See: https://ask.metafilter.com/251986/Do-doctors-actually-tell-their-patients-they-cannot-have-children
Monday, September 16, 2024
I never gave up hope or my faith
One day in August 2013, I was with friends as my children, Hudson, Lola, and Bella, then ages 3, 5, and 7, were having a play date. I started to not feel well and, when I went to the restroom, I noticed I had blood in my stool. I knew this wasn't normal, so I called my doctor and then headed to urgent care. I figured they would run some tests and maybe prescribe some medication and I told my husband, Scott, that I would be home shortly.
Then the lab test came back and the results showed a platelet count of 1,000. The typical number of platelets in the blood is usually 150,000 to 450,000, so my count was incredibly low. The doctor even repeated the test, assuming the equipment must have malfunctioned the first time. It had not.
Instead of going home with a prescription in hand, an ambulance took me to the hospital. I was admitted and ended up staying for about 43 days. After nearly a month and a half and countless tests, I was diagnosed with Stage II diffuse large B-cell non-Hodgkin lymphoma. I came to learn that this is a type of cancer that affects your white blood cells, or lymphocytes, and that it's particularly fast-moving and aggressive.
As you can imagine, I was scared. At 32 years old, I was a young mom with a wonderful husband and three beautiful children, with so much life left to live. A cancer diagnosis was the furthest thing from my mind. But, I came to find out that this cancer typically responds well to treatment, and my disease was caught in a relatively early stage, which would increase my chances for survival.
I began a standard protocol of chemotherapy. Halfway through treatment, a scan showed no tumors. I was ecstatic, but about seven months later, tests revealed that the cancer had returned. Next was a stem cell transplant, which was just the hardest treatment that you could ever imagine. But my body wasn't responding the way it should and the cancer was still there.
The transplant was unsuccessful. I was driving my kids in the car when I got the news from my doctor that my transplant had failed. It took everything in me to hold it together for them. When I got home, I lost it. I was completely heartbroken. I knew I was quickly running out of options.
At this point, my chances of survival were incredibly low. In fact, I was given only six months to live, but I didn't even know it. A doctor had shared that with my husband, but he didn't tell me because he wanted to protect me as best he could from the scary stuff while I focused on my treatment. He knew how important it was for me to continue to have hope. Sometimes, when you realize how dire things are, you do become hopeless, and it's so much harder to fight when you're hopeless.
When we finally met with my doctor, he told me that my only option left was a clinical trial. The challenge was that this clinical trial wasn't available in my home state of Kansas yet, and my doctor didn't know if I had enough time to even make it. You'd think that I would have been distressed by that news, but in that moment when faced with this life-or-death situation, all I felt was hope and faith instead of fear. I knew we would find a way.
This clinical trial, ZUMA-1 as it was called, was exploring an entirely new way of treating cancer in 2015 that the doctors told me was my best—and maybe only—chance for survival at that point. It was an immunotherapy called Chimeric Antigen Receptor T-cell therapy, or CAR T-cell therapy. This one-time therapy is designed to use my immune system to fight the cancer.
CAR T-cell therapy involves using your own T cells, a type of white blood cell, which were collected through a process called leukapheresis—blood withdrawal—and sent to a manufacturing facility where they add receptors to those T cells that match the protein on the cancer. These "supercharged" T cells are then infused into the body to fight the cancer.
My local hospital wasn't participating in this trial, so I had to travel to a hospital in Houston. I hopped on a plane to see if I qualified for this trial. I was a perfect fit and was quickly enrolled.
Nearly two years after my cancer journey had begun, I became just the third person in the world to take part in the clinical trial. ultimately this treatment developed by Kite Pharma became the first CAR T-cell therapy approved by the U.S. Food and Drug Administration in 2017 to treat the type of cancer that I had. By participating in the clinical trial, I helped pave the way for thousands of blood cancer patients like me who have been successfully treated since.
Within a month, scans showed that the cancer was gone. The same thing at 18 months. And now, nine years later, I'm still cancer-free. I never gave up hope or my faith, both in God and in the incredible doctors who were treating me. I'm grateful to be a survivor and for the opportunity to be a part of something as revolutionary as CAR T-cell therapy.
I truly feel that I'm here for a reason, that it wasn't my time to go. I believe that there were things that I was meant to accomplish, and I feel a responsibility to use my experience to help others.
I've been actively involved with the Leukemia and Lymphoma Society, as have my children who grew up with their mom fighting this battle. Over the years, we've helped to raise more than $200,000 for research. I never imagined that I could be passionate about something like this, but I just feel like that was part of what I was called to do in order to give back.
Today, I'm healthy and Scott and I are happier than we've ever been. Our children are now 18, 16, and 14. Bella just started college, Lola is playing on her high school golf team, and Hudson wants to be an oncologist. I think back on the years dealing with my cancer and just trying to survive, and I feel like I missed a really special time in my family's life. That makes me appreciate the time we have now even more.
I remember thinking that I could never imagine being normal and healthy again, and that I'd never be able to get back to a normal routine. I now know that my life isn't completely the same and I've changed as a person because of this experience. People often ask me about it, and I tell them I wouldn't take it back or go back in time and not have cancer, which may seem shocking. But it helped me look at life differently and I've grown—we've all grown—so much because of that and I would never want to take that away.
Emily Dumler was diagnosed with stage II diffused large B-cell non-Hodgkin lymphoma at the age of 32 in 2013 and given six months to live. With no other approved treatment options available, Emily was brave enough to try CAR T-cell therapy that was in clinical trial stages at the time. Within a month of the trial, Emily was declared cancer-free and remains so to this day. CAR T-cell therapy is now an approved treatment.
https://www.newsweek.com/i-was-given-six-months-live-wasnt-told-1948620
Then the lab test came back and the results showed a platelet count of 1,000. The typical number of platelets in the blood is usually 150,000 to 450,000, so my count was incredibly low. The doctor even repeated the test, assuming the equipment must have malfunctioned the first time. It had not.
Instead of going home with a prescription in hand, an ambulance took me to the hospital. I was admitted and ended up staying for about 43 days. After nearly a month and a half and countless tests, I was diagnosed with Stage II diffuse large B-cell non-Hodgkin lymphoma. I came to learn that this is a type of cancer that affects your white blood cells, or lymphocytes, and that it's particularly fast-moving and aggressive.
As you can imagine, I was scared. At 32 years old, I was a young mom with a wonderful husband and three beautiful children, with so much life left to live. A cancer diagnosis was the furthest thing from my mind. But, I came to find out that this cancer typically responds well to treatment, and my disease was caught in a relatively early stage, which would increase my chances for survival.
I began a standard protocol of chemotherapy. Halfway through treatment, a scan showed no tumors. I was ecstatic, but about seven months later, tests revealed that the cancer had returned. Next was a stem cell transplant, which was just the hardest treatment that you could ever imagine. But my body wasn't responding the way it should and the cancer was still there.
The transplant was unsuccessful. I was driving my kids in the car when I got the news from my doctor that my transplant had failed. It took everything in me to hold it together for them. When I got home, I lost it. I was completely heartbroken. I knew I was quickly running out of options.
At this point, my chances of survival were incredibly low. In fact, I was given only six months to live, but I didn't even know it. A doctor had shared that with my husband, but he didn't tell me because he wanted to protect me as best he could from the scary stuff while I focused on my treatment. He knew how important it was for me to continue to have hope. Sometimes, when you realize how dire things are, you do become hopeless, and it's so much harder to fight when you're hopeless.
When we finally met with my doctor, he told me that my only option left was a clinical trial. The challenge was that this clinical trial wasn't available in my home state of Kansas yet, and my doctor didn't know if I had enough time to even make it. You'd think that I would have been distressed by that news, but in that moment when faced with this life-or-death situation, all I felt was hope and faith instead of fear. I knew we would find a way.
This clinical trial, ZUMA-1 as it was called, was exploring an entirely new way of treating cancer in 2015 that the doctors told me was my best—and maybe only—chance for survival at that point. It was an immunotherapy called Chimeric Antigen Receptor T-cell therapy, or CAR T-cell therapy. This one-time therapy is designed to use my immune system to fight the cancer.
CAR T-cell therapy involves using your own T cells, a type of white blood cell, which were collected through a process called leukapheresis—blood withdrawal—and sent to a manufacturing facility where they add receptors to those T cells that match the protein on the cancer. These "supercharged" T cells are then infused into the body to fight the cancer.
My local hospital wasn't participating in this trial, so I had to travel to a hospital in Houston. I hopped on a plane to see if I qualified for this trial. I was a perfect fit and was quickly enrolled.
Nearly two years after my cancer journey had begun, I became just the third person in the world to take part in the clinical trial. ultimately this treatment developed by Kite Pharma became the first CAR T-cell therapy approved by the U.S. Food and Drug Administration in 2017 to treat the type of cancer that I had. By participating in the clinical trial, I helped pave the way for thousands of blood cancer patients like me who have been successfully treated since.
Within a month, scans showed that the cancer was gone. The same thing at 18 months. And now, nine years later, I'm still cancer-free. I never gave up hope or my faith, both in God and in the incredible doctors who were treating me. I'm grateful to be a survivor and for the opportunity to be a part of something as revolutionary as CAR T-cell therapy.
I truly feel that I'm here for a reason, that it wasn't my time to go. I believe that there were things that I was meant to accomplish, and I feel a responsibility to use my experience to help others.
I've been actively involved with the Leukemia and Lymphoma Society, as have my children who grew up with their mom fighting this battle. Over the years, we've helped to raise more than $200,000 for research. I never imagined that I could be passionate about something like this, but I just feel like that was part of what I was called to do in order to give back.
Today, I'm healthy and Scott and I are happier than we've ever been. Our children are now 18, 16, and 14. Bella just started college, Lola is playing on her high school golf team, and Hudson wants to be an oncologist. I think back on the years dealing with my cancer and just trying to survive, and I feel like I missed a really special time in my family's life. That makes me appreciate the time we have now even more.
I remember thinking that I could never imagine being normal and healthy again, and that I'd never be able to get back to a normal routine. I now know that my life isn't completely the same and I've changed as a person because of this experience. People often ask me about it, and I tell them I wouldn't take it back or go back in time and not have cancer, which may seem shocking. But it helped me look at life differently and I've grown—we've all grown—so much because of that and I would never want to take that away.
Emily Dumler was diagnosed with stage II diffused large B-cell non-Hodgkin lymphoma at the age of 32 in 2013 and given six months to live. With no other approved treatment options available, Emily was brave enough to try CAR T-cell therapy that was in clinical trial stages at the time. Within a month of the trial, Emily was declared cancer-free and remains so to this day. CAR T-cell therapy is now an approved treatment.
https://www.newsweek.com/i-was-given-six-months-live-wasnt-told-1948620
Sunday, September 15, 2024
Diffuse intrinsic pontine glioma 5
The family of an 11-year-old with an inoperable brain tumor are preparing for their last Christmas together after he was given six months to live -- just two weeks ago.
Reece Probert seemed perfectly healthy just last month, but his mom Jenna, 31, took him to the doctors when he suddenly developed a limp and then a slur.
Scans revealed he had a rare aggressive inoperable brain tumor which sufferers usually succumb to between six and 12 months after diagnosis.
His devastated family are rallying around to give him the best Christmas ever.
"It will be our last Christmas together and we want to make sure it's nice and comfortable and cozy for Reece," Jenna Probert, of Wombourne, South Staffordshire, said. "I want to make him feel like a king. He should feel like the most important person in the world. It will be emotional because it will be his last Christmas."
"We will decorate the whole house and make it look like Santa's grotto. It will be the most memorable Christmas ever," she said. "Reece knows he has cancer but doesn't know the reality of it. I can't face telling him. I just need him to be happy. Christmas will be a family day and we will give him anything he wants. We will just cherish it together as a family."
Reece Probert seemed perfectly healthy just last month, but his mom Jenna, 31, took him to the doctors when he suddenly developed a limp and then a slur.
Scans revealed he had a rare aggressive inoperable brain tumor which sufferers usually succumb to between six and 12 months after diagnosis.
His devastated family are rallying around to give him the best Christmas ever.
"It will be our last Christmas together and we want to make sure it's nice and comfortable and cozy for Reece," Jenna Probert, of Wombourne, South Staffordshire, said. "I want to make him feel like a king. He should feel like the most important person in the world. It will be emotional because it will be his last Christmas."
"We will decorate the whole house and make it look like Santa's grotto. It will be the most memorable Christmas ever," she said. "Reece knows he has cancer but doesn't know the reality of it. I can't face telling him. I just need him to be happy. Christmas will be a family day and we will give him anything he wants. We will just cherish it together as a family."
Reece Probert seemed perfectly healthy just last month, but his mom took him to the doctors when he suddenly developed a limp and then a slur.
Just six weeks ago, Reece was fit and healthy, but after returning from a trip to see his grandparents in Northern Ireland in November, his mom noticed unusual symptoms.
He had a limp and a sore hand, so his doctor sent him to the hospital for an X-ray, and for tests on his tendons.
But Probert really began to worry when Reece began to slur his words two weeks ago.
A neighbor, who had been diagnosed a benign brain tumor, noticed Reece struggling to speak and feared the worst, having suffered similar symptoms in the past.
Probert, a personal trainer, phoned 111 and was advised to take her son to the Russell's Hall Hospital, in Dudley, where doctors initially thought he had suffered a stroke.
But on Dec. 1, doctors at Birmingham Children's Hospital performed a CT scan and found an "abnormality" of the brain.
Two days later Probert was told her son had diffuse intrinsic pontine glioma (DIPG) - an aggressive cancer typically found in children.
"I collapsed when I was told that," she said. "I felt like my heart had been ripped out. It was a horrible feeling. They put him on steroids to reduce the swelling before he had the MRI scan."
"It was bad enough being told he had a stroke," she siad. "I was just praying that they had got it all wrong. I just started screaming 'no, no, no'. I couldn't breathe. It's the worst thing any mom can be told."
"Even the oncologist has tears in her eyes whilst she was telling me," Probert said. "We were taken into the family room and told that chemotherapy won't work and radiotherapy will only shrink the tumor. But it will come back and will eventually end his life."
"Most children die between six and 12 months from diagnosis," she said.
Reece is due to start his first round of radiotherapy to reduce the size of the tumor and give him more time.
Probert is now focused on making sure Reece has the most "amazing Christmas" with her, partner Robert Perry, 27, and his sister Trinity Alcock, 6.
"I've had to put the reality of it to the back of my mind," Probert said. "I'm just focused on enjoying him whilst we still have him. We want to make memories with him and just want to make sure he is happy and comfortable."
"Reece has been fantastic. He has taken it all in his stride and has been amazing," she said. "I couldn't be more proud of him. He is known as the class clown and his friends have been to visit him. For us, the next year is all about making him feel extra special."
Friends and family have launched fundraising campaigns and arranged charity events in a bid to raise money to ensure Reece has a Christmas to remember.
https://www.foxnews.com/health/boy-given-months-to-live-after-limp-led-to-terminal-brain-tumor-diagnosis
Just six weeks ago, Reece was fit and healthy, but after returning from a trip to see his grandparents in Northern Ireland in November, his mom noticed unusual symptoms.
He had a limp and a sore hand, so his doctor sent him to the hospital for an X-ray, and for tests on his tendons.
But Probert really began to worry when Reece began to slur his words two weeks ago.
A neighbor, who had been diagnosed a benign brain tumor, noticed Reece struggling to speak and feared the worst, having suffered similar symptoms in the past.
Probert, a personal trainer, phoned 111 and was advised to take her son to the Russell's Hall Hospital, in Dudley, where doctors initially thought he had suffered a stroke.
But on Dec. 1, doctors at Birmingham Children's Hospital performed a CT scan and found an "abnormality" of the brain.
Two days later Probert was told her son had diffuse intrinsic pontine glioma (DIPG) - an aggressive cancer typically found in children.
"I collapsed when I was told that," she said. "I felt like my heart had been ripped out. It was a horrible feeling. They put him on steroids to reduce the swelling before he had the MRI scan."
"It was bad enough being told he had a stroke," she siad. "I was just praying that they had got it all wrong. I just started screaming 'no, no, no'. I couldn't breathe. It's the worst thing any mom can be told."
"Even the oncologist has tears in her eyes whilst she was telling me," Probert said. "We were taken into the family room and told that chemotherapy won't work and radiotherapy will only shrink the tumor. But it will come back and will eventually end his life."
"Most children die between six and 12 months from diagnosis," she said.
Reece is due to start his first round of radiotherapy to reduce the size of the tumor and give him more time.
Probert is now focused on making sure Reece has the most "amazing Christmas" with her, partner Robert Perry, 27, and his sister Trinity Alcock, 6.
"I've had to put the reality of it to the back of my mind," Probert said. "I'm just focused on enjoying him whilst we still have him. We want to make memories with him and just want to make sure he is happy and comfortable."
"Reece has been fantastic. He has taken it all in his stride and has been amazing," she said. "I couldn't be more proud of him. He is known as the class clown and his friends have been to visit him. For us, the next year is all about making him feel extra special."
Friends and family have launched fundraising campaigns and arranged charity events in a bid to raise money to ensure Reece has a Christmas to remember.
https://www.foxnews.com/health/boy-given-months-to-live-after-limp-led-to-terminal-brain-tumor-diagnosis
3-methylcrotonyl-CoA carboxylase deficiency
Inspired by a patient identified on newborn screening
Abstract
3-methylcrotonyl-CoA carboxylase deficiency (3MCCD) is a hereditary disorder of leucine catabolism caused by pathogenetic variants in the MCCC1 or MCCC2 genes. Typically diagnosed through newborn screening (NBS), 3MCCD is characterized by elevation of 3-hydroxyisovalerylcarnitine (C5OH) in blood as well as increased excretion of 3-methylcrotonylglycine (3-MCG) in urine. While most diagnosed children remain asymptomatic, data on adults are scarce. To date, only 39 molecularly confirmed adult individuals have been reported, all being mothers diagnosed subsequent to their child NBS results. Herein, we present a 36-year-old asymptomatic man who was incidentally diagnosed with 3MCCD following his son NBS recall. Molecular analysis revealed compound heterozygosity for two pathogenic variants in the MCCC1 gene. This is the first molecularly confirmed adult man with 3MCCD reported. This case highlights the need for additional longitudinal follow-up data on individuals with 3MCCD to clarify the clinical significance of this condition and guide clinical practice, including NBS strategy.
Lin W, Wang K, Chen Y, Zheng Z, Lin Y. Newborn screening and genetic diagnosis of 3-methylcrotonyl-CoA carboxylase deficiency in Quanzhou,China. Mol Genet Metab Rep. 2024 Aug 2;40:101127. doi: 10.1016/j.ymgmr.2024.101127. PMID: 39188588; PMCID: PMC11345313.
Abstract
Background and aims: 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is an autosomal recessive leucine catabolism condition caused by 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency due to MCCC1/MCCC2 variants. We investigated its incidence and features in Quanzhou, China.
Materials and methods: We screened 643,606 newborns (January 2014 to December 2022) for elevated 3-hydroxyisovalerylcarnitine (C5OH) levels using tandem mass spectrometry (MS/MS). Molecular analyses identified MCCC1/MCCC2 variants in suspected 3-MCCD cases.
Results: Seventeen neonates, two maternal patients, and one paternal patient had 3-MCCD. Its incidence in the Quanzhou study population was 1/37,859 newborns. All patients and neonates with 3-MCCD exhibited increased C5OH concentrations. Most patients [76.5%(13/17)] had increased urinary 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA) levels. Eight neonates and all adults with 3-MCCD had secondary carnitine deficiency. We identified seventeen variants, including 6 novel ones.MCCC1and MCCC2 variants were found in 47.1% and 52.9% of patients,with c.1331G > A (31.3%) and c.351_353delTGG (50.0%) being the most prevalent, respectively. Clinical symptoms were observed in 11.8% of patients.
Conclusion: We identified six new MCCC1/MCCC2 variants, enhancing our understanding of the 3-MCCD molecular profile. Secondary carnitine deficiency occurred in eight neonates and all adult patients. Although clinical symptoms were observed in 11.8% of patients, whether they were related to 3-MCCD remain unclear. Therefore, further studies are required to decide whether 3-MCCD and C5OH indicators should continue to be used.
Jagadish A, Sclater K, Lapinski T, Adkins K, Selzer L. A Unique Presentation of 3-Methylcrotonyl-CoA Carboxylase Deficiency. Cureus. 2023 May 23;15(5):e39401. doi: 10.7759/cureus.39401. PMID: 37362523; PMCID: PMC10287026.
Abstract
3-methylcrotonyl-CoA carboxylase deficiency is an autosomal recessive disorder resulting in impaired leucine metabolism. The condition is typically diagnosed with newborn screening; patients diagnosed at a later stage generally present with symptoms including metabolic disturbances, seizures, failure to thrive, or delayed development. We present the case of a child diagnosed at 12 months of age who was noted to have recurrent viral infections and nonspecific gastrointestinal symptoms of vomiting, hematochezia, and gaseous distention of the abdomen. Newborn screening did not reveal any abnormalities. Evaluation for underlying immunodeficiency was unremarkable; genetic testing revealed bi-allelic mutations in MCCC2, a known association of 3-methylcrotonyl-CoA carboxylase deficiency. It is important to consider genetic disorders when evaluating patients even if the newborn screening is unremarkable.
Wang H, Liu S, Wang B, Yang Y, Yu B, Wang L, Wang T. 3-Methylcrotonyl-CoA carboxylase deficiency newborn screening in a population of 536,008: is routine screening necessary? J Pediatr Endocrinol Metab. 2019 Dec 18;32(12):1321-1326. doi: 10.1515/jpem-2018-0536. PMID: 31730530.
Abstract
Objective To evaluate whether 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD) should be routinely screened in newborns. Methods Dried blood spots (DBS) were collected and analyzed by tandem mass spectrometry (TMS). Blood samples were collected from infants with positive 3-MCCD results. Targeted sequencing was performed using the extended panel for inherited metabolic diseases to detect 306 genes. The sequencing libraries were quantified and used for massively parallel sequencing on the Illumina HiSeq 2500 platform. Results A total of 536,008 infants underwent newborn screening (NBS) and 14 cases of 3-MCCD were diagnosed. The incidence of 3-MCCD in Jiangsu province was 1:38,286. During the last 3 years of follow-up, none of the subjects with 3-MCCD exhibited obvious clinical symptoms. Only two children had mild feeding difficulties and vomiting. Eleven patients had complex variants of the MCCC1 gene, and three patients had mutations in MCCC2. In total, 17 types of MCCC1 or MCCC2 variants were found, and c.639 + 2t > a was the most common mutation. Conclusions As far as the current results are concerned, 3-MCCD may be benign in Jiangsu province. However, additional investigations and a longer follow-up period are necessary to decide whether NBS of 3-MCCD is necessary or not.
Thursday, September 12, 2024
Mirdametinib in children and adults with neurofibromatosis type 1-associated symptomatic inoperable plexiform neurofibroma
Christopher L. Moertel, Angela C. Hirbe, Hans H. Shuhaiber, David Viskochil, Alpa Sidhu, Kevin J. Bielamowicz, Michael Weber, Jack Li, L. Mary Smith, Lauren Weintraub,
Rene Y. McNall-Knapp, Fouad M. Hajjar, Nicholas K. Foreman, Timothy R. Gershon, Dusica Babovic-Vuksanovic. ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma. Meeting Abstract: 2024 ASCO Annual Meeting I Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology May 29, 2024
Abstract
Background: PN in patients (pts) with NF1 can cause pain, disfigurement, impaired quality of life (QoL), and can undergo malignant transformation. ReNeu (NCT03962543), a multicenter, open-label, Phase 2b study, evaluated efficacy and safety of the highly selective, oral, investigational MEK1/2 inhibitor mirdametinib in adult (≥18 y) and pediatric (2-17 y) pts with inoperable NF1 PN causing significant morbidities. Methods: Mirdametinib was administered as a capsule or dispersible tablet (2 mg/m2 BID, max 4 mg BID) without regard to food in 3 wk on/1 wk off 28-d cycles. The primary endpoint was confirmed objective response rate (ORR; percentage of pts with MRI-assessed ≥20% reduction of target PN volume by blinded independent central review [BICR] within the 24-cycle treatment phase). The minimum clinically relevant ORR (null) was defined as 23% for adults and 20% for pediatrics. Ptscould continue treatment in an optional long-term follow-up (LTFU) phase. Additional key endpoints were duration of response (DoR), time to response (TTR), change from baseline (BL) in target PN volume, pain severity (Numerical Rating Scale-11 [NRS-11]), pain interference (Pain Interference Index [PII]), health-related (HR) QoL (PedsQL), and safety. Results: All114 pts (58 adult, 56 pediatric) received mirdametinib. As of the 20 Sept 2023 data cutoff (DCO), BICR-confirmed ORR during the treatment phase was 41% (95% CI, 29-55; P<.001 vs null) in adults and 52% (95% CI, 38-65; P<.001 vs null) in pediatric pts. Two adult pts and 1 pediatric pt also had a confirmed response in the ongoing LTFU. Median (min, max) target PN volumetric best response from BL was -41% (-90, 13) and -42% (-91, 48) in adult and pediatric pts, respectively. As of the DCO, median treatment duration was 22 mo for each cohort and median DoR was not reached. Median (range) TTR was 7.8 (4-19) mo in adult pts and 7.9 (4-19) mo in pediatric pts. Adult and pediatric pts had statistically significant improvements from BL to cycle 13 in NRS-11, PII, and key PedsQL measures. Most frequent (≥35% pts) treatment-emergent adverse events (TEAEs) were dermatitis acneiform, diarrhea, nausea, and vomiting in adults and diarrhea, dermatitis acneiform, and vomiting in pediatric pts. 16% and 25% of adult and pediatric pts, respectively, had grade ≥3 treatment-related AEs, and 22% and 9%, respectively, discontinued due to TEAEs. Conclusions: In ReNeu, the largest multicenter NF1 PN trial reported to date, mirdametinib demonstrated a statistically significant ORR by BICR, with deep and durable PN volume reductions, significant improvements in pain severity, pain interference, and HRQoL, and a manageable safety profile in both adults and children. Together with a dispersible tablet formulation, these results underscore mirdametinib’s potential to become an important new treatment option for NF1 PN pts across all ages.
Wednesday, September 11, 2024
ROHHAD syndrome
Mom of 2 Describes 'Purgatory' of Not Knowing How Long Her Boys Will Live: 'There Is No Roadmap' (Exclusive)
Mandie Moore's young sons have the same debilitating rare disease. In her own words, she explains how she dedicates every day to improving their quality of life
When Mandie Moore’s 8-year-old son Max complained that his legs hurt during short walks in spring 2020, she worried something was wrong. Soon he had trouble getting down the driveway of their Roswell, Georgia, home.
After two years of visiting doctors and traveling to hospitals around the country, he was diagnosed with ROHHAD syndrome, an ultra-rare disorder that affects the respiratory, nervous and endocrine systems, according to the the National Association for Rare Disorders. There are only about 200 cases reported in literature and clinically to date, says Max's pediatric pulmonologist Dr. Ajay Kasi at Children’s Healthcare of Atlanta.
ROHHAD stands for rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. It causes extreme weight gain, difficulty breathing and other endocrine issues. It also reduces a child's life expectancy — 50 to 60% of cases end in early death. “It's an extremely rare disease which can be easily missed,” Kasi tells PEOPLE.
As Mandie and her husband Devon were coming to terms with Max's diagnosis, their younger son, Chance, began showing familiar symptoms of the syndrome. In 2023, the family learned he had the same disease, for which there is no treatment and no cure.
Mandie sat down with PEOPLE to share how she copes while striving to make memories for her boys, who are now 12 and 9. This is her story:
When Max was first diagnosed, I let out the biggest exhale ever. We finally had a name for it. But then the doctors said, "This isn't like cancer, where we can give you a guidebook of what's going to happen. There is no roadmap."
Because so few kids have ROHHAD, we don't know what our future will be or when the kids will decline. It could be in a day, a year, in five years. That's the hardest thing — living in this state of limbo. It's almost like purgatory. You allow yourself to build a little more hope for the future, but you have to be cautious and realistic. We try to live in the moment and face things as they come up.
I think the kids feel it. Chance has been asking me a lot of questions: What does heaven look like? What happens when you die? The kids are pretty intuitive about how their body feels.
Quality of life is the biggest thing for our family. Making decisions to do a medical intervention, like inserting a tracheostomy [a procedure to help air and oxygen reach the lungs by creating an opening into the windpipe from outside the neck] was really hard, especially because the boys had lived their whole lives — I hate the word "normal" — but in a more typical way. So to say that they struggled is an understatement. Max asked me about the trach, "Will I die without it?" I said, "Yes, you probably will."
Max had a cardiac arrest after his trach was put in two years ago. I remember being in the pediatric ICU watching them do CPR, I was holding his feet, and we were screaming, "Please don't go. Please stay." But we were planning his funeral. We didn't know the answers to questions like, “Would he want to be an organ donor?” Because he was 10, and who knows that at 10 years old? But it's conversations that we've since had with both of them.
There's a small Facebook community that I belong to for ROHHAD parents, about 200 members. We lost a girl who was 9 a week ago. We lost a 12-year-old two months ago. It's constant loss. But there's a 27-year-old guy in Texas, he still lives at home. But that's really the only outlier. The rest of the stories involve a lot of loss during the teenage years.
Max has a great quality of life. He's very happy. That's all I want. I want him here and I want him happy. I don't really care what it looks like. Chance is getting there. Still, they both struggle with depression and anxiety at times. Grief shows up differently for everybody — I think I'm always going to be working through mine. But we're all in different stages and Chance is still having a harder time. He just did his Make-A-Wish trip, but it took several tries because he kept getting sicker.
For us, making memories has become really important. They're very intentional now. Whereas before they got sick, we took vacations, we did all the things that families do. Now, if Max wakes at 5 a.m. and says, "I want to go see the sunrise," we go outside — even if we want to stay in bed. Yesterday, he wanted to look at the cotton candy sky, so we did.
We give them as many experiences as we can. We went fishing in St. Augustine, Fla., and Chance caught a fish. I bought tickets to Ed Sheeran’s concert in May. We took the boys to Disney in December. If they say I want to do something, then we do it.
Right now, Max is doing well. It doesn't look good from other people's standards, but by our standards, he's good. But it changes so fast. As soon as you get one thing under control, there's something else, because ROHHAD affects the entire body. It’s constant whack-a-mole. You beat a problem down, you can exhale for a few minutes, and then something else pops up.
There’s this pressure to be super mom and to act like you're fine all the time, and you're not fine all the time. Nobody living like this is fine. I go to bed sad every night, and that's okay to say. I sit in the dark a lot and think about the things they will never get a chance to experience. And it's okay to have therapy and address your mental health and your family's mental health, because this isn't a normal life. Knowing there is an expiration date, but not knowing when it's going to be — that's not normal.
Max is happy with his life and I think that that's something that's given me perspective. He's been dealt a real crap hand, but to be able to find happiness in simple things, and to want to keep on living, and to keep on fighting, and keep on learning — he wants to be a marine biologist. Even though he's got a trach and can't go underwater, he has an innocence, and it's just lovely that he wants to go to college. He's got plans for himself.
Even with his struggles, Chance is our funny joke guy. He heals everything with humor. This ordeal is still a big change for him because he was super active, and super physical, and played sports and did all the things, and now it's a completely different life for him. But he just wants to make people smile. He wants to make people laugh. He, too, has plans. He hopes to be a police officer.
I had to give up my career as an ICU nurse practitioner. I stopped working when Max started getting sick. I quit right around the time of his cardiac arrest. If I hear "code blue", it brings back the trauma. It's not possible for me to do that anymore.
I’m in school studying to become a licensed clinical social worker. It's my way of healing. I want to be a therapist and work with kids and their families who have undergone medical trauma. One of the reasons I decided to go back to school is because I'm faced with the reality that one day, what has been my entire world, will no longer be.
I always tell people who are dealing with a rare disease: If you can't get out of bed for a day, let somebody else help you out. Give yourself grace — but always get back up.
https://people.com/mom-shares-how-she-copes-not-knowing-how-long-2-boys-will-live-exclusive-8703830
See: https://childnervoussystem.blogspot.com/2015/08/rohhad.html
Stevens-Johnson syndrome
At 8 years old, Paige LaCombe was diagnosed with a rare and life-threatening skin disease called Stevens-Johnson syndrome.
The now 19-year-old recalls her yearslong recovery journey at Shriners Children’s Hospital, where she underwent more than 20 surgeries
She is hoping her story helps raise awareness about the condition, which is caused by an allergic reaction to medication
Paige LaCombe had a typical childhood in Scott, Louisiana, where she enjoyed school and extracurricular activities like soccer and dance. But everything changed for her in the second grade.
At just 8 years old, Paige started a new medication to help with breakthrough seizures for epilepsy. An allergic reaction to the medication caused a rare and debilitating skin condition that left her hospitalized and fighting for her life.
It started on March 23, 2013, when Paige woke up her parents in the middle of the night complaining of a burning and tingling sensation.
“She kept saying that she felt like she had bugs crawling on her,” her mother, Renee LaCombe, 40, tells PEOPLE. “We flipped on the lights and that’s when we realized. She had puffy lips, her eyes were completely red, her face was swollen, and she was developing what looked like a rash. Plus, she was having a really high fever.”
“We saw her and immediately rushed her to the hospital. And that's when things just went completely south,” she says.
At the hospital, Paige was initially misdiagnosed with pink eye and strep throat. Her symptoms continued to worsen but doctors were unable to figure out what was wrong.
“It was silent from the doctors. That's when I kind of knew, oh, this is not good,” Paige, now 19, tells PEOPLE. “I vividly remember thinking, ‘Am I going to die?’ Because at this point I could see my skin starting to blister. It was so scary.”
“It progressed while she was in the ER really quickly where anybody would touch her, her skin would just literally fall off,” Renee explains. “Paige was burning from the inside out. It was something that was not physically seen so by the time her skin started sloughing, she was already having all those feelings on the inside.”
As doctors struggled to provide answers, Renee turned to her sister-in-law, a nurse in Texas. Renee sent her photos of Paige and details about her condition. After extensive research, her sister-in-law believed Paige might be suffering from a skin disease called Stevens-Johnson syndrome. She recommended the family visit Shriners Children’s Hospital Galveston in Texas.
Renee approached Paige’s doctors about the possibility, but they surprisingly “didn’t align” with the diagnosis. So after three days, she made the difficult decision to get Paige discharged and transferred to the renowned pediatric burn center.
“If we would’ve stayed at the local hospital, she would not be alive,” Renee says.
And immediately after arriving at Shriners, she got answers for her little girl.
Paige’s diagnosis of Stevens-Johnson syndrome was confirmed. SJS is a rare and serious skin disorder caused by an allergic reaction to a medication.
Symptoms include a fever, sore mouth and throat, fatigue, burning eyes, red or purple rashes and blisters on the skin. As these erosions (painful open wounds that look like burns) develop, the top layer of affected skin dies and starts to shed, according to the Cleveland Clinic. The erosions typically spread to the eyes, chest, mouth, nose, throat, urinary tract, and genitals.
Paige was later diagnosed with the most severe form of SJS, called toxic epidermal necrolysis (TEN), where at least 30% of the skin is affected. In her case, 80% of her body was experiencing these painful blisters. According to the National Institutes of Health, about 30% of people who develop TEN do not survive.
“I was a hot mess. I truly was,” Renee says of her daughter’s diagnosis. “The first thing that the physicians told us was, ‘This is not good, but we're going to try our best to do everything that we can.'
Paige admits that she was “completely out of it” due to the excruciating pain and doesn’t even remember the three-hour ambulance ride from the local hospital to Shriners. “I had no sign of relief at that point,” she says. “I blacked out for a long period of time.”
“I finally woke up after, I'm not even sure what number surgery, but I opened my eyes in a whole new environment,” she continues. “I saw my parents, saw the doctors, and looked down and saw myself gauzed up like a mummy. That was frightening but I thought, hey, I'm still alive.”
ter being admitted to Shriners, Paige began a seven-year recovery journey that included more than 20 surgeries. Those procedures consisted of extensive wound care including 10 skin grafts using pig skin. She also underwent 11 corneal grafts, which involved using placenta tissue and bolstering her eyes shut to prevent her from going blind.
Paige missed second grade entirely and spent third through ninth grades in and out of the hospital. Renee admits that she “still lives with the guilt today” that her daughter was suffering due to a single medication. She did everything she could to give Paige back the life she lost.
“I saw my daughter decline really, really bad where we weren't sure if she was going to make it. It was horrible. It was very overwhelming. It definitely felt like I was in Grey’s Anatomy with the amount of doctors making circles,” Renee recalls. “But I'm thankful that it was a one-stop shop at Shriners and they literally did everything that they could to ensure minimal effects once she left the hospital.”
“They were so encouraging and they helped me through everything,” Paige stresses. “Even though my darkest point in life was at Shriners, I think of Shriners like a second family. I felt taken care of. I felt loved because the staff truly worked together for the better good of the patient. I still view Shriners as not only my lifesaver but my second home.”
Paige has since made a remarkable recovery, saying that she’s “healed beautifully. But she’s still dealing with some lasting effects of TEN. She regularly sees an ophthalmologist to address damage to her eyes. The teen uses a daily steroid to treat the blood vessels and she wears a prosthetic device — “basically like glass contacts” — to keep her eyes hydrated, doing whatever’s necessary to mitigate the risk of her becoming blind.
Additionally, because of the scar tissue that has developed, doctors say they don't know if Paige will be able to have children.
“I’m blessed to be alive,” says Paige, now a patient ambassador for Shriners Hospital. “Some days I have bad days with my eyes, but I can't complain. I'm very thankful to be here today.”
“It's been a journey. Stevens-Johnson syndrome is horrendous and most don't survive from this,” her mother adds. “Poor thing, this child is a miracle. She’s been through hell and back. We're unsure of motherhood and we're unsure of her vision. But right now she's thriving. It's amazing how she finally turned the corner.”
Today, Paige is a sophomore at South Louisiana Community College pursuing a degree in business management and marketing. Calling herself a social butterfly, she’s excited to feel a “sense of normalcy” being around her peers without visiting doctors every other day.
Additionally, both Paige and Renee want her story to help raise awareness about SJS and TEN, telling PEOPLE that they’ve been able to connect with other families navigating the disease.
“I hope that people take the time to maybe learn and educate themselves before they take a medication to not end up in this position,” Paige says.
“Educate before you medicate,” Renee stresses. “Ask the questions with your doctors, educate yourself. Don't feel intimidated with physicians. Know more about what some risks to taking medications are. Every day, I beat myself up for not asking more. So I have tried my hardest to turn this negative event in Paige's life into something positive.”
https://people.com/teen-recalls-burning-from-the-inside-out-rare-disease-exclusive-8709725
Tuesday, September 10, 2024
DYT-TOR1A dystonia
Inspired by a patient
Fan Y, Si Z, Wang L, Zhang L. DYT-TOR1A dystonia: an update on pathogenesis and treatment. Front Neurosci. 2023 Aug 10;17:1216929. doi: 10.3389/fnins.2023.1216929. PMID: 37638318; PMCID: PMC10448058.
Abstract
DYT-TOR1A dystonia is a neurological disorder characterized by involuntary muscle contractions and abnormal movements. It is a severe genetic form of dystonia caused by mutations in the TOR1A gene. TorsinA is a member of the AAA + family of adenosine triphosphatases (ATPases) involved in a variety of cellular functions, including protein folding, lipid metabolism, cytoskeletal organization, and nucleocytoskeletal coupling. Almost all patients with TOR1A-related dystonia harbor the same mutation, an in-frame GAG deletion (ΔGAG) in the last of its 5 exons. This recurrent variant results in the deletion of one of two tandem glutamic acid residues (i.e., E302/303) in a protein named torsinA [torsinA(△E)]. Although the mutation is hereditary, not all carriers will develop DYT-TOR1A dystonia, indicating the involvement of other factors in the disease process. The current understanding of the pathophysiology of DYT-TOR1A dystonia involves multiple factors, including abnormal protein folding, signaling between neurons and glial cells, and dysfunction of the protein quality control system. As there are currently no curative treatments for DYT-TOR1A dystonia, progress in research provides insight into its pathogenesis, leading to potential therapeutic and preventative strategies. This review summarizes the latest research advances in the pathogenesis, diagnosis, and treatment of DYT-TOR1A dystonia.
Katragadda P, Holla VV, Kamble N, Yadav R, Pal PK. Haloperidol in Managing DYT-TOR1A Dystonia: Unveiling a Dramatic Therapeutic Response. J Mov Disord. 2024 Jul;17(3):342-344. doi: 10.14802/jmd.24029. Epub 2024 Apr 9. PMID: 38589017; PMCID: PMC11300396. (no abstract)
Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, MartÃnez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R. The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders. Brain. 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831; PMCID: PMC10393417.
Abstract
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Fan Y, Si Z, Wang L, Zhang L. DYT-TOR1A dystonia: an update on pathogenesis and treatment. Front Neurosci. 2023 Aug 10;17:1216929. doi: 10.3389/fnins.2023.1216929. PMID: 37638318; PMCID: PMC10448058.
Abstract
DYT-TOR1A dystonia is a neurological disorder characterized by involuntary muscle contractions and abnormal movements. It is a severe genetic form of dystonia caused by mutations in the TOR1A gene. TorsinA is a member of the AAA + family of adenosine triphosphatases (ATPases) involved in a variety of cellular functions, including protein folding, lipid metabolism, cytoskeletal organization, and nucleocytoskeletal coupling. Almost all patients with TOR1A-related dystonia harbor the same mutation, an in-frame GAG deletion (ΔGAG) in the last of its 5 exons. This recurrent variant results in the deletion of one of two tandem glutamic acid residues (i.e., E302/303) in a protein named torsinA [torsinA(△E)]. Although the mutation is hereditary, not all carriers will develop DYT-TOR1A dystonia, indicating the involvement of other factors in the disease process. The current understanding of the pathophysiology of DYT-TOR1A dystonia involves multiple factors, including abnormal protein folding, signaling between neurons and glial cells, and dysfunction of the protein quality control system. As there are currently no curative treatments for DYT-TOR1A dystonia, progress in research provides insight into its pathogenesis, leading to potential therapeutic and preventative strategies. This review summarizes the latest research advances in the pathogenesis, diagnosis, and treatment of DYT-TOR1A dystonia.
Katragadda P, Holla VV, Kamble N, Yadav R, Pal PK. Haloperidol in Managing DYT-TOR1A Dystonia: Unveiling a Dramatic Therapeutic Response. J Mov Disord. 2024 Jul;17(3):342-344. doi: 10.14802/jmd.24029. Epub 2024 Apr 9. PMID: 38589017; PMCID: PMC11300396. (no abstract)
Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, MartÃnez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R. The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders. Brain. 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831; PMCID: PMC10393417.
Abstract
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Smartphone usage and health outcomes of adolescents
Adolescents who use smartphones for more than 4 hours per day may be at higher risk of adverse mental health outcomes, a study has suggested.
The research, published in the journal PLOS ONE, analyzed data on more than 50,000 South Korean adolescents taking part in an ongoing survey.
The research found that smartphone usage for more than 4 hours a day was associated with higher rates of stress, suicidal thoughts and substance use compared to usage of below 4 hours per day.
It is important to note that the study does not confirm a causal relationship between smartphone use and adverse health outcomes. Nevertheless, the findings could help to inform usage guidelines for adolescents, the authors said.
Smartphones have become widespread among among young people and evidence suggests that their use has increased significantly in recent years. But a growing body of evidence has shown that this usage is associated with a higher risk of many adverse health effects in adolescents—including sleep difficulties, eye-related problems, psychiatric disorders and even musculoskeletal issues.
Recent research has also found that at least some daily internet usage may be associated with better physical and mental health outcomes in adolescents.
To examine the relationship between adolescent smartphone use and health, a team of South Korean researchers analyzed survey data collected between 2017 and 2020. This data included the approximate number of daily hours each participant spent on a smartphone as well as a variety of other health measures.
The analysis took into account other factors that could be linked to health outcomes, such as age, sex and socioeconomic status.
The researchers found that the proportion of adolescents in the study who used a smartphone for more than 2 hours a day in 2020 was more than 85 percent—up from around 64 percent in 2017.
The study revealed that adverse health outcomes were prominent in those who used a smartphone for more than 4 hours per day. However, adolescents using smartphones 2–4 hours per day showed no increased adverse health outcomes compared to non-users, except for smartphone overdependence. Finally, adolescents that used a smartphone only for 1-2 hours a day actually appeared to encounter fewer problems than those who did not use one at all.
"This implies that appropriate smartphone usage can be prosocial and enjoying smartphone use should not be conceptualized as a behavioral addiction such as gambling and playing video games," the authors wrote in the study. "Children and teenagers spend considerable time using smart devices as a social platform for peer relationships."
"Using a smartphone for 4 hours a day seems to be generally acceptable. From our results, using smartphones for less than 2 hours a day even seems beneficial for mental health outcomes compared to non-use."
Given that a causal relationship has not been demonstrated, the authors said caution must be taken in interpreting the results of the study, which do not imply that using a smartphone for more than 4 hours a day is always undesirable. Nevertheless, the results suggest that smartphone usage beyond certain levels could "significantly" affect health outcomes.
In addition, the study has other limitations. For example, it relied on individuals' self-answered questionnaires on smartphone usage time and health outcomes, which may not be completely reliable. Furthermore, the researchers could not specify the smartphone usage time according to the purpose—for example, social media use, education, online shopping—which could have affected the health outcomes.
Overall, the researchers said the study will provide useful information for establishing smartphone usage guidelines for adolescents and young adults.
Kevin Koban, a postdoctoral researcher in the Department of Communication at the University of Vienna in Austria, who was not involved in the paper, told Newsweek the study is "well-conducted" and its results closely correspond to recent findings on the effect of smartphones, and media in general.
"The study certainly has its limitations, most notably concerning its cross-sectional survey design and reliance on self-report measurements, which does not allow for causal interpretations and makes it vulnerable to answering biases, respectively," he said.
This "should be taken very seriously when interpreting the findings. However, this doesn't mean the study is inherently flawed or shouldn't be considered," he said.
Some research has previously suggested that moderate levels of digital media use among young people appears to be just right for balancing out the potentially beneficial and harmful consequences of use.
"This so-coined Goldilocks Hypothesis is supported here again in a different setting, indicating that it may indeed be valid, which challenges some accepted assumptions about what healthy smartphone use may look like," Koban said.
The main implication of the study, according to Koban, is that even when one disregards how exactly smartphones are used and only focuses on the overall frequency, there seems to be an optimal level of smartphone engagement that is moderate in length.
"This creates obvious challenges for some publicly prevalent positions, like perhaps outdated and overly cautious screen time limits or other restrictive parental mediation ideals," he said. "Instead, it points toward the necessity of a more nuanced view to find the optimal balance across media, contexts, and individuals."
The results from South Korea might not necessarily be applicable to other adolescent populations. But comparable findings from other industrialized regions suggest that the similarities between different populations might outweigh the contextual differences, according to Koban.
With regards to potential causal mechanisms, Koban said different ones might be relevant depending on the direction of any given effect—that is, whether excessive smartphone use causes adverse mental health outcomes, or problematic mental health conditions cause excessive smartphone use.
"For example, excessive smartphone use could result in other, perhaps more beneficial activities being somewhat neglected or[...]exposure to stress-inducing information," he said. "The other way around, mental health issues may possibly come with an over-reliance on smartphone use as a coping tool.
"Generally, it is improbable that there is a single causal factor here; instead, it is much more likely that we talk about an individually variable combination of several underlying mechanisms that might be responsible in either way."
https://www.newsweek.com/scientists-reveal-smartphone-time-adolescents-1850188
Cha JH, Choi YJ, Ryu S, Moon JH. Association between smartphone usage and health outcomes of adolescents: A propensity analysis using the Korea youth risk behavior survey. PLoS One. 2023 Dec 6;18(12):e0294553. doi: 10.1371/journal.pone.0294553. PMID: 38055658; PMCID: PMC10699629.
Abstract
Objectives: We aimed to investigate the association between smartphone use and adverse behavioral health outcomes using nationwide Korea Youth Risk Behavior Web-based Survey data for 2017 and 2020.
Methods: The 2020 data (N = 54,809) were used to analyze the relationships between daily smartphone usage time (non-user, 0-2 h [hour], 2-4 h, 4-6 h, 6-8 h, and > 8 h), and adverse health outcomes (stress, sleep, depression, suicide, substance use, and smartphone overdependence). A 1:1 propensity score matching (PSM) was used to control for confounding variables.
Results: A total of 40,998 adolescents with < 4 h/day and > 4 h/day of usage were included. Adolescents' mean smartphone usage time in 2020 increased compared to that in 2017 (weighted % of > 2 h/day; 64.3% vs. 85.7%). The curvilinear relationships between smartphone usage time and adverse health outcomes were prominent after > 4 h/day. Adolescents using smartphones 2-4 h/day showed no increased adverse health outcomes compared to non-users, except for smartphone overdependence. Using a smartphone > 4 h/day was significantly associated with stress perception (1.16; 1.11-1.22), suicidal ideation (1.22; 1.13-1.31), and substance use (alcohol, 1.66; 1.57-1.75) after PSM.
Conclusions: Our study demonstrated the curvilinear relationship between smartphone usage time and adverse health outcomes in adolescents. Our findings can help establish smartphone usage guidelines for adolescents.
The research, published in the journal PLOS ONE, analyzed data on more than 50,000 South Korean adolescents taking part in an ongoing survey.
The research found that smartphone usage for more than 4 hours a day was associated with higher rates of stress, suicidal thoughts and substance use compared to usage of below 4 hours per day.
It is important to note that the study does not confirm a causal relationship between smartphone use and adverse health outcomes. Nevertheless, the findings could help to inform usage guidelines for adolescents, the authors said.
Smartphones have become widespread among among young people and evidence suggests that their use has increased significantly in recent years. But a growing body of evidence has shown that this usage is associated with a higher risk of many adverse health effects in adolescents—including sleep difficulties, eye-related problems, psychiatric disorders and even musculoskeletal issues.
Recent research has also found that at least some daily internet usage may be associated with better physical and mental health outcomes in adolescents.
To examine the relationship between adolescent smartphone use and health, a team of South Korean researchers analyzed survey data collected between 2017 and 2020. This data included the approximate number of daily hours each participant spent on a smartphone as well as a variety of other health measures.
The analysis took into account other factors that could be linked to health outcomes, such as age, sex and socioeconomic status.
The researchers found that the proportion of adolescents in the study who used a smartphone for more than 2 hours a day in 2020 was more than 85 percent—up from around 64 percent in 2017.
The study revealed that adverse health outcomes were prominent in those who used a smartphone for more than 4 hours per day. However, adolescents using smartphones 2–4 hours per day showed no increased adverse health outcomes compared to non-users, except for smartphone overdependence. Finally, adolescents that used a smartphone only for 1-2 hours a day actually appeared to encounter fewer problems than those who did not use one at all.
"This implies that appropriate smartphone usage can be prosocial and enjoying smartphone use should not be conceptualized as a behavioral addiction such as gambling and playing video games," the authors wrote in the study. "Children and teenagers spend considerable time using smart devices as a social platform for peer relationships."
"Using a smartphone for 4 hours a day seems to be generally acceptable. From our results, using smartphones for less than 2 hours a day even seems beneficial for mental health outcomes compared to non-use."
Given that a causal relationship has not been demonstrated, the authors said caution must be taken in interpreting the results of the study, which do not imply that using a smartphone for more than 4 hours a day is always undesirable. Nevertheless, the results suggest that smartphone usage beyond certain levels could "significantly" affect health outcomes.
In addition, the study has other limitations. For example, it relied on individuals' self-answered questionnaires on smartphone usage time and health outcomes, which may not be completely reliable. Furthermore, the researchers could not specify the smartphone usage time according to the purpose—for example, social media use, education, online shopping—which could have affected the health outcomes.
Overall, the researchers said the study will provide useful information for establishing smartphone usage guidelines for adolescents and young adults.
Kevin Koban, a postdoctoral researcher in the Department of Communication at the University of Vienna in Austria, who was not involved in the paper, told Newsweek the study is "well-conducted" and its results closely correspond to recent findings on the effect of smartphones, and media in general.
"The study certainly has its limitations, most notably concerning its cross-sectional survey design and reliance on self-report measurements, which does not allow for causal interpretations and makes it vulnerable to answering biases, respectively," he said.
This "should be taken very seriously when interpreting the findings. However, this doesn't mean the study is inherently flawed or shouldn't be considered," he said.
Some research has previously suggested that moderate levels of digital media use among young people appears to be just right for balancing out the potentially beneficial and harmful consequences of use.
"This so-coined Goldilocks Hypothesis is supported here again in a different setting, indicating that it may indeed be valid, which challenges some accepted assumptions about what healthy smartphone use may look like," Koban said.
The main implication of the study, according to Koban, is that even when one disregards how exactly smartphones are used and only focuses on the overall frequency, there seems to be an optimal level of smartphone engagement that is moderate in length.
"This creates obvious challenges for some publicly prevalent positions, like perhaps outdated and overly cautious screen time limits or other restrictive parental mediation ideals," he said. "Instead, it points toward the necessity of a more nuanced view to find the optimal balance across media, contexts, and individuals."
The results from South Korea might not necessarily be applicable to other adolescent populations. But comparable findings from other industrialized regions suggest that the similarities between different populations might outweigh the contextual differences, according to Koban.
With regards to potential causal mechanisms, Koban said different ones might be relevant depending on the direction of any given effect—that is, whether excessive smartphone use causes adverse mental health outcomes, or problematic mental health conditions cause excessive smartphone use.
"For example, excessive smartphone use could result in other, perhaps more beneficial activities being somewhat neglected or[...]exposure to stress-inducing information," he said. "The other way around, mental health issues may possibly come with an over-reliance on smartphone use as a coping tool.
"Generally, it is improbable that there is a single causal factor here; instead, it is much more likely that we talk about an individually variable combination of several underlying mechanisms that might be responsible in either way."
https://www.newsweek.com/scientists-reveal-smartphone-time-adolescents-1850188
Cha JH, Choi YJ, Ryu S, Moon JH. Association between smartphone usage and health outcomes of adolescents: A propensity analysis using the Korea youth risk behavior survey. PLoS One. 2023 Dec 6;18(12):e0294553. doi: 10.1371/journal.pone.0294553. PMID: 38055658; PMCID: PMC10699629.
Abstract
Objectives: We aimed to investigate the association between smartphone use and adverse behavioral health outcomes using nationwide Korea Youth Risk Behavior Web-based Survey data for 2017 and 2020.
Methods: The 2020 data (N = 54,809) were used to analyze the relationships between daily smartphone usage time (non-user, 0-2 h [hour], 2-4 h, 4-6 h, 6-8 h, and > 8 h), and adverse health outcomes (stress, sleep, depression, suicide, substance use, and smartphone overdependence). A 1:1 propensity score matching (PSM) was used to control for confounding variables.
Results: A total of 40,998 adolescents with < 4 h/day and > 4 h/day of usage were included. Adolescents' mean smartphone usage time in 2020 increased compared to that in 2017 (weighted % of > 2 h/day; 64.3% vs. 85.7%). The curvilinear relationships between smartphone usage time and adverse health outcomes were prominent after > 4 h/day. Adolescents using smartphones 2-4 h/day showed no increased adverse health outcomes compared to non-users, except for smartphone overdependence. Using a smartphone > 4 h/day was significantly associated with stress perception (1.16; 1.11-1.22), suicidal ideation (1.22; 1.13-1.31), and substance use (alcohol, 1.66; 1.57-1.75) after PSM.
Conclusions: Our study demonstrated the curvilinear relationship between smartphone usage time and adverse health outcomes in adolescents. Our findings can help establish smartphone usage guidelines for adolescents.
Tuesday, September 3, 2024
Stiff person syndrome
A little-known neurological disorder has been thrust into the spotlight after a documentary revealed singer Celine Dion’s struggle with stiff person syndrome (SPS).
The disease is rare, affecting only one or two people for every million. Yet for those who are diagnosed, it can have a devastating impact, causing muscle rigidity, pain and spasms.
Two people who are living with stiff person syndrome — Carrie Robinette, 45, from San Diego, California, and Corwyn Wilkey, 44, who lives in Anchorage, Alaska — shared with Fox News Digital the details of their experience.
Path to diagnosis
Robinette, a Navy wife and mother who was working as a full-time defense consultant, had been dealing with multiple health issues — pain, neuropathy, fatigue, migraines, asthma, allergies, thyroid and endocrine issues, kidney issues, even cancer — for more than 15 years.
"I was honestly ‘always sick’ from the time I was born," she said in a phone interview with Fox News Digital.
"Also, even as far back as high school, I had incredibly tight muscles in my legs, and there were countless times that I woke up crying with charley horse cramps in my calves."
Then, in May 2023, Robinette began experiencing painful, full-body spasms.
That kicked off a year of testing and visits to specialists in rheumatology, nephrology, endocrinology and neurology.
"After learning more and going back through my medical history, we realized that symptoms we previously blamed on other causes were likely early signs of stiff person syndrome."
Over the last year, as Robinette’s "constellation of symptoms" intensified, the doctors finally narrowed it down.
"It is beyond frustrating to literally not know at the start of each day if it will be a good day or a bad day."
"There is not a consensus within the SPS community on exact diagnostic criteria, and some doctors seem hesitant to diagnose rare diseases, so the journey to diagnosis is complicated by how rare the illness is," Robinette said.
"Definitive testing is not readily available."
These days, Robinette’s biggest challenge is frequent pain.
"Even if my body is not actively spasming, it feels like my muscles are sore, even bruised — all day, every day," she said. "I think eventually, we grow accustomed to our pain, so it just becomes the new normal."
Some days, Robinette can walk and move "almost like normal," while other days she can’t walk without a cane or walker.
She regularly uses a mobility chair when traveling any distance beyond 50 feet.
"It is beyond frustrating to literally not know at the start of each day if it will be a good day or a bad day."
'Initial symptoms'
Wilkey, a father of young children who works as an interpretive media publications specialist for Alaska State Park and is also a singer, first noticed muscle spasms in his larynx while performing with his band.
"Like Celine Dion, my initial symptoms were throat and facial spasms that have progressed into full-body seizures," he told Fox News Digital via email.
Wilkey was officially diagnosed with stiff person syndrome in 2021 at the Mayo Clinic in Rochester, Minnesota.
"The most prominent physical challenges are muscle stiffness and rigidity, seizure-like muscle spasms, cognitive distortion and decline, chronic pain and fatigue, PTSD, loss of coordination and fine motor control, headaches, joint pain, back pain, and inability to coordinate my body the way I want to," he said.
Wilkey’s full-body spasms are sometimes strong enough to dislocate and even fracture bones, he said.
James Chung, M.D., PhD, chief medical officer at Kyverna Therapeutics in Emeryville, California, noted that diagnosis of stiff person syndrome is a complex process. (He has not treated either of the patients mentioned in this article.)
"We start with a detailed clinical evaluation, looking for characteristic muscle rigidity and spasms," Chung, who focuses on drug development for autoimmune diseases, told Fox News Digital via email.
Blood tests are also needed to detect the antibodies that are found in a majority of cases, he said.
"Given the rarity of SPS, patients often feel misunderstood, even by health care professionals."
"Electromyography (EMG) is essential, showing continuous motor unit activity in affected muscles," he said.
In many cases, doctors will perform a lumbar puncture (spinal tap) to analyze cerebrospinal fluid for elevated antibodies and to rule out other conditions, along with imaging scans.
"SPS is often a diagnosis of exclusion due to its rarity," Chung said.
Limited treatments
While there is currently no cure for stiff person syndrome, therapies can help manage symptoms and improve patients’ quality of life.
Treatments are highly personalized for each patient, according to Chung.
In most cases, patients take medications like diazepam and baclofen to reduce muscle stiffness and spasms, and may take intravenous immunotherapies to help reduce autoantibodies.
"Pain management often involves a combination of medications," Chung said. "Physical and occupational therapy are vital."
Some current medications can have intense side effects, however.
Robinette has experienced hallucinations, loss of muscle control, nausea, vomiting and brain fog.
"For now, unfortunately, I am currently battling my condition without any helpful medications, and it is nearly unbearable," she said.
Kyverna Therapeutics is currently developing a new CAR-T cell therapy, KYV-101, that aims to "reset" the immune systems of patients with autoimmune diseases, according to Chung.
"This approach could potentially offer a more targeted treatment that addresses the root cause of SPS rather than just managing symptoms," he said.
The drug has recently gotten FDA approval to enter phase 2 clinical trials.
"I can really see it being the life-changing treatment that so many people with SPS and other autoimmune conditions need," said Robinette. "I just wish science moved faster!"
Mental and emotional effects
Many patients with stiff person syndrome struggle with anxiety about experiencing spasms in public, which often leads to social isolation, according to Chung.
"Depression is common, stemming from chronic pain, loss of independence and the disease's unpredictable nature," he told Fox News Digital.
"Patients also frequently experience frustration with the medical system due to misdiagnosis or dismissal of symptoms," he added.
"Given the rarity of SPS, patients often feel misunderstood, even by health care professionals."
When Wilkey received his diagnosis, he struggled with treatment-resistant depression, PTSD and complex regional pain syndrome, he told Fox News Digital.
"The difficulties associated with the disease destroyed my marriage and, for a time, turned me into a rage monster," he said.
"It has felt very much like receiving a death sentence."
To treat his "incredible" pain, Wilkey was prescribed oxycodone and morphine, which ultimately led to addiction.
"I became unable to function and felt like a burden on my family, which led me to attempt suicide," he said.
Wilkey underwent a period of hospitalization, intensive therapy and pain rehabilitation programs.
"I lost everything — my marriage, all my money, my home and even my children for a time," he said.
Today, Wilkey continues to participate in palliative care therapy — as SPS is considered a progressive and terminal disease — as well as psychedelic-assisted therapy for PTSD and depression.
Robinette has also experienced mental and emotional challenges stemming from her disease.
"This past year, on my journey with SPS, my family and I have really been put through the wringer," she told Fox News Digital.
"It takes a toll to feel like you are in a medical crisis and yet know that even if you go to the hospital, no one will help you."
"Seizing, in 10 out of 10 pain, losing control of muscles, and having the body twist and contort into a terrifying, seemingly endless episode — some of these events last 10 to 60 minutes, which feels like an eternity."
The hardest part, she said, is that some doctors have told her, "It could be in your head," or "We can't help you because we aren't sure what it is."
"It takes a toll to feel like you are in a medical crisis and yet know that even if you go to the hospital, no one will help you," Robinette said.
"I think it would make a world of difference to SPS patients to not have the added stress of having to constantly have to advocate for care."
Stress management is crucial for SPS patients, Chung said, as emotional stress can trigger or worsen spasms.
"Supporting mental health is a key component of comprehensive SPS care."
Who is most at risk?
Stiff person syndrome is a progressive and ultimately terminal neuromuscular autoimmune disease.
SPS shows certain demographic patterns, Chung said.
"It is incredibly empowering to know that you are not alone."
"Women are more commonly affected, with a 2:1 ratio compared to men," he said.
The typical age of diagnosis is between 30 and 60 years of age.
"There's a strong association with other autoimmune disorders," Chung said, which can complicate the diagnosis process.
"About 30% to 40% of SPS patients have type 1 diabetes, and we see higher rates of thyroiditis, vitiligo and pernicious anemia," the doctor went on.
"This clustering suggests a genetic predisposition to autoimmunity, although we haven't identified specific genes for SPS."
Advice for handling a diagnosis
For those who are living with stiff person syndrome, Chung said the best course of action is to get education from reliable sources and to build a strong support network.
"Work closely with a multidisciplinary medical team, be proactive in your treatment and communicate openly with your health care providers," he advised.
The doctor also recommended practicing stress-reduction techniques and staying as physically active as safely possible under professional guidance.
Wilkey’s best advice: "Don't try and go it alone."
He said, "You will drive yourself insane and beat your head against the wall, trying to cope on your own. Connecting with other survivors and developing a solid support system of crucial allies is essential."
For Robinette, sharing her story has been a helpful coping mechanism.
"It is incredibly empowering to know that you are not alone," she said.
"I believe that the more our voices rise, the more chance we all have of being heard."
Those seeking more information and resources for stiff person syndrome can visit The Stiff Person Syndrome Research Foundation at www.stiffperson.org.
https://www.foxnews.com/health/stiff-person-syndrome-patients-share-like-live-disease
Monday, September 2, 2024
MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects
Inspired by a patient
Abstract
The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).
A treatment for SPG50
When his infant son was diagnosed with a rare, fatal disease, a Canadian father was dismayed to discover there was no treatment or cure. So he set out to make one himself.
Terry Pirovolakis, an IT director in Toronto, Ontario, welcomed his third son in Dec. 2017. It was a "normal, healthy birth," he told Fox News Digital — but within six months, he and his wife, Georgia Pirovolakis, noticed their baby, Michael, was not lifting his head.
"He just didn’t seem like he was meeting his milestones," Pirovolakis said.
After months of doctors’ appointments, physiotherapy and genetic testing — what Pirovolakis describes as an "18-month diagnostic odyssey" — a neurologist diagnosed baby Michael with spastic paraplegia 50 (SPG50), a neurological disorder that affects fewer than 100 people in the world.
"They told us to just go home and love him — and said he would be paralyzed from the waist down by age 10, and quadriplegic by age 20," Pirovolakis said.
"They said he’d never walk or talk, and would need support for the rest of his life."
What is SPG50?
Spastic paraplegia 50 (SPG50) is a neurological disorder that affects a child’s development, gradually leading to cognitive impairment, muscle weakness, speech impairment and paralysis, according to the National Organization for Rare Disorders.
Most people with the disease will die by the time they reach their 20s.
"Children with SPG50 may experience early developmental delays, muscle weakness and spasticity, but they continue to strive and adapt," Dr. Eve Elizabeth Penney, an epidemiologist at the Texas Department of State Health Services and medical contributor for Drugwatch, told Fox News Digital.
"Over time, these symptoms can worsen, making it hard for affected individuals to walk and perform daily activities," added Penney, who was not involved in Michael Pirovolakis’ care.
"The prognosis varies from person to person, but it’s generally a progressive condition, meaning symptoms can become more severe over time," she also said.
In the absence of a cure, most families can only manage symptoms through physical therapy, occupational therapy, speech therapy and medications to help control spasticity or seizures, Penney said.
"Managing SPG50 requires a comprehensive, multidisciplinary approach to address its various symptoms and challenges," she added.
A father’s mission
There is no treatment currently approved by the U.S. Food and Drug Administration (FDA) for SPG50.
After the shock of the diagnosis, Pirovolakis immediately started researching, with a focus on finding a gene therapy that could help his son.
"They said he would be paralyzed from the waist down by age 10, and quadriplegic by age 20."
A month after his baby’s diagnosis, Pirovolakis flew to Washington, D.C., for a gene therapy conference, where he met with several experts. He also visited Sheffield, England, and the National Institutes of Health at the University of Cambridge, where scientists had been studying the disease.
"We then liquidated our life savings, refinanced our home and paid a team at the University of Texas Southwestern Medical Center to create a proof of concept to start Michael's gene therapy," Pirovolakis said.
After successful tests showed the gene therapy was effective at stopping the disease’s progression in mice and in human cells, Pirovolakis worked with a small drug company in Spain to manufacture the drug.
On Dec. 30, 2021, Health Canada granted approval to move forward with the gene therapy for Michael Pirovolakis.
"On March 24, 2022, my son was the first person to ever get treated with gene therapy at SickKids in Toronto," Pirovolakis said.
The procedure, which involves injecting cerebral spinal fluid through a lumbar puncture, does come with risks — but the potential benefits are life-saving.
‘I couldn’t let them die’
After Michael Pirovolakis received the one-time treatment, there were three more doses left.
"We decided that we had to help other kids," Pirovolakis said.
"When I heard that no one was going to do anything about it, I had to — I couldn't let them die."
Pirovolakis opened up a Phase 2 study in the U.S., which treated three children two years ago.
One of those was 6-month-old Jack Lockard, the youngest child to ever receive the treatment.
"Jack has thrived since then," Rebekah Lockard, the boy’s mother, told Fox News Digital.
"He is sitting independently, banging toys together, drinking from a straw cup and working really hard on crawling."
She added, "Doctors and therapists share the same sentiment: The treatment works!"
Other children who participated in the trial have experienced similar results, Lockard said.
"They've all shown that their disease has stopped progressing and their cognition has improved."
There are more children who still need the treatment — including Lockard’s first child, 3-year-old Naomi, who also has SPG50 — but are unable to access it because the clinical trial has now run out of money, as Fox News Digital previously reported.
‘Time is of the essence'
It costs about $1 million to make the drug for each child, Pirovolakis said, and another $300,000 or so to treat the patient in the U.S. at the hospital.
Pirovolakis has approached pharmaceutical companies, but all of them have declined to manufacture the drug.
"We want to make sure the trial moves on and these kids get treated."
"No investor is going to give you money to treat a disease that is not going to make money," he said. "That's the dilemma we're in."
While Pirovolakis and his team are actively working to secure grants and investors, it’s largely up to the parents to raise funds for the next phase of the clinical trial.
So far, Lockard has raised more than $90,000 via GoFundMe (called "Naomi and Jack Battle SPG50") to get her daughter’s treatment, but that is only a fraction of what is needed.
Penney noted that treatment for SPG50 is challenging and expensive to develop — "mainly because it’s a sporadic disease."
The doctor told Fox News Digital, "Pharmaceutical companies often prioritize conditions that affect larger populations, with a more significant potential for recouping research and development costs."
"The market is much smaller for rare diseases like SPG50, making it financially less viable for companies to invest in creating a treatment."
To devote himself to the cause, Pirovolakis quit his job and started a nonprofit in California, which now has five employees and 20 consultants.
The company — called Elpida Therapeutics, after the Greek word for "hope" — will run a Phase 3 study for SPG50 at the NIH in November.
Without the backing of major drug companies, however, there isn’t funding available to get the therapies to the children who need them.
Eight doses of the drug for SPG50 were produced in Spain and have been flown to the U.S.
"The treatment is here, just literally sitting in a refrigerator, ready to go," Lockard said. "Doctors are ready. There just isn't enough money to make it happen."
There are currently four families in the U.S. who are trying to raise the money that's needed, according to Pirovolakis.
"Time is of the essence," he said. "We want to make sure the trial moves on and these kids get treated."
The end goal
Looking ahead to the Phase 3 clinical trial at the NIH, Pirovolakis’ goal is to treat eight children with SPG50.
"If we can show that it works in all eight children — and we can prove to the FDA that it is making a difference — then the drug will get approved and every child can get it," he said.
Ideally, after the drug is approved — which could take three to five years, Pirovolakis estimates — SPG50 will be added to hospitals’ newborn screening programs and every child with the disease will be able to get the therapy.
Elpida Therapeutics has partnered with the Columbus Children’s Foundation (Fundación Columbus in Spain) and CureSPG50 to help save children with the disease.
"Our partnership with Elpida is driven by an unwavering commitment to leaving no child behind," Sheila Mikhail, co-founder of the CCF, said in a statement to Fox News Digital.
"At the Columbus Children's Foundation and Fundacion Columbus, as a global organization, we believe that every child deserves a chance for a healthy future. Together, we're making groundbreaking strides in treating ultra-rare genetic disorders, ensuring that no child is left to face these challenges alone."
"The biggest challenge in providing treatment for children with rare diseases often comes down to a lack of funding and vision."
Pirovolakis said he gets several calls each week from families around the world, asking for help saving their children.
"Unfortunately, the biggest challenge in providing treatment for children with rare diseases often comes down to a lack of funding and vision," he told Fox News Digital.
"The technology to cure our children is already here. I hope that someone with immense wealth — and more importantly, the vision and influence — will step in," he said.
"Their support could not only impact a handful of diseases and children, but extend hope to thousands of rare diseases and millions of children, both this generation and the next."
Currently, 40 million Americans are living with a rare disease, and one in 10 will be afflicted by a potentially treatable rare condition.
Pirovolakis added, "Someone you know or love will likely be affected by a rare disease."
https://www.foxnews.com/health/father-created-drug-save-his-son-from-rare-disease-now-other-families-desperate-get
A rare, fatal disease called SPG50 affects fewer than 100 people in the world — and one of them is Naomi Lockard, a 3-year-old in Colorado.
An experimental genetic therapy has shown promise in stopping the disease’s progression — but it is far too expensive for most families to afford.
Rebekah Lockard, the girl’s mother, is on a mission to raise the funds needed to save her daughter’s life.
Spastic paraplegia 50 (SPG50) is a neurological disorder that affects a child’s development, gradually leading to cognitive impairment, muscle weakness, speech impairment and paralysis, according to the National Organization for Rare Disorders.
Most people with the disease will die by the time they reach their 20s.
When Naomi Lockard was born in 2021, her parents immediately noticed some developmental delays.
By around six months, when she still "wasn't really moving," Lockard said, they started the baby in physical therapy, which didn’t help.
Eventually, an MRI and full genetic testing panel revealed the shocking diagnosis of SPG50.
At the time, Lockard was just a month away from giving birth to her second child — which added another element of fear given that the condition is genetic.
"My husband and I each have one healthy copy of this gene, but we each have one mutated copy," she told Fox News Digital in a phone interview.
"Naomi got both mutated copies, and there was a 25% chance that Jack (the second baby) would also get both mutated copies."
"It was a lot of panic at first, a lot of tears, because it's a horrible condition," Lockard said.
A few weeks later, after Lockard gave birth, another round of genetic testing revealed the family’s worst fear: Baby Jack also had SPG50.
"Children with SPG50 may experience early developmental delays, muscle weakness, and spasticity, but they continue to strive and adapt," Dr. Eve Elizabeth Penney, an epidemiologist at the Texas Department of State Health Services and medical contributor for Drugwatch, told Fox News Digital.
Fewer than 100 people in the world are known to have SPG50.
"Over time, these symptoms can worsen, making it hard for affected individuals to walk and perform daily activities," added Penney, who was not involved in the Lockard children's care.
"The prognosis varies from person to person, but it’s generally a progressive condition, meaning symptoms can become more severe over time."
A glimmer of hope
There is currently no FDA-approved treatment for SPG50, but the Lockards found hope when they enrolled in a clinical trial for an experimental gene therapy that was started by another parent, Terry Pirovolakis.
"It’s kind of like a transplant for genes," Lockard told Fox News Digital. "It functions like a treatment, or maybe even a cure."
The procedure, which involves injecting cerebral spinal fluid through a lumbar puncture, does come with risks.
"But it's worth the risk, because it's the only thing that could possibly help prevent the condition from getting worse," Lockard said.
Her newly diagnosed baby — who was just shy of six months old — received the gene therapy treatment first, as there was a better chance of stopping the disease at a younger age.
He was the youngest child ever to receive an intrathecal (spinal) gene therapy treatment.
"Jack has thrived since then," Lockard said. "He is sitting independently, banging toys together, drinking from a straw cup, and working really hard on crawling."
She added, "Doctors and therapists share the same sentiment: The treatment works!"
Other children who participated in the trial have experienced similar results, Lockard said.
"They've all shown that their disease has stopped progressing and their cognition has improved," she said.
Lockard’s daughter, Naomi, has not yet received the therapy.
"We can’t help but compare Jack and Naomi, and we see how he's meeting these milestones. He's caught up to her developmentally, and he’ll probably surpass her within the next few months, even though they're two years apart," Lockard said.
"Naomi just turned 3, and she only learned to crawl about six months ago. She can't walk or talk, and her cognitive level is probably that of a 9-month-old."
"Kids develop paralysis in elementary school, become quadriplegic in high school and pass away in their 20s."
Although her daughter will likely always have deficiencies, as she’s missed the "critical window" of development, the gene therapy could still stop further progression.
"If they can treat her before she gets the paralysis, the hope is that she'll never develop that," Lockard said.
If her daughter doesn’t receive the therapy, she will likely experience the typical trajectory of the disease, Lockard said.
"Kids develop paralysis in elementary school, become quadriplegic in high school and pass away in their 20s — never learning to talk, and losing any ability to move over the course of their short lives."
The problem is that the clinical trial has run out of funding.
Cost and complexity
Dr. Penney noted that treatment for SPG50 is challenging and expensive to develop — "mainly because it’s a sporadic disease."
The doctor told Fox News Digital, "Pharmaceutical companies often prioritize conditions that affect larger populations, with a more significant potential for recouping research and development costs."
"The market is much smaller for rare diseases like SPG50, making it financially less viable for companies to invest in creating a treatment."
Developing treatments for genetic disorders requires significant research, time and specialized technology, Penney added, all of which add to the cost and complexity.
In the absence of a cure, most families can only manage symptoms through physical therapy, occupational therapy, speech therapy and medications to help control spasticity or seizures, Penney said.
"Managing SPG50 requires a comprehensive, multidisciplinary approach to address its various symptoms and challenges," Penney said.
Fighting to keep hope alive
The experimental trial that potentially saved Jack Lockard’s life was started by another parent, Terry Pirovolakis.
Pirovolakis, based in Canada, found out in 2017 that his youngest son, Michael, had SPG50.
"They told us he would be paralyzed from the waist down by the age of 10, and a quadriplegic by the age of 20," Pirovolakis told Fox News Digital in an interview. "They said he would need support for the rest of his life."
Pirovolakis refused to accept that. He immediately started doing research and traveling around the world to gene therapy conferences, speaking with medical experts about his son’s disease.
Eventually, he liquidated his life savings, refinanced his home and paid a team of scientists at the University of Texas Southwester Medical Center to create a "proof of concept" for a genetic treatment for his son.
"I couldn't just let these kids die. I had to do something."
After seeing positive results in mice studies, as well as in cells from his son and a few other children with SPG50, Pirovolakis partnered with a small company in Spain to manufacture the drug.
In Dec. 2021, Health Canada granted Pirovolakis permission to move forward with the gene therapy for his son.
"After that, we had three more doses, and we decided that we had to help other kids," Pirovolakis said.
"I couldn't just let these kids die. I had to do something."
He opened a Phase 2 study in the U.S., in which three more children with SPG50 were treated — including Jack Lockard.
"I tried to give the therapy to pharmaceutical companies, but no one wanted to make it, so I quit my job and started a nonprofit, Elpida Therapeutics, in California," Pirovolakis said.
"We now have five employees and 20 consultants, and our goal is to save kids with five diseases, almost all of them fatal."
Next, Pirovolakis will start a Phase 3 study at the National Institute of Health for SPG50, with future trials planned for other diseases.
"Doctors are ready. There just isn't enough money to make it happen."
The problem is that without the backing of major drug companies, there isn’t funding available to dose the therapies to the children who need it.
"They have eight doses that were produced in Spain and have been flown to the U.S.," Lockard said.
"It’s here, just literally sitting in a refrigerator, ready to go. Doctors are ready. There just isn't enough money to make it happen."
It costs about $1 million to make the drug for each child, Pirovolakis said, and another $300,000 or so to treat each patient in the U.S. at the hospital.
While Pirovolakis and his team are actively working to secure grants and investors, it’s largely up to the parents to raise funds for the next phase of the clinical trial.
So far, Lockard has raised $50,000 via a GoFundMe fundraiser (called "Naomi and Jack Battle SPG50"), but that is only a fraction of what is needed to get her daughter treated.
"Right now, there are four families in the U.S. who are trying really hard to fundraise the money that's needed, because time is of the essence," he said.
"We want to make sure the trial moves on and these kids get treated."
The end goal
Looking ahead to the Phase 3 clinical trial at the NIH, Pirovolakis’ goal is to treat eight children with SPG50.
"If we can show that it works in all eight children — and we can prove to the FDA that it is making a difference — then the drug will get approved and every child can get it," he said.
"I get calls at least five times a week from families around the world, asking to help me save their kids."
Ideally, after the drug is approved — which could take three to five years, Pirovolakis estimates — SPG50 will be added to hospitals’ newborn screening programs and every child with the disease will be able to get the therapy.
"I get calls at least five times a week from families around the world, asking to help me save their kids," he said.
"It’s tough — there's only so much you can do, and unfortunately, this is a money problem. It's just heartbreaking."
https://www.foxnews.com/health/mother-frantic-save-clinical-trial-could-cure-daughter-treatment-sitting-fridge
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