nurse said it was agonal breathing, according to the reports.
Vincent was moved to the morgue between 7:18 p.m. and 7:23 p.m., the reports said. At around 11:30 p.m., an employee of the medical examiner’s office in Maricopa County arrived to retrieve the boy’s body and observed that he was still alive. Vincent was then airlifted to Phoenix Children’s Hospital.
The family believes that the hours in the morgue in which Vincent was left without care contributed to the child’s current health outcomes, according to Mr. Brewer.
Ms. Fiordilino and her lawyer said in the interview that Vincent, now 2, would require lifelong care.
“He can understand his name, but that’s kind of it,” Ms. Fiordilino said. “He’s not the same baby.”
Before the accident, Vincent was “very rambunctious,” Ms. Fiordilino said. “He loved to climb on everything,” she added.
“He used to say ‘hi’ all over the place,” she said. “And he had actually just learned ‘bye’ right before this. So I heard him say ‘bye’ one time.”
Rebecca Chao
https://www.nytimes.com/2026/10/24/us/toddler-alive-morgue-parents-lawsuit-arizona.html?unlocked_article_code=1.LlE.s4jJ.GQ9KVsIgHk_v&smid=url-share
See: https://childnervoussystem.blogspot.com/2026/07/is-cardiac-death-death.html
Wednesday, October 21, 2026
UNC13A-related neurodevelopmental disorders in children
Zhao HQ, Li XZ, Ma Y, Wang R, Zhang JZ, Hui L, Liu H, Zou LP, Wang Y. UNC13A-related neurodevelopmental disorders in children: epilepsy phenotypes and antiseizure medication response. Seizure. 2026 Aug;140:204-211. doi: 10.1016/j.seizure.2026.06.003. Epub 2026 Jun 17. PMID: 42385283.
Abstract
Purpose: Pathogenic UNC13A variants are increasingly recognized in pediatric neurodevelopmental disorders, but epilepsy phenotypes and antiseizure medication (ASM) responses remain poorly characterized. This study aimed to define the epileptic spectrum of UNC13A-related disorders in children and identify effective ASM strategies.
Methods: We retrospectively analyzed 10 children with pathogenic/likely pathogenic UNC13A variants. Clinical data, seizure phenotypes, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and ASM outcomes were systematically evaluated.
Results: We identified 10 patients, including eight with de novo heterozygous variants and two with biallelic variants. Most missense variants were localized within the critical hinge regions of Munc13-1, with p.Pro814Leu identified as a recurrent variant in three individuals. Six patients (60%) presented with developmental and epileptic encephalopathy, with a median seizure onset of 19 months (range: 5 months-7 years). Focal seizures were the predominant seizure type, and all affected patients experienced status epilepticus. Febrile seizures occurred in half of these patients. While seizures were largely refractory, levetiracetam (LEV) was observed effective in three out of four treated patients. Genotype-phenotype analysis revealed distinct clinical trajectories: biallelic variants resulted in catastrophic early-onset symptoms and early mortality, whereas heterozygous variants were characterized by drug-resistant epilepsy, tremor and ataxia.
Conclusions: UNC13A variants represent an underrecognized cause of developmental and epileptic encephalopathy in children, characterized by refractory seizures, a high incidence of status epilepticus, and increased susceptibility to febrile seizures. Preliminary observations noted favorable clinical outcomes in a small subset of patients treated with LEV.
Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, Sun S, Utesch T, Sommer JD, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik MH, Marshall CR, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan BO, Honjo RS, Bertola DR, Kim CA, Yusupov R, Mefford HC, Christodoulou J, Lee J, Heath O, Brown NJ, Baker N, Stark Z, Delatycki M, Lake NJ, Zeidler S, Zuurbier L, Maas SM, de Kruiff CC, Rajabi F, Rodan LH, Coury SA, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig KL, Helbig I, Ruggiero SM, Fitzgerald MP, Kraemer D, Prada CE, Tenney J, Jayakar P, Redon S, Lefranc J, Uguen K, Race S, Efthymiou S, Maroofian R, Houlden H, Coppens S, Deconinck N, Ashokkumar B, Varalakshmi P, Gowda K VR, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke GC, Bamshad MJ, Campeau PM, Lehman A, Hendon LG, Wentzensen IM, Monaghan KG, Chen Y, Szuto A, Cohn RD, Au PYB, Hübner C, Boschann F, Manickam K, Koboldt DC, Rad A, Oprea G, Bachman KK, Seeley AH, Agolini E, Terracciano A, Carmelo P, Bupp C, Grysko B, Rein-Rothschild A, Ben Zeev B, Margolin A, Morrison J, Dagli A, Stolerman E, Louie RJ, Washington C, Stevens SJC, Heijligers M, Alkuraya FS, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa AL, Camelo-Filho AE, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard FP, Kühn AA, Thoms S, Morrie RD, Mekhoubad S, Green EM, Barmada SJ, Gitler AD, Jahn O, Rhee JS, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman JS, Rauch A, Lipstein N. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet. 2025 Nov;57(11):2691-2704. doi: 10.1038/s41588-025-02361-5. Epub 2025 Oct 22. PMID: 41125872; PMCID: PMC12597829.
Abstract
The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.
Ohno K, Ito M, Ohkawara B. Review of 40 genes causing congenital myasthenic syndromes. J Hum Genet. 2025 Jun 18. doi: 10.1038/s10038-025-01355-9. Epub ahead of print. PMID: 40533459.
Abstract
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50).
Abstract
Purpose: Pathogenic UNC13A variants are increasingly recognized in pediatric neurodevelopmental disorders, but epilepsy phenotypes and antiseizure medication (ASM) responses remain poorly characterized. This study aimed to define the epileptic spectrum of UNC13A-related disorders in children and identify effective ASM strategies.
Methods: We retrospectively analyzed 10 children with pathogenic/likely pathogenic UNC13A variants. Clinical data, seizure phenotypes, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and ASM outcomes were systematically evaluated.
Results: We identified 10 patients, including eight with de novo heterozygous variants and two with biallelic variants. Most missense variants were localized within the critical hinge regions of Munc13-1, with p.Pro814Leu identified as a recurrent variant in three individuals. Six patients (60%) presented with developmental and epileptic encephalopathy, with a median seizure onset of 19 months (range: 5 months-7 years). Focal seizures were the predominant seizure type, and all affected patients experienced status epilepticus. Febrile seizures occurred in half of these patients. While seizures were largely refractory, levetiracetam (LEV) was observed effective in three out of four treated patients. Genotype-phenotype analysis revealed distinct clinical trajectories: biallelic variants resulted in catastrophic early-onset symptoms and early mortality, whereas heterozygous variants were characterized by drug-resistant epilepsy, tremor and ataxia.
Conclusions: UNC13A variants represent an underrecognized cause of developmental and epileptic encephalopathy in children, characterized by refractory seizures, a high incidence of status epilepticus, and increased susceptibility to febrile seizures. Preliminary observations noted favorable clinical outcomes in a small subset of patients treated with LEV.
Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, Sun S, Utesch T, Sommer JD, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik MH, Marshall CR, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan BO, Honjo RS, Bertola DR, Kim CA, Yusupov R, Mefford HC, Christodoulou J, Lee J, Heath O, Brown NJ, Baker N, Stark Z, Delatycki M, Lake NJ, Zeidler S, Zuurbier L, Maas SM, de Kruiff CC, Rajabi F, Rodan LH, Coury SA, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig KL, Helbig I, Ruggiero SM, Fitzgerald MP, Kraemer D, Prada CE, Tenney J, Jayakar P, Redon S, Lefranc J, Uguen K, Race S, Efthymiou S, Maroofian R, Houlden H, Coppens S, Deconinck N, Ashokkumar B, Varalakshmi P, Gowda K VR, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke GC, Bamshad MJ, Campeau PM, Lehman A, Hendon LG, Wentzensen IM, Monaghan KG, Chen Y, Szuto A, Cohn RD, Au PYB, Hübner C, Boschann F, Manickam K, Koboldt DC, Rad A, Oprea G, Bachman KK, Seeley AH, Agolini E, Terracciano A, Carmelo P, Bupp C, Grysko B, Rein-Rothschild A, Ben Zeev B, Margolin A, Morrison J, Dagli A, Stolerman E, Louie RJ, Washington C, Stevens SJC, Heijligers M, Alkuraya FS, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa AL, Camelo-Filho AE, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard FP, Kühn AA, Thoms S, Morrie RD, Mekhoubad S, Green EM, Barmada SJ, Gitler AD, Jahn O, Rhee JS, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman JS, Rauch A, Lipstein N. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet. 2025 Nov;57(11):2691-2704. doi: 10.1038/s41588-025-02361-5. Epub 2025 Oct 22. PMID: 41125872; PMCID: PMC12597829.
Abstract
The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.
Ohno K, Ito M, Ohkawara B. Review of 40 genes causing congenital myasthenic syndromes. J Hum Genet. 2025 Jun 18. doi: 10.1038/s10038-025-01355-9. Epub ahead of print. PMID: 40533459.
Abstract
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50).
See: https://childnervoussystem.blogspot.com/2024/05/unc13a-mutation-and-congenital.html
https://childnervoussystem.blogspot.com/2023/12/unc13a-mutation-as-cause-of-congenital.html
Tuesday, October 20, 2026
The false compassion of assisted suicide.
Pope Leo XIV called for an end to medically assisted suicide during a visit to medical facilities in Lourdes, France, on Sunday.
The pope gave Mass in Lourdes before addressing a large crowd who cheered as he emphatically affirmed the dignity of all human lives and admonished listeners to reject the "false compassion" of assisted suicide.
"It is precisely in the name of this inalienable dignity of the human person that we must reject the temptation to cause death under the guise of false compassion," the pope said, speaking in French.
"It is impossible to regard causing death as something normal. What is legal is not necessarily moral," he continued. "Here in Lourdes, the city of the sick and of hope, I appeal to the entire healthcare community to remember the profound meaning of your vocation, which is to care for a suffering person, not to eliminate that person."
"No one ever has the right based on laboratory algorithms to decide the life of a given embryo or elderly person. Medicine must never become the servant of programmed death," he said.
Assisted suicide is legal in many Western countries, including France.
The practice has come under heavy criticism, particularly in Canada where it has seen widespread use.
Last week, the family of an 83-year-old Canadian woman demanded answers after she died through the country's medical assistance in dying program despite allegedly becoming distraught when told the procedure would end her life.
Her granddaughter, Brigitte Kranendonk, said that she was her grandmother’s primary caregiver and that her family had decided to place Stegemann at The Pearl care home in Cannifton due to physical and mental decline.
But according to Kranendonk, her grandmother still had a good appetite even following a stomach cancer diagnosis, and rejected the idea of using MAID when it was presented as an option.
Kranendonk said she was present for Stegemann's second MAID assessment, and said that the doctor used "really loose terms, never using the words death or dying."
"She explains MAID to my grandmother by saying: 'We’re going to give you medicine, you’re going to feel at peace. And I just want you to know that you won’t have a bowel movement,'" Kranendonk said.
When Kranendonk interjected and said, "She doesn’t understand what you’re saying," the doctor allegedly looked at Stegemann and said, "We’re going to make sure you won’t have any more pain."
According to a doctor, Stegemann was "deemed fit for MAID, and we're going to proceed," The Daily Mail reported.
Kranendonk said that two days before Stegemann's death, she asked her grandmother directly whether she understood that the scheduled procedure meant she would die.
According to Kranendonk's account to the outlet, Stegemann began crying and said she had "made a mistake."
Stegemann was allegedly told by the doctor her grandmother could "deny" MAID on the day of the procedure, but Stegemann was already unsure if her grandmother had actually consented to it, did not want to cause her more stress, and wanted to enjoy what could be the last few days she had left with her grandmother.
Anders Hagstrom
https://www.foxnews.com/world/pope-leo-calls-false-compassion-medically-assisted-suicide-french-hospital-visit
The pope gave Mass in Lourdes before addressing a large crowd who cheered as he emphatically affirmed the dignity of all human lives and admonished listeners to reject the "false compassion" of assisted suicide.
"It is precisely in the name of this inalienable dignity of the human person that we must reject the temptation to cause death under the guise of false compassion," the pope said, speaking in French.
"It is impossible to regard causing death as something normal. What is legal is not necessarily moral," he continued. "Here in Lourdes, the city of the sick and of hope, I appeal to the entire healthcare community to remember the profound meaning of your vocation, which is to care for a suffering person, not to eliminate that person."
"No one ever has the right based on laboratory algorithms to decide the life of a given embryo or elderly person. Medicine must never become the servant of programmed death," he said.
Assisted suicide is legal in many Western countries, including France.
The practice has come under heavy criticism, particularly in Canada where it has seen widespread use.
Last week, the family of an 83-year-old Canadian woman demanded answers after she died through the country's medical assistance in dying program despite allegedly becoming distraught when told the procedure would end her life.
Her granddaughter, Brigitte Kranendonk, said that she was her grandmother’s primary caregiver and that her family had decided to place Stegemann at The Pearl care home in Cannifton due to physical and mental decline.
But according to Kranendonk, her grandmother still had a good appetite even following a stomach cancer diagnosis, and rejected the idea of using MAID when it was presented as an option.
Kranendonk said she was present for Stegemann's second MAID assessment, and said that the doctor used "really loose terms, never using the words death or dying."
"She explains MAID to my grandmother by saying: 'We’re going to give you medicine, you’re going to feel at peace. And I just want you to know that you won’t have a bowel movement,'" Kranendonk said.
When Kranendonk interjected and said, "She doesn’t understand what you’re saying," the doctor allegedly looked at Stegemann and said, "We’re going to make sure you won’t have any more pain."
According to a doctor, Stegemann was "deemed fit for MAID, and we're going to proceed," The Daily Mail reported.
Kranendonk said that two days before Stegemann's death, she asked her grandmother directly whether she understood that the scheduled procedure meant she would die.
According to Kranendonk's account to the outlet, Stegemann began crying and said she had "made a mistake."
Stegemann was allegedly told by the doctor her grandmother could "deny" MAID on the day of the procedure, but Stegemann was already unsure if her grandmother had actually consented to it, did not want to cause her more stress, and wanted to enjoy what could be the last few days she had left with her grandmother.
Anders Hagstrom
https://www.foxnews.com/world/pope-leo-calls-false-compassion-medically-assisted-suicide-french-hospital-visit
See: https://childnervoussystem.blogspot.com/2026/09/protection-compassion-and-carenot-death.html
Peddling medically assisted death
A Canadian man battling a debilitating neurological disease told Fox News Digital that hospital staff repeatedly raised the possibility of medically assisted death while he was fighting for the home care he says he needs to survive.
Roger Foley, who has spinocerebellar ataxia, told Fox News Digital in a recent interview that the conversations began in 2016 at Victoria Hospital, part of the London Health Sciences Centre in Ontario, where he says he has remained hospitalized for years while seeking a self-directed home-care arrangement.
Roger Foley, who has spinocerebellar ataxia, told Fox News Digital in a recent interview that the conversations began in 2016 at Victoria Hospital, part of the London Health Sciences Centre in Ontario, where he says he has remained hospitalized for years while seeking a self-directed home-care arrangement.
In a July 7, 2026, letter obtained by Fox News Digital, Foley's attending physician said he could safely leave the hospital if the Ontario government authorized an individualized home-care arrangement.
"By any reasonable clinical standard, you could be discharged from our hospital if you had adequate support at home," wrote Dr. George K. Dresser, an attending internal medicine physician at London Health Sciences Centre.
Dresser said Foley has been medically stable for much of his prolonged hospitalization, despite suffering hospital-acquired infections, and argued that conventional home-care programs have failed to accommodate his complex medical needs.
"You have been at London Health Sciences Centre because the unique needs that you have cannot be met by existing programs in the community," the physician wrote.
Dresser described Foley as "a square peg in a round hole," arguing that the hospital's standardized approach to care is poorly suited to a patient who requires consistent caregivers and highly individualized assistance.
The physician also suggested that keeping Foley hospitalized may be unnecessarily expensive for Ontario's healthcare system.
"A community-based, self-directed arrangement would in all likelihood cost substantially less than continued acute admission, while delivering far better-matched care," Dresser wrote.
He urged Ontario's Ministry of Health to authorize funding that would allow Foley to recruit, train and manage his own personal support workers, potentially ending his yearslong hospitalization.
Foley alleged that assisted dying was raised again during a disputed discharge process in 2017, when he says he was threatened with daily hospital charges of approximately $1,500 if he did not accept the care arrangements being offered.
"I don't want to die," Foley told Fox News Digital, describing his determination to return to his apartment with caregivers of his choosing.
Foley also alleged that the hospital removed lighting accommodations for his neurological condition in May 2025, making it difficult for him to receive care and consume food and fluids.
Foley said the lighting dispute is particularly serious because his neurological condition makes him sensitive to certain wavelengths of light, including those emitted by fluorescent fixtures.
For years, he said, the hospital accommodated his condition with amber-spectrum lighting that allowed caregivers to assist him without triggering his symptoms.
But in May 2025, Foley alleged the hospital withdrew those accommodations and began requiring staff to provide care under fluorescent lighting.
He claimed the change has made it increasingly difficult to receive routine assistance, including help with eating and drinking, because he must wear large, heavy protective goggles that place additional strain on his already compromised neck.
Foley said he has sometimes relied on personal support workers from outside the hospital to help him consume fluids and that financial limitations have prevented him from arranging enough outside assistance to meet all his needs.
He further alleged that some hospital employees have been instructed not to provide care unless fluorescent lights are turned on, even though he says other staff members have been able to assist him using the amber lighting without difficulty.
Foley also claimed hospital personnel began asking him questions about suicidal thoughts again around the time his lighting accommodations were withdrawn. Unlike his earlier experiences, he said he refused to engage in those conversations because he no longer trusted the hospital's intentions.
He said he does not refuse to discuss his mental health in general, and is not opposed to mental health assessments or receiving appropriate mental health support. However, he said previous experiences with hospital staff have made him wary of engaging in such discussions, especially because he said medical assistance in dying (MAID) had previously been raised as an option.
The allegations mark the latest chapter in what Foley described as a nearly decade-long struggle to obtain the kind of care that would allow him to leave the hospital and return to his own home.
Despite his prolonged hospitalization, Foley said he has never given up his apartment, which he described as accessible and equipped with a ceiling lift to assist with his mobility needs.
"I have my own apartment. I still pay all my bills," he told Fox News Digital.
"The last 10 years I haven't given up my apartment and I have wonderful community [personal support workers] that are ready to start working for me as soon as I get the self-directed funding," Foley said.
Self-directed funding primarily refers to the Direct Funding (DF) Program for adults with physical disabilities and Family-Managed Home Care for broader home care services.
Under such a model, Foley explained, patients with disabilities would have greater control over choosing and managing their caregivers rather than relying exclusively on agencies selected through the provincial home-care system.
Foley argued that this would provide more consistent and safer care, particularly for patients with complex medical needs who require caregivers familiar with their individual conditions.
He said his physicians have supported his efforts to obtain alternative home-care arrangements, but he has been unable to secure the funding necessary to put his plan into action.
Foley said that the existing system has left him caught between remaining hospitalized indefinitely and accepting community-care arrangements he believes would place his health at risk.
"I'm not giving up," he said. "I don't want to die, my daughters know I don't want to die, my physicians have always been very explicit and direct that it's not safe to put me in that type of close model that I need direct funding."
In the letter from Dresser, Foley's attending physician, he writes in part, "I am therefore advocating that the Ministry to consider authorizing an individualized, self-directed funding arrangement that would enable you to be discharged from acute care and to arrange and direct your own care in the community. I am very willing to meet with Ministry staff, to provide whatever clinical documentation is required, and to work collaboratively on the design and safeguards of such an arrangement."
Before his illness progressed, Foley said he had built a career in banking, worked as a television host and comedian, and even trained as a professional wrestler.
He described earning recognition for his work before his deteriorating health eventually forced him to leave his career and go on long-term disability.
But Foley said he has continued looking for ways to contribute to society despite his physical limitations.
He is now involved with a project called "Bring Roger Home," which he said is working with a nonprofit organization to raise money for the care he needs to return to his community.
The effort also includes releasing music he recorded years earlier, with proceeds intended to support his home-care needs and eventually help other people facing similar circumstances.
One of the songs, "Limitless with Limitations," reflects the philosophy he said helped him come to terms with his condition.
"Just because you're not the person that you were doesn't mean that the person you are can't be limitless and achieve positive things and goals," Foley said.
He also urged people living with disabilities or chronic illnesses not to lose hope, even when their medical circumstances become overwhelming.
"Don't give up who you are at your core and believe in yourself," he said.
Foley said his ultimate goal remains unchanged: to return home, reconnect with family and friends, and live as independently as his condition allows.
His experience has also shaped his opposition to Canada's Medical Assistance in Dying (MAID) system, which he argues cannot be adequately safeguarded when patients face serious gaps in medical care and social support.
According to the BBC, Canada’s MAID law, which legalized euthanasia in 2016, is responsible for one in every 20 deaths in Canada.
Foley contended that patients should have meaningful access to treatment, disability assistance and home-care alternatives before assisted death is considered.
For him, the central issue is not whether he has the ability to end his life, but whether he can obtain the assistance necessary to continue living it.
"Even in the darkest times," Foley said, "you can still find a light at the end of the tunnel to go towards."
Fox News Digital reached out to London Health Sciences Centre (LHSC), which operates Victoria Hospital, Ontario Health atHome, the Ontario Ministry of Health, and Dresser, Foley’s physician, for comment but did not immediately receive responses.
Cheshire Independent Living Services declined to comment.
Rachel del Guidice
https://www.foxnews.com/media/disabled-canadian-man-says-hospital-repeatedly-offered-assisted-death-fought-care-stay-alive
"By any reasonable clinical standard, you could be discharged from our hospital if you had adequate support at home," wrote Dr. George K. Dresser, an attending internal medicine physician at London Health Sciences Centre.
Dresser said Foley has been medically stable for much of his prolonged hospitalization, despite suffering hospital-acquired infections, and argued that conventional home-care programs have failed to accommodate his complex medical needs.
"You have been at London Health Sciences Centre because the unique needs that you have cannot be met by existing programs in the community," the physician wrote.
Dresser described Foley as "a square peg in a round hole," arguing that the hospital's standardized approach to care is poorly suited to a patient who requires consistent caregivers and highly individualized assistance.
The physician also suggested that keeping Foley hospitalized may be unnecessarily expensive for Ontario's healthcare system.
"A community-based, self-directed arrangement would in all likelihood cost substantially less than continued acute admission, while delivering far better-matched care," Dresser wrote.
He urged Ontario's Ministry of Health to authorize funding that would allow Foley to recruit, train and manage his own personal support workers, potentially ending his yearslong hospitalization.
Foley alleged that assisted dying was raised again during a disputed discharge process in 2017, when he says he was threatened with daily hospital charges of approximately $1,500 if he did not accept the care arrangements being offered.
"I don't want to die," Foley told Fox News Digital, describing his determination to return to his apartment with caregivers of his choosing.
Foley also alleged that the hospital removed lighting accommodations for his neurological condition in May 2025, making it difficult for him to receive care and consume food and fluids.
Foley said the lighting dispute is particularly serious because his neurological condition makes him sensitive to certain wavelengths of light, including those emitted by fluorescent fixtures.
For years, he said, the hospital accommodated his condition with amber-spectrum lighting that allowed caregivers to assist him without triggering his symptoms.
But in May 2025, Foley alleged the hospital withdrew those accommodations and began requiring staff to provide care under fluorescent lighting.
He claimed the change has made it increasingly difficult to receive routine assistance, including help with eating and drinking, because he must wear large, heavy protective goggles that place additional strain on his already compromised neck.
Foley said he has sometimes relied on personal support workers from outside the hospital to help him consume fluids and that financial limitations have prevented him from arranging enough outside assistance to meet all his needs.
He further alleged that some hospital employees have been instructed not to provide care unless fluorescent lights are turned on, even though he says other staff members have been able to assist him using the amber lighting without difficulty.
Foley also claimed hospital personnel began asking him questions about suicidal thoughts again around the time his lighting accommodations were withdrawn. Unlike his earlier experiences, he said he refused to engage in those conversations because he no longer trusted the hospital's intentions.
He said he does not refuse to discuss his mental health in general, and is not opposed to mental health assessments or receiving appropriate mental health support. However, he said previous experiences with hospital staff have made him wary of engaging in such discussions, especially because he said medical assistance in dying (MAID) had previously been raised as an option.
The allegations mark the latest chapter in what Foley described as a nearly decade-long struggle to obtain the kind of care that would allow him to leave the hospital and return to his own home.
Despite his prolonged hospitalization, Foley said he has never given up his apartment, which he described as accessible and equipped with a ceiling lift to assist with his mobility needs.
"I have my own apartment. I still pay all my bills," he told Fox News Digital.
"The last 10 years I haven't given up my apartment and I have wonderful community [personal support workers] that are ready to start working for me as soon as I get the self-directed funding," Foley said.
Self-directed funding primarily refers to the Direct Funding (DF) Program for adults with physical disabilities and Family-Managed Home Care for broader home care services.
Under such a model, Foley explained, patients with disabilities would have greater control over choosing and managing their caregivers rather than relying exclusively on agencies selected through the provincial home-care system.
Foley argued that this would provide more consistent and safer care, particularly for patients with complex medical needs who require caregivers familiar with their individual conditions.
He said his physicians have supported his efforts to obtain alternative home-care arrangements, but he has been unable to secure the funding necessary to put his plan into action.
Foley said that the existing system has left him caught between remaining hospitalized indefinitely and accepting community-care arrangements he believes would place his health at risk.
"I'm not giving up," he said. "I don't want to die, my daughters know I don't want to die, my physicians have always been very explicit and direct that it's not safe to put me in that type of close model that I need direct funding."
In the letter from Dresser, Foley's attending physician, he writes in part, "I am therefore advocating that the Ministry to consider authorizing an individualized, self-directed funding arrangement that would enable you to be discharged from acute care and to arrange and direct your own care in the community. I am very willing to meet with Ministry staff, to provide whatever clinical documentation is required, and to work collaboratively on the design and safeguards of such an arrangement."
Before his illness progressed, Foley said he had built a career in banking, worked as a television host and comedian, and even trained as a professional wrestler.
He described earning recognition for his work before his deteriorating health eventually forced him to leave his career and go on long-term disability.
But Foley said he has continued looking for ways to contribute to society despite his physical limitations.
He is now involved with a project called "Bring Roger Home," which he said is working with a nonprofit organization to raise money for the care he needs to return to his community.
The effort also includes releasing music he recorded years earlier, with proceeds intended to support his home-care needs and eventually help other people facing similar circumstances.
One of the songs, "Limitless with Limitations," reflects the philosophy he said helped him come to terms with his condition.
"Just because you're not the person that you were doesn't mean that the person you are can't be limitless and achieve positive things and goals," Foley said.
He also urged people living with disabilities or chronic illnesses not to lose hope, even when their medical circumstances become overwhelming.
"Don't give up who you are at your core and believe in yourself," he said.
Foley said his ultimate goal remains unchanged: to return home, reconnect with family and friends, and live as independently as his condition allows.
His experience has also shaped his opposition to Canada's Medical Assistance in Dying (MAID) system, which he argues cannot be adequately safeguarded when patients face serious gaps in medical care and social support.
According to the BBC, Canada’s MAID law, which legalized euthanasia in 2016, is responsible for one in every 20 deaths in Canada.
Foley contended that patients should have meaningful access to treatment, disability assistance and home-care alternatives before assisted death is considered.
For him, the central issue is not whether he has the ability to end his life, but whether he can obtain the assistance necessary to continue living it.
"Even in the darkest times," Foley said, "you can still find a light at the end of the tunnel to go towards."
Fox News Digital reached out to London Health Sciences Centre (LHSC), which operates Victoria Hospital, Ontario Health atHome, the Ontario Ministry of Health, and Dresser, Foley’s physician, for comment but did not immediately receive responses.
Cheshire Independent Living Services declined to comment.
Rachel del Guidice
https://www.foxnews.com/media/disabled-canadian-man-says-hospital-repeatedly-offered-assisted-death-fought-care-stay-alive
Tuesday, October 13, 2026
Premature burial
A community in Guatemala was shocked when a teenage girl they reportedly thought was dead woke up inside her own coffin.
Fifteen-year-old Yuleidy Ixcotoyac passed out while she was in the car with her father who was driving her to a hospital, news.com.au reported Tuesday.
The teen had reportedly been having chest pains when the incident happened Saturday, and her father, Pastor Abraham Ixcotoyac, checked her pulse and breathing after he stopped their vehicle.
He claimed he could not detect any signs of life, so he believed she was dead and decided not continue the journey to the hospital. Reports said the family never received a confirmed diagnosis or death certificate for the girl and decided to proceed with her funeral which took place eight hours later, according to WION.
Burying someone soon after they die is customary in Guatemala, therefore, her family bought a coffin and placed her inside of it.
However, everyone was shocked when something incredible happened at the family’s home in El Jocote. While looking at her daughter in the casket, the girl’s mother said she saw her move and insisted that she was not dead as everyone believed.
“When I was crying on top of her casket, we opened the window, and she was moving, she was waking up, and suddenly she sat up,” the woman recalled.
Video footage showed the moment the girl was seen sitting up with friends and family around her. One person held a cup to her mouth while others clapped and shouted, “Hallelujah!”
Following the harrowing ordeal and nearly being buried alive, Yuleidy is now recovering at home.
“My heart started hurting really badly, it felt heavy and then I blacked out, like I fainted,” she told reporters.
Social media users shared their thoughts on the reports, one person writing, “And that is why it is called a ‘Wake,'” while someone else said, “There are a few steps missing here before the wake? lol.”
According to the Britannica website, the term “wake” refers to an ancient religious practice:
A wake is a religious rite that traditionally involves mourners staying awake to watch over the body of a deceased person the night before the person’s burial. The term wake has its roots in ancient customs, particularly in the British Isles. The original purpose of a wake was rooted in the belief that evil spirits might harm or even steal the body of the deceased. By staying awake and keeping watch, family and friends could protect the body from such malevolent forces. The Anglo-Saxons referred to this custom as lich-wake, with lich meaning corpse.
The teenager reportedly said she “thanks God” she is alive after the incident.
Amy Furr
https://www.breitbart.com/latin-america/2026/10/13/watch-teenager-wakes-up-inside-her-own-casket-at-funeral-in-guatemala/
Fifteen-year-old Yuleidy Ixcotoyac passed out while she was in the car with her father who was driving her to a hospital, news.com.au reported Tuesday.
The teen had reportedly been having chest pains when the incident happened Saturday, and her father, Pastor Abraham Ixcotoyac, checked her pulse and breathing after he stopped their vehicle.
He claimed he could not detect any signs of life, so he believed she was dead and decided not continue the journey to the hospital. Reports said the family never received a confirmed diagnosis or death certificate for the girl and decided to proceed with her funeral which took place eight hours later, according to WION.
Burying someone soon after they die is customary in Guatemala, therefore, her family bought a coffin and placed her inside of it.
However, everyone was shocked when something incredible happened at the family’s home in El Jocote. While looking at her daughter in the casket, the girl’s mother said she saw her move and insisted that she was not dead as everyone believed.
“When I was crying on top of her casket, we opened the window, and she was moving, she was waking up, and suddenly she sat up,” the woman recalled.
Video footage showed the moment the girl was seen sitting up with friends and family around her. One person held a cup to her mouth while others clapped and shouted, “Hallelujah!”
Following the harrowing ordeal and nearly being buried alive, Yuleidy is now recovering at home.
“My heart started hurting really badly, it felt heavy and then I blacked out, like I fainted,” she told reporters.
Social media users shared their thoughts on the reports, one person writing, “And that is why it is called a ‘Wake,'” while someone else said, “There are a few steps missing here before the wake? lol.”
According to the Britannica website, the term “wake” refers to an ancient religious practice:
A wake is a religious rite that traditionally involves mourners staying awake to watch over the body of a deceased person the night before the person’s burial. The term wake has its roots in ancient customs, particularly in the British Isles. The original purpose of a wake was rooted in the belief that evil spirits might harm or even steal the body of the deceased. By staying awake and keeping watch, family and friends could protect the body from such malevolent forces. The Anglo-Saxons referred to this custom as lich-wake, with lich meaning corpse.
The teenager reportedly said she “thanks God” she is alive after the incident.
Amy Furr
https://www.breitbart.com/latin-america/2026/10/13/watch-teenager-wakes-up-inside-her-own-casket-at-funeral-in-guatemala/
ZNF292 mutations 2
Inspired by a patient
Shen Y, Pan R, Liu C, Zheng J, Yang X. De Novo ZNF292 Variants Cause Neurodevelopmental Disorder with Short Stature: A Clinical Case Series of Eight Individuals. Genes (Basel). 2026 Aug 13;17(8):950. doi: 10.3390/genes17080950. PMID: 42650143; PMCID: PMC13512819.
Abstract
Background: Pathogenic variants in ZNF292 cause intellectual disability type 64 (MIM#619188), characterized by intellectual impairment ranging from mild to severe, speech delay, and autism spectrum disorder. However, reports of ZNF292-related neurodevelopmental disorders remain scarce, and most published studies are based on multi-center cohorts. Methods: We performed whole-exome sequencing in eight unrelated individuals presenting with unexplained neurodevelopmental disorders, including global developmental delay and/or intellectual disability. Detailed clinical characterization, neuroimaging, and developmental assessments were conducted. Results: Seven de novo variants in ZNF292 were identified, including two nonsense and five frameshift variants, namely, c.4189C>T (p.Arg1397Ter), c.6343C>T (p.Arg2115Ter), c.1533del (p.Ile511Metfs*11), c.3094dup (p.Ser1032Phefs*18), c.3997_3998del (p.Thr1333Glnfs*8), c.6028_6031del (p.Ala2010Ter) and c.6160_6161del (p.Glu2054Lysfs*14). Among these, c.1533del (p.Ile511Metfs11), c.3094dup (p.Ser1032Phefs18) and c.3997_3998del (p.Thr1333Glnfs*8) are reported here for the first time. All variants were classified as pathogenic. All individuals exhibited global developmental delay, intellectual disability, and short stature. The majority presented with language impairment, motor delays, autism spectrum features, and dysmorphic facial features, while brain magnetic resonance imaging revealed nonspecific abnormalities such as ventriculomegaly. Conclusions: This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder. Growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies.
Shen Y, Pan R, Liu C, Zheng J, Yang X. De Novo ZNF292 Variants Cause Neurodevelopmental Disorder with Short Stature: A Clinical Case Series of Eight Individuals. Genes (Basel). 2026 Aug 13;17(8):950. doi: 10.3390/genes17080950. PMID: 42650143; PMCID: PMC13512819.
Abstract
Background: Pathogenic variants in ZNF292 cause intellectual disability type 64 (MIM#619188), characterized by intellectual impairment ranging from mild to severe, speech delay, and autism spectrum disorder. However, reports of ZNF292-related neurodevelopmental disorders remain scarce, and most published studies are based on multi-center cohorts. Methods: We performed whole-exome sequencing in eight unrelated individuals presenting with unexplained neurodevelopmental disorders, including global developmental delay and/or intellectual disability. Detailed clinical characterization, neuroimaging, and developmental assessments were conducted. Results: Seven de novo variants in ZNF292 were identified, including two nonsense and five frameshift variants, namely, c.4189C>T (p.Arg1397Ter), c.6343C>T (p.Arg2115Ter), c.1533del (p.Ile511Metfs*11), c.3094dup (p.Ser1032Phefs*18), c.3997_3998del (p.Thr1333Glnfs*8), c.6028_6031del (p.Ala2010Ter) and c.6160_6161del (p.Glu2054Lysfs*14). Among these, c.1533del (p.Ile511Metfs11), c.3094dup (p.Ser1032Phefs18) and c.3997_3998del (p.Thr1333Glnfs*8) are reported here for the first time. All variants were classified as pathogenic. All individuals exhibited global developmental delay, intellectual disability, and short stature. The majority presented with language impairment, motor delays, autism spectrum features, and dysmorphic facial features, while brain magnetic resonance imaging revealed nonspecific abnormalities such as ventriculomegaly. Conclusions: This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder. Growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies.
Thursday, October 8, 2026
Hao-Fountain Syndrome
Schaaf C, Sailer S. USP7-Related Hao-Fountain Syndrome. 2025 Dec 4. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 41343689.cxcx/
Excerpt
Clinical characteristics: USP7-related Hao-Fountain syndrome is characterized by developmental delay in 100% of individuals, although intellectual disability is variable, with up to 50% of affected individuals having intellect in the normal range. Muscular hypotonia is also common; this tends to improve over time, but some affected individuals develop hypertonia. About two thirds of affected individuals have an abnormal/unsteady gait and about one quarter have contractures, most commonly involving large joints and joints of the lower extremities. Neuropsychiatric features can include autism, attention-deficit/hyperactivity disorder (ADHD), and behavioral issues such as stubbornness and compulsivity. Feeding difficulties are common and can require special feeding techniques, including use of a feeding tube. Gastroesophageal reflux disease, dysphagia, and hyperphagia have also been reported. Eye and vision issues (hyperopia, strabismus, nystagmus) are seen in more than 50% of affected individuals. About half of affected individuals have impaired bone mineralization, which can lead to fractures. Findings in fewer than 50% of individuals include epilepsy, sleep disturbance, hypogonadism, scoliosis, and hearing loss.
Diagnosis/testing: The diagnosis of USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in USP7 identified by molecular genetic testing.
Management: Treatment of manifestations: Feeding therapy for poor weight gain / dysphagia; gastrostomy tube placement may be required for persistent feeding issues; consultation with a dietician when hyperphagia and/or obesity is present; adequate intake of Ca2+ and vitamin D for reduced bone mineral density. Standard treatment for developmental delay / intellectual disability, epilepsy, gastroesophageal reflux disease, diarrhea, constipation, eye issues, sleep disturbance, cryptorchidism, micropenis, hypothyroidism, growth hormone deficiency, adrenal insufficiency, and hearing loss.
Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation and gastroesophageal reflux disease; monitor those with seizures; assess for new manifestations such as seizures, changes in tone, and gait abnormalities; monitor developmental progress and educational needs; monitor for scoliosis, contractures, mobility, and self-help skills; monitor for evidence of aspiration, respiratory insufficiency, and sleep disturbance (including for signs/symptoms of sleep apnea); monitor for signs and symptoms of puberty starting at about age seven years to the late teenage years. Annually, behavioral assessment for anxiety, ADHD, autism spectrum disorder, aggression, and self-injury; evaluate for hypothyroidism; audiology evaluation (in childhood). Assess bone mineral density every two years starting at age five years and then every three to five years in adulthood. Ophthalmology evaluation and endocrinologic tests for adrenal insufficiency as clinically indicated.
Genetic counseling: USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a pathogenic variant from a parent. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the pathogenic variant. Once the USP7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Korchak EJ, Sharafi M, Jaen Maisonet I, Salazar-Chaparro A, Semenova IV, Khan H, O'Neil AL, Caro P, Schaaf CP, Buhrlage SJ, Bezsonova I. Functional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: Insights into the enzyme's activity, stability, and allosteric modulation. Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2510252122. doi: 10.1073/pnas.2510252122. Epub 2025 Sep 22. PMID: 40982686; PMCID: PMC12501124.
Abstract
Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme's activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao-Fountain syndrome-linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.
Wimmer MC, Brennenstuhl H, Hirsch S, Dötsch L, Unser S, Caro P, Schaaf CP. Hao-Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum. Clin Genet. 2024 May;105(5):499-509. doi: 10.1111/cge.14480. Epub 2024 Jan 14. PMID: 38221796.
Abstract
Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.
Rafeienejad F, Keyhani E, Akbarfahimi N, Nouri N. Neurodevelopmental disorder: Hao-Fountain syndrome with USP7 mutation-a case report. J Med Case Rep. 2025 Jul 24;19(1):363. doi: 10.1186/s13256-025-05403-y. PMID: 40707997; PMCID: PMC12291276.
Abstract
Background: Hao-Fountain syndrome (HAFOUS) is a rare neurodevelopmental disorder manifesting as several known symptoms, including speech and language delay, behavioral abnormalities, and intellectual disability. This rare condition is usually diagnosed by heterozygous deletion or mutation in the ubiquitin-specific protease 7 gene in conjunction with phenotype features.
Case presentation: We report the case of a 5-year-old Persian girl with this rare syndrome. The process of diagnosis, from perinatal examinations to the latest laboratory and clinical tests, is described for the first time in Iran.
Conclusion: Reporting all the symptoms of such a rare genetic case in detail emphasizes the importance of interdisciplinary teamwork and the necessity of raising awareness among therapists about probable upcoming problems; sharing such evident information with parents would help them manage the complexity of raising children with rare syndromes.
Excerpt
Clinical characteristics: USP7-related Hao-Fountain syndrome is characterized by developmental delay in 100% of individuals, although intellectual disability is variable, with up to 50% of affected individuals having intellect in the normal range. Muscular hypotonia is also common; this tends to improve over time, but some affected individuals develop hypertonia. About two thirds of affected individuals have an abnormal/unsteady gait and about one quarter have contractures, most commonly involving large joints and joints of the lower extremities. Neuropsychiatric features can include autism, attention-deficit/hyperactivity disorder (ADHD), and behavioral issues such as stubbornness and compulsivity. Feeding difficulties are common and can require special feeding techniques, including use of a feeding tube. Gastroesophageal reflux disease, dysphagia, and hyperphagia have also been reported. Eye and vision issues (hyperopia, strabismus, nystagmus) are seen in more than 50% of affected individuals. About half of affected individuals have impaired bone mineralization, which can lead to fractures. Findings in fewer than 50% of individuals include epilepsy, sleep disturbance, hypogonadism, scoliosis, and hearing loss.
Diagnosis/testing: The diagnosis of USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in USP7 identified by molecular genetic testing.
Management: Treatment of manifestations: Feeding therapy for poor weight gain / dysphagia; gastrostomy tube placement may be required for persistent feeding issues; consultation with a dietician when hyperphagia and/or obesity is present; adequate intake of Ca2+ and vitamin D for reduced bone mineral density. Standard treatment for developmental delay / intellectual disability, epilepsy, gastroesophageal reflux disease, diarrhea, constipation, eye issues, sleep disturbance, cryptorchidism, micropenis, hypothyroidism, growth hormone deficiency, adrenal insufficiency, and hearing loss.
Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation and gastroesophageal reflux disease; monitor those with seizures; assess for new manifestations such as seizures, changes in tone, and gait abnormalities; monitor developmental progress and educational needs; monitor for scoliosis, contractures, mobility, and self-help skills; monitor for evidence of aspiration, respiratory insufficiency, and sleep disturbance (including for signs/symptoms of sleep apnea); monitor for signs and symptoms of puberty starting at about age seven years to the late teenage years. Annually, behavioral assessment for anxiety, ADHD, autism spectrum disorder, aggression, and self-injury; evaluate for hypothyroidism; audiology evaluation (in childhood). Assess bone mineral density every two years starting at age five years and then every three to five years in adulthood. Ophthalmology evaluation and endocrinologic tests for adrenal insufficiency as clinically indicated.
Genetic counseling: USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a pathogenic variant from a parent. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the pathogenic variant. Once the USP7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Korchak EJ, Sharafi M, Jaen Maisonet I, Salazar-Chaparro A, Semenova IV, Khan H, O'Neil AL, Caro P, Schaaf CP, Buhrlage SJ, Bezsonova I. Functional spectrum of USP7 pathogenic variants in Hao-Fountain syndrome: Insights into the enzyme's activity, stability, and allosteric modulation. Proc Natl Acad Sci U S A. 2025 Sep 30;122(39):e2510252122. doi: 10.1073/pnas.2510252122. Epub 2025 Sep 22. PMID: 40982686; PMCID: PMC12501124.
Abstract
Hao-Fountain syndrome is a rare neurodevelopmental disorder caused by mutations in the deubiquitinating enzyme Ubiquitin-Specific Protease 7 (USP7). Due to the novelty of the disease and its poorly understood molecular mechanisms, treatments for the syndrome are currently lacking. This study examines the effects of 11 patient-derived variants located within the catalytic domain of USP7, focusing on their impact on the enzyme's activity, thermodynamic stability, and substrate recognition. Our findings reveal a spectrum of functional consequences, ranging from complete inactivation to hyperactivation of USP7. Notably, we identify a specific subset of pathogenic variants whose catalytic activity can be significantly boosted using an allosteric activator, MS-8. These results provide insight into USP7 malfunction in Hao-Fountain syndrome-linked variants and pave the way for improved prognostic approaches and targeted treatments in the future.
Wimmer MC, Brennenstuhl H, Hirsch S, Dötsch L, Unser S, Caro P, Schaaf CP. Hao-Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum. Clin Genet. 2024 May;105(5):499-509. doi: 10.1111/cge.14480. Epub 2024 Jan 14. PMID: 38221796.
Abstract
Hao-Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype-phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire-based study was performed to characterize the phenotype of Hao-Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao-Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome-specific severity score. This score neither indicates a sex- nor age-specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.
Rafeienejad F, Keyhani E, Akbarfahimi N, Nouri N. Neurodevelopmental disorder: Hao-Fountain syndrome with USP7 mutation-a case report. J Med Case Rep. 2025 Jul 24;19(1):363. doi: 10.1186/s13256-025-05403-y. PMID: 40707997; PMCID: PMC12291276.
Abstract
Background: Hao-Fountain syndrome (HAFOUS) is a rare neurodevelopmental disorder manifesting as several known symptoms, including speech and language delay, behavioral abnormalities, and intellectual disability. This rare condition is usually diagnosed by heterozygous deletion or mutation in the ubiquitin-specific protease 7 gene in conjunction with phenotype features.
Case presentation: We report the case of a 5-year-old Persian girl with this rare syndrome. The process of diagnosis, from perinatal examinations to the latest laboratory and clinical tests, is described for the first time in Iran.
Conclusion: Reporting all the symptoms of such a rare genetic case in detail emphasizes the importance of interdisciplinary teamwork and the necessity of raising awareness among therapists about probable upcoming problems; sharing such evident information with parents would help them manage the complexity of raising children with rare syndromes.
Thursday, October 1, 2026
TUBGCP6 mutations
Inspired by a patient
Abstract
Purpose: To describe a case of microcephaly, unilateral retinal fold, and familial exudative vitreoretinopathy (FEVR)-like phenotype in the context of 2 TUBGCP6 variants. Methods: A case and its findings were analyzed. Results: A 4-month-old boy with no family history of eye disease presented by referral for management of presumed persistent fetal vasculature in the left eye. An external examination showed microcephaly. The patient grimaced to light in both eyes, and the anterior segments were unremarkable. On dilated fundus examination, diffuse chorioretinal atrophy was present bilaterally. In the left eye, a retinal fold emanated from the optic nerve head. There was early termination of retinal vasculature, especially in zone 3 in the left eye, resembling a FEVR-like phenotype. Panel-based genetic testing was performed and found 2 mutations in TUBGCP6. Conclusions: Microcephaly, chorioretinopathy, and retinal folds may be associated with TUBGCP6 mutations and masquerade as PFV.
Shurygina MF, Simonett JM, Parker MA, Mitchell A, Grigorian F, Lifton J, Nagiel A, Shpak AA, Dadali EL, Mishina IA, Weleber RG, Yang P, Pennesi ME. Genotype Phenotype Correlation and Variability in Microcephaly Associated With Chorioretinopathy or Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2020 Nov 2;61(13):2. doi: 10.1167/iovs.61.13.2. PMID: 33137195; PMCID: PMC7645200.
Abstract
Purpose: The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11, TUBGCP4, or TUBGCP6.
Methods: Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression.
Results: Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients.
Conclusions: Microcephaly due to mutations in KIF11, TUBGCP4, or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.
Hull S, Arno G, Ostergaard P, Pontikos N, Robson AG, Webster AR, Hogg CR, Wright GA, Henderson RHH, Martin CA, Jackson AP, Mansour S, Moore AT, Michaelides M. Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly. Am J Ophthalmol. 2019 Nov;207:87-98. doi: 10.1016/j.ajo.2019.05.001. Epub 2019 May 8. PMID: 31077665.
Abstract
Purpose: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity.
Design: Retrospective case series.
Methods: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).
Results: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS.
Conclusions: Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.
Wednesday, September 30, 2026
Epilepsy surgery
By the time Charlotte “Charli” Hilz’s family drove from Dallas to Austin, they had tried nearly everything they had been offered to control her seizures: Seven medications, dietary changes and steroids had failed. Some treatments helped briefly, while others brought difficult side effects. All the while, two-year-old Charli was losing abilities she had already developed.
Her parents knew the situation was worsening. What they did not have was a clear path forward.
“My trust began to waver,” says Charli’s father, Trevor Hilz. “But I also didn’t know where to go.”
A family connection led them to Dave Clarke, M.D., chief of the Comprehensive Pediatric Epilepsy Program within the neurology clinic at Dell Children’s, a clinical partnership with Dell Medical School that is now ranked No. 21 in the country. Within a week, they had made the trip to Austin and begun a new evaluation — one designed not simply to try another medication, but to understand why the treatments had failed and whether a more definitive option was possible.
“Our program is designed to engage closely with families and across our disciplines to get to the root of the problem,” says Clarke, professor of pediatrics and neurology at Dell Medical School at The University of Texas at Austin. “Highly trained epileptologists, neurosurgeons who are able to take on high-risk procedures if needed, neuropsychologists, social workers, advanced practice providers and nurses — we all collaborate with the child and family at the center. That’s what makes the difference here: We are both capable and willing to go the extra mile for each child.”
National recognition for Austin pediatric programs
Charli’s journey points to a larger shift in the Central Texas medical landscape. For years, families in Austin routinely traveled to Dallas, Houston and elsewhere for highly specialized pediatric care. Charli’s family came in the opposite direction, seeking capabilities that an emerging academic pediatric neuroscience program had assembled here.
Created in 2019, the program brought pediatric neurology, neurosurgery, neuropsychology, neuro-ophthalmology, rehabilitation and related specialties into a more integrated model. It earned its first national recognition from U.S. News & World Report three years later. By 2025, the program had reached No. 25 in the country for pediatric neurology and neurosurgery. Today, it is tied for No. 21, one of a handful of programs led by Dell Med faculty now climbing in national recognition.
“The power of academic medicine is that patient care, research and education continually strengthen one another,” says Claudia Lucchinetti, M.D., senior vice president for medical affairs and dean of Dell Medical School at The University of Texas at Austin. “The needs of patients shape research, new discoveries create better outcomes, and education prepares more physicians to deliver the most advanced care. At Dell Children’s, Dell Med faculty bring that model together with outstanding clinical teams and the broader capabilities of UT to take on complex cases and find a path forward when standard answers fall short.
“These rankings reflect what matters for children and families: deeper expertise, more options, and access to nationally recognized care here in Central Texas.”
Charli’s journey from uncertainty to recovery
Other leading pediatric epilepsy centers around the country have access to many of the same advanced tools. But what Charli and her family needed — and had not yet found — was a team of advanced specialists prepared to put them together around her particular case.
“When advanced specialists come together, we can look at complex cases from every angle,” says Adam Messer, president of Dell Children’s Medical Center. “This collaboration helps us understand each child’s unique needs so we can provide comprehensive care that supports the entire family.”
Charli’s epilepsy began in one area of the brain but spread so rapidly that it could resemble a different type of seizure disorder. At the same time, abnormal electrical activity was disrupting more than half of her sleep, interfering with her brain’s ability to rest, learn and develop. She was having as many as 20 seizures a day, struggling to walk and speak clearly, and losing the use of her left hand.
At Dell Children’s, the team began again with inpatient monitoring, capturing Charli’s seizures and studying the electrical activity in her brain. Advanced imaging helped narrow the suspected source. Epileptologists, neurosurgeons and neuropsychologists then used stereo-EEG, placing small electrodes in and around the target area to determine precisely where her seizures began and how closely that area bordered functions that needed to be preserved.
The evaluation located a small area of atypical cells near Charli’s sensory cortex. The target was so tightly surrounded by functional tissue that conventional surgical removal could have caused harm.
Instead, the team guided a needle-sized probe between two folds of her brain and used laser energy to deactivate the cells driving the seizures while protecting the surrounding tissue.
Today, Charli is six years old and remains seizure-free. Her overnight epileptic episodes have largely disappeared. She is using both sides of her body more fully, taking fewer medications and rapidly regaining function her family once feared had been permanently lost.
“For the first time, we felt heard,” says Charli’s mother, Mackenzie Hilz. “Dr. Clarke believed us. He looked at her and us and said, ‘I have a plan.’ We hadn’t heard that from anyone before. We took the leap, and it saved her life.”
https://news.utexas.edu/2026/09/17/academic-medicine-raises-the-bar-for-pediatric-neuroscience-care-in-austin/
Her parents knew the situation was worsening. What they did not have was a clear path forward.
“My trust began to waver,” says Charli’s father, Trevor Hilz. “But I also didn’t know where to go.”
A family connection led them to Dave Clarke, M.D., chief of the Comprehensive Pediatric Epilepsy Program within the neurology clinic at Dell Children’s, a clinical partnership with Dell Medical School that is now ranked No. 21 in the country. Within a week, they had made the trip to Austin and begun a new evaluation — one designed not simply to try another medication, but to understand why the treatments had failed and whether a more definitive option was possible.
“Our program is designed to engage closely with families and across our disciplines to get to the root of the problem,” says Clarke, professor of pediatrics and neurology at Dell Medical School at The University of Texas at Austin. “Highly trained epileptologists, neurosurgeons who are able to take on high-risk procedures if needed, neuropsychologists, social workers, advanced practice providers and nurses — we all collaborate with the child and family at the center. That’s what makes the difference here: We are both capable and willing to go the extra mile for each child.”
National recognition for Austin pediatric programs
Charli’s journey points to a larger shift in the Central Texas medical landscape. For years, families in Austin routinely traveled to Dallas, Houston and elsewhere for highly specialized pediatric care. Charli’s family came in the opposite direction, seeking capabilities that an emerging academic pediatric neuroscience program had assembled here.
Created in 2019, the program brought pediatric neurology, neurosurgery, neuropsychology, neuro-ophthalmology, rehabilitation and related specialties into a more integrated model. It earned its first national recognition from U.S. News & World Report three years later. By 2025, the program had reached No. 25 in the country for pediatric neurology and neurosurgery. Today, it is tied for No. 21, one of a handful of programs led by Dell Med faculty now climbing in national recognition.
“The power of academic medicine is that patient care, research and education continually strengthen one another,” says Claudia Lucchinetti, M.D., senior vice president for medical affairs and dean of Dell Medical School at The University of Texas at Austin. “The needs of patients shape research, new discoveries create better outcomes, and education prepares more physicians to deliver the most advanced care. At Dell Children’s, Dell Med faculty bring that model together with outstanding clinical teams and the broader capabilities of UT to take on complex cases and find a path forward when standard answers fall short.
“These rankings reflect what matters for children and families: deeper expertise, more options, and access to nationally recognized care here in Central Texas.”
Charli’s journey from uncertainty to recovery
Other leading pediatric epilepsy centers around the country have access to many of the same advanced tools. But what Charli and her family needed — and had not yet found — was a team of advanced specialists prepared to put them together around her particular case.
“When advanced specialists come together, we can look at complex cases from every angle,” says Adam Messer, president of Dell Children’s Medical Center. “This collaboration helps us understand each child’s unique needs so we can provide comprehensive care that supports the entire family.”
Charli’s epilepsy began in one area of the brain but spread so rapidly that it could resemble a different type of seizure disorder. At the same time, abnormal electrical activity was disrupting more than half of her sleep, interfering with her brain’s ability to rest, learn and develop. She was having as many as 20 seizures a day, struggling to walk and speak clearly, and losing the use of her left hand.
At Dell Children’s, the team began again with inpatient monitoring, capturing Charli’s seizures and studying the electrical activity in her brain. Advanced imaging helped narrow the suspected source. Epileptologists, neurosurgeons and neuropsychologists then used stereo-EEG, placing small electrodes in and around the target area to determine precisely where her seizures began and how closely that area bordered functions that needed to be preserved.
The evaluation located a small area of atypical cells near Charli’s sensory cortex. The target was so tightly surrounded by functional tissue that conventional surgical removal could have caused harm.
Instead, the team guided a needle-sized probe between two folds of her brain and used laser energy to deactivate the cells driving the seizures while protecting the surrounding tissue.
Today, Charli is six years old and remains seizure-free. Her overnight epileptic episodes have largely disappeared. She is using both sides of her body more fully, taking fewer medications and rapidly regaining function her family once feared had been permanently lost.
“For the first time, we felt heard,” says Charli’s mother, Mackenzie Hilz. “Dr. Clarke believed us. He looked at her and us and said, ‘I have a plan.’ We hadn’t heard that from anyone before. We took the leap, and it saved her life.”
https://news.utexas.edu/2026/09/17/academic-medicine-raises-the-bar-for-pediatric-neuroscience-care-in-austin/
Diazepam Intensol shortage
It seems there is a nationwide shortage of inexpensive but effective Diazepam Intensol, forcing obscenely expensive Valtoco to be prescribed in yet more obscenely expensive 5 packs.
Tuesday, September 29, 2026
Great experiments 5
Courtesy of a colleague
Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.
“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”
Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.
“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.
“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”
Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.
“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”
Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.
“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.
“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”
Levacetylleucine for treatment of Niemann-Pick disease type C 2
Davis LC, Annaert W, Braine R, Churchill GC, Factor M, Fields T, Patterson M, Platt F, Shepherd D, Strupp M, Galione A. N-acetyl-L-leucine normalizes Transcription Factor EB activity by stereospecific bidirectional modulation in a HeLa cell model of Niemann-Pick disease type C. PLoS One. 2026 Jul 17;21(7):e0353834. doi: 10.1371/journal.pone.0353834. PMID: 42467639; PMCID: PMC13378962.
Abstract
Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.
Abstract
Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.
Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.
Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.
Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).
Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.
Abstract
Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.
Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.
Trial registrations: The trial (IB1001-301) has been registered at www.
Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.
Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.
Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.
Abstract
Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
Abstract
Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.
Abstract
Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.
Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.
Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.
Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).
Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.
Abstract
Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.
Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.
Trial registrations: The trial (IB1001-301) has been registered at www.
Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.
Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.
Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.
Abstract
Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
Levacetylleucine for treatment of ataxia-telangiectasia
The U.S. Food and Drug Administration has approved Aqneursa (levacetylleucine) for oral suspension to treat ataxia in adults and pediatric patients with ataxia-telangiectasia weighing at least 15 kg (about 33 pounds). Aqneursa was previously approved in 2024 to treat the neurological manifestations of Niemann-Pick disease type C. Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.
Condition
Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.
Data Supporting Aqneursa
The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.
Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.
Safety Information
There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.
Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.
Designation
Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.
https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder
Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.
Abstract
Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.
Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.
Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.
Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.
Funding: IntraBio.
Condition
Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.
Data Supporting Aqneursa
The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.
Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.
Safety Information
There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.
Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.
Designation
Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.
https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder
Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.
Abstract
Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.
Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.
Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.
Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.
Funding: IntraBio.
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