Acute disseminated encephalomyelitis 2

Jamie Lynn Sigler is sharing why her son Beau is her “hero” after receiving a life-altering diagnosis nearly two years ago.

The 44-year-old mother of two shared how she is navigating life after her eldest son was diagnosed with ADEM in the upcoming Tuesday, May 12, episode of Amanda Hirsch’s Not Skinny But Not Fat podcast.

Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory condition that affects the brain and spinal cord. Sigler described the condition as encephalitis.

“He got a random virus at camp and instead of his body,” the Sopranos star said of her 14-year-old in a preview clip shared exclusively with PEOPLE, adding that “lakes and camp” don’t seem to be the best mix.

“Instead of making antibodies to fight the virus, his body made dumb antibodies and attacked itself,” she explained.

Sigler shares Beau with her husband, Cutter Dykstra. The couple welcomed Beau in August 2013 and married in 2016. They are also mom and dad to his brother, Jack Adam Dykstra, who was born in January 2018.

The Mob Town actress recalled how it took approximately a week for doctors to find out what was wrong with Beau after he exhibited symptoms such as a high fever and loss of appetite. Before doctors revealed the diagnosis, Sigler said her “mother's intuition” knew all along that something wasn’t right.

“I remember when we were leaving the ER the day before we finally got admitted, they're sending us home again and my feet literally didn't want to move,” she said. “I was like, I know in my soul that there is something seriously wrong that they are missing.”

“But what finally got us admitted was when he lost the ability to urinate, and that's when they were able to really understand what was going on,” Sigler continued. “And that was the most painful and traumatic time of my life, but also a moment where I felt more love than I've ever felt and support... I kind of learned who I am and what I've become in that moment.”

The actress added that the situation helped her to become a better advocate for her son’s needs.

“Even when with the doctors, right? Like you're at their mercy,” she said. “They're saving your child's life, but also my opinion mattered. Like, I had a say in his care. I had a say in what they were doing. And he is a miracle.”

Looking back on the experience, Sigler told Hirsch, “There were times that we all thought we were going to lose him.”

She also called Beau “a fighter,” noting that the last couple of years haven't "been easy for him.”

“His recovery has been really hard,” she said, adding that it feels like he’s become a different kid since the incident.

“And that's been hard for me as a mom,” Sigler said. “It has, and I'm trying to give myself as much grace as I can through that because it's like you have this version of your kid for so long, for 10 years. Like I know who Beau is. I know him.”

During Beau’s recovery, “he was in a severe state of psychosis for a while,” before behaving as if he were “Buddy the Elf,” Sigler said.

The mother of two also said that while her eldest began seeing everything as “beautiful” and “great,” it was “a lot” and he was “bullied so much at school for it and it was really devastating.”

“But he's also my hero,” she said, adding that she placed him with a therapist who “helped us as a family remind Beau of who he is.”

Angel Saunders

https://people.com/jamie-lynn-sigler-details-life-since-son-beau-was-diagnosed-with-adem-11972014

Jamie-Lynn Sigler has learned to live with pain since being diagnosed with multiple sclerosis when she was 20 — but nothing prepared her for the kind of anguish she faced last summer when her 11-year-old son Beau was hospitalized with a rare, life-threatening autoimmune condition.

"Those were the hardest days I've ever had in my entire life," Sigler, 43, tells PEOPLE. "It was probably the most helpless I've ever been."

Their crisis began last July after her "healthy, active" son suffered a week of high fevers and headaches that culminated in his being unable to urinate. "He was screaming in pain," The Sopranos actress says.

Beau was admitted to Dell Children's Medical Center in their hometown of Austin, Texas, and diagnosed with a rare autoimmune condition known as acute disseminated encephalomyelitis, or ADEM, which causes inflammation of the central nervous system and can develop after a viral or bacterial infection.

Over the next two weeks in the hospital, "he got worse every day," Sigler says. "He lost his ability to walk, and then to talk. Then he couldn't eat or move his mouth." He lost 25 lbs. "There was nothing recognizable about my son."

Doctors put him on a 24-hour IV of epinephrine to keep him alive because the inflammation in his spine and brain prevented him from regulating his own blood pressure and heart rate. "My husband and I would look at each other like, "Is this really happening?'" Sigler says of her husband of nine years, Cutter Dykstra. "Truly, we thought he was going to die."

For more than a month, Sigler stayed at the hospital by Beau's side while Dykstra cared for their younger son, Jack, 7, and she drew upon her years of experience managing the challenges of MS.

"It was wild to watch my son have neurological issues that mirrored mine in very many ways," she says. "My experience understanding the body and inflammation and the brain helped. From 6 a.m. till 8 p.m., I was on it. I was a coach. I would speak to him and tell him he could do it." But, she says, "the nights were when I could fall apart and just be a mom and be completely heartbroken and terrified."

Sigler relied on family and friends for support, including her MeSsy podcast co-host Christina Applegate. "She was there for me in a really scary moment. We sat in prayer together."

Asking for help doesn't come easily to Sigler. "My friends joke that on my tombstone it's going to say in quotes, 'I'm fine.' But for the first time in my life I was actually able to accept help because it wasn't for me — or it didn't seem like it was for me in that moment — it was for Beau," she says. "To realize how loved and supported you are, it's something I'm going to take with me for the rest of my life."

And then, 33 days after he was admitted, Beau was able to walk out of the hospital. "The care that we received, the attention that every family receives, was unparalleled," Sigler says of Dell Children's.

At first, "we were just in a constant state of gratitude." But, she says, "there's still a road of recovery." Beau is back in school, back on his baseball team and is working with a personal trainer to regain his strength. "There's some residual things physically we deal with, and because of what he sees me deal with, he knows I understand. I know it's hard to not be able to do something that you used to be able to do."

The psychological toll of the trauma can be an even greater challenge. Although Beau doesn't remember anything from his hospitalization, "mentally he went through something profound and he's trying to figure out how to integrate that back into life and still be the 11-year-old little boy he was," Sigler says. "When you have a near-death experience, there's an intense amount of gratitude you have for life, and he constantly wants to express it, which is beautiful. He wants to go up and tell everyone he loves them and how amazing they are. But for another 11-year-old, that's not how you do things."

She's had to adjust as well. "My son is different than the 10-year-old Beau that entered the hospital in July," says Sigler. "We joke, calling him Beau 2.0. The person that's really benefited from what happened this summer is my little one, Jack, because they don't fight anymore!"

Beau is also learning guitar and has developed a love for songwriting: "It's been how he channels his emotions."

Stress can exacerbate a disease like multiple sclerosis, but Sigler says helping Beau recover has actually given her strength. "Sometimes when you take the focus off yourself and make yourself a service, your body shows up for you," says Sigler, a spokesperson for Novartis who developed a guide with the drug company to help others manage life with the degenerative neurological disease. "There's been no big fallout. I am okay. I'm not struggling physically like I think a lot of people anticipated."

And, she says, she's been inspired by watching her son. "I saw the way a body can heal, and that was something I needed to see. And I saw Beau's commitment to his healing. That's added another layer of discipline I've had for myself and my health."

Sigler, who's in the process of writing a memoir, says that as traumatic as the experience was, it "slowed our family down in such a beautiful way. We are so present with each other. There's just not a lot more we need than being at home, just the four of us."

Eileen Finan

https://people.com/jamie-lynn-sigler-fell-apart-terrified-fearing-son-was-going-to-die-exclusive-11691337

Jamie-Lynn Sigler's son Beau has finally left the hospital.

The Sopranos actress, 43, shared a heartwarming video on Instagram over the weekend of her 10-year-old son Beau “busting out” of the hospital to cheers from medical staff after being diagnosed with the rare inflammatory autoimmune disorder, acute disseminated encephalomyelitis (ADEM).

“After 33 days, we are busting out of here! My brave boy, you are a walking miracle,” Sigler wrote alongside the clip shared on Aug. 16. “The rest of this story will be Beau’s to tell, if he chooses to one day.”

“Thank you to the INCREDIBLE staff at Dells Children’s Hospital. The way you take care of your patients and the way you guide their families through the process, I just don’t have enough words,” she continued. “I’m in awe of your patience, dedication, and expertise … But, no offense ... I hope we never see you again✌️.”

“Thank you all for the love and prayers. They worked. 🙏🏻🩷,” Sigler concluded.

The preview photo of the post showed Beau standing with his back to the camera in what appeared to be a waiting room pointing to himself as a caption above him read, “Heros this way,” with an arrow pointing to the left.



In the video shared, a smiling Beau walked down the hospital corridor to loud cheers from medical staff and patients, who lined each side of the corridor as they watched him leave. At one point, the 10-year-old skipped down the hallway as he high-fived some of those cheering him on.

Following Beau's hospital exit, Sigler also reshared a post on her Instagram Stories about having a “Lifequake,” defining it as, “A significant, sudden and unexpected shift in the trajectory of your life that initially feels devastating but has the beneficial outcome of catalyzing personal growth, transformation and rebirth."

Her latest hopeful post regarding Beau comes after revealing his “nightmare” diagnosis on Instagram on Aug. 6.

“4 weeks ago, what seemed like a normal virus for our son, turned into a nightmare,” she wrote alongside a photo of her and Beau smiling at the time. “Beau has what we believe to be, ADEM.”

ADEM is an acute, rapidly progressive autoimmune disease that affects the brain and spinal cord, which is typically caused by inflammation due to a prior infection or immunization, per the National Institute of Health.

“To say this has been hard, is an understatement, and I’ve never felt more broken,” Sigler continued, adding, however, that she has also never felt more love” from her supportive friends and family, including her husband Cutter Dykstra and son Jack, 6.

Sigler shared on her MeSsy podcast with Christina Applegate that ahead of Beau being admitted to the hospital, his symptoms included having a 105-degree fever, "screaming" that his head hurt, and being unable to eat and urinate.

“It was and has been like the darkest, hardest, most f---ed up thing I’ve ever been through,” Sigler said on the podcast on Aug. 6, adding that she thought her son was "dying."

Escher Walcott

https://people.com/jamie-lynn-sigler-son-beau-leaves-hospital-after-33-days-autoimmune-disorder-diagnosis-8697978

Diffusional kurtosis imaging in neonatal encephalopathy

Moss HG, Yazdani M, Jensen JH, Katikaneni L, Wiest DB, Wagner CL, Jenkins DD. Neonatal encephalopathy: a diffusional kurtosis imaging analysis of white matter to assess injury severity and recovery. Pediatr Res. 2025 Oct 30. doi: 10.1038/s41390-025-04434-x. Epub ahead of print. PMID: 41168400.

Abstract

Background: Diffusional kurtosis imaging (DKI) may be more sensitive to white matter (WM) injury than diffusion tensor imaging (DTI) in infants with neonatal encephalopathy (NE) presumed from hypoxic ischemic encephalopathy (HIE). We hypothesized that DKI would differentiate encephalopathy severity, predict outcomes, and indicate treatment response.

Methods: DKI was acquired using 3 T MRI in neonates with HIE on day 4-10 following hypothermia (n = 21, HIE-C), or day 5-6 (n = 16, NVD-A) and 2-6 weeks (n = 18, NVD-R) in infants who received N-acetylcysteine and vitamin D (NVD) with hypothermia. We utilized tensor-derived diffusion metrics in generalized linear models to estimate Peabody Gross Motor, Cognitive Adaptive, Clinical Linguistic, and Auditory Milestones test scores.

Results: Mean kurtosis differentiated stage 3 and 2 encephalopathy in all cohorts. The recovery scan predicted outcomes better than the acute scan. Kurtosis metrics and Vitamin D dose were significant determinants of gross motor and cognitive scores in NVD-R group.

Conclusion: Kurtosis reflects the degree of acute CNS injury and was sensitive to treatment effects in term infants with a clinical diagnosis of HIE. Our data are consistent with prior work in adult stroke, which indicates that diffusivity and kurtosis at different stages of recovery capture distinct aspects of WM injury.

Impact: Diffusional kurtosis imaging (DKI) is an advanced diffusion MRI modality rarely applied in pediatric imaging that quantifies the complexity of water movement in white matter (WM), and which offers increased sensitivity to the severity of injury and recovery after neonatal encephalopathy due to presumed hypoxic-ischemic brain injury. We demonstrate that kurtosis in early-myelinating WM tracts differentiates the severity of neonatal encephalopathy (NE) better than diffusivity, which may have therapeutic implications. DKI provides complementary information about WM injury and recovery after NE beyond current methods, which are lacking in subjective clinical MRI assessments. DKI indicates the effect of therapeutics on WM injury in NE.

Functional neurological disorder

Courtesy of a colleague

A young woman will have both her legs surgically amputated after they bent at a 45-degree angle upwards.

Megan Dixon, 21, has been left with unbearable, constant pain for the past eight years when her legs were fixed completely straight.

Megan, who also suffers from functional neurological disorder (FND), has bewildered doctors who have not been able to find a cause of her condition.

But she says it has taken them so long to take action that her only choice left is to have them both amputated as she struggles with basic, daily tasks.

Megan, from Cambridgeshire, is fundraising for an electric wheelchair to bring back her independence post-amputation – having not walked since she was 14.

She said: “It was the hardest when I met with the amputee clinic and they said amputation was my best and only option.

“I was hoping deep down they would say there was another way.

“But this is my reality now, and I haven’t fully come to terms with it yet.”

Megan first became ill when she was 13-years-old, suffering from whooping cough and glandular fever.

A year later, she found her legs began to stop working, and she hasn’t walked since.

Megan, who was initially diagnosed with myalgic encephalomyelitis (ME), had physiotherapy, but her legs had locked straight.

She said, “From there I got worse and worse.

“I started to go into a comatose-like state. When I was 16, I stopped being able to sit up by myself, and I started to lose the ability to speak.

“My paediatrician was concerned I’d had a stroke, so I was rushed to hospital.

“I was supposed to be in for tests over four days – I came out a year and a half later.”

At Bristol Hospital, Megan lost her speech, mobility, strength, and her sight.

She was diagnosed with FND, a condition where the brain struggles to send and receive signals correctly.

She became paralysed from the neck down, needing an NG tube in her nose for feeding.

Megan said: “I could feel my bones in my legs grating together, but I kept being told the pain was in my head and it wasn’t real.

“I was silently screaming for 24-hours a day.

“When I went into a coma-like state, I had no idea what was going on. No one could wake me up.

“I could feel my bones in my legs grating together, but I kept being told the pain was in my head, and it wasn’t real,” Megan said.

“My legs were completely locked straight, and even under anaesthetic, they couldn’t bend my knees.

“My left leg had started to bend the wrong way by ten degrees.”

Meg was discharged from the children’s hospital when she turned 18 and said she was left in the community for a year, ‘with no help whatsoever’.

Doctors remained baffled as to why Megan’s legs had locked and began to bend.

She said, “I had essentially been left to rot and die in bed.

“My family complained about my care, and I was sent to a private nursing home specializing in neurological disorders.

“I was completely paralysed from the neck down, and I had to work on getting all of my functions back.

“But equally, my legs got worse and worse.

“I’d seen six different surgeons and was turned away by five.

“When I finally found a surgeon to help me, it had been so long that the damage in my knees was irreversible.

“My left knee is bent at a 45-degree angle, and my right is close behind. My only option left is amputation.”

As well as battling seizures and chronic pain, Megan said even day-to-day tasks have been extraordinarily difficult due to her legs.

She explained: “I can’t walk on my own, so I have to bum shuffle everywhere or use my wheelchair.

“Getting from the floor to the bed is absolute agony for me because of the weight and pressure through my knees.

“I have to be carried to the bed or the toilet, and simple tasks take me so much longer.”

Megan is due to have her legs amputated in August and is fundraising for an electric wheelchair and other medical equipment to give her independence back.

She added: “Despite not being able to walk since I was 14, I’ve only really been in a wheelchair since I was 19 because I spent so long bedbound or in a coma.

“I want to be able to go out with my partner, visiting the zoo, and have him by my side holding hands – as opposed to being on a day out with my carer.

“This is my last resort and my only option.”

Megan’s message of hope: “If something doesn’t feel right in your body, please listen to it and trust yourself. For six years I was dismissed, and as a result the only surgery now available to me is, regrettably, amputation.

“If you are facing amputation, I want to be honest with you—there are no words that can truly make it easier. It is a devastating and life-changing experience, and something I would never wish on anyone.

“All you can do is take it one day at a time. There will be days when it feels overwhelming, and that’s okay. Allow yourself to feel everything that comes with this journey. Struggling doesn’t mean you are weak—it means you are human.

Megan Dixon in a wheelchair with her legs bent at a 45-degree angle, with Oliver Carrick standing behind her.

“But even in the darkest moments, try to hold on to the smallest positives. Sometimes hope comes in the smallest forms: a kind word, a moment of strength, or simply getting through another day.

“Keep fighting for the life that comes after. None of us should have to face something like this, but if it leads to a future where life is a little more bearable, a little less painful, and holds more independence. Then all of this will be worth it.”

You can find Megan’s GoFundMe here.

 
Faye Mayern,

https://nypost.com/2026/05/11/lifestyle/21-year-old-to-have-legs-amputated-after-legs-locked-straight-bent-backwards/

Neurofibromatosis 1 homozygosity

Alghamdi M, Monies D, Alsohime F, Temsah H, Almodaihsh F, Aldawasri M, Alsultan A, Alkuraya FS. Implications of mosaicism in variant interpretation: A case of a de novo homozygous NF1 variant. Eur J Med Genet. 2021 Jul;64(7):104236. doi: 10.1016/j.ejmg.2021.104236. Epub 2021 May 20. PMID: 33965620.

Abstract

Neurofibromatosis type 1 is a common multisystem autosomal dominant syndrome caused by pathogenic heterozygous variants in the neurofibromin gene (NF1). It is associated with a substantially increased cancer risk. Mosaicism for NF1 has been clinically well-established for "second hit" variants in skin lesions and tumor tissues. Here, we report on a 3-month-old boy with multiple café au lait macules (CAMs) and juvenile myelomonocytic leukemia (JMML) who was found to carry a previously established pathogenic NF1 variant (c.586+5G>A), as revealed by whole-exome sequencing. Surprisingly, however, this variant was detected in the homozygous state in the patient and was absent in the parents and siblings. Deep sequencing of this variant using blood, buccal swabs and skin samples was performed. As expected for an NF1 gene mutation promoting JMML, the variant was detected in 90.6% of the blood DNA reads, in sharp contrast to the mere 5% and 0.74% of reads in the saliva- and skin fibroblast-derived DNA, respectively. Our analysis, therefore, confirmed postzygotic origin of the variant followed by a mitotic event resulting in its homozygosity, although we could not differentiate between the possibilities of a gene conversion and mitotic crossover. Apparently de novo homozygous variants should trigger a careful investigation into mosaicism to achieve accurate interpretation.

Schinzel-Giedion syndrome

Inspired by a patient

Liu WL, He ZX, Li F, Ai R, Ma HW. Schinzel-Giedion syndrome: a novel case, review and revised diagnostic criteria. J Genet. 2018 Mar;97(1):35-46. PMID: 29666323.

Abstract

Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant inheritance disorder. Heterozygous de novo mutations in the SETBP1 gene have been identified as the genetic cause of SGS. Here, we report a novel case with the syndrome with a novel insertion mutation in SETBP1. We also present a review of SGS cases, and first revise diagnostic criteria of SGS based on clinicalfindings and/or SETBP1 mutation worldwide. A revised diagnostic criteria and typing of SGS can be determined. Type I (complex and classic type) SGS patients present a development delay and typical facial features (prominent forehead, midface retraction, and short and upturned nose) associated with hydronephrosis or two of the characteristic skeletal anomalies (a sclerotic skull base, wideoccipital synchondrosis, increased cortical density or thickness, and broad ribs). Type II (middle type) patients show development delay and the distinctive facial phenotype (midface retraction, short and upturned nose), lacking both hydronephrosis and typical skeletal abnormalities, with existence of SETBP1mutation. Type III (simple type) patients with SETBP1 alteration show their major symptom is development delay, in which expressive language delay is the most striking feature. Central nervous system involvement with development delay in which expressive language delay is much more obviously affected is the most prominent feature of SGS. There is another indication that severity of phenotype of SGS may be inversely correlated with degree of SETBP1 alteration, besides gain-of-function or dominant-negative effects in SETBP1 alteration causing SGS.

Duis J, van Bon BWM. Schinzel-Giedion Syndrome. 2024 Mar 7. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 38452171.

Excerpt

Clinical characteristics: Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment. Other findings can include poor weight gain often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance. Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain. Anomalies of the liver, spleen, and/or pancreas are less common. Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.

To date, more than 50 individuals have been reported with molecularly confirmed classic SGS.

Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot. The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date.

Diagnosis/testing: The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a 12-base-pair region in exon 4 encoding a canonical degron). The diagnosis of atypical SGS syndrome is established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic variant adjacent to – but not within – the mutational hot spot.

Management: Treatment of manifestations: There is no cure for classic or atypical SGS. Supportive treatment to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology, oncology, urology, nephrology, audiology, gastroenterology, orthopedics, cardiology, and medical genetics.

Surveillance: At each visit, evaluate for feeding issues (including nutritional status and safety of oral intake), gastrointestinal issues, respiratory issues, neurologic manifestations (including seizures, changes in tone, movement disorders, mood, irritability, and alertness), kidney and urinary tract manifestations, and musculoskeletal manifestations. In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia.

Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.

Genetic counseling: Classic and atypical SGS are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant. Rarely, individuals diagnosed with SGS have the disorder as the result of a pathogenic variant inherited from a parent. Sib recurrence of clinically defined classic SGS, presumed to be due to parental germline mosaicism, has been reported in two families. Transmission of a SETBP1 pathogenic missense variant from an unaffected parent to a child with atypical SGS has been reported in one family (of note, the possibility of mosaicism in the unaffected parent was not excluded). Once the SETBP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Morison LD, Summerfield N, Bradley D, van Bon BW, Morgan AT. Schinzel-Giedion syndrome: communication, feeding and motor skills in 16 individuals. Neurogenetics. 2025 Aug 27;26(1):64. doi: 10.1007/s10048-025-00846-3. PMID: 40859069; PMCID: PMC12380911.

Abstract

Schinzel-Giedion Syndrome (SGS) is a rare neurodevelopmental disorder caused by pathogenic SETBP1 gain-of-function variants. SGS medical features have been well described. Associated skills critical to quality of life have such as communication, feeding, and motor skills are yet to be characterised. Here we used standardised caregiver report tools to characterise these skills as well as the medical features, in 16 children with SGS (median = 5 years, 7 months, range 6 months to 12.5 years). Vineland-3 scores reflected severe impairment in communication, daily living, socialisation and motor skills. Average receptive and expressive language skills were equivalent to a 0-to-1-month-old. Average motor skills were slightly stronger with age equivalents of 2-months-old for gross motor skills and 4-months for fine motor skills. 13/16 (81%) children could attend to someone's voice, and 15/16 (94%) could make happy vocalisations. One individual (6%) could follow basic instructions. Despite a relatively homogenous phenotype, some children presented with relative strengths when compared to the rest of the cohort. Our expanded phenotype of SGS allows better targeted therapies and supports, highlighting the importance of early feeding intervention and augmentative and alternative communication (e.g., assistive technology for communication). Given the severity of the SGS profile, our data highlight the need for sensitive measurement tools for detecting subtle skill changes in SGS in response to precision medicine interventions.

2q13 duplication

Inspired by a colleague's patient

Messina C, Zuccarello M. Parietal Lobe Epilepsy Associated With 2q13 Duplication: Expanding the Neurogenetic Spectrum. Cureus. 2025 Aug 19;17(8):e90456. doi: 10.7759/cureus.90456. PMID: 40979016; PMCID: PMC12444579.

Abstract

Copy number variations (CNVs) involving the 2q13 region have been associated with a wide range of phenotypes, including developmental delay, dysmorphic features, hypotonia, and congenital heart defects. However, parietal lobe epilepsy has not yet been reported in association with 2q13 duplication. We describe the case of a 20-year-old woman with a duplication of the 2q13 region identified during childhood, who later presented with recurrent, brief episodes of right upper limb paresthesia spreading to other limbs, followed by transient pain. Her past medical history included dyspraxia, polycystic ovary syndrome, atrial fibrillation, and intellectual disability. Electroencephalography (EEG) revealed interictal epileptiform discharges, consisting of paroxysmal sharp theta waves in the left parietal and temporal regions, spreading to adjacent and contralateral areas, particularly during hyperventilation. Based on clinical and EEG features, a diagnosis of parietal lobe epilepsy was established. Treatment with levetiracetam resulted in significant clinical improvement, characterized by complete resolution of the previously described episodes of recurrent, brief right upper limb paresthesia spreading to other limbs, followed by transient pain, as well as a reduction of epileptiform abnormalities on EEG. The duplicated region includes several genes involved in neuronal development, synaptic regulation, and myelination, such as MERTK, TMEM87B, and FBLN7. Their altered expression may contribute to cortical excitability and epileptogenesis. This case adds to the phenotypic variability reported in individuals with 2q13 duplication and underscores the importance of further studies to explore possible gene-specific contributions to neurological findings. This is the first report linking 2q13 duplication with parietal epilepsy, underlining the importance of considering CNVs in unexplained focal epilepsy presentations.

Digilio MC, Dentici ML, Loddo S, Laino L, Calcagni G, Genovese S, Capolino R, Bottillo I, Calvieri G, Dallapiccola B, Marino B, Novelli A, Versacci P. Congenital heart defects in the recurrent 2q13 deletion syndrome. Eur J Med Genet. 2022 Jan;65(1):104381. doi: 10.1016/j.ejmg.2021.104381. Epub 2021 Nov 8. PMID: 34763108.

Abstract

The recurrent 2q13 deletion syndrome is a rare genetic disorder associated with developmental delay, cardiac and urogenital malformations, and minor facial anomalies. Congenital heart defects (CHDs) are the most frequent malformations associated with del2q13. Experimental studies in zebrafish suggest that two genes mapping within the 2q13 critical region (FBLN7 and TMEM87B) could confer susceptibility to congenital heart defects in affected individuals. We reviewed the cardiac characteristics in four patients with 2q13 deletion admitted to our hospitals, and in published patients. Two of our patients had congenital heart defects, consisting in partial anomalous pulmonary venous connection, ostium secundum atrial septal defect ostium secundum, and small muscular ventricular septal defect in one of them, and aortic valve insufficiency with partial fusion of two commissures (incomplete bicuspid aortic valve) and mitral valve insufficiency due to trivial mitral valve prolapse in the other. The anatomic types of CHD in del2q13 syndrome are highly variable and distributed widely, including laterality defects, complex atrioventricular septal defect, septal anomalies, and cardiomyopathies. Cardiac evaluation should be part of the clinical workup at diagnosis of 2q13 deletion.

Riley KN, Catalano LM, Bernat JA, Adams SD, Martin DM, Lalani SR, Patel A, Burnside RD, Innis JW, Rudd MK. Recurrent deletions and duplications of chromosome 2q11.2 and 2q13 are associated with variable outcomes. Am J Med Genet A. 2015 Nov;167A(11):2664-73. doi: 10.1002/ajmg.a.37269. Epub 2015 Jul 31. PMID: 26227573.

Abstract

Copy number variation (CNV) in the long arm of chromosome 2 has been implicated in developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), congenital anomalies, and psychiatric disorders. Here we describe 14 new subjects with recurrent deletions and duplications of chromosome 2q11.2, 2q13, and 2q11.2-2q13. Though diverse phenotypes are associated with these CNVs, some common features have emerged. Subjects with 2q11.2 deletions often exhibit DD, speech delay, and attention deficit hyperactivity disorder (ADHD), whereas those with 2q11.2 duplications have DD, gastroesophageal reflux, and short stature. Congenital heart defects (CHDs), hypotonia, dysmorphic features, and abnormal head size are common in those with 2q13 deletions. In the 2q13 duplication cohort, we report dysmorphic features, DD, and abnormal head size. Two individuals with large duplications spanning 2q11.2-2q13 have dysmorphic features, hypotonia, and DD. This compilation of clinical features associated with 2q CNVs provides information that will be useful for healthcare providers and for families of affected children. However, the reduced penetrance and variable expressivity associated with these recurrent CNVs makes genetic counseling and prediction of outcomes challenging. © 2015 Wiley Periodicals, Inc.

Costain G, Lionel AC, Fu F, Stavropoulos DJ, Gazzellone MJ, Marshall CR, Scherer SW, Bassett AS. Adult neuropsychiatric expression and familial segregation of 2q13 duplications. Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):337-44. doi: 10.1002/ajmg.b.32236. Epub 2014 May 8. PMID: 24807792; PMCID: PMC4464821.

Abstract

New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later-onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression.

Early diagnostic changes in autism spectrum disorder

Yeom JS, Kim YS, Park JS, Park ES, Seo JH, Lim JY, Woo HO. Early Diagnostic Changes in Autism Spectrum Disorder: A Retrospective Study. Ann Child Neurol. 2026;34(2):136-143.

Abstract

Purpose
Autism spectrum disorder (ASD) exhibits heterogeneous developmental trajectories; however, longitudinal studies using the Korean Childhood Autism Rating Scale (K-CARS) are scarce. This study examined diagnostic changes and related developmental characteristics through repeated K-CARS assessments.

Methods
We retrospectively reviewed the medical records of children who underwent repeated K-CARS assessments between May 2021 and December 2024 at Gyeongsang National University Hospital. Based on diagnostic status at the initial (T1) and follow-up (T2) evaluations, participants were classified as having persistent ASD (ASD at T1 and T2), emerging ASD (non-ASD at T1 but ASD at T2), or desisting ASD (ASD at T1 but non-ASD at T2). Developmental profiles were evaluated using the social quotient (SQ), visual-motor integration (VMI), and language quotients.

Results
Forty-three children (32 boys; median age, 2.9 years at T1 and 4.3 years at T2) were included. Twenty-two met ASD criteria at T1, and 15 (68%) retained the diagnosis at T2. Across the cohort, 15 (35%) had persistent ASD, 21 (49%) had emerging ASD, and seven (16%) had desisting ASD. The desisting group showed higher baseline VMI and better outcomes at follow-up. The emerging group initially had higher SQ and VMI than the persistent group, but these differences disappeared over time. Higher baseline VMI was associated with desisting status and higher baseline SQ with emerging ASD (odds ratios, 3.14 and 2.59 per standard deviation increase, respectively; P=0.06 and P=0.07).

Conclusion
Early ASD diagnoses were generally stable yet variable, supporting repeated assessment. Baseline VMI and SQ may relate to later diagnostic changes.

KIF1A associated neurological disorder (KAND)

Father shares daughter’s rare neurological disorder, partnership with Murdoch research center

KIF1A.org founder Luke Rosen discusses his daughter’s battle with a rare neurological disorder and the Murdoch Children’s Research Institute’s work to advance potential treatments on ‘Fox & Friends.’

KIF1A Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative disorder often described as a form of childhood dementia that currently has no cure, but researchers at the Murdoch Children’s Research Institute (MCRI) in Australia are working to change that.

"[Their research] is helping all of the kids, which is really incredible," said Luke Rosen, founder of KIF1A.org, whose daughter Susannah was diagnosed with the disorder at age 2.

"And the folks at Murdoch, I say they're extended family to us, and they really are."

KAND is a severe and progressive condition. Children can experience seizures and, over time, lose cognitive function, motor skills and vision. The disorder affects each patient differently, often making it difficult to diagnose.

Rosen said what sets MCRI apart is its personal approach — with researchers taking the time to truly know the families they’re trying to help.

"The first thing [a researcher] said to me is, 'How's Susannah? How's she doing?' And he really got to know our family, and he travels and so does their whole team... to our yearly Scientific and Family Conference, so they really get to meet all the families."

A new Fox Nation special spotlights MCRI’s work, as well as families like the Rosens who are working with researchers to treat the debilitating disorder.

Rosen has since dedicated his life to advancing research and finding treatment options. He works closely with MCRI in an effort that is already showing promise.

Susannah was among the first patients to receive antisense oligonucleotide (ASO) therapy, and her family says they’ve seen meaningful improvements in her condition.

While the treatment is not yet approved in Australia, Rosen continues working with doctors to expand access with the hope that, eventually, families won’t have to travel for care.

"Their research is really translational research that helps everybody," Rosen said.

"While we don't have a therapeutic yet from Australia, they're really working hard to develop it, and they're accelerating that entire process. What's special about Murdoch is they work in multimodalities, so there's gene therapy and then traditional drug development, and then they work non-sequentially, and they are just trying to throw as many shots on goal as we can for the kids."

"Hope Starts Here," hosted by Fox News' Benjamin Hall, is available now on Fox Nation.

Taylor Penley

https://www.foxnews.com/media/researchers-race-treat-rare-childhood-dementia-cure-giving-families-new-hope

Lin Q, Verden D, Christodoulou J, Gold WA, Kaur S. KIF1A-associated neurological disorders: therapeutic opportunities and challenges. Eur J Hum Genet. 2025 Nov 27. doi: 10.1038/s41431-025-01978-8. Epub ahead of print. PMID: 41310149.

Abstract

KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.

Chen Z, Chai Y, Guo Z, Fu X, Li W, Zhang J, Ou G, Wang H. Allele-specific conformational rescue of KIF1A T99M by genetic suppressors in a C. elegans model of KIF1A-associated neurological disorder. J Cell Sci. 2025 Oct 1;138(19):jcs264216. doi: 10.1242/jcs.264216. Epub 2025 Oct 14. PMID: 40964787.

Abstract

KIF1A-associated neurological disorder (KAND) arises from mutations in the microtubule motor KIF1A, disrupting synaptic vesicle transport. Here, we investigate the pathogenic T99M substitution in the P-loop of KIF1A, which induces steric hindrance, impairing ATP/ADP coordination and motor activity. Using CRISPR-engineered Caenorhabditis elegans expressing the homologous UNC-104(T95M) mutation, we conducted forward genetic screens and identified recurrent intragenic suppressors (T95V and T95I; T95V/I) that restored animal motility and synaptic vesicle distribution. Molecular dynamics simulations revealed that replacing the methionine residue with valine or isoleucine residues alleviated steric clashes in the nucleotide-binding pocket and stabilized Mg2+-ATP coordination. Biochemical assays showed that T95V/I partially recovered microtubule gliding velocity and processivity, demonstrating that even modest motor reactivation mitigates neuronal dysfunction. Inspired by prior success showing that treatment with the plant flavonol fisetin rescues the effects of the KIF1A R11Q variant, we propose allele-specific conformational stabilization as a therapeutic strategy for KAND. Our findings highlight the structural plasticity of motor domains and provide a framework for precision therapies targeting pathogenic variants through genetic suppressors.

See: https://childnervoussystem.blogspot.com/2020/01/kif1a-mutations.html

Adjunctive cannabidiol in intractable pediatric epilepsy

Shim Y, Yang DH, Byeon JH, Eun BL. Adjunctive cannabidiol in intractable pediatric epilepsy: A retrospective study on tolerability, efficacy, and safety across genetic and nongenetic etiologies. Medicine (Baltimore). 2026 Jan 30;105(5):e47425. doi: 10.1097/MD.0000000000047425. PMID: 41630268; PMCID: PMC12863898.

Abstract

This retrospective cohort study evaluated the tolerability, efficacy, and safety of adjunctive cannabidiol (CBD) therapy in pediatric-onset intractable epilepsy across diverse genetic and nongenetic etiologies. Twenty-nine patients aged 6 to 24 years, treated at Korea University Hospitals between April 2019 and May 2024, were included. The median follow-up duration was 14.3 months. Confirmed genetic etiologies included SCN1A-related epilepsy (6.9%); GABRB3-, SCN2A-, KCNT1-, KIF1A-, and COL4A1-related epilepsies (3.4% each); Angelman syndrome and Down syndrome (3.4% each). Presumed genetic etiologies included hemimegalencephaly (3.4%) and cortical dysplasia (6.9%). Acquired causes included hypoxic brain injury (6.9%) and CNS infection (10.3%). In 41.4% of cases, the etiology was unidentified; among them, 58.3% had a history of infantile spasms. At CBD initiation, patients were receiving a median of 5 antiseizure medications, most commonly valproic acid (93.1%), clobazam (82.8%), and levetiracetam (75.9%). The median maintenance dose of CBD was 14.2 mg/kg/d. The retention rate was above 86% at both 12 and 24 months. At 12 months, 79.3% achieved a ≥50% reduction in seizure frequency, and 34.5% achieved a ≥75% reduction without generalized motor seizures. One patient with a GABRB3 variant achieved seizure freedom. Adverse events occurred in 37.9%, most commonly somnolence and lethargy. These were mild and resolved with antiseizure medication adjustments. CBD was discontinued in 3 patients due to pneumonia, lethargy, or seizure aggravation. CBD therapy demonstrated favorable retention, efficacy, and safety profiles in pediatric-onset intractable epilepsy across a spectrum of etiologies.

González-Alguacil E, García Peñas JJ, Lamagrande Casanova N, Santana Cabrera EM, Duat Rodríguez A, Soto Insuga V. Cannabidiol as Adjunctive Treatment in Drug-Resistant Epilepsy With Epileptic Spasms Beyond Two Years of Age. Pediatr Neurol. 2026 Jan;174:81-85. doi: 10.1016/j.pediatrneurol.2025.10.013. Epub 2025 Oct 24. PMID: 41197417.

Abstract

Background: To assess the efficacy and safety of adjunctive cannabidiol (CBD) in children with drug-resistant epileptic spasms (ES) beyond age 2 years.

Methods: We conducted a retrospective longitudinal study of patients with childhood epileptic spasms (CESs) treated with purified CBD (Epidyolex) at Niño Jesus Hospital in Madrid, Spain, from 2020 to 2024. All patients were older than 2 years and had drug-resistant epilepsy and ES as the primary seizure type. Efficacy was assessed by comparing ES frequency before and after CBD treatment, with a good response defined as a ≥50% reduction in ES. Adverse effects (AEs) were recorded to assess safety and tolerability.

Results: Of the 53 patients included, 58.5% achieved a ≥50% reduction in ES frequency, 15% of whom attained complete freedom from ES. Patients with malformations of cortical development and Down syndrome showed the highest response rates. Clobazam was the most frequently associated medication (77.3%), indicating a potential synergistic effect. AEs were reported in 62.2% of patients, with drowsiness, hyperammonemia, and behavioral disturbances being the most common. CBD was discontinued in 17% due to lack of efficacy and in 11.3% due to AEs.

Conclusions: CBD appears to be an effective and well-tolerated adjunctive treatment for drug-resistant ES in children older than 2 years. Significant response rates were found, particularly in patients with Down syndrome and malformations of cortical development. Future studies with larger cohorts and longer follow-up are needed to validate these findings and explore the potential for earlier use of CBD in treatment-resistant epilepsy.

Herlopian A, Hess EJ, Barnett J, Geffrey AL, Pollack SF, Skirvin L, Bruno P, Sourbron J, Thiele EA. Cannabidiol in treatment of refractory epileptic spasms: An open-label study. Epilepsy Behav. 2020 May;106:106988. doi: 10.1016/j.yebeh.2020.106988. Epub 2020 Mar 10. PMID: 32169600.

Abstract

Objective: This study aimed to evaluate clinical efficacy and safety of purified pharmaceutical cannabidiol (CBD) as an adjunctive therapy in refractory childhood-onset epileptic spasms (ES).

Methods: Nine patients with ES were enrolled in an Institutional Review Board (IRB)- and Food and Drug Administration (FDA)-approved expanded access investigational new drug trial. Patients received plant-derived highly purified CBD in oral solution in addition to their baseline medications at an initial dosage of 5 mg/kg/day, which was increased by 5 mg/kg/day every week to an initial target dosage of 25 mg/kg/day. Seizure frequency, adverse event, and parents' subjective reports of cognitive and behavioral changes were recorded after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment. Responder rates (percent of patients with >50% reduction in ES frequency from baseline) were calculated. Electrographic changes were studied in relation to CBD initiation and clinical response.

Results: Overall, the responder rates in 9 patients were 67%, 78%, 67%, 56%, 78%, 78%, and 78% after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment, respectively. Three out of nine patients (33%) were ES free after two months of treatment. Parents reported subjective improvements in cognitive and behavioral domains. Side effects, primarily drowsiness, were seen in 89% of patients (n = 8). Eight of the nine (89%) patients had electroencephalographic (EEG) studies prior to and after initiation of CBD. Three out of five patients (60%) had resolution in their hypsarrhythmia pattern.

Significance: Purified pharmaceutical CBD may be an effective and safe adjunctive therapy in refractory ES and may also be associated with improvements in electrographic findings.

Disease-modifying therapies for Rett syndrome

Samanta D. Disease-modifying therapies for Rett syndrome: a review for neurologists. Front Neurol. 2026 Jan 20;17:1766679. doi: 10.3389/fneur.2026.1766679. PMID: 41641323; PMCID: PMC12864443.

Abstract

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder affecting approximately 1 in 10,000-15,000 females, most often caused by loss-of-function mutations in MECP2. Until the recent approval of trofinetide, management relied exclusively on symptomatic treatment and multidisciplinary supportive care. The therapeutic landscape is now undergoing a rapid shift, driven by multiple gene therapy approaches designed to restore functional MeCP2 expression and achieve true disease modification. As these therapies progress toward potential regulatory approval, neurologists will play central roles in identifying eligible patients, counseling families, supporting clinical trial enrollment, delivering treatments, monitoring long-term outcomes, and advocating for equitable access. This review provides neurologists with the essential framework needed to understand and navigate this evolving field. We examine in detail the two most advanced gene replacement therapies currently in clinical trials. TSHA-102 uses an intrathecally delivered miniMECP2 transgene regulated by a microRNA-based autoregulatory system, whereas NGN-401 delivers full-length MECP2 via intracerebroventricular administration using a synthetic expression-feedback circuit. Both approaches have shown encouraging early efficacy, with treated children achieving developmental gains that exceed natural history expectations. However, they differ substantially in molecular design, regulatory control, delivery method, and safety considerations. We also highlight challenges unique to RTT gene therapy, including the narrow therapeutic window between insufficient expression and MeCP2 overexpression toxicity, the impact of X-chromosome inactivation mosaicism, and lessons learned from a fatal hyperinflammatory adverse event. Beyond AAV-mediated gene replacement, we review next-generation strategies in preclinical development-CRISPR-Cas9 genome editing for permanent mutation correction, ADAR-based RNA editing, translation readthrough for nonsense variants, and X-chromosome reactivation to restore endogenous MECP2 expression. Finally, we address key translational considerations such as optimal timing of intervention, dosing constraints, outcome measurement in severely impaired populations, long-term safety surveillance, and barriers to broad and equitable access. The RTT gene therapy experience serves as a model for precision medicine in other monogenic neurodevelopmental disorders, illustrating both the transformative promise and the substantial complexities of translating genetic science into meaningful clinical benefit.

Percy AK, Ananth A, Neul JL. Rett Syndrome: The Emerging Landscape of Treatment Strategies. CNS Drugs. 2024 Nov;38(11):851-867. doi: 10.1007/s40263-024-01106-y. Epub 2024 Sep 9. PMID: 39251501; PMCID: PMC11486803.

Abstract

Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (MECP2) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation-IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype-genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal MECP2 gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editing, and X-chromosome reactivation. Taken together, progress in understanding and treating RTT over the past 40 years has been remarkable. This suggests that further advances can be expected.

Testing the brain death testers

Simulation-Based Training Closes Competency Gap in Brain Death Determination

Brain death determination is "the diagnosis we cannot get wrong,” warned Nicholas Morris, MD, associate professor of neurology and director of the neurocritical care fellowship program at the University of Maryland School of Medicine in Baltimore. “It’s literally a life-and-death mistake if you make an error.”

Yet an interim analysis of an ongoing, multicenter study presented in April at the AAN Annual Meeting in Chicago suggests that most neurology trainees arrive at the simulation lab woefully underprepared to perform it, and that a rigorous, simulation-based, mastery learning curriculum can reliably close that gap.

In preliminary results from the study, neurology residents and neurocritical care fellows scored a mean of just 51.4 percent on a pretest assessment of brain death/death by neurologic criteria (BD/DNC) determination skills, well below the curriculum's minimum passing score (MPS) of 89 percent. After completing an online didactic course offered through the Neurocritical Care Society (NCS), participants improved to a mean of 81.2 percent, but it was only after a session of mentored deliberate practice in the simulation center that scores reached a mean of 97.9 percent, with all but one of the 18 people who completed the curriculum achieving the MPS.

"What we really want to do is make sure that we are training our learners to the very highest standards so that when they get out into independent practice, we can be confident that they have mastered this skill,” said Dr. Morris, the study’s presenting author.

The study, which began enrolling participants in August 2025 and remains ongoing, uses a pretest-posttest design across more than a dozen institutions. Trainees are randomized to one of three simulated BD/DNC cases as a pretest and then complete the NCS online brain death determination course and undergo a second simulation assessment. Those who have not yet passed engage in deliberate practice with a facilitator until they achieve competency.

Performance is scored using a checklist developed through a Delphi process involving the authors of the 2023 AAN/AAP Brain Death/Death by Neurologic Criteria Consensus Guideline. Since the abstract was submitted, enrollment has grown substantially; Dr. Morris told Neurology Today that approximately 82 participants have now started the curriculum, and roughly 60 have completed post-testing.

The low pretest scores, while striking, did not surprise Dr. Morris, who noted that prior survey data published in Neurology have shown that even board-certified neurologists performing BD/DNC determinations in clinical practice sometimes skip critical steps, including the apnea test.

"There's a lot of intricacy to brain death determination, and our checklist reflects that," he said. "So many different things have to be done correctly and completely."

Gary Gronseth, MD, professor and chair of neurology at the University of Kansas Medical Center in Kansas City and a co-author of the 2023 BD/DNC guideline, agreed that the gap is both real and underappreciated.

"It's a very complex process,” said Dr. Gronseth, who was not involved in the study. “Conceptually, it seems straightforward, but it's extraordinarily detail-oriented. Many neurology residents rotate through neurocritical care, but there may not be a brain death case that comes to them, so they simply don't get exposed to it. That's the fundamental challenge for program directors."

The jump from post-didactic to post-deliberate practice scores—from 81 to nearly 98 percent—underscores a key distinction: knowledge and performance are not the same thing.

"There's always a difference between what you know and what you can actually do," Dr. Morris said. "The online course has a 100 percent multiple-choice test at the end, but passing a knowledge test doesn't prove you can perform the procedure. That's where the gap is."

"This isn't something we can address by having residents, or even board-certified neurologists, just take an online course and a test," Dr. Gronseth said. "It has serious implications not only for program directors, who need to be actively working to ensure residents get hands-on exposure, but for community-based neurologists in practice, who may encounter a brain death case only rarely and have no mechanism for maintaining competency. Do we need something analogous to ACLS, like a recertification program with simulation? That's a real and difficult question."

The simulation-based mastery learning model is resource-intensive, with each participant spending roughly three hours between the simulation assessments and the online course, plus additional time for deliberate practice and long-term follow-up. It may not be appropriate for all trainees equally, Dr. Morris acknowledged.

"If someone is going into neurocritical care and this will be a routine part of their practice, the investment is clearly worth it," he said. "If they're unlikely to ever be asked to do this, perhaps a less-intensive approach makes sense."

His group is exploring artificial intelligence-based feedback and virtual-reality platforms as potential lower-resource alternatives, though he believes some form of directly observed hands-on assessment will remain essential.

The study also served as the launching pad for CRESCENT, a new multicenter consortium focused on collaborative education research in neurology.

"What we've been able to achieve is a collaboration among multiple institutions to do education research in neurology, which I'm not sure has ever been done before at this scale," Dr. Morris said. He hopes it will provide the infrastructure to test other educational interventions across training programs nationwide.

"When this study is complete, I hope it will provide the impetus for all neurology programs to ensure that every resident receives formal training in brain death determination that includes hands-on experience, whether through supervised cases or simulation,” Dr. Gronseth said.

Disclosures: Dr. Morris’s institution has received research support from the National Institute of Neurological Disorders and Stroke and the American Academy of Neurology (AAN). Dr. Morris has received compensation for serving as a webinar speaker for Kreg Therapeutics and serves as a non-compensated editorial board member for the AAN and the Neurocritical Care Society.

Gina Shaw

A Simulation-based Mastery Learning Curriculum to Assess and Ensure Competency in Brain Death/Death by Neurological Criteria Determination: Preliminary Results. Nicholas Morris, Amjad Elmashala, Matthew Bevers, Galina Gheihman, Jamie LaBuzetta, Tracey Fan, Shivani Ghoshal, Justine Cormier, Casey Albin, Brittany Lachance, Melissa Pergakis, Matthew Hoerth, Nina Massad, Jenna Ford, Jon Rosenberg, Hera Kamdar, Hannah Kirsch, Lauren Koffman, Xin Zhou1, Sarah Wahlster, Sean Marinelli, Stefanie Cappucci, Rachel Beekman, Reem El-Ghawanmeh, Ariane Lewis, David Greer, William McGaghie, Daniel Harrison. 2026 AAN Annual Meeting Abstract 4711


Objective:
To evaluate if simulation-based mastery learning (SBML) can achieve uniform competency among neurology trainees in brain death / death by neurological criteria (BD/DNC) determination.

Background:
The ACGME Milestones suggest that neurology trainees should be able to properly perform BD/DNC determination by graduation. Data on physician knowledge, comfort, and competency with performing BD/DNC determinations demonstrate opportunities for improvement. We hypothesized that SBML could close the gap between ACGME expectations and practice in BD/DNC determination.

Design/Methods:
In August 2025, we began enrolling in an ongoing multicenter pretest-posttest study of SBML. We randomized neurology trainees to one of three simulated cases of BD/DNC determination as a pretest, followed by didactic training (the Neurocritical Care Society online Brain Death Determination course). We assessed participants using a different randomly selected simulated case immediately after taking the course, and again after deliberate practice. We scored performance using a checklist derived from a Delphi process involving authors of 2023 BD/DNC Guidelines with a minimum passing score (MPS = 89%) derived from Angoff standard setting determined by members of UCNS and ACGME Neurocritical Care examination committees. We performed repeated measures ANOVA for comparison among those that completed the curriculum.

Results:
Thirty neurology residents (5 PGY-2, 14 PGY-3, 11 PGY-4) and five neurocritical care fellows have enrolled and 18 completed the curriculum (17 in progress). Eleven (31%) previously received training in BD/DNC determination, 24 (69%) previously observed a BD/DNC evaluation, and 14 (40%) previously performed a BD/DNC evaluation with supervision. Among the 18 that completed the curriculum, performance improved across assessments (pretest mean (SD) 51.4% (12.9%) vs. post-online course mean (SD) 81.2% (10.2%) vs post-deliberate practice mean (SD) 97.9% (3.5%), F (2,34) = 144.01, p < .001). All but one participant achieved the MPS.

Conclusions:
SBML achieved near uniform competency in BD/DNC determination skills among neurology trainees that completed the SBML curriculum.

Simulation-based Brain Death Determination Training for Neurology Residents (P5-5.025).Noelia Morales, Cesar Escamilla Ocanas, Gabriel Torrealba Acosta, Catherine Garcia, Lintu Ramachandran, and Mohammad Hirzallah. Neurology April 8, 2025 issue 104 (7_Supplement_1) 5569
https://doi.org/10.1212/WNL.0000000000212451

Abstract

Objective:
N/A

Background:

Brain death determination is an essential skill every neurologist should have. Despite the availability of clear guidelines for brain death determination, there is significant variability in practice both, within the United States and internationally. Previous studies have shown neurology residents have limited exposure to brain death examination and typically do not perform this task independently. However, they are expected to be proficient in determining brain death by the end of residency.


Design/Methods:
A simulation-based brain death determination workshop was generated for second year neurology residents, and conducted for three consecutive years from 2022 to 2024. Two questionaries (Form A and B) were generated, each with 14 premises that evaluated different educational competencies on brain death determination guidelines.

The workshop was divided in two parts. The first part consisted of a 60 minute lecture given covering the above-mentioned competencies, based on the 2023 pediatric and adult BD/DNC consensus guideline by a neurocritical care attending. followed by a questionnaire.

Residents then teamed up in groups of 2. High fidelity mannequins were used to simulate patients in five different clinical scenarios. We asked teams to take turns leading each encounter. A debriefing session was conducted after each case to provide immediate feedback. After completing the simulations, the residents received the second questionnaire, ensuring it was a different version from the initial one. Questionnaire results had no identifiable information.

Results:
19 neurology residents completed the brain death determination workshop. 18 out of 19 demonstrated an improvement in performance following the completion of the workshop. Mean pre-workshop score was 63.68 % ± 17.80, while the mean post-workshop score increased to 89.71 % ± 9.4 (p<0.0001).

Conclusions:
Conducting a simulation-based workshop early during neurology training might help increase the level of confidence and proficiency performing a comprehensive brain death examination prior to the completion of residency.

Preimplantation genetic testing for neurofibromatosis type 1:

Ironically, if the parents of the affected prospective parent had opted for preimplantation genetic testing the affected prospective parent would not have been born.

Vernimmen V, Paulussen ADC, Dreesen JCFM, van Golde RJ, Zamani Esteki M, Coonen E, van Buul-van Zwet ML, Homminga I, Derijck AAHA, Brandts L, Stumpel CTRM, de Die-Smulders CEM. Preimplantation genetic testing for Neurofibromatosis type 1: more than 20 years of clinical experience. Eur J Hum Genet. 2023 Aug;31(8):918-924. doi: 10.1038/s41431-023-01404-x. Epub 2023 Jun 19. PMID: 37337089; PMCID: PMC10400537.

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.

Vernimmen V, De Rycke M, Moutou C, Dreesen J, Blok MJ, van Minkelen R, Lauer-Zillhardt J, Verdyck P, Keymolen K, van Uum C, Homminga I, Brandts L, Stumpel CTRM, Coonen E, Heijligers M, van Zelst-Stams W, Zamani Esteki M, van den Wijngaard A, de Die-Smulders CEM, Paulussen ADC. Preimplantation genetic testing for neurofibromatosis type 1: molecular genetic aspects and impact on reproductive counseling. Hum Reprod. 2026 Feb 1;41(2):285-295. doi: 10.1093/humrep/deaf224. PMID: 41289058; PMCID: PMC12864152.

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.

Zheng W, Yang C, Yang S, Sun S, Mu M, Rao M, Zu R, Yan J, Ren B, Yang R, Guan Y. Obstetric and neonatal outcomes of pregnancies resulting from preimplantation genetic testing: a systematic review and meta-analysis. Hum Reprod Update. 2021 Oct 18;27(6):989-1012. doi: 10.1093/humupd/dmab027. PMID: 34473268.

Abstract

Background: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain.

Objective and rationale: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI.

Search methods: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET).

Outcomes: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies.

Wider implications: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.

Antenatal presentation of MRPS22-related mitochondrial disease confirmed with rapid proteomics

L. N.Semcesen, M.Ball, D. H.Hock, et al., “Antenatal Presentation of MRPS22-Related Mitochondrial Disease Confirmed With Rapid Proteomics,” JIMD Reports67, no. 3 (2026): e70092, https://doi.org/10.1002/jmd2.70092.

Abstract

MRPS22-related mitochondrial disease (MIM#611719) is a rare autosomal recessive disorder caused by defects in the mitochondrial ribosomal protein S22, a component of the small mitoribosomal subunit essential for mitochondrial translation. Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal-onset MRPS22-related mitochondrial disease and the use of multi-omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20 + 2 weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in MRPS22 (NM_020191.4: c.509G>A; p.(Arg170His) and c.565C>G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22-related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi-omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.

Key Points

MRPS22-related mitochondrial disease should be considered in the differential diagnosis of fetal hydrops and multiple congenital anomalies, particularly in the presence of corpus callosum agenesis.

Rapid proteomic analysis confirmed the pathogenicity of MRPS22 variants identified by genomic autopsy, demonstrating the utility of multi-omic diagnostics following pregnancy loss.

Treatment practices and outcomes in continuous spike and wave during slow wave sleep

Baumer FM, McNamara NA, Fine AL, Pestana-Knight E, Shellhaas RA, He Z, Arndt DH, Gaillard WD, Kelley SA, Nagan M, Ostendorf AP, Singhal NS, Speltz L, Chapman KE. Treatment Practices and Outcomes in Continuous Spike and Wave during Slow Wave Sleep: A Multicenter Collaboration. J Pediatr. 2021 May;232:220-228.e3. doi: 10.1016/j.jpeds.2021.01.032. Epub 2021 Jan 20. PMID: 33484700; PMCID: PMC8934740.

Abstract

Objectives: To determine how continuous spike and wave during slow wave sleep (CSWS) is currently managed and to compare the effectiveness of current treatment strategies using a database from 11 pediatric epilepsy centers in the US.

Study design: This retrospective study gathered information on baseline clinical characteristics, CSWS etiology, and treatment(s) in consecutive patients seen between 2014 and 2016 at 11 epilepsy referral centers. Treatments were categorized as benzodiazepines, steroids, other antiseizure medications (ASMs), or other therapies. Two measures of treatment response (clinical improvement as noted by the treating physician; and electroencephalography improvement) were compared across therapies, controlling for baseline variables.

Results: Eighty-one children underwent 153 treatment trials during the study period (68 trials of benzodiazepines, 25 of steroids, 45 of ASMs, 14 of other therapies). Children most frequently received benzodiazepines (62%) or ASMs (27%) as first line therapy. Treatment choice did not differ based on baseline clinical variables, nor did these variables correlate with outcome. After adjusting for baseline variables, children had a greater odds of clinical improvement with benzodiazepines (OR 3.32, 95%CI 1.57-7.04, P = .002) or steroids (OR 4.04, 95%CI 1.41-11.59, P = .01) than with ASMs and a greater odds of electroencephalography improvement after steroids (OR 3.36, 95% CI 1.09-10.33, P = .03) than after ASMs.

Conclusions: Benzodiazepines and ASMs are the most frequent initial therapy prescribed for CSWS in the US. Our data suggests that ASMs are inferior to benzodiazepines and steroids and support earlier use of these therapies. Multicenter prospective studies that rigorously assess treatment protocols and outcomes are needed.

Euthanasia story

A physically healthy British woman heartbroken over the death of her only son is heading to Switzerland to end her own life at an assisted suicide clinic.

Wendy Duffy, 56, attempted to take her own life after her son died four years ago — but is soon bound for Switzerland, where assisted suicide is legal, after her application was accepted by a clinic, according to the London Times.

Duffy, a former care worker from the West Midlands, told the Daily Mail that she paid Pegasos, a Swiss assisted-dying nonprofit organization, $13,500 to euthanize herself under its care, saying suicide is the only way her “spirit can be free.”

“I could step off a motorway bridge or a tower block but that would leave anyone finding me dealing with that for the rest of their lives,” she said.

She said she’s been forced to travel to Switzerland as a hotly debated right-to-die bill has stalled in Parliament over the last year.

Duffy’s son, Marcus, died at the age of 23 after choking on a tomato that became lodged in his windpipe while he was sleeping.

Nine months later, she tried to kill herself by overdosing and had to be put on a ventilator for two weeks.

Ultimately, she said, no amount of medication or therapy can make her whole again and that she “can’t wait” to die.

She’s already chosen what she will wear on her deathbed and told the Daily Mail that Lady Gaga and Bruno Mars’ “Die With A Smile” will be playing as she passes on. Once she’s dead, she’s requested that all the belongings she brought with her be donated.

Duffy said her siblings, four sisters and two brothers, are understanding of her decision — but she knows it will be difficult to say goodbye to them forever.

“I will call them when I get to Switzerland. It will be a hard call where I’ll say goodbye and thank them,” she said. “But they will get it. They know. Honestly, 100%, they know that I’m not happy, that I don’t want to be here.”

Patrick Reilly

https://nypost.com/2026/04/23/world-news/physically-healthy-mom-to-end-life-by-euthanasia-at-swiss-clinic-after-death-of-her-son/

Digenic muscular dystrophy due to SRPK3 and TTN variants

Inspired by a patient

Töpf A, Cox D, Zaharieva IT, Di Leo V, Sarparanta J, Jonson PH, Sealy IM, Smolnikov A, White RJ, Vihola A, Savarese M, Merteroglu M, Wali N, Laricchia KM, Venturini C, Vroling B, Stenton SL, Cummings BB, Harris E, Marini-Bettolo C, Diaz-Manera J, Henderson M, Barresi R, Duff J, England EM, Patrick J, Al-Husayni S, Biancalana V, Beggs AH, Bodi I, Bommireddipalli S, Bönnemann CG, Cairns A, Chiew MT, Claeys KG, Cooper ST, Davis MR, Donkervoort S, Erasmus CE, Fassad MR, Genetti CA, Grosmann C, Jungbluth H, Kamsteeg EJ, Lornage X, Löscher WN, Malfatti E, Manzur A, Martí P, Mongini TE, Muelas N, Nishikawa A, O'Donnell-Luria A, Ogonuki N, O'Grady GL, O'Heir E, Paquay S, Phadke R, Pletcher BA, Romero NB, Schouten M, Shah S, Smuts I, Sznajer Y, Tasca G, Taylor RW, Tuite A, Van den Bergh P, VanNoy G, Voermans NC, Wanschitz JV, Wraige E, Yoshimura K, Oates EC, Nakagawa O, Nishino I, Laporte J, Vilchez JJ, MacArthur DG, Sarkozy A, Cordell HJ, Udd B, Busch-Nentwich EM, Muntoni F, Straub V. Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy. Nat Genet. 2024 Mar;56(3):395-407. doi: 10.1038/s41588-023-01651-0. Epub 2024 Mar 1. PMID: 38429495; PMCID: PMC10937387.

Abstract

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

Sharkova I, Borovikov A, Konovalov F, Nefedova M, Shchagina O, Kutsev S, Murtazina A. Clinical and Genetic Analysis of Digenic Muscular Dystrophy due to SRPK3 and TTN Variants in Two Siblings. Clin Genet. 2025 May;107(5):547-551. doi: 10.1111/cge.14673. Epub 2024 Dec 12. PMID: 39667923.

Abstract

We present a family with two male siblings diagnosed with a newly described digenic myopathy, involving likely pathogenic loss-of-function variants in the SRPK3 and TTN genes: hemizygous p.(Pro68ArgfsTer55) and heterozygous p.(Trp14174Ter), respectively. Both siblings experienced prenatal disease onset, characterized by weak fetal movements, but showed significant clinical improvement over two last years of our follow-up. Key features included early onset, delayed motor development, and prominent axial and proximal weakness, while adult variants' carriers remained asymptomatic, without any myopathic or cardiac manifestations. Lower limb MRI revealed distinctive abnormalities, with different patterns between the siblings: the older brother showed more pronounced involvement of the thigh muscles, while the younger brother exhibited greater changes in the lower leg muscles. Given the early stage of the disease in our patients and the initial changes observed on MRI, we suggest that the semitendinosus and vastus lateralis muscles are primarily involved at the thigh level in SRPK3/TTN-myopathy. This case highlights the importance of considering digenic inheritance in neuromuscular disorders and underscores the necessity of comprehensive genetic analysis in similar cases.

Reproductive decision-making in individuals with neurofibromatosis type 1

Kowal K, Domaradzki J. "To have children or not?" Between desire, responsibility, luck, and guilt: reproductive decision-making in individuals with neurofibromatosis type 1. Orphanet J Rare Dis. 2025 Oct 21;20(1):531. doi: 10.1186/s13023-025-04061-z. PMID: 41121384; PMCID: PMC12542219.

Abstract

Background

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder with a 50% chance of being passed to offspring. Its hereditary nature presents individuals with complex reproductive dilemmas. This study explores the complexity of decision-making and reproductive choices faced by people with NF1 regarding parenthood.

Results

Genetic risk is a key factor shaping reproductive decisions. For some individuals, the decision not to have children is seen as a protective and morally responsible practice, aiming to spare potential offspring from the stigma and isolation they themselves experienced. Some women were also concerned for their own physical and emotional health, especially in relation to pregnancy and caregiving. Medical professionals’ opinions significantly influence choices, sometimes outweighing personal desires for parenthood and shaping perceptions of reproductive responsibility. Parents who were unaware of their diagnosis at the time of conception express guilt and regret. Despite the risks, many still wish to have children but struggle with the fear of passing on the NF1 mutation and potential difficulties in bonding with a child who may also be affected. Individuals who realized procreative plans despite severe NF1 treat parenthood as an important element of their non-disease identity and a source of emotional strength.

Conclusions

For individuals with NF1, reproductive decision-making is a complex dilemma, in which procreation anxiety intersects with hopes for parenthood, a sense of responsibility for the child’s future, and personal identity.

https://www.youtube.com/watch?v=056dMq2upWs

https://www.youtube.com/watch?v=hETXFdKOc6M

https://www.youtube.com/watch?v=toJsm1FL0RU

Retinoblastoma

It was September 2025, about a month after her daughter Miley turned 2, when she began noticing brief signs of what looked like a lazy eye. After contacting her pediatrician, she was referred to an ophthalmologist, with an appointment scheduled for December.

Because strabismus — commonly known as a “lazy eye” — affects about 2 to 4 percent of young children, according to the American Association for Pediatric Ophthalmology and Strabismus, there was no immediate concern.

Still, as the weeks passed, something didn't sit right.

Then one night in November, while giving Miley a bath, Kristen noticed something she couldn't brush off.

“I noticed she had a white pupil in the bathtub when she looked at me in the light. It looked like a glow in her eye,” the mom tells PEOPLE exclusively. “I panicked and started googling but was trying not to freak myself out.”

Even then, she tried to keep her fears in check.

But later that night, after Miley had gone to sleep, Kristen kept searching — until she came across a story that changed everything.

“I ended up researching after she went to bed and saw an article of a mom that found out her daughter had a tumor on a baby monitor because her daughter's eye was just black,” she says. “I then looked at the monitor and Miley's eye was black.”

In that moment, everything shifted.

Although her husband tried to reassure her, Kristen couldn't shake the feeling something wasn't right.

The next morning, on Nov. 9, the family drove to the emergency room, where her fears were confirmed. There, her daughter was diagnosed with retinoblastoma.

“It was dreadful. I felt alone," Kristen says. "I didn't know anyone with a child with cancer personally. I didn't know anyone with one eye. It was truly scary and I felt so scared for her future.”

Retinoblastoma is a rare type of eye cancer that typically begins in the retina — the light-sensitive tissue at the back of the eye — and most often affects young children, according to the Mayo Clinic. One of the most common warning signs is a white reflection in the pupil, sometimes noticeable in certain lighting or photos.

Just days earlier, life for Kristen and her family had felt steady and full. The 29-year-old, who lives near Cleveland, Ohio, shares a blended household with her husband — whom she met while they were both serving in the Air Force — along with his 13-year-old daughter, their 2½-year-old Miley and their 7-month-old baby. With a master's degree in social work, she was used to being the one helping others.

Less than two weeks later, the next step was clear. On Nov. 21, Miley underwent surgery to remove her eye.

“Her tumor ended up being grade E. Which typically means that the eye needs removed. They don't believe she had vision for a few months. It was hard to process this because she didn't even act like she had vision from one eye.”

In the days that followed, Kristen found herself looking back — wondering if there had been signs she missed.

But there weren't.

“My family and I are very attentive and we had no idea. it's amazing to me how well she adapted.”

And in many ways, Miley never stopped being Miley.

Now 2½, she still fills their home with energy and personality.

“She is so funny and loves to make us laugh, she loves to dance, she is empathetic and feels everyone's emotions around her. She loves princess dresses, painting her nails, all the girl things. But she also loves dinosaurs and helping her dad work with his tools.”

Still, the journey didn't end with surgery.

After doctors performed a biopsy, they determined the cancer had entered a high-risk area — meaning Miley would need chemotherapy.

“They told us she needs 6 rounds of chemo. She has her last round of chemo next month.”

Since then, their lives have revolved around treatment schedules and hospital stays.

“So far, she has needed 2 days of chemo a month. Three days total at the hospital with the last day being de-accessing her port and giving her a shot that helps raise her white blood cell count to help her fight infection during her treatment.”

But for Kristen, the hardest part has been the emotional toll.

“The most challenging part has been watching her be poked and prodded. Having her ask us to ‘just go home.'”

At home, a new routine brought its own challenges.

“We also have had to take out her prosthetic eye and clean it. Put it back in. This has been a hard adjustment for our whole family.”

And yet, through every step, Miley has led the way.

“Miley has blown us away. She has been so positive. She's been resilient. She has truly lead the way with her positivity. She is the strongest person that I know.”

In the midst of it all, Kristen found herself searching for connection — which ultimately led her to start sharing Miley's journey on TikTok.

“I am someone who really thrives having a community when I am going through something. I wanted to share Miley's story to help others who are facing hard times. I also want to give Miley a sense of purpose. So she can see that her hardship has helped others. I also wanted to give Miley a sense of community.”

What started as a way to cope quickly turned into something much bigger.

“Since posting Miley's journey, I have met SO many amazing men and women; girls and boys; with one eye. Miley now has so many people I can connect her with in her life so she never feels alone!”

The response, she says, has helped reshape how she sees the future.

“I have had people share their personal testimonies how having one eye has never stopped them. It has truly helped to give me positivity in something that seemed so so dreadful. The response from everyone else has also been so positive. There has been so much love and support. It's truly helped me to keep going and to be strong.”

At first, going viral came with complicated emotions.

“I felt guilty when she went viral at first. But as I stated, if I didn't, she wouldn't have this huge community of people.”

Now, she sees the impact more clearly.

“I have friends now with kids who have one eye who are her age and I can connect with. She has friends now who can relate with her. I have also had others reach out to me who are just now entering the journey who I have been able to help.”

Looking back, Kristen hopes sharing Miley's story will encourage other parents to trust their instincts.

“I hope people are just aware of the signs. Please, if you see a glow in your child's pupil. Go to the ER. In general, advocate for your kids. You as a parent know best!”

And for parents facing similar situations, she has one message.

“I would say - you are amazing. It's not your fault. Try not to carry guilt because we don't know what we don't know. I, myself, carry guilt for somehow not just KNOWING about this possibly diagnosis and getting her in sooner. But, we can only do what we can with the information we have.”

Jordan Greene

https://people.com/alarming-detail-baby-monitor-days-later-daughter-rare-diagnosis-exclusive-11954332