ARHGEF9 mutations

Inspired by a patient with recurrent febrile seizures.

Yang H, Liao H, Gan S, Xiao T, Wu L. ARHGEF9 gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration. Mol Genet Genomic Med. 2022 Jul;10(7):e1967. doi: 10.1002/mgg3.1967. Epub 2022 May 31. PMID: 35638461; PMCID: PMC9266599.

Abstract

Background: The ARHGEF9 gene variants have phenotypic heterogeneity, the number of reported clinical cases are limited and the genotype-phenotype relationship is still unpredictable.

Methods: Clinical data of the patients and their family members were gathered in a retrospective study. The exome sequencing that was performed on peripheral blood samples was applied for genetic analysis. We used the ARHGEF9 gene as a key word to search the PubMed database for cases of ARHGEF9 gene variants that have previously been reported and summarized the reported ARHGEF9 gene variant sites, their corresponding clinical phenotypes, and effective treatment.

Results: We described five patients with developmental and epileptic encephalopathy caused by ARHGEF9 gene variants. Among them, the antiepileptic treatment of valproic acid and levetiracetam was effective in two cases individually. The exome sequencing results showed five children with point mutations in the ARHGEF9 gene: p.R365H, p.M388V, p.D213E, and p.R63H. So far, a total of 40 children with ARHGEF9 gene variants have been reported. Their main clinical phenotypes include developmental delay, epilepsy, epileptic encephalopathy, and autism spectrum disorders. The variants reported in the literature, including 22 de novo variants, nine maternal variants, and one unknown variant. There were 20 variants associated with epileptic phenotypes, of which six variants are effective for valproic acid treatment.

Conclusion: The genotypes and phenotypes of ARHGEF9 gene variants represent a wide spectrum, and the clinical phenotype of epilepsy is often refractory and the prognosis is poor. The p.R365H, p.M388V, p.D213E, and p.R63H variants have not been reported in the current literature, and our study has expanded the genotype spectrum of ARHGEF9 gene. Our findings indicate that levetiracetam and valproic acid can effectively control seizures in children with epileptic phenotype caused by ARGHEF9 gene variations. These findings will help clinicians improve the level of diagnosis and treatment of the genetic disease.

Scala M, Zonneveld-Huijssoon E, Brienza M, Mecarelli O, van der Hout AH, Zambrelli E, Turner K, Zara F, Peron A, Vignoli A, Striano P. De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females. Neurogenetics. 2021 Mar;22(1):87-94. doi: 10.1007/s10048-020-00622-5. Epub 2020 Sep 17. PMID: 32939676.

Abstract

Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)-ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)-based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females.

Klein KM, Pendziwiat M, Eilam A, Gilad R, Blatt I, Rosenow F, Kanaan M, Helbig I, Afawi Z; Israeli-Palestinian Epilepsy Family Consortium. The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures. J Neurol. 2017 Jul;264(7):1421-1425. doi: 10.1007/s00415-017-8539-3. Epub 2017 Jun 15. PMID: 28620718.

Abstract

Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy.

DHX37 gene variants and ribosomopathy

Menetrey A, Tarnopolsky M, Yoganathan S, Shroff M, Gorodetsky C. Child Neurology: Clinical and Imaging Findings in a Child With DHX37 Gene Variant: A Ribosomopathy Masquerading as Cerebral Palsy. Neurology. 2025 Oct 7;105(7):e214126. doi: 10.1212/WNL.0000000000214126. Epub 2025 Sep 11. PMID: 40934457.

Abstract

DEAH-Box helicase 37 (DHX37) gene, encoding an RNA-helicase, is essential for ribosome biogenesis. Pathogenic variants in the DHX37 gene result in a spectrum of ribosomopathies ranging from neurodevelopmental disorders with possible brain, vertebral, and/or cardiac anomalies (NEDBAVC syndrome, OMIM #618731) as well as disorders of sex development. Here, we describe a young boy with DHX37-related neurodevelopmental disorder with clinical and imaging findings masquerading as cerebral palsy. A 7.5-year-old boy presented with global developmental delay and generalized chorea of 6 months duration. He was born at 37 weeks gestation after an uneventful pregnancy with a birth weight of 2668 g. He had primary microcephaly and intractable epilepsy from infancy. Examination revealed microcephaly, spastic quadriparesis, generalized choreoathetosis and dystonia. MRI of the brain revealed T2-weighted hyperintensity in bilateral corticospinal tracts, posterior limb of the internal capsule (PLIC), corona radiata, external capsule, periventricular and deep white matter, as well as subcortical cysts. Diffusion-weighted images showed high signal in bilateral corticospinal tract and PLIC. As there were red flags pointing away from cerebral palsy such as primary microcephaly, refractory seizures, late-onset movement disorder, and persistent high signal on diffusion-weighted imaging, whole genome sequencing (WGS) was sent. WGS revealed a homozygous variant c.2417G>A (p.Ser806Asn) in the DHX37 gene. He was managed with antiseizure medications and clonazepam. DHX37-related neurodevelopmental disorder should be included in the differential for cerebral palsy mimic as affected children have global developmental delay, primary microcephaly, seizures, and movement disorders and thus may masquerade as sequel of hypoxic ischemic encephalopathy.

McElreavey K, Pailhoux E, Bashamboo A. DHX37 and 46,XY DSD: A New Ribosomopathy? Sex Dev. 2022;16(2-3):194-206. doi: 10.1159/000522004. Epub 2022 Jul 14. PMID: 35835064.

Abstract

Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear. The relationship between DHX37 and human congenital disorders is complex as compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies. Here, we will give a brief overview of ribosome biogenesis and the role of DHX37 in this process. We will discuss variants in DHX37, their contribution to human disease in the general context of human ribosomopathies, and the possible disease mechanisms that may be involved.

Jiang W, Yu J, Mao Y, Tang Y, Cao L, Du Q, Li J, Yang J. Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development. Mol Genet Genomic Med. 2024 May;12(5):e2453. doi: 10.1002/mgg3.2453. PMID: 38769888; PMCID: PMC11106588.

Abstract

Background: 46,XY sex reversal 11 (SRXY11) [OMIM#273250] is characterized by genital ambiguity that may range from mild male genital defects to gonadal sex reversal in severe cases. DHX37 is an RNA helicase that has recently been reported as a cause of SRXY11. So far, a total of 21 variants in DHX37 have been reported in 58 cases with 46,XY disorders of sex development (DSD).

Methods: Whole exome sequencing (WES) was conducted to screen for variations in patients with 46,XY DSD. The subcellular localization of mutant DHX37 proteins was detected by immunofluorescence. And the levels of mutant DHX37 proteins were detected via Western blotting.

Results: A novel pathogenic variant of DHX37 was identified in a patient with 46,XY DSD c.2012G > C (p.Arg671Thr). Bioinformatics analysis showed that the protein function of the variant was impaired. Compared with the structure of the wild-type DHX37 protein, the number of hydrogen bonds and interacting amino acids of the variant protein were changed to varying degrees. In vitro assays revealed that the variant had no significant effect on the intracellular localization of the protein but significantly reduced the expression level of the protein.

Conclusions: Our finding further expands the spectrum of the DHX37 variant and could assist in the molecular diagnosis of 46,XY DSD patients.

Medicine only goes so far

As her husband, Rabbi Meshulom Weiss, shared with JEM’s My Encounter:

When we went to see the Rebbe for a blessing a few days before our wedding, she started to cry and asked that I leave the room so she could speak to the Rebbe alone. Puzzled, I complied.

After twenty minutes, she came out no longer crying, and she said nothing to me about it until after we were married. Then she confessed, “I hope that you won’t be upset about what I told the Rebbe. I had wanted to call the wedding off because I am very impatient and have a bad temper; I feared that my temperament made me unsuitable to be a wife and mother. I told the Rebbe that I would rather not get married than to get married only to get divorced. But the Rebbe just smiled at me and said, ‘G-d will bless you with many children, and these children will teach you patience. Meanwhile, do volunteer work – preferably in a hospital with children – and you will find your patience growing. But don’t call off the wedding.”

Having the Rebbe’s promise of many children, we looked forward to starting our family, but months came and went, and my wife – who was eighteen at the time we got married – did not get pregnant. When we sought the advice of a gynecologist, she was informed that she had an undeveloped womb – what is called an “infantile uterus” – which meant she could not bear children. My wife was absolutely devastated to hear this, so we went to get a second opinion and a third opinion, both of which only confirmed the first.

Then we called New York and reported this news to the Rebbe. His response was to reiterate the promise of many children and to give us a blessing. A month later my wife became pregnant with our first child, a boy whom we named Mordechai. And as it turned out, he was the first of fifteen!

After our sixth or seventh child was born, the doctor called me in and said, “Listen, your wife is having a child every year. This is not good for her body. You must give her a rest.” He scared the daylights out of me. I came home and reported this to my wife, who said, “Let’s consult a rabbi. We need to know what the opinion of Jewish law in a case such as ours.”

The rabbi we consulted ruled that, if the doctor said my wife’s life was in danger, we had to listen to him and take a break from having children. Maybe have no more kids at all.

We accepted that decision, but shortly thereafter, we had an opportunity to be in New York, and my wife decided to pose this question to the Rebbe. She told him about the doctor’s opinion and the rabbi’s opinion. She also said, “Despite these opinions, I don’t want to stop having children. But my husband has been scared by the doctor and he fears something might happen to me.”

Hearing that, the Rebbe called me in and said, “Meshulom, don’t mix in G-d’s business. If your wife is not supposed to have any more children, she won’t. And if she is, she will. It’s not up to you.”

Even though the Rebbe usually referred people to a rabbinic authority in such situations, he made an exception in our case. With that we continued and had a total of fifteen beautiful children, thank G-d, each of whom is a tremendous blessing.

But there is postscript to the story.

Years later, when my wife was older, she went to see a gynecologist again. He examined her and said, “You must be very disappointed – as a religious woman, you undoubtedly wanted many children, but with your infantile uterus you obviously never could have any.”

My wife said nothing, but she went out the door laughing. When she came home and told me about it, we had a good laugh together. And I said to her, “All those doctors could not have been wrong. But something amazing happened. The Rebbe promised you that you would have many children and gave you a blessing. Without the Rebbe’s blessing, without his advice and foresight, none of our children would be here!”

https://anash.org/mrs-eileen-weiss-86-ah/

Sunflower syndrome redux

Inspired by patients

Capobianco F 3rd, Beal R, Vemuri P, Bhatia S. A Girl Who Seeks the Light: Diagnosis of Sunflower Syndrome and Review of Management Options. Neurol India. 2025 Mar 1;73(2):346-348. doi: 10.4103/neurol-india.Neurol-India-D-23-00564. Epub 2025 Apr 3. PMID: 40176229.

Abstract

Sunflower syndrome (SS) is a rare self-induced, reflexive epilepsy with photic triggers having highly unique and specific clinical features as patients will characteristically flap their fingers in front of their eyes upon exposure to bright light. Many clinicians are perhaps unaware of this entity, making SS prone to infrequent consideration and misdiagnosis. The purpose of this case is to increase awareness of this diagnosis. We present an adolescent girl in whom this diagnosis was missed/delayed and discuss workup/management in hopes of minimizing holdup in care for individuals affected by this syndrome.

Baumer FM, Julich K, Friedman J, Nespeca M, Thiele EA, Bhatia S, Joshi C. Sunflower Syndrome: A Survey of Provider Awareness and Management Preferences. Pediatr Neurol. 2024 Mar;152:177-183. doi: 10.1016/j.pediatrneurol.2023.11.013. Epub 2023 Nov 30. PMID: 38295719; PMCID: PMC10936539.

Abstract

Background: Sunflower syndrome is a rare photosensitive pediatric epilepsy characterized by stereotyped hand-waving in response to bright lights. These stereotyped movements with maintained awareness can be mistaken for a movement disorder. This study assessed neurology providers' diagnostic reasoning, evaluation, and treatment of Sunflower syndrome.

Methods: A 32-question anonymized electronic survey, including a clinical vignette and video of hand-waving in sunlight, was distributed to child neurology providers to assess (1) initial diagnosis and evaluation based on clinical information, (2) updated diagnosis and management after electroencephalography (EEG), and (3) prior experience with Sunflower syndrome.

Results: Among 277 viewed surveys, 211 respondents provided information about initial diagnosis and evaluation, 200 about updated diagnosis, 191 about management, and 189 about prior clinical experience. Most providers (135, 64%) suspected seizure, whereas fewer suspected movement disorders (29, 14%) or were unsure of the diagnosis (37, 22%). EEG was recommended by 180 (85%). After EEG, 189 (95%) diagnosed epilepsy, 111 of whom specifically diagnosed Sunflower syndrome. The majority (149, 78%) recommended antiseizure medications (ASMs) and sun avoidance (181, 95%). Only 103 (55%) had managed Sunflower syndrome. Epileptologists and those with prior clinical experience were more likely to suspect a seizure, order an EEG, and offer ASMs than those without prior experience.

Conclusions: Although many providers had not managed Sunflower syndrome, the majority recognized this presentation as concerning for epilepsy. Epilepsy training and prior clinical experience are associated with improved recognition and appropriate treatment. Educational initiatives that increase awareness of Sunflower syndrome may improve patient care.

Sourbron J, Proost R, Vandenneucker J, Ticcinelli V, Roelens F, Schoonjans AS, Sercu E, Verhelst H, Jansen K, Lagae L. Seizure quantification in sunflower syndrome by a wrist-worn device. Epileptic Disord. 2025 Apr;27(2):219-227. doi: 10.1002/epd2.20318. Epub 2024 Dec 5. PMID: 39636535.

Abstract

Objective: Sunflower syndrome is a rare photosensitive childhood-onset epilepsy, featuring repetitive handwaving events (HWE) triggered by light. Objective documentation of these HWE can be difficult due to the numerous events occurring daily and/or caregivers who document the seizures but are not always present. Hence, seizure diaries can be underreporting.

Methods: We performed a feasibility study in three Belgian Sunflower syndrome individuals to assess the possibility to quantify the HWE by a wrist-worn wearable device (Axivity AX6). We conducted a structured exercise aiming to capture patterns of possible confounders in a controlled environment. Subsequently, patients wore the device for three to six consecutive days and nights at home. Spectral power analyses were performed to characterize the frequency signature of the different movements.

Results: The HWE of patient A and B showed homogeneity and narrow-band frequencies. Patient C did not experience any HWE at the start of the study due to proper seizure control. Regarding HWE, there was a higher spectral power for Gyroscope Z (Gz) compared to Gy. The inter-subject variability for HWE frequency peaks was in the 3-6 Hz range. Computer analysis by visual annotation, without checking the seizure diary, detected 71% of the HWE if the HWE lasted for longer than 5 s (sensitivity 64%). For shorter HWE duration, the detection rate was 50% but seemed to be higher if there was a concordant change of eye movement (63%) (sensitivity 36%). The most obvious confounder was toothbrushing (TB). However, TB showed a different pattern: that is, higher or comparable spectral power for Gy compared to Gz. There was also a higher or comparable spectral power for Gy compared to Gz for "waving hello".

Significance: We show that the wearable movement sensor Axivity AX6 can detect HWE in Sunflower syndrome individuals and distinguish them from confounders in a real-world setting.

Sunflower syndrome: ocular treatment

Inspired by patients

Geenen KR, Yap SV, Tsega L, Cantrell S, Bruno PL, Thiele EA. Efficacy and tolerability of blue-tinted contact lenses in the treatment of Sunflower syndrome: A questionnaire-based study. Epilepsy Behav. 2026 Mar;176:110921. doi: 10.1016/j.yebeh.2026.110921. Epub 2026 Jan 31. PMID: 41621154.

Abstract

Aim: The goal of this study was to assess the efficacy and tolerability of the Cantrell Notch Filtering soft contact lens as a treatment for patients with Sunflower syndrome.

Methods: A questionnaire was distributed to patients with Sunflower syndrome that were being treated with the Cantrell Notch Filtering contact lenses. The survey was hosted on REDCap, and covered topics pertaining to the respondent's history of Sunflower syndrome, including frequency of seizures, tolerability of the lenses, and the perceived benefit of the lenses with regard to reduction of handwaving episodes.

Results: Nineteen people participated in this study. Sixteen of the 19 respondents provided numerical data regarding the frequency of handwaving episodes with and without contact lenses. At the time of survey completion, the average length of time that patients reported wearing the contact lenses was 11.5 months (range: 1 week-2 years 6 months). There was an average 72.9% reduction in handwaving episodes with the use of the contact lenses. Many respondents were able to reduce the use of other non-pharmacological interventions, such as hats and sunglasses, while wearing the contact lenses. However, 10 respondents (52.6%) reported difficulty with tolerability of the contact lenses, including stinging, burning, and color distortion. Of note, these contact lenses filter light between 250 and 650 nm, compared to a Zeiss Z1 lens which filters light between 550 and 700 nm.

Conclusion: The Cantrell Notch Filtering contact lens for Sunflower syndrome may be a beneficial non-pharmacological treatment option for some patients with Sunflower syndrome, although many patients have difficulty with tolerability.

Geenen KR, Yap SV, Tsega L, Dowless D, Bruno PL, Thiele EA. Eye patches and seizure frequency in young people with Sunflower syndrome. Dev Med Child Neurol. 2026 Jan 10. doi: 10.1111/dmcn.70140. Epub ahead of print. PMID: 41518217.

Abstract

The goal of this study was to assess the impact of wearing an eye patch on seizure frequency in patients with Sunflower syndrome, a reflex photosensitive epilepsy. Caregivers were instructed to record the number of handwaving episodes (HWEs) that occurred per hour under each of the following conditions: (1) no eye patch, (2) wearing an eye patch on the eye ipsilateral to the hand involved in handwaving, and (3) wearing an eye patch on the eye contralateral to the hand involved in handwaving. Patients performed each trial three times, for a total of nine 1-hour trials. Seven patients (five females, two males; age range 8 years 10 months-21 years 5 months, median age = 11 years 2 months) participated in this study. All patients experienced a decrease in HWEs while wearing an eye patch on either eye. Across all patients, the median frequency of HWEs with no eye patch (baseline) was 136 HWEs/hour. When patching the contralateral eye, the median frequency was 26 HWEs/hour. When patching the ipsilateral eye, the median frequency was 23 HWEs/hour. The findings in this study suggest that blocking sensory input to one eye may significantly reduce seizure frequency in patients with Sunflower syndrome. This may inform theories around the pathophysiology of Sunflower syndrome and provide insight into more effective treatment options.

Congenital CMV story

Courtesy of my daughter

Jess Markins' daughter was just a little over 24 hours old when her whole world was rocked.

The mom and content creator, who has been sharing her 2-year-old daughter Caroline's journey on TikTok, tells PEOPLE that she first learned that something might be wrong with Caroline during her pregnancy at her 20-week anatomy scan.

"Doctors noticed growth restriction and some abnormalities on the ultrasound," she explains. "We went through additional testing and very close monitoring for the rest of my pregnancy, but I was mostly told that she was just small."

Markins says that she was told Caroline would be evaluated more thoroughly once she was born, since nothing stood out strongly enough to give a clear diagnosis. And for the first 24 hours of Caroline's life, everything was relatively normal.

"After that, everything changed. A routine brain ultrasound showed calcifications, and she was diagnosed with microcephaly," says Markins. "That led to an MRI, which revealed more extensive abnormalities in her brain."

"Around the same time, she failed her newborn hearing screening. Because of [the state of] Virginia's guidelines, that meant she needed to be tested for congenital CMV — something I had never even heard of before."

According to the CDC, cytomegalovirus (CMV) is a common virus that infects people of all ages. However, when a baby is born after being infected with CMV during pregnancy, it is called congenital CMV. About 1 in 200 babies are born with congenital CMV infection, and about 1 in 5 babies with congenital CMV infection will have birth defects or other long-term health issues.

"When Caroline was one week old, we got the results: she tested positive for congenital CMV," says Markins. "My first reaction was fear — there were so many unknowns. I clung to the hope that she might be one of the children who test positive, but remain asymptomatic.

But as Markins and her partner Chris began meeting with specialists, it became clear that Caroline was symptomatic and would need significant medical support. She began antiviral medication during her first weeks of life, and early intervention began shortly after. Caroline had physical therapy at 2 months old, occupational therapy at 6 months and speech therapy by her first birthday.

"At first, I think I was in a bit of denial, hoping things might not be as serious as they seemed," she says. "But I also knew that giving Caroline every available resource could only help her. Early intervention became something I was incredibly passionate about right from the start. Even in the middle of fear and uncertainty, I knew action was something I could control."

Now two years later, Caroline's days are very structured. Markins says her daughter gets up very early — sometimes around 2 a.m. — and will watch a few TV shows while she tries to sleep a little more. They officially begin the day at 6:30 or 7 a.m., where Caroline gets her first G-tube (gastronomy tube) of the day.

"Caroline sees multiple specialists and has therapy every week, so some days are very busy and involve a lot of driving and time at clinics," says Markins. "On days we're home, we focus on movement and play. She spends time stretching, using her swing and doing floor activities like assisted sitting and rolling."

"She also uses supportive equipment like her activity chair and stander, depending on her energy level that day. Throughout the day, we incorporate her eye-gaze device so she can communicate and make choices," she continues.

Caroline is able to communicate through her eye-gaze device, which is a form of augmentative and alternative communication (AAC) that uses eye tracking. She can select words or phrases on a screen by just looking at them.

"Her communication journey has been incredible to watch. We started when she was about a year old with simple buttons, which gave her very limited ways to express herself. But the more she worked in speech therapy, the more we realized she had a lot to say," explains Markins.

"We moved to picture boards, where she began communicating with her eyes, and as she got older, she had a formal eye-gaze evaluation. She did so well that she now uses her eye-gaze device as her primary way to communicate."

Markins says that Caroline's vocabulary is "constantly growing" and that they are always adding new words and updating her device to match her growing interests and personality.

"And trust me, she has a big personality. Caroline is funny, sassy and very opinionated," says the proud mom. "If you don't understand what she's saying, she will absolutely repeat herself until you do."

Right now, Markins says some of her daughter's favorite things to say are "watch" followed by the name of a television program, and she's been asking for "drink water" because she enjoys taking small sips by mouth.

Caroline also has an About Me page on her device, where she can share her name, age and birthday. Markins says Caroline loves to tell people all about herself, and adds that her favorite button right now is "big news." She's set to become a big sister this summer.

"She tells anyone and everyone, and she is so proud and excited," says Markins.

When they don't have the eye-gaze device, Markins and her family use head taps to help her make choices. But even without any tools, she says that Caroline is incredibly expressive.

"You can see what she's feeling just by watching her face. Her smile is warm and contagious, and she makes it very clear what she thinks," says Markins. "For us, communication is about giving her as much autonomy and voice as possible — and watching her personality shine through has been one of the greatest gifts."

Throughout this journey, Markins says she and her husband have been very fortunate to rely on a strong support system around them. Both of their families live within 30 minutes, and they've been leaning on their local community recently.

"We’re currently fundraising for adaptive equipment and a wheelchair-accessible van for Caroline, and the way people have rallied around her has been overwhelming in the best way," she says. "Seeing how much love and care people have for her truly blows me away."

"Day to day, my husband is my biggest teammate. He works incredibly hard — seven days a week — to support our family financially so I can stay home and be Caroline’s full-time caregiver and be present for both of our girls," she continues. "That kind of partnership makes everything we do possible."

Caroline also has a big sister named Emersynn, who is only 13 months older than her. The two sisters have grown up together, and Emersynn has never known life without medical equipment, therapy visits and extra care for Caroline.

"What amazes me most is how naturally Emersynn has adapted. From the time she was very little, we never had to constantly tell her 'don’t touch' or worry about her interfering with Caroline’s equipment," says Markins. "When Caroline had feeding tubes taped to her face, Emersynn didn’t pull at them. With her feeding pump or medical supplies, she’s always been curious but respectful. Even with Caroline’s hearing aids, she asks questions but doesn’t try to grab or remove them."

"Emersynn just wants to be involved. She watches closely, asks questions, and cheers Caroline on in the sweetest ways. When Caroline uses her eye-gaze device, takes a sip of water, or activates a toy, Emersynn is right there clapping and cheering her on. She is truly one of Caroline’s biggest supporters."

Since sharing Caroline's story on TikTok, Markins says she's found a community online from other parents who are walking the same path as her. She's also been able to advocate for her daughter and provide an example of a medically complex and disabled child.

"When Caroline was first diagnosed, I found myself searching for other parents who were living this kind of life. Watching medical moms and disability parents share their experiences made me feel less alone," Markins tells PEOPLE. "Seeing how they adapted their homes, routines, and expectations to give their children full, meaningful lives was incredibly powerful for me."

"At some point, I realized I wanted to be that person for someone else. I wanted to be the mom I wish I had been able to watch when I was newly navigating diagnoses, equipment, and a completely different version of parenthood than I had imagined," she says. "There’s also such a lack of representation for medically complex and disabled children. Our world is built for able-bodied people, and families like ours often have to fight and advocate just to access basic opportunities."

Markins says she feels a responsibility to share their family's story to help create more awareness, more understanding and more inclusion for kids like Caroline.

"I want people to see that disability is not something to hide away — it’s a part of life, and these children deserve to be seen, supported, and celebrated," she says. "I would choose Caroline in every lifetime, a hundred times over. What I would change is not her — it’s the way society views and supports people with disabilities. If sharing our story helps even one person better understand or shift their perspective, then it’s worth it."

Hannah Sacks

https://people.com/2-year-old-girl-communicates-with-eye-gaze-device-exclusive-11913019

Compassion in the UK

February 5

Dear Shmuly,

Today we attended a full-day meeting to work out the legal aspects surrounding your care. Here in England, they don’t place a high value on life that isn’t “productive.” Under UK law, if a patient is dependent on life-sustaining treatment without the prospect of significant recovery, it’s often judged to be not “in their best interests” to continue. These life-or-death decisions end up in the hands of NHS trusts and the courts. So even though every breath you took — with the help of the ventilator — meant the world to us, we knew we wouldn’t be able to fight the NHS forever.We didn’t want a court case, so Tatty and I, along with our legal team, went to many meetings as we tried to work out an agreement with the hospital administration through the courts.

Today I had to join an in-person meeting.

Last night I slept at home and noticed an empty picture frame I’d bought before Tatty and I got married. The placeholder paper read: Today is a good day. And I thought, Today is a good day, but tomorrow can’t be.

But tonight, after ten long, long hours of discussion, migraines, exhaustion, and the brick wall of a quickly-going-nowhere back-and-forth, I looked at that frame again and realized: Good is relative. Our situation isn’t great, and it looks like we’re going to have to take your case to court, but there are moments of goodness and even humor and laughter laced through all the frustration.

I’ve tried to notice the small hugs Hashem sends. That moment of sunlight on your face. The nurse who gave me a birthday card with your footprints. The friend who texts at exactly the right time.

Small hugs, but when I look for them, I find them.

Love, Mommy

June 30

Dear Shmuly,

The court process dragged on longer than we expected; hearings were postponed, and dates kept getting moved as we struggled to reach an agreementabout your long-term care — with the hospital denying that you had quality of life, and we insisting that your very existence was valuable.

First the hearing was pushed off until after Pesach. Then after Shavuos. When I heard about the latest delay, I said, “It looks like Shmuly’s going to livethrough all the Yamim Tovim!” It was another hug from Hashem, a confirmation of your life.

But I knew the end was coming, and instead of feeling robbed, I felt grateful. You could have died right away, Shmuly. Or much earlier. Every extra day was agift. And we chose to accept it.

The finalized legal decisions included one week so we could say goodbye properly. The family came. Grandparents. Siblings. Aunts. Uncles. Friends. Wecaptured those moments with you.

But the uncertainty was crushing. We didn’t know what would happen once the ventilator was removed. Would it be peaceful, or would our time together bepunctuated by alarms ringing as you struggled to breathe? Would it be minutes? Hours? How long would we have to cherish the last few moments?

Nothing was certain. But I bought you a final set of soft, cuddly pajamas, and you stayed in them until the end.

By the time Monday came, I was prepared — at least intellectually — to give you back. Nothing could prepare my emotions. The pain I carried in my heartwas excruciating, stealing my breath at the thought of losing you. But we’d been living in the shadow of this goodbye for months, and I wanted the momentto be as perfect as possible. Tatty and I were in the room with you, and everything was calm and gentle.

The hospital wanted to extubate you, but doing that could have caused you to die immediately. We needed to make sure you had a chance, so we worked tocreate a plan that would reduce your support gradually and safely. With the help of our supporters, the court honored the Torah way of doing this transition,avoiding immediate death.

The doctors switched your ventilator to a CPAP mask (a machine that gently pushes air into your lungs to help you breathe) and helped keep your airwayopen. They reduced your breathing support slowly and carefully, only when they thought you could handle it.

In the end, you surprised everyone, Shmuly. You breathed on your own for nearly ten hours.

For the first eight hours, you were perfectly calm. I held you the entire time, listening to each breath. For the first time since you were a newborn, I could seeyour whole face… no tubes or machinery covering you. And that’s the picture I remember.

One striking detail about your life is that the timing of your birth, cardiac arrest, and passing, all took place at night, the start of the new Jewish day. Every dayof your life was complete. The 16 days before the hospital and the 307 days in the hospital, 323 days in total, were all whole.

In the final two hours, you struggled for breath. I held your hand and stroked you as the sun set and the sky turned pink behind you. I whispered Shema,faltered through Hamalach, and sang softly.

And then, peacefully, you passed away.

I was there the whole time. I was always there.

We fought for you all the way, Shmuly. And in the end, you fought for yourself.

Love, Mommy

See: https://mishpacha.com/23-million-seconds/

Miracle on ice

Awesome World ·

Stuart Handel

In December 1980, a young woman named Jean Hilliard, just 19 years old, was driving home through the bitter cold of Lengby, Minnesota. The temperature that night plunged to a brutal –30°C (–22°F). When her car slid off the icy road and stalled, she decided to walk through the snow toward a friend’s house nearly two miles away.

But only 15 feet from the door, Jean’s body finally gave in to the cold. She collapsed, unconscious, and remained there for six long hours, her body completely frozen solid by the time dawn arrived.

When her friend discovered her the next morning, Jean’s skin was stiff as wood, her eyes glassy, and her body too frozen to bend. Even hospital thermometers couldn’t register her temperature. Doctors had little hope.

Yet, they refused to give up. They wrapped her in warm blankets and slowly raised her body temperature with heating pads. Hours passed — then something incredible happened. Jean’s body began to soften. Her pulse faintly returned. Against all odds, she woke up.

After 49 days in the hospital, Jean not only survived but made a full recovery — with no brain damage or amputations.

To this day, her case remains one of the most extraordinary medical recoveries ever recorded — a story that continues to remind us that even when life seems frozen beyond repair, miracles can still thaw the impossible.

Comment

Bangsar Fan

Grok Fact Check: Fact Check: Jean Hilliard’s Hypothermia Survival
The story of Jean Hilliard’s 1980 survival in Lengby, Minnesota, is mostly true. On December 20, 19-year-old Jean’s car skidded into a ditch in –30°C (–22°F) weather. She walked ~2 miles toward a friend’s house, collapsing 15 feet from the door. Found after ~6 hours, her body was rigid, pale, with a core temperature (~27°C) too low for standard thermometers. Doctors at Fosston Hospital used blankets and heating pads; she awoke hours later, defying grim odds. After 49 days in hospital, she fully recovered with no brain damage or amputations.
Accuracy: 95%. “Frozen solid” is slightly exaggerated (faint pulse remained), and distance is approximate. Verified by Montreal Gazette (1980), MPR (2018), Snopes (2015). A rare hypothermia survival case.

https://www.facebook.com/groups/988897155023132/posts/1914787879100717/

Sameer Karthik

Kind hearted psychopath9y

What are some weird facts?

In 1980, a woman named Jean Hilliard in rural north western Minnesota, was involved in a car accident which resulted in car failure in sub-zero temperatures. She walked to a friend's house 2 miles away and collapsed 15 feet outside of the door. Temperatures dropped to −22 °F (−30 °C) and she was found "frozen stiff" at 7 a.m. after six hours in the cold. She was transported to Fosston Hospital where doctors said her skin was too hard to pierce with a hypodermic needle and her body temperature was too low to register on a thermometer. Her face was ashen and her eyes were solid with no response to light. Her pulse was slowed to approximately 12 beats per minute.

She was wrapped in an electric blanket.

The miraculous thing that happened was, 49 days after she was admitted, she was discharged from the hospital with no permanent damage to the brain or body besides frostbite.

Some people might be wondering how this was possible, but scientists explained this :

There's at least one possible scientific explanation.

In the article "Is Human Hibernation Possible," published in 2008 by the Annual Review of Medicine, Dr. Cheng Chi Lee of the University of Texas' Department of Biochemistry and Molecular Biology notes that

"Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state."

In a search for therapeutic uses of induced-hypothermia, Dr. Lee found a "natural biomolecule," 5' AMP, that "allows rapid initiation of hypometabolism in mammals" and that

"may eventually result in clinical applications where hypothermia has been shown to have tremendous lifesaving potential, such as trauma, heart attacks, strokes, and many major surgeries."

It is possible that Hilliard froze so quickly that her body skipped the phase where lasting tissue damage could be done and her body entered a hypometabolic state that allowed her basic life functions to continue until she was successfully thawed out.

https://www.quora.com/topic/Jean-Hilliard-1?q=jean%20hilliard

Lee CC. Is human hibernation possible? Annu Rev Med. 2008;59:177-86. doi: 10.1146/annurev.med.59.061506.110403. PMID: 18186703.

Abstract

The induction of hypometabolism in cells and organs to reduce ischemia damage holds enormous clinical promise in diverse fields, including treatment of stroke and heart attack. However, the thought that humans can undergo a severe hypometabolic state analogous to hibernation borders on science fiction. Some mammals can enter a severe hypothermic state during hibernation in which metabolic activity is extremely low, and yet full viability is restored when the animal arouses from such a state. To date, the underlying mechanism for hibernation or similar behaviors remains an enigma. The beneficial effect of hypothermia, which reduces cellular metabolic demands, has many well-established clinical applications. However, severe hypothermia induced by clinical drugs is extremely difficult and is associated with dramatically increased rates of cardiac arrest for nonhibernators. The recent discovery of a biomolecule, 5'-AMP, which allows nonhibernating mammals to rapidly and safely enter severe hypothermia could remove this impediment and enable the wide adoption of hypothermia as a routine clinical tool.

Service above and beyond the call of duty

 My name is Jessica, and I’m the mother of two amazing girls, an eight year old and my youngest, Madelynn, who is five. Madelynn is a true warrior. She has a bravery far beyond her years and the purest love for rollercoasters, Disney, and stuffed animals. As a family, we love spending time together, swimming, skiing, and playing board games. But behind our happiness is a daily battle that quietly shapes our lives. 

Madelynn was born with Tuberous Sclerosis Complex (TSC), a rare disease that causes benign tumors to grow in her brain, heart, kidneys, face, and eyes. We didn’t receive her formal diagnosis until she was 15 months old. Shortly after, her EEG showed sharp waves, an early warning sign that seizures were likely. Madelynn had her first seizure at age two. It was so severe that she had to be medevacked to the hospital. I remember every second of those 12 minutes, 12 minutes where we didn’t know if she would wake up. It was the worst day of my life. 

Since then, Madelynn has been on two anticonvulsion medications, including one we receive from PANTHERx, and she has been seizurefree for three and a half years. But missing even one dose could trigger another medical emergency. Status epilepticus, when a seizure lasts longer than five minutes or when seizures happen back-to-back it can be life threatening. There is nothing more terrifying than not knowing if your child will be okay. 

That fear became very real during a recent fun family ski trip. 

Madelynn takes six medications every day. Packing for travel is a meticulous process, syringes, pills, liquids, powders, and always her rescue medication. Despite  double and triple checking, one of her medications was left at home on the kitchen counter. And of course, it was the one medication we can only get from PANTHERx. I didn’t discover the mistake until Friday night when I went to give her evening dose. 

Upon discovering the missing medication, I knew immediately that we would have to end our trip and drive home, there was no way I could risk her missing that dose. 

Out of desperation, I called PANTHERx in a panic, barely able to speak through my tears. The woman on the phone was incredibly kind. She told me she would do everything in her power to help. 

We tried every possible option. Overnight delivery wasn’t possible—FedEx had stopped taking shipments. A friend back home couldn’t ship it because the FedEx location wouldn’t accept medication. And with FedEx closed on Sundays, nothing could get out the next day. PANTHERx even called local hospitals for alternatives. 

Then, when I was running out of hope, I got a call back.

They told me they had secured a courier who would drive six hours through the snow to deliver the medication directly to us. 

I cried. I couldn’t believe they were willing to do that for my family. I even offered to pay, but they told me they were simply happy to help a mom in need. That courier drove for hours on a weekend, in the snow to make sure my child didn’t miss a dose. 

As a mom of a child with complex medical needs, I live with constant worry. You never sleep the same way. But in that moment when I was scared, PANTHERx stepped in without hesitation. They’ve always been incredible. When Madelynn first needed medication and insurance hadn’t approved it yet, they sent it at no cost because she needed it immediately. 

If I could say anything to the team that helped us that weekend, it would be this: Thank you for helping me when you didn’t have to. Your kindness was above and beyond, and I will never forget it. 

To other families, I want you to know that there truly are good people in the world. I’m so grateful I made that phone call. I only wish I could get all of my daughter’s medications from PANTHERx. 

They didn’t just deliver medicine. They delivered peace of mind when I needed it most! 

https://pantherxrare.com/rarestories/a-vacation-saved/

AAV9 gene therapy in Type II GM1 gangliosidosis - A phase 1-2 trial

Lewis CJ, D'Souza P, Johnston JM, Acosta MT, Farmer C, Baker EH, Crowell A, Mojica Y, Ashraf S, Joseph L, Vézina G, Quezado Z, Yousef MH, Vardar Z, Shazeeb MS, Corti M, Blackwood M, Coleman K, Batista R, Thurm A, De Boever E, Gahl WA, Byrne BJ, Flotte TR, Jiang X, Gross AL, Keeler AM, Gray-Edwards H, Martin DR, Sena-Esteves M, Tifft CJ. AAV9 Gene Therapy in Type II GM1 Gangliosidosis - A Phase 1-2 Trial. N Engl J Med. 2026 Feb 6. doi: 10.1056/NEJMoa2510935. Epub ahead of print. PMID: 41665410.

Abstract


Background: GM1 gangliosidosis, caused by biallelic variants in GLB1, results from deficiency of lysosomal β-galactosidase, which degrades GM1 ganglioside. This fatal neurodegenerative disease currently has no effective therapy.

Methods: In a phase 1-2, open-label, dose-escalation study, we assessed immunosuppression and a single intravenous infusion of adeno-associated virus serotype 9 (AAV9) encoding β-galactosidase in children with type II GM1 gangliosidosis with late-infantile or juvenile onset. The primary end point was safety. Secondary end points included changes from baseline in the cerebrospinal fluid (CSF) GM1 ganglioside concentration and β-galactosidase activity, clinical assessments (including the Clinical Global Impression-Improvement [CGI-I] score, assessed on a scale from 1 [very much improved] to 7 [very much worse]), and neuroimaging patterns.

Results: Nine participants were enrolled. Over a 3-year period, 124 adverse events occurred, 30 of which (8 gastrointestinal events, 21 laboratory abnormalities associated with inflammation, and 1 tachycardia event) were deemed by the investigator as being possibly, probably, or definitely related to the gene therapy. Five serious adverse events occurred, including vomiting that led to hospitalization in one participant, which was attributed to the gene therapy. Serum aspartate and alanine aminotransferase levels increased in all participants and returned to baseline levels by 18 months. In all participants, the CSF β-galactosidase level increased and CSF GM1 ganglioside level decreased. Expressive communication and gross motor scores appeared stable, but fine motor and receptive communication scores decreased. The median CGI-I score was 3 (indicating minimal improvement) at 2 years and 4 (indicating no change) at 3 years; in historical controls, scores have been shown to increase (indicating worsening) over time. Neuroimaging showed patterns consistent with reduced rates of cerebral atrophy and favorable changes in myelination as compared with baseline.

Conclusions: In this study involving nine participants with type II GM1 gangliosidosis, a single infusion of AAV9 encoding β-galactosidase was associated with adverse events, including severe vomiting in one participant and elevated liver-enzyme levels in all participants. Secondary end-point results suggested improvements in biochemical markers and neuroimaging patterns and stable or reduced rates of developmental deterioration in some measures.

Grieving parents of a 26-year-old man against Canada’s medical assistance in dying laws

Mother sounds alarm on social media addiction after losing teen son to suicide

Maurine Molak shares her story after her 16-year-old son, David, died by suicide in 2016 and argues safeguards 'don't work' as tech giants face trial over the alleged addictive and harmful nature of social media platforms.

The grieving parents of a 26-year-old man are speaking out against Canada’s medical assistance in dying (MAID) laws, arguing the system failed to protect their "vulnerable" son from being euthanized, despite a history of mental illness.

Kiano Vafaeian was euthanized on Dec. 30, 2025, in British Columbia. His family says he was diagnosed with Type 1 diabetes at age 4 and began struggling with mental health after a car accident at 17. 

His mother, Margaret Marsilla of Ontario, said his depression was often seasonal, yet he became "obsessed" with MAID after losing vision in one eye in 2022.

"He kept on emphasizing about how he could get approved," Marsilla told Fox News Digital. "We never thought there would be a chance that any doctor would approve a 22- or 23-year-old at that time for MAID because of diabetes or blindness."

MAID was legalized in Canada in June 2016. The law allows patients with "grievous and irremediable" medical conditions to request a lethal drug that is either physician or self-administered, to end their lives.

In 2022, after a Toronto doctor initially approved Vafaeian’s request, the family launched a public pressure campaign on social media to voice their opposition. The outcry led the doctor to withdraw approval. While Vafaeian was initially angry, his family said he showed signs of improvement over the following year, even moving in with them in 2024.

"He tried his best when he was in one of those good highs of life," Marsilla said. "Then winter, fall started coming around, he started changing and then everything that we had worked for from spring and summertime just disappeared… he would start talking about MAID again."

The family said Vafaeian was rejected by multiple doctors in Ontario before he sought out Dr. Ellen Wiebe, a prominent MAID provider, in British Columbia. Marsilla believes Wiebe "coached" her son on what to say to meet the criteria for "Track 2" patients — those whose natural deaths are not reasonably imminent.

"We believe that she was coaching him... on how to deteriorate his body and what she can possibly approve him for and what she can get away with approving him for," Marsilla said. "Because if he had spoken back in 2024, and he was a good candidate for approving MAID, she would have done it right away, but she didn't."

Vafaeian’s parents say they were not notified of the approval and only learned of his death days after it occurred. They noted his medical records did not substantiate the "severe peripheral neuropathy" listed on his death certificate as a qualifying factor.

"This whole process came to us as a shock," said Joseph Caprara, Vafaeian’s stepfather.

In 2021, eligibility for MAID was expanded to include applicants with "grievous and irremediable conditions" whose deaths are not reasonably foreseeable. The family is now advocating for the repeal of this "Track 2" provision and the passage of Bill C-218, a legislative effort to restrict MAID for patients whose underlying issue is solely mental illness.

"Realistically, safeguards for patients would be reaching out to their family members, giving them a whole bunch of different treatment options," Marsilla said. Instead, she claims the current system allows doctors to approve and euthanize patients within 90 days on Track 2. 

"How is that safe for patients?" she asked.

Marsilla has shared her son's story on social media, describing the situation as "disgusting on every level."

On Facebook, she wrote, "No parent should ever have to bury their child because a system—and a doctor—chose death over care, help, or love."

Caprara said their family hopes sharing their story will expose the risks these laws pose to the "vulnerable and disabled" and give states and other countries pause before implementing similar legislation.

"We don't want to see any other family member suffer, or any country introduce a piece of legislation that kills their disabled or vulnerable without appropriate proper treatment plans that could save their lives," he said.

In a statement to Fox News Digital, Dr. Wiebe said, "Like my colleagues, every patient I approve for Track 2 has unbearable suffering from a grievous and irremediable medical condition (not psychiatric) with an advanced state of decline in capability and consents to MAID fully informed about treatments to reduce the suffering."

New York Gov. Kathy Hochul signed an assisted suicide bill into law on Monday, making New York the 13th state, plus the District of Columbia, to legalize allowing physicians to aid terminally ill adults in dying by suicide. The law will go into effect in six months.

Kristine Parks 

https://www.foxnews.com/media/grieving-parents-demand-changes-after-26-year-old-son-euthanized-under-controversial-law

Truncating variants of TRIM8 and atypical neuro-renal syndrome:

Inspired by a colleague's patient

Weng PL, Majmundar AJ, Khan K, Lim TY, Shril S, Jin G, Musgrove J, Wang M, Ahram DF, Aggarwal VS, Bier LE, Heinzen EL, Onuchic-Whitford AC, Mann N, Buerger F, Schneider R, Deutsch K, Kitzler TM, Klämbt V, Kolb A, Mao Y, Moufawad El Achkar C, Mitrotti A, Martino J, Beck BB, Altmüller J, Benz MR, Yano S, Mikati MA, Gunduz T, Cope H, Shashi V; Undiagnosed Diseases Network; Trachtman H, Bodria M, Caridi G, Pisani I, Fiaccadori E, AbuMaziad AS, Martinez-Agosto JA, Yadin O, Zuckerman J, Kim A; UCLA Clinical Genomics Center; John-Kroegel U, Tyndall AV, Parboosingh JS, Innes AM, Bierzynska A, Koziell AB, Muorah M, Saleem MA, Hoefele J, Riedhammer KM, Gharavi AG, Jobanputra V, Pierce-Hoffman E, Seaby EG, O'Donnell-Luria A, Rehm HL, Mane S, D'Agati VD, Pollak MR, Ghiggeri GM, Lifton RP, Goldstein DB, Davis EE, Hildebrandt F, Sanna-Cherchi S. De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis. Am J Hum Genet. 2021 Feb 4;108(2):357-367. doi: 10.1016/j.ajhg.2021.01.008. Epub 2021 Jan 27. PMID: 33508234; PMCID: PMC7895901.

Abstract

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Sakai Y, Fukai R, Matsushita Y, Miyake N, Saitsu H, Akamine S, Torio M, Sasazuki M, Ishizaki Y, Sanefuji M, Torisu H, Shaw CA, Matsumoto N, Hara T. De Novo Truncating Mutation of TRIM8 Causes Early-Onset Epileptic Encephalopathy. Ann Hum Genet. 2016 Jul;80(4):235-40. doi: 10.1111/ahg.12157. PMID: 27346735.

Abstract

Background: Early-onset epileptic encephalopathy (EOEE) is a heterogeneous group of neurodevelopmental disorders characterised by infantile-onset intractable epilepsy and unfavourable developmental outcomes. Hundreds of mutations have been reported to cause EOEE; however, little is known about the clinical features of individuals with rare variants.

Case report and methods: We present a 10-year-old boy with severe developmental delay. He started experiencing recurrent focal seizures at 2 months old. Serial electroencephalograms persistently detected epileptiform discharges from the left hemisphere. Whole-exome sequencing and array-comparative genome hybridization were performed to search for de novo variations. Two-week-old C57Bl/6 mice were used for immunofluorescence studies.

Results: This case had a paternally inherited, 0.2-Mb duplication at chromosome 22q11.22. The whole-exome sequencing identified a de novo truncating mutation of tripartite motif containing 8 (TRIM8) (NM_030912:c.1099_1100insG:p.C367fs), one of the epileptic encephalopathy-associated genes. We verified that the murine homologues of these genes are expressed in the postnatal mouse brain.

Conclusion: This is the second case of EOEE caused by a de novo truncating mutation of TRIM8. Further studies are required to determine the functional roles of TRIM8 in the postnatal development of the human brain and its functional relationships with other EOEE-associated genes.

Li W, Guo H. De novo truncating variants of TRIM8 and atypical neuro-renal syndrome: a case report and literature review. Ital J Pediatr. 2023 Apr 15;49(1):46. doi: 10.1186/s13052-023-01453-4. PMID: 37061734; PMCID: PMC10105407.

Abstract

Background: The TRIM8 gene encodes a protein that participates in various biological processes. TRIM8 variants can lead to early termination of protein translation, which can cause a rare disease called neuro-renal syndrome. This syndrome is characterized by epilepsy, psychomotor retardation, and focal segmental glomerulosclerosis. However, we found that some patients may not present the above typical triad, and the reason may be related to their variant sites.

Case presentation: We report a case of a 6-year-old boy with nephrotic-range proteinuria as the first prominent manifestation of TRIM8 variant. He had stage 3 chronic kidney disease at the time of presentation, specific facial features, and a neurogenic bladder. He had not experienced seizures previously. There were no apparent abnormalities in his growth, intelligence, or motor development. The results of whole exome sequencing showed a TRIM8 variant. Renal biopsy revealed focal segmental glomerulosclerosis and renal tubular cystic dilatation. He did not respond to hormone and angiotensin-converting enzyme inhibitor treatment; however, the symptoms of neurogenic bladder were relieved after treatment with Solifenacin.

Conclusion: In this case, renal disease was the prominent manifestation; the patient had no other obvious neurological symptoms except a neurogenic bladder. Notably, the variant site is the closest to the C-terminal to date. Based on the analysis of previously reported cases, we found that as the TRIM8 variant became closer to the C-terminal, the renal lesions became more prominent, and there were fewer neurologic lesions. Our findings provide a new understanding of neuro-renal syndrome caused by TRIM8 variant. Patients may only have kidney disease as a prominent manifestation. At the same time, we found that we should also pay attention to the eye lesions of these patients. Therefore, gene analysis is helpful in identifying the etiology and guiding the prognosis of patients with hormone-resistant proteinuria. We suggest that TRIM8 should be included in gene panels designed for the genetic evaluation of hormone-resistant proteinuria.

15q11.2 microdeletions

Inspired by a patient

Basarir G, Erdogan I, Ozyilmaz B, Gencpinar P, Dundar NO. Beyond the Copy Number Differences: The Phenotypic Diversity of Children With 15q11.2 Microdeletions and Microduplications. J Child Neurol. 2025 Oct;40(9):784-793. doi: 10.1177/08830738251366862. Epub 2025 Aug 26. PMID: 40856583.

Abstract

15q11.2 BP1-BP2 copy number variants involving NIPA1, NIPA2, CYFIP1, and TUBGCP5 genes may not warrant a clinical outcome because of the phenotypic variability and low penetrance. The study aims to provide a greater understanding of the phenotypic diversity associated with these copy number variants. We conducted a retrospective analysis of 37 pediatric patients with deletions or duplications in 15q11.2 BP1-BP2 region, and compared the results systemically with the previous literature. Of the 37 patients, 67.6% had microduplications and 32.4% had microdeletions. The mean copy number variant size was 482 ± 157 kb. Patients had a variety of phenotypes including neurodevelopmental delay, hypotonia, speech impairment, intellectual and learning disability, behavioral and psychiatric symptoms, epilepsy and seizures, neuroimaging abnormalities, and dysmorphism. These findings, in combination with previous reports, confirm that copy number variants in this region are linked to phenotypes ranging from normal to severe neurodevelopmental and neuropsychiatric features. Our data also confirm that microcephaly is a particularly prevalent phenotype in patients with microdeletions, rather than in those with microduplications.

Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O, Holder-Espinasse M, Delobel B, Duban B, Vallee L, Cuisset JM, Lemaitre MP, Vantyghem MC, Pigeyre M, Lanco-Dosen S, Plessis G, Gerard M, Decamp M, Mathieu M, Morin G, Jedraszak G, Bilan F, Gilbert-Dussardier B, Fauvert D, Roume J, Cormier-Daire V, Caumes R, Puechberty J, Genevieve D, Sarda P, Pinson L, Blanchet P, Lemeur N, Sheth F, Manouvrier-Hanu S, Andrieux J. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015 Mar;58(3):140-7. doi: 10.1016/j.ejmg.2015.01.002. Epub 2015 Jan 14. PMID: 25596525.

Abstract

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.

Picinelli C, Lintas C, Piras IS, Gabriele S, Sacco R, Brogna C, Persico AM. Recurrent 15q11.2 BP1-BP2 microdeletions and microduplications in the etiology of neurodevelopmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1088-1098. doi: 10.1002/ajmg.b.32480. Epub 2016 Aug 26. PMID: 27566550.

Abstract

Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg2+ levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples.

Baldwin I, Shafer RL, Hossain WA, Gunewardena S, Veatch OJ, Mosconi MW, Butler MG. Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families. Int J Mol Sci. 2021 Feb 7;22(4):1660. doi: 10.3390/ijms22041660. PMID: 33562221; PMCID: PMC7914695.

Abstract

The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

Intellectual function and psychiatric comorbidities in patients with epilepsy with eyelid myoclonia

Padilla, Hannah, Eva C. Alden , Isha Snehal∙ Jeffrey W. Britton ,Lily C. Wong-Kisiel, Elaine C. Wirrell, Kelsey M. Smith. Intellectual function and psychiatric comorbidities in patients with epilepsy with eyelid myoclonia Epilepsy & Behavior, Volume 176, 110918

Abstract

Background
Epilepsy with Eyelid Myoclonia (EEM) is a rare childhood-onset epilepsy syndrome. There is limited data about cognitive function and psychiatric comorbidities in patients with EEM.

Design/Methods
A database of 134 patients with EEM was reviewed for patients who underwent neuropsychological testing. Psychiatric comorbidities and psychometric test scores were identified. Group comparison was performed between those who underwent neuropsychological testing and those who did not. In addition, we evaluated whether clinical factors were associated with IQ score.

Results
Fourteen patients underwent neuropsychological testing (12 females, 85.7%), with a median age at testing of 17 (range 7–22). Median IQ was 79 (range 56–110); 7 patients had below average IQ. Other median results of neuropsychometric measures were: Verbal Comprehension Index 85.5 (range 66–116), Perceptual Reasoning Index or Visual Spatial Index 81.5 (range 67–100), Working Memory Index 77 (range 54–100), Processing Speed Index 84 (range 53–94), and Reading Standardized Scores 84 (range 64–126). Common psychiatric comorbidities were anxiety (n = 10), depression (n = 7), ADHD (n = 6), and autism (n = 2). Those who underwent neuropsychological testing had a younger age of epilepsy onset, longer follow-up at our institution, and were more likely to have myoclonic seizures or psychosis than those who did not undergo neuropsychological testing. No clinical factors were statistically associated with IQ score.

Conclusions
EEM is associated with a wide range of cognitive abilities, with half of our patients having a below average IQ. Psychiatric comorbidities were common. Identifying cognitive impairment and psychiatric comorbidities is crucial to implement appropriate management strategies.

Superior semicircular canal dehiscence syndrome

Courtesy of a colleague, who wrote: "OK, maybe you all have seen this often, but I haven’t seen this knowingly until the last year and 2 kids with intractable 'dizziness' and headaches were fixed with surgical repair by ENT."

Lazarou I, Sideris G, Papadimitriou N, Delides A, Korres G. Third Window Syndrome: An Up-to-Date Systematic Review of Causes, Diagnosis, and Treatment. J Audiol Otol. 2025 Apr;29(2):86-94. doi: 10.7874/jao.2024.00696. Epub 2025 Apr 18. PMID: 40296471; PMCID: PMC12046203.

Abstract

Third window syndrome (TWS) is an inner ear condition caused by an additional compliant point in the otic capsule that disrupts auditory and vestibular functions. Superior semicircular canal dehiscence is the most common cause, presenting with hearing loss, vertigo, and autophony, significantly impairing quality of life. This study evaluated the pathophysiology, diagnostics, treatments, and recent advancements in TWS while identifying research gaps. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 70 studies from Embase, MEDLINE, Cochrane, and UpToDate databases were analyzed. TWS affects inner ear mechanics, enhancing bone conduction and reducing air conduction. Diagnosis involves clinical evaluations, high-resolution imaging, and functional tests such as vestibular evoked myogenic potentials, which are known for their high sensitivity and specificity. Management strategies range from vestibular rehabilitation and pharmacotherapy to surgical interventions, including transmastoid and middle cranial fossa approaches, which achieve over 75% success. Emerging minimally invasive techniques, such as underwater endoscopic ear surgery and round window reinforcement, show promise but carry risks like cerebrospinal fluid leakage and inconsistent symptom relief. Advancements in TWS management have improved outcomes, yet gaps remain, particularly in terms of false-positive imaging and long-term efficacy. Future studies should prioritize predictive models and minimally invasive techniques. A multidisciplinary approach is essential to improve patient care.

Suzuki M, Ota Y, Takanami T, Yoshino R, Masuda H. Superior canal dehiscence syndrome: A review. Auris Nasus Larynx. 2024 Feb;51(1):113-119. doi: 10.1016/j.anl.2023.08.004. Epub 2023 Aug 26. PMID: 37640595.

Abstract

Superior canal dehiscence syndrome (SCDS) is a vestibular disorder in which the presence of a pathological third window in the labyrinth causes several vestibular and cochlear symptoms. Herein, we review the diagnostic criteria and treatment of SCDS. The cause of SCDS is considered to be congenital or acquired; however, its etiology is not well known. Symptoms: Vertigo and/or oscillopsia induced by loud sounds (Tullio phenomenon) or stimuli that change the middle ear or intracranial pressure (fistula symptoms) with vestibular symptoms and hyperacusis and aural fullness with cochlear symptoms are characteristic clinical complaints of this syndrome. Neurological tests: Vertical-torsional eye movements can be observed when the Tullio phenomenon or fistula symptoms are induced. Conductive hearing loss with both a decrease in the bone conduction threshold at lower frequencies and an increase in the air conduction threshold at lower frequencies may be present on audiometry. Cervical and/or ocular vestibular evoked myogenic potentials are effective in strongly suspecting the presence of a pathologic third window in the labyrinth. Computed tomography (CT) imaging: High-resolution CT findings with multiplanar reconstruction in the plane of the superior semicircular canal consistent with dehiscence indicate SCDS. The Pöschl view along the plane of the superior semicircular canal and the Stenvers view perpendicular to it are recommended as CT imaging conditions. Findings from all three major diagnostic categories (symptoms, neurological tests, and/or CT imaging) are needed to diagnose SCDS. The surgical approaches for SCDS are as follows: the 1) middle cranial fossa approach, 2) transmastoid approach, and 3) round window and oval window reinforcement. Each technique has advantages and disadvantages.

Kontorinis G, Lenarz T. Superior semicircular canal dehiscence: a narrative review. J Laryngol Otol. 2022 Apr;136(4):284-292. doi: 10.1017/S0022215121002826. Epub 2021 Oct 7. PMID: 34615564.

Abstract

Background: Described just over 20 years ago, superior semicircular canal dehiscence remains a relatively unknown and easily missed cause of dizziness and auditory symptoms.

Objective: This review focused on the origin, presenting symptoms and underlying pathophysiology of superior semicircular canal dehiscence, and the available treatment options.

Main findings and conclusion: The bony dehiscence acts as a 'third window', affecting inner-ear homeostasis, and resulting in hypersensitivity and a vestibular response to lower sound level stimuli. The third window effect explains the pressure- and sound-induced vertigo, oscillopsia, and nystagmus, as well as autophony, conductive hyperacusis and tinnitus. The origin of superior semicircular canal dehiscence is linked to the combination of a congenital or developmental factor, and a 'second event' like head trauma, rapid pressure changes or age-related factors. Computed tomography of the temporal bone and reduced vestibular-evoked myogenic potential thresholds can confirm the diagnosis. Despite only retrospective cohorts, surgery is considered a safe treatment option, targeting mainly vestibular but also auditory symptoms, with transmastoid approaches gaining popularity.

Ward BK, van de Berg R, van Rompaey V, Bisdorff A, Hullar TE, Welgampola MS, Carey JP. Superior semicircular canal dehiscence syndrome: Diagnostic criteria consensus document of the committee for the classification of vestibular disorders of the Bárány Society. J Vestib Res. 2021;31(3):131-141. doi: 10.3233/VES-200004. PMID: 33522990; PMCID: PMC9249274.

Abstract

This paper describes the diagnostic criteria for superior semicircular canal dehiscence syndrome (SCDS) as put forth by the classification committee of the Bárány Society. In addition to the presence of a dehiscence of the superior semicircular canal on high resolution imaging, patients diagnosed with SCDS must also have symptoms and physiological tests that are both consistent with the pathophysiology of a 'third mobile window' syndrome and not better accounted for by another vestibular disease or disorder. The diagnosis of SCDS therefore requires a combination of A) at least one symptom consistent with SCDS and attributable to 'third mobile window' pathophysiology including 1) hyperacusis to bone conducted sound, 2) sound-induced vertigo and/or oscillopsia time-locked to the stimulus, 3) pressure-induced vertigo and/or oscillopsia time-locked to the stimulus, or 4) pulsatile tinnitus; B) at least 1 physiologic test or sign indicating that a 'third mobile window' is transmitting pressure including 1) eye movements in the plane of the affected superior semicircular canal when sound or pressure is applied to the affected ear, 2) low-frequency negative bone conduction thresholds on pure tone audiometry, or 3) enhanced vestibular-evoked myogenic potential (VEMP) responses (low cervical VEMP thresholds or elevated ocular VEMP amplitudes); and C) high resolution computed tomography (CT) scan with multiplanar reconstruction in the plane of the superior semicircular canal consistent with a dehiscence. Thus, patients who meet at least one criterion in each of the three major diagnostic categories (symptoms, physiologic tests, and imaging) are considered to have SCDS.

Misinformation about Tourette Syndrome from major media network

Müller-Vahl KR, Szejko N, Hartmann A, Debes NM, Hedderly T, Parnes M, Abi-Jaoude E, Smilowska K, Nilles C, Coffman K, E Cavanna A, Quezada J, Eccles C, Termine C, Schmitt S, Cramer C, Klages CS, Alvarez-Fischer D, Klansoe SM, Gilbert DL. Call for action: misinformation about tourette syndrome from major media network. Eur Child Adolesc Psychiatry. 2026 Jan 20. doi: 10.1007/s00787-025-02939-8. Epub ahead of print. PMID: 41557034.

No abstract

Excerpt: 

“Stop that! It’s not Tourette’s but a new type of mass sociogenic illness” - this was the title of an article published in BRAIN in August 2021 which received much public interest with a total of 108,647 views as of June 14th 2025. What prompted this commentary? Beginning in 2019, the incidence of adolescents and adults presenting for medical attention with impairing, dramatic, functional tic-like behaviors (FTLB) dramatically increased. As this increase reached global proportions during the COVID-19 pandemic and lockdowns, experts in Tourette Syndrome (TS) and FTLB realized this “outbreak” was a distinct clinical entity that could be confused with chronic tic disorders such as TS. FTLB is not TS, although some individuals may have both conditions FTLB is best conceptualized as a subtype of functional neurological disorder (FND). Subsequent actions by international academic collaborations, individual physicians, and advocacy groups contributed to a better clinical understanding of this disorder and formulation of diagnostic criteria Important factors that helped to raise awareness about this rapidly expanding clinical presentation of FTLB were international collaborations and efforts which provided physicians with assistance in making accurate diagnoses and providing appropriate treatments.

TS is defined as a chronic, childhood-onset disorder with combined motor and vocal tics lasting for at least a year. On average, tics start at the age of five to seven years, most typically with mild simple motor tics such as eye blinking and grimacing, followed by simple vocal tics such as sniffling and coughing, typically about two years later. Tics typically wax and wane and reach their maximum at age 10 to 12 years.

FND usually presents to clinicians as “disease mimics”. For example, individuals may manifest symptoms that resemble seizures, dissociative episodes, paralysis or weakness, tremor, or tics. Prior to 2019, FND presenting as TS was considered a very rare phenotype of FND that primarily presented with movements and sounds that overlapped more closely with standard clinical presentations of TS. Since 2019, however, individuals with FND mimicking TS presented much more commonly with predominantly complex movements and vocalizations such as obscene and socially unaccepted words, phrases and gestures, throwing objects, self-injurious behaviors, and long verbal phrases . The term FTLB has come into wider use as a result of this phenomenon.

In 2023, an international group of Tourette experts, including many of the authors of this commentary, established diagnostic criteria for FTLB based on a Delphi consensus that outlined supportive factors for the diagnosis of FTLB and the differential diagnosis of TS . They proposed that a clinically definite diagnosis of FTLB can be confirmed by an age at first symptom onset of 12 years or older, rapid onset and evolution of symptoms, and at least four of nine further phenomenological features as outlined in Table 2. Although there are clear “positive signs” for the diagnosis of FTLB, a better description of this patient group is needed to exclude circular reasoning due to a lack of clinical benchmarks.

Linked to the rise in FTLBs were two popular influencers, a young German man, who created the YouTube channel “Gewitter im Kopf” (eng. “Thunderstorm in the brain”) and a young English woman, who used the name “This Trippy Hippie” on TikTok. During the COVID-19 pandemic, these videos attracted tens of millions of views. In studies from several different countries and across continents, it could be clearly demonstrated that these presentations on social media directly influenced not only onset, but also clinical presentation of FTLB. In particular, according to an international database including 294 patients from ten tertiary referral centers for tic disorders from eight countries (Canada, United Kingdom, Germany, Australia, United States, Italy, Hungary, and France), FTLB was mainly seen in young female patients with mean age of 15 years (median 14 years; range, 8– 53 years), a demographic profile quite different from TS. In fact, there is about a 4:1 predominance ratio of the male sex in TS, while FND, including FTLB, is mainly seen in females. Furthermore, an overlap could be demonstrated in the type of movements (mainly complex arm and hand movements, head banging and tapping) and vocalizations (often with a large number of swear words, whistles, insults, and comments) as well as socially inappropriate behaviors (including spilling drinks, hitting, and throwing food and objects) between social media influencers and patients. Even more, depending on the place of residence and language of the patient, differences between clinical pattern and sex distribution were found, suggesting that exposure to particular social media content influences clinical presentation.. In this context, it is also important to mention that, while such behaviors are completely atypical for TS, mass use of social media easily creates misconceptions about TS.

SUPT16H-associated neurodevelopmental disorder and neurocristopathy

Lee E, Sim S, Choi HJ, Liang EY, Le C, Bina R, Cohen R, George E, Kim SY, Bhat G, Falsey E, Sidlow R, Clinard K, Ben-Shachar S, England E, Menendez B, Herman I, Nielsen S, Punetha J, Bhola P, Hamm JA, Keeney MA, Sitzman N, Berger S, Mehta L, Conn AJ, Downie L, Ashfaq M, Northrup H, Bruel AL, Odent S, Szot JO, Martinez NN, Park S, Refkin J, Good JM, Maurer F, Le Caignec C, Coman DJ, Anderson E, Richards LJ, Dean RJ, Yang C, Choi C, Hwang BJ, Lee JS, Dobyns WB, Choi M, Sherr EH, Chae JH, Kee Y, Argilli E. SUPT16H-associated neurodevelopmental disorder and neurocristopathy: genetic and phenotypic spectrum. Hum Mol Genet. 2026 Jan 20:ddag003. doi: 10.1093/hmg/ddag003. Epub ahead of print. PMID: 41556401.

Abstract

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes such as developmental delay, craniofacial anomalies, and hypotonia. Structural and functional analyses of selected SUPT16H variants demonstrated differential rescue of developmental defects in supt16h-deficient embryos, indicating variant-specific LOF effects in vivo. The presence of non-neural manifestations, including facial and ear anomalies, suggested a role for SUPT16H in neural crest development. Consistently, supt16h loss impaired neural crest cell migration and differentiation and triggered p53-dependent apoptosis in the central nervous system (CNS) and neural crest-derived pharyngeal arches. Notably, supt16h deficiency impaired oligodendrocyte specification in the CNS and perturbed differentiation of neural crest-derived Schwann cells in the peripheral nervous system, providing a plausible basis for hypotonia. These findings uncover a previously unrecognized role of SUPT16H in neural crest development, linking chromatin regulation to neural crest-derived lineage specification and differentiation, thereby defining SUPT16H deficiency as a neurocristopathy that broadens the clinical and mechanistic landscape of SUPT16H-associated disorders.

Oliveira DV, Kato A, Nakamura K, Ikura T, Okada M, Kobayashi J, Yanagihara H, Saito Y, Tauchi H, Komatsu K. Histone chaperone FACT regulates homologous recombination by chromatin remodeling through interaction with RNF20. J Cell Sci. 2014 Feb 15;127(Pt 4):763-72. doi: 10.1242/jcs.135855. Epub 2013 Dec 19. PMID: 24357716.

Abstract

The E3 ubiquitin ligase RNF20 regulates chromatin structure through ubiquitylation of histone H2B, so that early homologous recombination repair (HRR) proteins can access the DNA in eukaryotes during repair. However, it remains unresolved how RNF20 itself approaches the DNA in the presence of chromatin structure. Here, we identified the histone chaperone FACT as a key protein in the early steps of HRR. Depletion of SUPT16H, a component of FACT, caused pronounced defects in accumulations of repair proteins and, consequently, decreased HRR activity. This led to enhanced sensitivity to ionizing radiation (IR) and mitomycin-C in a fashion similar to RNF20-deficient cells, indicating that SUPT16H is essential for RNF20-mediated pathway. Indeed, SUPT16H directly bound to RNF20 in vivo, and mutation at the RING-finger domain in RNF20 abolished its interaction and accumulation, as well as that of RAD51 and BRCA1, at sites of DNA double-strand breaks (DSBs), whereas the localization of SUPT16H remained intact. Interestingly, PAF1, which has been implicated in transcription as a mediator of FACT and RNF20 association, was dispensable for DNA-damage-induced interaction of RNF20 with SUPT16H. Furthermore, depletion of SUPT16H caused pronounced defects in RNF20-mediated H2B ubiquitylation and thereby, impaired accumulation of the chromatin remodeling factor SNF2h. Consistent with this observation, the defective phenotypes of SUPT16H were effectively counteracted by enforced nucleosome relaxation. Taken together, our results indicate a primary role of FACT in RNF20 recruitment and the resulting chromatin remodeling for initiation of HRR.

Unraveling SUDEP: Mechanisms of seizure-induced cardiac and respiratory impairment

Wenker IC, Gehlbach BK, Isom LL, et al. Unraveling SUDEP: Mechanisms of Seizure-Induced Cardiac and Respiratory Impairment. Epilepsy Currents. 2026;0(0). doi:10.1177/15357597261416723

Abstract

People with epilepsy have a markedly increased risk of premature mortality, with sudden unexpected death in epilepsy (SUDEP) accounting for approximately half of epilepsy-related deaths. Although rarely witnessed, converging evidence indicates that SUDEP arises from seizure-triggered cardiorespiratory failure mediated by central and peripheral mechanisms. In this article, we explore mechanisms of SUDEP related to respiratory, cardiac, and autonomic control of vital functions. Specifically, we examine how seizure propagation to a discrete amygdala subregion can induce profound ictal and postictal apnea; how complementary genetic and animal studies reveal that ion channelopathies affecting genes expressed in both brain and heart produce intrinsic neuronal and cardiac electrical dysfunction; and how emerging evidence implicates stress physiology and hypothalamic–pituitary–adrenal axis dysfunction as underrecognized contributors to SUDEP risk. Together, these findings support a multifactorial model in which respiratory suppression, cardiac vulnerability, autonomic dysregulation, and stress-responsive mechanisms converge to produce fatal outcomes.

Where on the receptor the antibodies actually bind in anti-NMDAR encephalitis

Junhoe Kim et al. Cryo-EM of autoantibody-bound NMDA receptors reveals antigenic hotspots in an active immunization model of anti-NMDAR encephalitis.Sci. Adv.12,eaeb4249(2026).DOI:10.1126/sciadv.aeb4249

Abstract

Autoantibodies targeting synaptic membrane proteins are associated with autoimmune encephalitis manifested by seizures, psychosis, and memory dysfunction. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, a prototype of these autoimmune synaptic disorders, is unexpectedly common. Unfortunately, how the native repertoire of anti-NMDAR autoantibodies recognizes NMDARs and the precise locations of antigenic epitopes remain poorly understood. Here, we used an active immunization model that closely mimics the human disease to immunize adult mice with intact GluN1/GluN2A receptors, resulting in fulminant autoimmune encephalitis. Serum was collected at 6 weeks postimmunization for single-particle cryo–electron microscopy of GluN1/GluN2A receptors complexed with purified polyclonal anti-NMDAR autoantibody fragments. Native autoantibodies recognized two distinct binding sites on the GluN1 amino-terminal domain, which we confirmed using monoclonal antibodies bound to native NMDARs purified from mouse brain. Structural analysis of autoantibody-bound NMDAR complexes identified antigenic hotspots within the GluN1 amino-terminal domain. These hotspots provide potential targets for therapeutic intervention.
_________________________________________________________________________

Some serious brain disorders begin with symptoms that are easy to misinterpret.

A person may become confused, forgetful or paranoid and be treated for mental illness before doctors realize the underlying problem isn’t psychological at all. Instead, the body’s immune system — meant to fight infection — is attacking the brain.

Researchers at Oregon Health & Science University say they have identified, in new detail, how that attack happens. Their findings, published last week in Science Advances, could lead to more precise treatments and earlier diagnosis of an autoimmune condition known as anti-NMDA receptor encephalitis.

The disease affects roughly one in a million people each year and often strikes young adults. It occurs when the immune system produces antibodies — proteins designed to fight disease — that mistakenly latch onto something called an NMDA receptor, which helps brain cells communicate and plays a key role in memory, learning and normal thinking.

Scientists have long known antibodies were involved but did not fully understand where they attached or why current treatments don’t always work.

“What we wanted to understand was where on the receptor the antibodies actually bind,” said co-author Dr. Gary Westbrook, a neurologist and senior scientist at OHSU’s Vollum institute. “That’s important because it provides a clue to how one could design more specific treatments to deal with the disorder.”

To find out, the OHSU team used a mouse model of the disease to examine the entire ensemble of antibodies involved, rather than studying one antibody one at a time.

The researchers also relied on an advanced imaging method called cryo-electron microscopy, which allows scientists to see biological structures at near-atomic detail. OHSU houses one of only three national cryo-electron microscopy centers at its South Waterfront campus.
What they found surprised them.

“We found that the antibodies don’t bind everywhere,” said Eric Gouaux, a senior scientist at OHSU and an investigator with the Howard Hughes Medical Institute. “They don’t coat the receptor like a layer of paint. Instead, they bind to just a few very specific areas.”
The antibodies don’t immediately shut down the receptor. Instead, they act more like glue, causing receptors to clump together and get pulled inside brain cells, where they can’t do their job. That’s when symptoms begin to escalate.

“It can begin in a rather occult way,” Westbrook said. “Someone may be behaving a little funny, and people don’t quite know what’s happening. It may be days or weeks before the full picture becomes clear.”

But Westbrook said diagnosing the disorder early is notoriously difficult because its symptoms can mimic psychiatric illness, viral infections or other neurological disorders. He said many patients are first referred to a psychiatrist before the immune cause is identified — a pattern described in the book and film Brain on Fire, which brought public attention to the disease.

“That delay can be dangerous,” Westbrook said. “By the time the disease is diagnosed, patients may already be very sick.”

If diagnosis is delayed, symptoms can worsen, leading to seizures or extreme states such as catatonia, in which patients may be unable to move or speak, according to researchers.

Westbrook said the mouse model used in the study helps overcome that limitation, by allowing researchers to study the disease from its earliest moments — something that isn’t possible in people.

Gouaux said the findings are especially important for drug development. He said current treatments rely on broadly suppressing the immune system. While many patients improve, recovery can be slow and relapses are common, he said.

“Now that we know exactly how and where the antibodies bind, the most straightforward approach would be to simply block that interaction,” he said.

The research could also improve diagnosis by making antibody tests more specific. Gouaux said current blood tests can detect NMDA receptor antibodies but can’t show where they bind or reliably predict who will develop the disease — something the new findings could help address.

Kristine de Leon

 
https://www.oregonlive.com/health/2026/01/ohsu-researchers-identify-key-trigger-behind-brain-disorder-often-mistaken-for-mental-illness.html