Sulforaphane and autism

McGuinness G, Kim Y. Sulforaphane treatment for autism spectrum disorder: A systematic review. EXCLI J. 2020 Jun 26;19:892-903. doi: 10.17179/excli2020-2487. PMID: 33013262; PMCID: PMC7527484.

Abstract

Autism Spectrum Disorder (ASD) is defined as a neurodevelopmental condition characterized by social communication impairment, delayed development, social function deficit, and repetitive behaviors. The Center for Disease Control reports an increase in ASD diagnosis rates every year. This systematic review evaluated the use of sulforaphane (SFN) therapy as a potential treatment option for individuals with ASD. PubMed.gov, PubMed Central, Natural Medicines, BoardVitals, Google Scholar and Medline were searched for studies measuring the effects of SFN on behavior and cognitive function. All five clinical trials included in this systematic review showed a significant positive correlation between SFN use and ASD behavior and cognitive function. The current evidence shows with minimal side effects observed, SFN appears to be a safe and effective treatment option for treating ASD.

Zhang X, He Q, Zhu YY, Lorimer GH, Bayram H, Ghiladi RA, Wang J. Emerging Promise of Sulforaphane in Autism: A Comprehensive Review of Its Therapeutic Potential and Mechanisms. ACS Chem Neurosci. 2026 Aug 5;17(15):2880-2892. doi: 10.1021/acschemneuro.6c00282. PMID: 42473985.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that emerges in early childhood and significantly impacts the quality of life for individuals and families. Currently, there are no specific medications available for ASD. Increasing attention is now focused on bioactive compounds with anti-inflammatory and antioxidant properties. Sulforaphane (SFN), a key member of the isothiocyanate family, is abundant in cruciferous vegetables. It exhibits potent antioxidant and anti-inflammatory effects with minimal side effects, while oxidative stress and inflammation are recognized triggers in ASD pathogenesis. As research deepens, SFN's physiological activities─including antioxidant, neuroprotective, and anti-inflammatory properties are gaining heightened attention. Building on prior studies, this review comprehensively summarizes seven potential pathways through which SFN protects neurodevelopment or reverses ASD-related neural damage, including Keap1/Nrf2/ARE; MAPKs; NF-κB; HSR; AhR/CYP1; Sirtuin-FOXO; and mTOR/autophagy signaling pathways, elucidating the potential mechanisms underlying its multifaceted actions. This review offers new insights for the comprehensive utilization of sulforaphane and the treatment of ASD.

Long J, Liao X, Tang Z, Han K, Chen J, Wang X, Liu J, Zhang Y, Zhang H. Investigating the clinical efficacy, safety and molecular mechanism of sulforaphane in autism spectrum disorder: an integrated study combining meta-analysis, network pharmacology, and computational biology. BMC Pharmacol Toxicol. 2025 Nov 22;26(1):217. doi: 10.1186/s40360-025-01052-5. PMID: 41275316; PMCID: PMC12751817.

Abstract

Background: Sulforaphane, a natural antioxidant rich in cruciferous vegetables, has emerged as a promising dietary supplement for autism spectrum disorder (ASD). However, its therapeutic efficacy remains controversial, and the pharmacological mechanisms are not fully elucidated.

Methods: Eligible randomized controlled trials were retrieved from PubMed, Web of Science, Embase, and Cochrane Library databases. Review Manager 5.4 was used for meta-analysis and bias risk assessment. Network pharmacology, Mendelian randomization, GEO data analyses, molecular docking, and molecular dynamics simulation were employed to explore the mechanisms of sulforaphane in ASD.

Results: Six trials involving 333 participants were included in the meta-analysis. Pooled results demonstrated that both 4-5 weeks and 8-10 weeks of sulforaphane supplementation significantly decreased the scores on the Social Responsiveness Scale compared to placebo controls. No significant difference was observed in the incidence of adverse events. Network pharmacology identified 10 core targets of sulforaphane in ASD, including AKT1, EGFR, HSP90AA1, SRC, CASP3, STAT1, MAPK1, MMP9, MAPK8, and JAK2. These targets were implicated in the PI3K-Akt signaling pathway, MAPK signaling pathway, Chemokine signaling pathway, Chemical carcinogenesis - reactive oxygen species, TNF signaling pathway, Th17 cell differentiation, mTOR signaling pathway, and IL-17 signaling pathway. Mendelian randomization further revealed an inverse association between STAT1 levels and ASD risk. GEO transcriptomic data provided independent validation for the network pharmacology predictions. The binding energies between sulforaphane and the top 10 core targets are all ≤ -4.0 kcal/mol. Molecular dynamics simulations further validated the stable interaction between MMP-9 and sulforaphane.

Conclusion: Sulforaphane may serve as an efficacious and safe adjunctive therapy for ASD, mediated by its anti-oxidant and anti-inflammatory effects along with the modulation of autophagy.

Guo J, Wang Y, He W, Lou M, Peng Y, Shi H, Lian A. Effects of sulforaphane on ABC and SRS scales in patients with autism spectrum disorder: a meta-analysis. Brain Dev. 2025 Apr;47(2):104321. doi: 10.1016/j.braindev.2025.104321. Epub 2025 Feb 14. PMID: 39951914.

Abstract

Autism spectrum disorder (ASD) has become an increasingly prominent global health issue. Sulforaphane is a phytochemical with multiple functions that target many of the same biochemical and molecular pathways (biomarkers) associated with ASD. This study aimed to conduct a meta-analysis based on sulforaphane's effect on Aberrant Behavior Checklist (ABC) and Social Responsiveness Scale (SRS) in patients with ASD. We conducted comprehensive searches in the PubMed, Medline, Cochrane, EMBASE, and Web of Science databases from their inception. The modified Cochrane risk of bias tool was used to check the risk of bias of the included studies. Review Manager 5.3 software was used to conduct this meta-analysis. The results of this meta-analysis showed that sulforaphane significantly improved irritability and hyperactivity symptoms, suggesting that sulforaphane has the potential for the combined treatment of autism. Additional studies are needed to confirm and explore the effect of sulforaphane.

Ou J, Smith RC, Tobe RH, Lin J, Arriaza J, Fahey JW, Liu R, Zeng Y, Liu Y, Huang L, Shen Y, Li Y, Cheng D, Cornblatt B, Davis JM, Zhao J, Wu R, Jin H. Efficacy of Sulforaphane in Treatment of Children with Autism Spectrum Disorder: A Randomized Double-Blind Placebo-Controlled Multi-center Trial. J Autism Dev Disord. 2024 Feb;54(2):628-641. doi: 10.1007/s10803-022-05784-9. Epub 2022 Nov 24. PMID: 36427174.

Abstract

Sulforaphane has been reported to possibly improve core symptoms associated with autism spectrum disorders from mostly small size studies. Here we present results of a larger randomized clinical trial (N = 108) in China. There were no significant changes in caregiver rated scales between sulforaphane and placebo groups. However, clinician rated scales showed a significant improvement in the sulforaphane group, and one third of participants showed at least a 30% decrease in score by 12 weeks treatment. The effects of sulforaphane were seen across the full range of intelligence and greater in participants over 10 years. Sulforaphane was safe and well-tolerated even for young children. The inconsistent results between caregiver and clinician rated scales suggest more clinical trials are needed to confirm our findings.

Ecopipam for Tourette syndrome 3

Gilbert DL, Atkinson SD, Kim DJB, Miller MM, Rice PM, Flatt JA, Karkanias GB, Munschauer FE, Bittman RM, Wanaski SP, Cunniff TM, Tomczak KK. Efficacy and Safety of Ecopipam for Tourette Syndrome: A Phase 3 Randomized Clinical Trial. JAMA Neurol. 2026 Jul 1;83(7):645-653. doi: 10.1001/jamaneurol.2026.1431. PMID: 42189524; PMCID: PMC13213590.

Abstract

Importance: Current Tourette syndrome (TS) pharmacotherapy is hindered by adverse effects and high discontinuation rates.

Objective: To evaluate the safety and maintenance of effect of ecopipam, a selective dopamine D1 receptor antagonist, for up to 24 weeks for TS.

Design, setting, and participants: This randomized clinical trial was a phase 3, double-blind, placebo-controlled, randomized withdrawal study conducted between January 31, 2023, and February 4, 2025. Participants were enrolled at 77 sites in 12 countries. Individuals 6 years and older with TS were eligible.

Intervention: In the 12-week, open-label period, ecopipam was titrated over 3 to 4 weeks (target dose, 1.8 mg/kg per day). Responders (≥25% improvement in Yale Global Tic Severity Scale Total Tic Score [YGTSS-TTS] at weeks 8 and 12) were randomized to continue ecopipam or taper to placebo for the 12-week double-blind period.

Main outcomes and measures: Time to relapse (≥50% loss of open-label period YGTSS-TTS improvement) in participants aged 6 to 18 years (primary) and adults (exploratory).

Results: The trial enrolled 216 participants (n = 167 [77.3%] pediatric; 146 [67.6%] male and 70 [32.4%] female) to the open-label ecopipam period. Of these, 43 pediatric participants (mean [SD] age, 14.3 [5.5] years) and 8 adult participants were randomized to receive ecopipam; 47 pediatric (mean [SD] age, 14.0 [5.8] years) and 6 adult participants were randomized to receive placebo. Ecopipam significantly reduced the relapse risk vs placebo in pediatric participants (hazard ratio [HR], 0.47; 95% CI, 0.26-0.84; P = .008; n = 90). In adults, the effect was directionally similar (HR, 0.51; 95% CI, 0.11-2.30; P = .37; n = 14) but not significant. The most frequently reported adverse events with ecopipam (open-label and double-blind periods) were somnolence (n = 24 [11.1%]), anxiety (n = 21 [9.7%]), headache (n = 21 [9.7%]), insomnia (n = 19 [8.8%]), tic (n = 17 [7.9%]), and fatigue (n = 14 [6.5%]). Ecopipam did not have a clinically meaningful impact on weight, metabolic parameters, or psychiatric scale measures. Drug-induced movement disorders were not observed.

Conclusions and relevance: Ecopipam maintained clinically meaningful TS symptom improvements and was well tolerated for up to 24 weeks. Adverse events primarily affected the central nervous system

Panda PK, Panda P, Dawman L, Mishra AS, Kumar V, Sharawat IK. Safety and Efficacy of Ecopipam in Patients with Tourette Syndrome: A Systematic Review and Meta-analysis. CNS Drugs. 2025 Feb;39(2):127-142. doi: 10.1007/s40263-024-01140-w. Epub 2024 Dec 27. PMID: 39730854.

Abstract

Background and objectives: Ecopipam is a selective antagonist of the dopamine D1 receptor, and its efficacy and safety have recently been explored in several clinical trials involving patients with Tourette syndrome (TS). The objectives of this systematic review were to determine the pooled estimate for efficacy [in terms of reduction in tic Yale Global Tic Severity Scale (YGTSS) scores] and safety of oral ecopipam in subjects with TS.

Methods: All clinical trials that explored the efficacy and/or safety of ecopipam in patients with TS were included to determine the pooled estimate for change in YGTSS, Clinical Global Impression (CGI)-TS, and the severity of comorbid attention-deficit hyperactive disorder (ADHD), obsessive compulsion disorder (OCD), and depressive symptoms, as well as the nature and frequency of adverse effects. Case-series, retrospective studies, and case reports were excluded. Databases, such as PUBMED, EMBASE, Cochrane Central Register of Controlled Trials, and SCOPUS were searched to identify these trials using suitable combination of MESH terms/keywords on 15 June 2024. ROB 2.0 and ROBINS-I tool were used to assess the risk of bias in included randomized-controlled trials (RCTs) and non-randomized intervention studies, respectively, and the GRADE system to determine the certainty of the collated evidence.

Results: A total of 96 records were identified in the database search and 31 records were screened after removing duplicates. After excluding 23 irrelevant records, the full-text review included 8 records. Finally, six publications from three completed clinical trials (two RCTs, with one having an open-label extension) and one ongoing clinical trial were included. A total of 251 participants were included. The pooled estimate for mean change in YGTSS-TTS from baseline to the completion of the randomization period was statistically better in the ecopipam group compared with the placebo group [mean difference: - 3.0, 95% (confidence interval (CI) - 4.2 to - 1.9, I2 = 55%, p < 0.0001]. The ecopipam group also fared statistically better in terms of YGTSS-motor tic score, phonic tic score, as well as CGI-TS-S (p < 0.0001). Changes in depressive and obsessive-compulsive symptoms were comparable in both groups, as well as the incidence of adverse effects.

Conclusions: Ecopipam is effective in reducing the severity of tics in subjects with TS and has a good safety profile. However, only a limited number of studies were included in the review, with some having small sample sizes and short duration of follow-up.

Gilbert DL, Budman CL, Singer HS, Kurlan R, Chipkin RE. A D1 receptor antagonist, ecopipam, for treatment of tics in Tourette syndrome. Clin Neuropharmacol. 2014 Jan-Feb;37(1):26-30. doi: 10.1097/WNF.0000000000000017. PMID: 24434529.

Abstract

Objectives: Dysregulation of dopaminergic signaling has been hypothesized to underlie the motor and phonic tics in Tourette syndrome (TS). The objective of this trial was to evaluate the safety and tic-reducing activity of the selective dopamine D1 receptor antagonist ecopipam in adults with TS.

Methods: This was a multicenter, nonrandomized, open-label study of 50-mg ecopipam daily (weeks 1-2) and then 100 mg daily (weeks 3-8), taken orally before bedtime. The primary efficacy end point was the change in the Yale Global Tic Severity Scale (YGTSS) total tic score. Comorbid psychiatric symptoms and premonitory urges were rated; weight, serum metabolic studies, and adverse effects were monitored.

Results: Eighteen adults (15 men; 15 white, 2 African American, 1 Asian), with a mean age of 36.2 years (range, 18-63 years), were enrolled, and 15 completed the study. Mean (SD) YGTSS Total Tic score was 30.6 (8.8) at baseline and 25.3 (9.2) at 8 weeks (2-tailed paired t17 = 4.4; P = 0.0004). Mean (SD) YGTSS impairment score was 29.7 (10.9) at baseline and 22.8 (13.7) at final visit (t17 = 2.2; P = 0.04). There was no significant change in premonitory urges or psychiatric symptoms. Mean change in weight was -0.7 kg (P = 0.07). The most commonly reported adverse events were sedation (39%), fatigue (33%), insomnia (33%), somnolence (28%), anxiety (22%), headache (22%), and muscle twitching (22%).

Conclusions: In this open-label study in adults with TS, tics were reduced after 8 weeks of treatment with ecopipam. To confirm safety and efficacy, randomized, double blind, placebo-controlled trials are warranted.

Great experiments 4

Courtesy of a colleague

Garrow JS, Gardiner GT. Maintenance of weight loss in obese patients after jaw wiring. Br Med J (Clin Res Ed). 1981 Mar 14;282(6267):858-60. doi: 10.1136/bmj.282.6267.858. PMID: 6783203; PMCID: PMC1504679.

In treatment of obesity restriction of food intake is necessary to achieve good results. Various operations have been devised to prevent patients overeating, but in this study jaw wiring was used to limit food intake. This procedure produces weight loss in obese patients but when the wires are removed the weight is usually regained. This report studied a group of patients whose weight loss was maintained after the wires were removed. A nylon cord fastened round the waist of the patient after weight reduction was found to act as a psychological barrier to weight gain. Seven patients were followed for 4-14 months after removal of jaw wires and regained a mean of only 5.6 kg of the 31.8 kg lost while their jaws were wired. This procedure compares favourably with other treatments for severe obesity.

Oligodendroglioma

Busy Philipps is “grateful to be alive” after a shocking health scare.

The 47-year-old actress revealed this week that doctors discovered a rare, slow-growing malignant tumor in her brain earlier this year, despite her having no obvious symptoms.

Philipps opened up about the ordeal in a People cover story published Wednesday, saying she underwent two surgeries as a result of her grade 2 oligodendroglioma.

The “Dawson’s Creek” alum called the past six months the “weirdest” of her life, dubbing herself “the luckiest girl in the world” after following through with a full-body MRI scan her primary physician had initially talked her out of.

She ultimately decided to schedule the scan after speaking with her cousin-in-law, Dr. Justin Donlan, an internist who told her that “knowledge is power.”

Doctors spotted the tumor during a Prenuvo scan on Feb. 12, just one day after her former co-star James Van Der Beek died of colorectal cancer at age 48. The star had actually been considering canceling her appointment when her husband suggested the health check might be “the best thing” she could do for her late friend.

So, what exactly is an oligodendroglioma — and what subtle symptoms can signal the disease? Here’s what to know.

What are oligodendrogliomas?

An oligodendroglioma is a rare type of brain tumor that can also develop in the spinal cord. It starts in oligodendrocytes, cells that help support and protect the nerve cells responsible for sending messages throughout the brain and nervous system, according to the Cleveland Clinic.

Philipps was diagnosed with a grade 2 oligodendroglioma, which is considered a “low-grade” tumor by the World Health Organization. That means it typically grows slowly and is generally easier to treat than more aggressive brain tumors.

“It is considered malignant, but it has the best prognosis of all of the malignant gliomas,” Dr. Alexandra Miller, Philipps’ neuro-oncologist at NYU Langone, told People.

“It’s sort of defined as a cancerous tumor based on the ability of the tumor to regrow over time, rather than it looking very malignant under the microscope.”

Higher-grade oligodendrogliomas are more aggressive. As they become more advanced, the tumors can grow faster, damage surrounding brain tissue and become more difficult to treat.

How common is oligodendrogliomas?

Oligodendrogliomas are relatively rare, accounting for an estimated 1.3% of all brain tumors in the US. About 1,100 Americans are diagnosed with the tumor each year, according to the American Brain Tumor Association.

They are most often diagnosed in adults between the ages of 20 and 40. The tumors are considered extremely rare in children under 15.

What are the symptoms of oligodendrogliomas?

Oligodendrogliomas can cause different symptoms depending on where the tumor is located and how big it grows. The most common warning sign is a seizure, which affects nearly 80% of patients, according to Columbia University.

When a tumor develops in the frontal lobe, it can trigger personality or behavior changes, as well as weakness or partial paralysis on one side of the body, known as hemiparesis.

Other symptoms can include headaches, partial vision loss and trouble with speech or language. Tumors in the temporal lobe, however, can be especially sneaky, sometimes causing few noticeable symptoms and going undetected for years.

Philipps said doctors caught her tumor before she developed any obvious symptoms. Still, in the years before her diagnosis, she had told her former “Dawson’s Creek” co-star and close friend Michelle Williams that she felt like her brain was “broken.”

“I’ve been saying this for the last few years,” Philipps told People. “I wasn’t consciously aware that anything was really wrong, but there was something that was misfiring. Like, I could not get a handle on it.”

How are oligodendrogliomas treated?

Oligodendrogliomas are considered one of the more treatable types of brain cancer.

Surgery is usually the first line of attack, with doctors aiming to remove as much of the tumor as possible without damaging healthy brain tissue. Depending on the results, patients may also need radiation or chemotherapy.

For Philipps, that meant a roughly five-hour surgery on March 2 to remove the 2.6-centimeter mass from her brain. Doctors identified it as an oligodendroglioma after biopsying the tumor.

Her doctors told her that waiting until she developed seizures could have allowed the tumor to grow to two or three times its size — potentially making it more difficult to remove completely.

Philipps initially made it through the operation without incident, but later developed a staphylococcus infection in her incision. She needed a second surgery to clean out the infected area and remove one of the tiny titanium tacks doctors had used to hold her skull bone in place.

Are oligodendrogliomas deadly?

Many patients have a good chance of living for years after diagnosis.

The outlook is typically better when the tumor is caught early. Between 69% and 90% of people with low-grade oligodendrogliomas are still alive five years after diagnosis, according to the Cleveland Clinic, with survival rates potentially even higher among younger adults.

For people with high-grade oligodendrogliomas, the five-year survival rate ranges from 45% to 76%.

Philipps told People she feels grateful for going through with the Prenuvo scan that caught her tumor, saying she hopes she can inspire other people to listen to their gut.

“We are frequently told by doctors that there is nothing to worry about [when] you kind of know that there’s something to worry about,” she said. “There’s nothing to be afraid of in having information. It’s only empowering.” 

McKenzie Beard

https://nypost.com/health/what-is-oligodendroglioma/

Epiwatch for tonic-clonic seizure detection in children and adults

Krauss GL, Elizebath R, Shah S, et al. Phase III trial of epiwatch for tonic-clonic seizure detection in children and adults https://www.neurology.org/doi/10.1212/WN9.0000000000000111. Neurol Open Access. 2026; Epub 2026 May 27.

Abstract

Background and Objectives

Risks of sudden unexpected death in epilepsy are high in individuals with uncontrolled tonic-clonic seizures (TCSs), particularly in those who sleep alone. Wearable seizure detection devices can alert caregivers to provide timely intervention; however, current devices risk stigma and have high false alarm rates (FARs) that discourage consistent use and caregiver responses. EpiWatch is a seizure detection application (app) developed for the Apple Watch, designed to minimize FAR without compromising detection sensitivity or latency. We evaluated the sensitivity and FAR of EpiWatch for detecting TCSs in children and adults undergoing video-EEG monitoring.

Methods

We conducted a prospective, multicenter Phase III diagnostic accuracy study at 6 epilepsy monitoring units (EMUs) from September 2021 to October 2023. Children and adults aged 5 years and older with a history of TCSs or clinical potential for TCSs and who underwent video-EEG monitoring were eligible. Participants wore the EpiWatch device on the wrist contralateral to their seizure focus. EpiWatch detections were compared with TCS events classified by an independent Central Reader Panel of epileptologists blinded to device output. Co-primary end points were sensitivity and FAR per 24 hours. Secondary end points included detection latency and performance during sleep. Enrollment was slowed during COVID-19 restrictions, which extended the recruitment period.

Results

A total of 242 participants were enrolled (mean age 22.7 years; 54.1% female; 60.7% aged 5–21). EpiWatch detected 46 of 47 panel-verified TCSs; 1 seizure was missed when a caregiver restrained the participant's arm. The overall sensitivity was 98% (95% CI 95%–100%). There were 56 false alarms during 16,189 hours of monitoring, with a FAR of 0.08 per 24 hours (95% CI 0.02–0.12), equivalent to 1 false alarm every 12.4 days. All age groups had similarly low FARs. The median detection latency was 31.5 seconds. During sleep, all TCSs were detected, and all false alarms from sleep were associated with seizure activity. No adverse events occurred.

Discussion

EpiWatch detected TCSs with high sensitivity and a FAR approximately one-tenth that of other published devices. These findings were obtained in a controlled EMU environment; real-world performance may differ.

Classification of Evidence
This study provides Class I evidence that, in patients with a history of TCSs, the EpiWatch accurately detects TCSs, with a low FAR. EPW001.

Cerebellitis

When your child gets a cold, you expect they’ll probably have a runny nose, cough and maybe sneeze sometimes. You don’t expect to find them in bed one morning limp and unresponsive. Unfortunately, that’s how Britta and Ross found their then 2-year-old daughter Sydney in November 2024.

Symptoms and diagnosis of rare brain condition

Sydney had been showing signs of a slight cold for about a week. But when Britta went to check on her that morning in November, she knew something was wrong the moment she turned on the lights.

“She didn’t sit up. She was very lethargic. It was clear she was very sick,” she described.

The family rushed her to urgent care. The staff quickly called an ambulance to take Sydney to the Children’s Minnesota hospital in Minneapolis. When they arrived, the care team ran a series of tests, including a CT scan, an MRI, a spinal tap and an

Results showed she had a very rare case of cerebellitis, which is an inflammatory condition that affects the cerebellum, a part of the brain responsible for coordination and balance. That’s why she wasn’t moving or responding. The care team suspected it was caused by a combination of common cold viruses in her body at the same time and her brain just reacted.

Britta and Ross remembered the care team telling them the odds of this happening to their daughter were, “probably one in a million.”

As a result of the cerebellitis, Sydney’s cerebellum swelled, blocking the flow of fluid in her brain. As the fluid built up, it put pressure on her brain, a condition known as hydrocephalus.

Emergency brain surgery

Sydney’s condition was serious. She was moved to the pediatric intensive care unit (PICU) so she could be closely monitored. The hope was the brain swelling would eventually peak and begin to go down over five days. But on the fifth day, in the middle of the night, her breathing stopped. The care team rushed in, put in a breathing tube and told the family she needed emergency brain surgery.

During the emergency surgery, Kyle Halvorson, MD, pediatric neurosurgeon at Children’s Minnesota, put a device in Sydney’s skull to help drain the fluid that was building up. He also did a procedure to relieve pressure on the cerebellum and spinal cord.

“The first thing Dr. Halvorson told us after surgery was, ‘Everything went as planned.’ I began crying and hugging him. So many people saved her life,” said Britta.

And after being up all night, Britta and Ross fell asleep for a couple hours. They were woken up by the care team. Sydney needed another brain surgery.

“I just felt like my heart had been shattered and put back together so many times during all this,” Britta described. “You just keep digging for strength.”

Second brain surgery then slow recovery

The neurosurgery team explained that Sydney needed more invasive brain surgery because there was still a lot of fluid and swelling in her brain. The second brain surgery was with Meysam Kebriaei, MD, medical director of neurosurgery at Children’s Minnesota. During the second brain surgery, the drain in Sydney’s skull was adjusted to better release the extra fluid. The protective covering of her brain was also opened, and a small part of her cerebellum was removed.

After the second brain surgery, everything suggested Sydney had a great chance to get back to being the bubbly little girl her family loved. However, her road to get there was going to be slow.

Sydney spent the next four weeks in the PICU. Day by day she slowly got better. Her eye movements became more natural. After a week she gave a big smile. Eventually she was responding to requests to move her fingers and toes.

“This condition is incredibly rare, and not all patients survive,” said Dr. Kebriaei. “Our neurosurgery team, along with the teams from PICU, neurology, infectious disease, rehabilitation and so many others, joined together to do everything we knew how to care for Sydney and get her on the path to recovery. She is a very resilient girl.”

Rehabilitation for the effects of cerebellitis

While Sydney was getting better, the cerebellitis left her with significant challenges. She lost so much muscle tone she couldn’t hold her head up. She didn’t know how to swallow, had speech issues and needed help doing almost anything. The team at Children’s Minnesota recommended she go to the inpatient rehabilitation program at Gillette Children’s.

In mid-December, Sydney moved to Gillette Children’s where she received about two months of rehabilitation including daily physical therapy (PT), occupational therapy (OT), and speech therapy. She continues her PT and OT as an outpatient at the Children’s Minnesota rehabilitation clinic in Minnetonka. Her progress has been impressive. She’s once again walking, talking, running and trying to keep up with her two big sisters.

A family's gratitude

As Sydney continues to recover, the family is thankful for the team of experts who cared for her every step of the way.

“Truly how incredibly talented and collaborative the team was at Children’s [Minnesota] and how they worked together to come up with her next steps. It consistently exceeded our expectations,” said Britta. “That was the one thing that struck us the most was all of the different areas of deep expertise and how they really came together.”

Sydney with her parents and sisters

Nick Petersen

https://www.childrensmn.org/blog/sydneys-incredible-recovery-from-rare-brain-condition-likely-caused-by-common-cold-viruses/

Baby Gabriel

The surrogate who refused to have an abortion despite the wishes of the baby’s biological parents vowed Thursday to take the legal fight all the way to the Supreme Court — with her lawyer declaring, “She is the mother.”

Lincoln Wilson, an attorney for surrogate McKenna West, told The Post she’s planning a full-throttle court battle to become the legal parent of baby “Gabriel,” who was born in the Dallas area Wednesday.

“She is seeking parentage of the child because she gave birth in Texas, and in Texas, if you give birth to a child, it’s your child,” Wilson said.

Wilson said the reason the baby’s LA-based biological parents, Nausheen Gilkar and Omar Ahmed, currently have custody is because of a California order he considers “void.”

“We think that once that California judgment is removed … that basically she is the mother under Texas law,” Wilson said.

“We are taking that challenge up through the California courts, and we’ll take it up to the US Supreme Court if we have to.”

The biological parents had asked that their unborn child be aborted after he was diagnosed with a severe but treatable heart condition earlier this year.

The surrogacy contract between West, a nurse from Alaska, and the biological parents contained a clause that allowed terminations if there was an “anomaly” during the pregnancy.

But after the couple asked West to abort the fetus, she refused and instead traveled to Texas, where she would be recognized as the birth mother under state law.

Wilson said Thursday surrogacy contracts like the one in West’s case are common — but likened them to a “hitman contract.”

“These forced abortion clauses that demand that women have to be required to abort a child at the late term are quite common in surrogacy contracts,” he said.

“There’s some contracts the law doesn’t enforce. Like the law doesn’t enforce a hitman contract,” he said.

“This is basically a hitman contract, and we think that even if you accept a liberal view of abortion rights, the right to get an abortion also entails the right to not get an abortion.”

West currently has no legal authority over the baby to whom she gave birth, under a temporary restraining order filed by the couple.

The restraining order reportedly strips her of any decision-making about the infant’s care, including on medical decisions, and bars her from representing herself as a parent.

Wilson said the baby will soon undergo a series of heart surgeries at a hospital with an excellent track record.

“Within a few days, the first of three surgeries will be performed. It’s called the Norwood procedure,” Wilson said.

“But thankfully, we are at a hospital that has a 100% success rate in giving that procedure, so we know that she and well, at this point, baby Gabriel are in good hands.”

The fierce legal battle first began in April after the unborn child was diagnosed with the severe heart condition, hypoplastic left heart syndrome, at 20 weeks.

West, who named the baby Gabriel, was not allowed to see or hold the baby due to the court order.

Ahmed and Gilkar have reportedly picked a different name for the boy.

Kyra Breslin and Natalie O'Neill

https://nypost.com/2026/08/13/us-news/surrogate-mckenna-west-vows-legal-fight-against-bio-parents-she-is-the-mother/

Brain death determination controversy

Courtesy of my son

Annelise Camp, a 2-year-old girl whose parents sued to stop Texas Children’s Hospital from testing if she’s brain dead, died Monday after her breathing tube was removed.

In social media posts, Annelise’s family confirmed her death, ending a months-long legal dispute over whether hospitals need a family’s consent to test a patient for brain death. The New York Times first reported her death.

“Annelise is now with Jesus,” wrote her parents, Johnston Camp and Joy Camp, on the family’s GoFundMe page. “We pray that her legacy continues to inspire compassion, encourage meaningful change, and bring hope to families for years to come.”

                                   https://www.instagram.com/p/Dby1T05HxBT/

Rep. Steve Toth, R-The Woodlands, who has been in contact with Annelise’s father, said the family just told Annelise’s two siblings of her death.

“It’s been traumatic for the family,” said Toth in an interview with the Texas Tribune.

The Camps’ lawsuit, filed at the end of May, was part of a larger debate supported by anti-abortion advocates that challenged the use of brain death testing. The Camps had hoped that by preventing brain death testing and a determination of whether their daughter was brain dead, hospitals would be forced to keep Annelise on life-supporting services for as long as possible.

Under Texas law, brain death is the irreversible cessation of all brain function and hospitals are not required to obtain family consent before conducting the tests. Once a patient is declared brain dead, hospitals can withdraw life sustaining measures.

It is unclear why Annelise was extubated. According to a Facebook post from Steven Camp, her grandfather, Annelise passed shortly after the breathing tube was removed. The Camp family has not responded to requests for comment.

The family said in court filings that the testing conflicted with their religious beliefs. Texas Right to Life, who worked with the family, argued that a patient is alive as long as their heart is beating, even when breathing is sustained by a ventilator.

On Memorial Day, Annelise was pulled from a hotel swimming pool and taken to Texas Children’s Hospital, where she was placed on a ventilator. After three days, doctors said they had exhausted treatment options and recommended evaluating her for brain death to which her parents began legal action to block testing.

Annelise was transferred from Texas Children’s Hospital in Houston to Ochsner Medical Center in New Orleans, but was transferred back to a Texas hospital, Christus Mother Frances Hospital in Tyler, about a week ago, Toth said.

Toth hopes Annelise’s story will influence change by giving families in Texas and across the country more time on life-support services.

“Life is fragile, it shouldn’t be disposable,” Toth said.

Disclosure: Texas Children’s Hospital and The New York Times have been financial supporters of The Texas Tribune, a nonprofit, nonpartisan news organization that is funded in part by donations from members, foundations and corporate sponsors. Financial supporters play no role in The Texas Tribune’s journalism. Find a complete list of them here.

Katlyn Ma

https://www.texastribune.org/2026/08/07/texas-brain-death-testing-annelise-camp/

What happens when medical students rely on AI

Courtesy of my son

What happens when medical students rely on AI – and never develop their own judgment?

AI’s danger isn’t just in experts losing the ability to reason. It’s that trainees may never learn how to do so in the first place

In healthcare, there’s growing concern over doctors becoming less clinically adept as they increasingly rely on AI tools. But what about the trainees – medical students, residents and fellows – who are using these tools before they have built their own clinical judgment? The idea of deskilling implies that someone possessed an ability and then lost it. Here, the danger is not just deskilling but never-skilling. Although a doctor who has forgotten how to reason is recoverable, one who never learned how may not be.

OpenEvidence, essentially an AI chatbot for clinicians, has given this concern its most concrete form. About two-thirds of US doctors actively use OpenEvidence, asking about puzzling symptoms, drug interactions and clinical guidelines, getting responses within seconds, anchored in the latest research. Trainees, unsurprisingly, have also begun to use this AI tool in many of the same ways – but at a far more formative stage.

For example, trainees once asked to build a list of potential diagnoses might struggle and offer an incomplete set, learning what they missed, sometimes painfully. Now, trainees can simply ask OpenEvidence and get a nearly perfect answer, complete with possibilities they might have never considered and none of the embarrassment of having overlooked them. Repeating this answer on the wards may make the trainee look prepared and even impress the supervising doctor.

However, this performance can also conceal the very deficit that training is meant to reveal: that the struggle is the point. Medical training, more than most professions, is an apprenticeship. A student becomes a resident, a resident becomes a fellow, and a fellow becomes an attending – every step shaped by failure, uncertainty and increasing responsibility. With years of repetition and watchful supervision, the habits of clinical reasoning slowly become part of the physician’s inner architecture.

Technology has long shifted how people learn medicine, from advanced imaging to electronic medical records. But AI is different, not just expanding what doctors can see but inserting itself into the cognitive machinery that training is meant to build. As these tools become more capable and the physician’s role increasingly involves supervising them, experienced clinicians may have enough intuition and independent judgment to critically evaluate the machine’s answers. But for trainees whose understanding of medicine is being formed alongside AI, the relationship is more fraught. Can they really question the reasoning that shaped their own? What happens when the generation trained by AI becomes the generation responsible for catching its mistakes? With unchecked use among trainees, we risk creating supervisors of reasoning before we create reasoners.

The stakes of that question are growing: a recent study in Nature Medicine found that tools pulling from the latest medical literature, like OpenEvidence does, can be less reliable than they appear and, in some cases, less accurate than general-purpose AI chatbots. The problem of misplaced trust is already embedded in the AI that trainees are using today.

To be clear, many trainees sense the trap, telling us they know that tools such as OpenEvidence can become a crutch. But these trainees also feel stuck in an arms race: if everyone else is using AI to sound more prepared, opting out feels like unilateral disarmament. The solution, then, cannot rest on individual restraint. It has to be structural.

That is why medical schools and residency programs need to shape not just whether trainees use AI, but when. No one can police every search on every phone, nor should they. But supervising doctors can build a simple expectation – reason first, consult AI second – and assess accordingly. Trainees should have to make their unaided first pass visible, committing to a leading diagnosis, naming the dangerous possibilities to rule out, and explaining what to do next. In practice, that might mean a resident who admits a patient overnight first writes a brief “pre-AI assessment” after the history and physical exam. On rounds, when a new lab result or symptom changes the case, the attending might need to pause the team – before anyone can consult AI – to ask how this changes the diagnosis or treatment plan.

As AI becomes more deeply integrated into medicine, this will feel cumbersome and inefficient. But such friction is purposeful: the learning scientists Elizabeth and Robert Bjork describe how “desirable difficulties” slow performance in the moment but improve retention and transfer of skills over time. In fact, used after an independent attempt, AI could actually serve as a powerful tutor, showing trainees what they missed and what they overemphasized.

Sequencing, however, may not be enough on its own. Aviation thus offers a useful precedent: pilots in training are not taught to avoid autopilot but to preserve their manual competence. The Federal Aviation Administration even advises pilots to maintain manual flying skills by periodically disengaging automation and hand-flying. Medicine needs similar discipline, with trainees required to periodically work through no-AI cases and assessed on their unaided reasoning to reveal potential drift.

Finally, trainees should be taught to interrogate AI itself. Programs could run the medical equivalent of flight simulator drills, built from real clinical cases: for example, a polished AI-generated assessment with a subtle flaw. Afterward, attendings could debrief not only whether the trainee reached the right answer but also when they trusted the tool, when they questioned it, and when they found the flaw. Just as important, attendings should mix in AI outputs that are perfectly accurate, so students learn not reflexive skepticism but disciplined judgment.

None of this is an argument for making medical training harder for its own sake or romanticizing humiliation as pedagogy. In every generation of medicine, there is a temptation to confuse difficulty with virtue, but the struggle to independently reason through a patient’s case is not hazing but a core competency.

AI is here to stay, and patients stand to benefit from its speed and reach. But patients will also need doctors who can stand apart from the machine long enough to know when it is wrong, incomplete, or right for the wrong reason – doctors whose reasoning is not subordinated to it. Although AI can reason over the facts it is given, a trainee who has seen pneumonia that looks like pneumonia, then pneumonia that looks like heart failure, then heart failure that looks like pneumonia, develops a richer bedside judgment: what to notice, what to question, and when a familiar pattern should be distrusted. That is what medical training is trying to produce. AI should help augment this, not replace it.

Simar Bajaj and Joseph Sakran

Simar Bajaj is a medical student and Knight-Hennessy Scholar at Stanford University School of Medicine, as well as an award-winning journalist

Dr Joseph V Sakran is a trauma surgeon and public health expert who serves as executive vice-chair of surgery at Johns Hopkins Medicine

https://www.theguardian.com/commentisfree/2026/aug/10/ai-medical-students-judgment

Xia-Gibbs syndrome

Inspired by a patient

Shirai H, Oitani Y, Nishi E, Haraguchi K, Nakamura T, Ichinose F, Sanefuji M, Hattori A, Yanagi K, Shimojima Yamamoto K, Okamoto N, Matsuo M, Saitoh S, Yoshiura KI, Kaname T, Yamamoto T. Clinical and molecular profiles of patients with Xia-Gibbs syndrome: a cohort in Japan. Brain Dev. 2026 Apr;48(2):104509. doi: 10.1016/j.braindev.2026.104509. Epub 2026 Feb 6. PMID: 41653504.

Abstract

Background: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA binding motif containing 1 (AHDC1) gene. More than 100 patients with XGS have been reported. In this study, we describe the findings from a Japanese cohort of patients with XGS. To enhance understanding, we also conducted a systematic literature review of XGS.

Methods: We collected clinical and genetic information from seven new Japanese patients with XGS which were diagnosed through comprehensive genetic analysis. A systematic literature review was also conducted using PubMed.

Results: All Japanese patients carried premature truncation variants or deletions. The core clinical features were global developmental delay and hypotonia, which were consistent with those observed in the 106 previously reported patients identified in our literature review. In one patient with a frameshift variant, escape from nonsense-mediated mRNA decay was confirmed using the patient's sample.

Conclusion: The clinical and molecular profiles of Japanese patients with XGS were analyzed and compared with those of previously reported patients from other countries, confirming the consistent characteristics of XGS. This study provides direct evidence of nonsense-mediated mRNA decay escape. A comprehensive understanding of this expanding phenotype is crucial for accurate diagnosis and management.

Jiang N, Zhang L, Zheng Z, Du H, Chen S, Pan H. Phenotypic subtypes of Xia-Gibbs syndrome: a latent class analysis. Eur J Hum Genet. 2025 Dec;33(12):1558-1566. doi: 10.1038/s41431-024-01754-0. Epub 2024 Dec 9. Erratum in: Eur J Hum Genet. 2026 Jun;34(6):886-892. doi: 10.1038/s41431-025-01825-w. PMID: 39648204; PMCID: PMC12669642.

Abstract

Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder with considerable clinical heterogeneity. To further characterize the syndrome's heterogeneity, we applied latent class analysis (LCA) on reported cases to identify phenotypic subtypes. By searching PubMed, Embase, China National Knowledge Infrastructure and Wanfang databases from inception to February 2024, we enrolled 97 cases with nonsense, frameshift or missense variants in the AHDC1 gene. LCA was based on the following 6 phenotypes with moderate occurrence and low missingness: ataxia, seizure, autism, sleep apnea, short stature and scoliosis. After excluding cases with missing data on all LCA variables or with unmatched phenotype-genotype information, a total of 85 cases were selected for LCA. Models with 1-5 classes were compared based on Akaike Information Criterion, Bayesian Information Criterion, Sample-Size Adjusted BIC and entropy. We used multinomial logistic regression (MLR) analyses to investigate the phenotype-genotype association and potential predictors for class membership. LCA revealed 3 distinct classes labeled as Ataxia subtype (n = 11 [12.9%]), Sleep apnea & short stature subtype (n = 23 [27.1%]) and Neuropsychological subtype (n = 51 [60.0%]). The commonest Neuropsychological subtype was characterized by high estimated probabilities of seizure, ataxia and autism. By adjusting for sex, age and variant type, MLR showed no significant association between phenotypic subtype and variant position. Age and variant type were identified as predictors of class membership. The findings of this review offer novel insights for different presentations of XGS. It is possible to deliver targeted monitoring and treatment for each subtype in the early stage.

Romano F, Falco M, Cappuccio G, Brunetti-Pierri N, Lonardo F, Torella A, Digilio MC, Dentici ML, Alfieri P, Agolini E, Novelli A, Garavelli L, Accogli A; TUDP; Striano P, Scarano G, Nigro V, Scala M, Capra V. Genotype-phenotype spectrum and correlations in Xia-Gibbs syndrome: Report of five novel cases and literature review. Birth Defects Res. 2022 Aug 1;114(13):759-767. doi: 10.1002/bdr2.2058. Epub 2022 Jun 18. PMID: 35716097; PMCID: PMC9545659.

Abstract

Background: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA-binding motif-containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant-negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N-terminal are thought to determine a milder phenotype with better cognitive performances. However, clean-cut genotype-phenotype correlations are still lacking.

Cases: In this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in AHDC1. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities.

Conclusions: In this study, we report uncommon XGS features associated with five novel truncating variants in AHDC, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype-phenotype correlations in XGS.

Cinelli G, Della Vecchia S, Bergonzini P, Caramaschi E, Spezia E, Parenti C, Madeo SF, Lucaccioni L, Francesca C, Pugliese M, Raviglione F, Colonna C, Calabrese O, Stanghellini I, Marongiu MC, Biagioni E, Ferrari AR, Battini R, Iughetti L. Clinical, Behavioral and Neuroradiological Phenotype in an Italian Cohort of Patients With Xia Gibbs Syndrome: A Multicenter Cross-Sectional Study and Systematic Literature Review. Am J Med Genet A. 2026 Sep;200(9):2067-2079. doi: 10.1002/ajmg.a.70163. Epub 2026 Apr 30. PMID: 42059486.

Abstract

Heterozygous variants in the AHDC1 gene are associated with Xia Gibbs Syndrome (XGS), a genetic disorder with a highly variable phenotype. Cognitive impairment, motor delay, language delay, neonatal hypotonia, and sleep apnea are considered "cardinal" signs of the disease. In a multicenter cross-sectional study, we analyzed the genetic, epileptological, behavioral, and neuroradiological features of 15 patients with XGS harboring heterozygous variants in AHDC1. The phenotype of our patient cohort is almost overlapping with that already reported in the literature. Seizures begin between 2 and 9 years, while EEG is generally characterized by normal background activity with paroxysmal abnormalities in the posterior areas increased by sleep. We systematically analyzed brain imaging findings as the most frequent brain alteration: the thinning of the corpus callosum, followed by posterior fossa malformation and lateral ventricle morphology abnormalities. Regarding psychiatric disorders, we observed neurodevelopmental disorders such as ID, language disorders, Autism spectrum disorders (ASD), and ADHD in preschoolers, followed by a prevalence of externalizing problems during childhood and adolescence. Our study showed that epilepsy and brain anomalies are very common among XGS individuals. MRI changes are nonspecific, but their association with other clinical features of the syndrome can guide early diagnosis. EEG abnormalities are present in all epileptic patients in the temporal-occipital regions with the same characteristics, so we could hypothesize that these abnormalities could represent a recognizable EEG pattern of XGS. Behavioral disorders represent an important problem, and longitudinal evaluations are needed to improve the classification of the psychopathological spectrum in XGS.

Juvenile-onset ALS

See: https://childnervoussystem.blogspot.com/2015/06/mystery-illness.html

Esther and Rivka Herzfeld are members of an inspirational and beloved family that are well-known in the Teaneck community. Active members at Congregation Beth Aaron, all four children in the Herzfeld family have been diagnosed with juvenile-onset ALS, a neuromuscular degenerative disease. Esther’s husband (Rivka’s father) also suffers from a version of this disease, which developed in adulthood. The story of the Herzfelds has been featured in The Jewish Link in the past, particularly in 2015 during their successful quest for a van to allow their family mobility (“Herzfeld Family Gets Their Van,” July 9, 2015, https://jewishlink.news/herzfeld-family-gets-their-van/).

What always strikes people who get to know the Herzfelds is how they stubbornly refuse to allow their challenges to define them, or to hold them back. While one of the siblings, Rivka, works 40 hours a week, another, Racheli, is pursuing a master’s degree in social work. As they are all in their 20s and early 30s, they also have special interests, activities and friends. They are also highly intelligent critical thinkers who are focused on staying as active as possible so that when a cure is found for their condition, they will be ready to benefit from it.

However, as time has gone on, the needs of the family have increased manifold, even though they have their van and now live in a fully accessible house all on one floor. With communal assistance, they are putting together a fundraiser with the aim of allowing them to pay for an immense shortfall in their bills for the long term.

That’s why the mother and daughter are embarking on a speaking tour called “Life Rewritten,” planning to demonstrate their immense strength as a family and their hope for a better, more supportive future. As Esther explained: “I’m an English teacher, and storytelling is important to me. I emphasize the role of strong women and the role they play in the life cycle of a whole family, and I thought about the irony of my inability to control my own story.” She emphasized that this is the case for many families. “Many people plan a life, and their lives are then derailed. We’re not the only ones.”

Juvenile-onset ALS, an extremely rare condition, affects limb strength, breath support and swallowing, among other basic functions. “Everyone knows about ALS because of Lou Gehrig and Stephen Hawking, and that type of ALS shows up for people in their 50s, 60s, or even 70s. That type of ALS is fatal,” Esther explained. The type of ALS her children and husband have is different, and much less well-known, even among doctors. “My children were studied by neurologists for years and given multiple wrong diagnoses. Finally, right before COVID, they started honing in on what neurons were affected, and because it was similar to ALS, they decided to call it juvenile-onset ALS. Baruch Hashem, it’s not fatal, but it affects daily living.” Of about 100 known cases, the Herzfelds make up five.

Because the condition wasn’t identified until recently, it was a process of years to figure out why the Herzfeld children couldn’t live life as normal. “At first, they were just tripping and falling and dropping things. In retrospect, we realize this was the beginning of the degeneration of the muscles.”

Esther and Rivka recounted that each child developed symptoms at a different stage in their life. While Tzipora was the first to mention that something felt wrong at age 6, Rivka didn’t experience symptoms until her senior year of high school. “I remember saying to my parents, ‘Do you think I have what Tzipora has?’ and they sort of quietly chuckled and said, ‘Yeah, of course you have what Tzipora has.’”

To explain the mechanisms of the condition, Rivka analogized the story of Bavel. “Our sphingolipids, the messengers from the brain to the muscles, are being sent in English. But the muscles are reading the messages from the neurons in Sanskrit. Our muscles can sometimes do the actions, but more slowly, and sometimes can’t do them at all, because they don’t understand Sanskrit.” Rivka clarified, however, that “it doesn’t impact our intellectual capability and our thinking, which is such a bracha.” In her mother’s words, “You’re not fast in your legs, but you’re fast in your mind.”

At this point in time, all four Herzfeld children are wheelchair- or scooter-bound. In their first family house on Schley Place in Teaneck, which they lived in until recently, it was nearly impossible for everyone to fit in the house at a time. “It was like putting corks in a dam that was going to burst,” said Esther. “We got a stairlift, and a ramp, and another ramp, but it was brutally uncomfortable.”

A few years ago, thanks to a previous campaign, the Herzfelds were able to move into a house on Queen Anne Road, which “took the pressure out of the pressure cooker,” said Esther. “There was no need to be fighting over who could get the door or pass each other in the hallway.” According to Rivka, “It’s such a mechaye [relief] to not worry about the house being an obstacle.”

However, the obstacles of navigation within the home are only a small challenge to the Herzfeld family. Between the cost of the electricity, the medical equipment, therapy required that isn’t covered by insurance, and the staggering cost of having multiple aides for 22 hours a day, the family is struggling financially.

Unfortunately, government funding only pays for 40 hours a week for home care per person, which is not enough to cover the needs of the family, which has five members who require full care 22 hours each day. It means, they have to pay cash to their aides to the tune of close to $6,000 each week.

While many have asked the Herzfelds why the government can’t stretch more to help them, Rivka believes that her case specifically is confusing for a disability office to make space for, and possibly out of their comfort zone. For example: “I am a working person, but I have a full disability that is congenital, but didn’t occur until I was 17. All of those things make it extremely complicated for people to understand, especially the government. There’s a $25,000-a-month need, every single month. This is critical to the maintenance of our family.”

Beyond that, all family members take physical and other types of therapy with hand specialists and others at not-insignificant costs, which insurances can often limit or not cover because “they’re not getting better.”

With “Life Rewritten,” the Herzfelds are hoping to take their lives back into their own hands. Currently, they only have enough money for another few weeks of therapy. “I’m afraid to look at the fund total,” Esther said. “I’m just taking out the money. I’m hoping that December 28th will help.” Rivka added: “It’s Kislev, and it should be a month of light. It should be a month in which people can see the light that we can give and not just take. A month of miracles.”

Rabbi Daniel Fridman of the Jewish Center of Teaneck is helping to spearhead the campaign. He shared his thoughts on the importance of helping the Herzfelds. “Chazal describe the Jewish people as possessed of certain indelible characteristics. Amongst these are our status as rachmanim, merciful people, and gomlei chasadim, active purveyors of loving kindness. We invite the entire community to join us to learn about the story of the Herzfeld family, and in doing so, to express these two qualities.”

On Dec. 28, the “Life Rewritten” campaign begins. Please join at Jewish Center of Teaneck, where Esther and Rivka will tell their story and ask for help, allowing them to begin to rewrite their life story. They also recently appeared on The Jewish Link “Pitch Meeting” podcast: youtube.com/watch?v=tTQ7jRrreuw&t=4s. To donate to the campaign, visit thechesedfund.com/herzfeld/the-herzfeld-family.

Eliana Birman

https://jewishlink.news/herzfeld-family-launches-life-rewritten-speaking-tour-and-dec-28-fundraiser/

Gene replacement therapy for SURF1-related Leigh syndrome.

Ling Q, Rioux M, Hu Y, Lee M, Gray SJ. Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related Leigh syndrome. Mol Ther Methods Clin Dev. 2021 Sep 7;23:158-168. doi: 10.1016/j.omtm.2021.09.001. PMID: 34703839; PMCID: PMC8517205.

Abstract

SURF1 (surfeit locus protein 1)-related Leigh syndrome is an early-onset neurodegenerative disorder, characterized by reduction in complex IV activity, resulting in disrupted mitochondrial function. Currently, there are no treatment options available. To test our hypothesis that adeno-associated viral vector serotype 9 (AAV9)/human SURF1 (hSURF1) gene replacement therapy can provide a potentially meaningful and long-term therapeutic benefit, we conducted preclinical efficacy studies using SURF1 knockout mice and safety evaluations with wild-type (WT) mice. Our data indicate that with a single intrathecal (i.t.) administration, our treatment partially and significantly rescued complex IV activity in all tissues tested, including liver, brain, and muscle. Accordingly, complex IV content (examined via MT-CO1 protein expression level) also increased with our treatment. In a separate group of mice, AAV9/hSURF1 mitigated the blood lactic acidosis induced by exhaustive exercise at 9 months post-dosing. A toxicity study in WT mice showed no adverse effects in either the in-life portion or after microscopic examination of major tissues up to a year following the same treatment regimen. Taken together, our data suggest a single dose, i.t. administration of AAV9/hSURF1 is safe and effective in improving biochemical abnormalities induced by SURF1 deficiency with potential applicability for SURF1-related Leigh syndrome patients.

Mitochondrial transfer therapy

Nakai, R., Varnum, S., Field, R.L. et al. Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome. Nat Metab 6, 1886–1896 (2024). https://doi.org/10.1038/s42255-024-01125-5

Abstract

Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4−/− peritoneal macrophages. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations, and mitochondria transplantation was shown to minimize ischaemic damage to the heart, brain and limbs. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4−/− mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4−/− mice, whereas mitochondria from Ndufs4−/− mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4−/− mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS.

15q26.3 deletions

Inspired by a patient

Sivakumaran TA, Grebe TA. 15q26.3 deletions distal to IGF1R cause growth retardation, congenital heart defect and skeletal anomalies: Case report and review of literature. Am J Med Genet A. 2023 Sep;191(9):2392-2397. doi: 10.1002/ajmg.a.63350. Epub 2023 Jul 12. PMID: 37434556.

Abstract

15q26 deletion is a rare genomic disorder characterized by intrauterine and postnatal growth retardation, microcephaly, intellectual disability, and congenital malformations. Here, we report a 4-month-old female with intrauterine growth retardation, short stature, pulmonary hypertension, atrial septal defect and congenital bowing of long bones of the legs. Chromosomal microarray analysis showed a de novo deletion of approximately 2.1 Mb at 15q26.3 region that does not include IGF1R. Our analysis of patients documented in the literature and the DECIPHER database with 15q26 deletions distal to IGF1R, including 10 patients with de novo pure deletions, allowed us to define the smallest region of overlap to 686 kb. This region includes ALDH1A3, LRRK1, CHSY1, SELENOS, SNRPA1, and PCSK6. We propose haploinsufficiency of one or more genes, besides IGF1R, within this region may contribute to the clinical findings in patients with 15q26.3 deletion.

Dincer BT, Ozdemir EM, Cetincelik U, Ucar A. Drayer Syndrome due to Chromosome 15q26.3 Deletion: Response to Growth Hormone Treatment. Sisli Etfal Hastan Tip Bul. 2024 Dec 24;58(4):521-523. doi: 10.14744/SEMB.2024.01879. PMID: 39816431; PMCID: PMC11729826.

Abstract

Chromosome 15q26 deletion is a rare condition that causes short stature and is associated with intrauterine growth restriction (IUGR), failure to thrive, congenital heart disease and many congenital malformations. The insulin growth factor receptor (IGF-1R) on chromosome 15 has many important roles, especially in growth regulation. Our case is an 18-month-old small for gestational age girl who presented with severe short stature, microcephaly and minor dysmorphic features. Chromosome microarray revealed 15q26 deletion including the IGF1R gene. Recombinant growth hormone (rGH) has been used in patients with IGF-1R defects with variable treatment responses. The reason for rGH unresponsiveness in some patients with terminal chromosome 15q deletion is still unclear. Herein we discuss the use of rGH in a patient with heterozygous IGF1R deletion and emphasize the need for further follow-up regarding other endocrine disorders.

Benbouchta Y, De Leeuw N, Amasdl S, Sbiti A, Smeets D, Sadki K, Sefiani A. 15q26 deletion in a patient with congenital heart defect, growth restriction and intellectual disability: case report and literature review. Ital J Pediatr. 2021 Sep 16;47(1):188. doi: 10.1186/s13052-021-01121-5. PMID: 34530895; PMCID: PMC8447573.

Abstract

Background: 15q26 deletion is a relatively rare chromosomal disorder, and it is described only in few cases. Patients with this aberration show many signs and symptoms, particularly pre- and postnatal growth restriction, developmental delay, microcephaly, intellectual disability and various congenital malformations.

Case presentation: We report on a girl, 4 years old, of consanguineous parents, with a 15q26 deletion. Clinical manifestations included failure to thrive, developmental delay, microcephaly, dysmorphic facies with broad forehead, hypertelorism, narrowed eyelid slits and protruding columella. The patient also showed skeletal abnormalities, especially clinodactyly of the 5th finger, varus equine right foot and left club foot. Additionally, she had teething delay and divergent strabismus. Heart ultrasound displayed two atrial septal defects with left-to-right shunt, enlarging the right cavities. Routine cytogenetic analysis revealed a shortened 15q chromosome. Subsequent array analysis disclosed a terminal 9.15 Mb deletion at subband 15q26.1-q26.3. Four candidate genes associated with 15q26 deletion phenotype were within the deleted region, i.e. IGF1R, NR2F2, CHD2 and MEF2A.

Poot M, Verrijn Stuart AA, van Daalen E, van Iperen A, van Binsbergen E, Hochstenbach R. Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases. Eur J Med Genet. 2013 Jul;56(7):346-50. doi: 10.1016/j.ejmg.2013.04.001. Epub 2013 Apr 16. PMID: 23603061.

Abstract

Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree of pre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26 we found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, attention-deficit-hyperactivity disorder, hearing loss and autism, have been found. We discuss clinical ramifications for cases with a loss of 15q26 detected by prenatal array-CGH.

O'Riordan AM, McGrath N, Sharif F, Murphy NP, Franklin O, Lynch SA, O'Grady MJ. Expanding the clinical spectrum of chromosome 15q26 terminal deletions associated with IGF-1 resistance. Eur J Pediatr. 2017 Jan;176(1):137-142. doi: 10.1007/s00431-016-2802-y. Epub 2016 Nov 8. PMID: 27826649.

Abstract

Haploinsufficiency of the insulin-like growth factor-1 receptor (IGF1R) gene on chromosome 15q26.3 is associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. Terminal deletions of chromosome 15q26 arising more proximally may also be associated with congenital heart disease, epilepsy, diaphragmatic hernia and renal anomalies. We report three additional cases of 15q26 terminal deletions with novel features which may further expand the spectrum of this rarely reported contiguous gene syndrome. Phenotypic features including neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been reported previously. Similarly, laboratory features of insulin-like growth factor 1 (IGF-1) resistance are described, including markedly elevated IGF-1 of up to +4.7 SDS. In one patient, the elevated IGF-1 declined over time and this coincided with a period of spontaneous growth acceleration.

Conclusion: Deletions of 15q26 are a potential risk factor for aortic root dilatation, neonatal lymphedema and aplasia cutis in addition to causing growth restriction. What is Known: • Terminal deletions of chromosome 15q26 are associated with impaired prenatal and postnatal growth, developmental delay, dysmorphic features and skeletal abnormalities. What is New: • Neonatal lymphedema, aplasia cutis congenita and aortic root dilatation have not been previously described in 15q26 terminal deletions and may represent novel features. • IGF-1 levels may be increased up to 4.7 SDS.

Infantile spasms--therapeutic thoughts

Wang M, Zhao F, Sun L, Yu Y, Zhang H. Ketogenic diets therapy in the management of epileptic spasms syndrome. Front Pediatr. 2024 Nov 6;12:1472982. doi: 10.3389/fped.2024.1472982. PMID: 39568784; PMCID: PMC11576165.

Abstract

Infantile Epileptic Spasm Syndrome (IESS) is a group of infantile spasm syndromes of various etiologies that typically present in early infancy, predispose to refractory epilepsy, and leave intellectual disability. Ketogenic diet therapy (KDT) is a non-pharmacologic treatment modality for medically refractory IESS. Recent scientific evidence supported the efficacy, safety, and tolerability of KDT for the treatment of IESS. KDT not only reduces the frequency of seizures in infants with IESS, but also improve their cognition and long-term prognosis. Recently, it has also received increasing attention as a potential treatment for neurological disorders. This reviewed the recent research progress of KDTs for the treatment of IESS, and discussed the different types and the mechanisms of KDTs, the expansion of KDT applications, the influencing factors, and future research issues.

Reyes Valenzuela G, Gallo A, Calvo A, Chacón S, Fasulo L, Galicchio S, Adi J, Fortini PS, Caraballo R. Purified cannabidiol as add-on therapy in children with treatment-resistant infantile epileptic spasms syndrome. Seizure. 2024 Feb;115:94-99. doi: 10.1016/j.seizure.2024.01.010. Epub 2024 Jan 15. PMID: 38237316.

Abstract

Objective: The aim of this study was to assess efficacy, safety, and tolerability of highly purified cannabidiol oil (CBD) as add-on therapy for the treatment of a series of patients with infantile epileptic spasms syndrome (IESS) who were resistant to antiseizure medications and ketogenic dietary therapy.

Material and methods: We conducted a retrospective analysis of the medical records of 28 infants with treatment-resistant IESS aged 6 to 21 months who received highly purified CBD between July 2021 and June 2023. Data were collected on neurological examinations, EEG, Video-EEG and polygraphic recordings, imaging studies, laboratory testing, and seizure frequency, type, and duration, and adverse effects. As the primary outcome, a reduction of frequency of epileptic spasms (ES) was assessed. ES freedom was considered after a minimal time of 1 month without ES.

Results: Sixteen male and 12 female patients, aged 6-21 months, who received CBD for treatment-resistant IESS were included. The etiology was structural in 10, Down syndrome in seven, genetic in nine, and unknown in two. Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2-50). Prior to CBD initiation, patients had a median of 69 ES in clusters per day (range, 41-75) and of 10 focal seizures per week (range, 7-13). After a mean and median follow-up of 15 and 12.5 months (range, 6-26 months), seven patients were ES free and 12 had a >50 % ES reduction. Five of seven patients (71 %) with Down syndrome and 3/5 (60 %) with cerebral palsy responded well. Adverse effects were mild. EEG improvements correlated with ES reductions.

Conclusion: In this study evaluating the use of CBD in children with IESS, 19/28 (67.8 %) had a more than 50 % ES reduction with good tolerability.

Matsuura R, Hamano SI, Hirata Y, Takeda R, Takeuchi H, Koichihara R, Kikuchi K, Oka A. Long-term analysis of adrenocorticotropic hormone monotherapy for infantile epileptic spasms syndrome with periventricular leukomalacia. Seizure. 2023 Jul;109:40-44. doi: 10.1016/j.seizure.2023.05.012. Epub 2023 May 16. PMID: 37207538.

Abstract

Purpose: Infantile epileptic spasms syndrome (IESS) with periventricular leukomalacia (PVL) has a poor neurological prognosis. Adrenocorticotropic hormone (ACTH) and vigabatrin therapies are the recommended first-line treatments for IESS. However, ACTH monotherapy for IESS with PVL has not been studied in detail. We analysed long-term outcomes of ACTH monotherapy for IESS with PVL.

Methods: We retrospectively examined 12 patients with IESS and PVL at Saitama Children's Medical Center between January 1993 and September 2022. We evaluated seizure outcomes 3 months post-ACTH therapy and at the last visit. We also assessed electroencephalography findings and developmental outcomes. A positive response was defined as complete remission of epileptic spasms, no other seizure types, and hypsarrhythmia resolution post-ACTH therapy.

Results: The median onset age of epileptic spasms was 7 (range: 3-14) months. The median age at initiation of ACTH therapy was 9 (7-17) months. Seven of 12 patients (58.3%) showed a positive response. The median age at the last visit was 5 years and 6 months (1 year and 5 months-22 years and 2 months). At the last visit, only 2 of 7 initial responders remained seizure-free who demonstrated normal electroencephalography findings within 1-month post-ACTH therapy. Patients with epileptic discharge in the parieto-occipital region within 1-month post-ACTH therapy showed relapse of epileptic spasms or other seizure types.

Conclusion: Patients having epileptic discharge in the parietal or occipital regions on electroencephalography within 1-month post-ACTH therapy may be at a high risk of epileptic spasm recurrence or other seizure types in the long term.

Snyder HE, Jain P, RamachandranNair R, Jones KC, Whitney R. Genetic Advancements in Infantile Epileptic Spasms Syndrome and Opportunities for Precision Medicine. Genes (Basel). 2024 Feb 21;15(3):266. doi: 10.3390/genes15030266. PMID: 38540325; PMCID: PMC10970414.

Abstract

Infantile epileptic spasms syndrome (IESS) is a devastating developmental epileptic encephalopathy (DEE) consisting of epileptic spasms, as well as one or both of developmental regression or stagnation and hypsarrhythmia on EEG. A myriad of aetiologies are associated with the development of IESS; broadly, 60% of cases are thought to be structural, metabolic or infectious in nature, with the remainder genetic or of unknown cause. Epilepsy genetics is a growing field, and over 28 copy number variants and 70 single gene pathogenic variants related to IESS have been discovered to date. While not exhaustive, some of the most commonly reported genetic aetiologies include trisomy 21 and pathogenic variants in genes such as TSC1, TSC2, CDKL5, ARX, KCNQ2, STXBP1 and SCN2A. Understanding the genetic mechanisms of IESS may provide the opportunity to better discern IESS pathophysiology and improve treatments for this condition. This narrative review presents an overview of our current understanding of IESS genetics, with an emphasis on animal models of IESS pathogenesis, the spectrum of genetic aetiologies of IESS (i.e., chromosomal disorders, single-gene disorders, trinucleotide repeat disorders and mitochondrial disorders), as well as available genetic testing methods and their respective diagnostic yields. Future opportunities as they relate to precision medicine and epilepsy genetics in the treatment of IESS are also explored.

SETD1A mutations

Inspired by a patient

Lan M, Wang Y, Li S, Zhao L, Liu P, Hu W. Case report: De novo variant of SETD1A causes infantile epileptic spasms syndrome. Front Neurol. 2023 Oct 19;14:1278035. doi: 10.3389/fneur.2023.1278035. PMID: 37928142; PMCID: PMC10620521.

Abstract

Infantile epileptic spasms syndrome (IESS) is one of the most common epileptic encephalopathies of infancy, with typical clinical features defined by a triad of epileptic spasms, hypsarrhythmia, and developmental delay. Genetic factors are important causes of IESS. The SETD1A (SET Domain Containing 1A) gene encodes a histone lysine methyltransferase that activates gene transcription through histone H3 lysine K4 methylation. Mutations in the SETD1A gene have been associated with schizophrenia, and some have been reported to cause seizures. Herein, we report a case of IESS caused by a SETD1A gene mutation. Video electroencephalography showed hypsarrhythmia. No specific findings were obtained after brain MRI and metabolic work-up. The seizures disappeared after treatment with adrenocorticotropic hormone, vitamin B6, and valproic acid during hospitalization. Genetic testing revealed that the child had a variant (NM_014712.3:c.3005_3,006 delAG, p.Glu1002Glyfs*20) in exon 12 of the SETD1A gene, representing a de novo mutation. There have been no previous reports on the SETD1A gene causing infantile spasms. We also summarize the existing literature on SETD1A gene-related epilepsy to provide a reference for clinical diagnosis and treatment.

Lease R, Oshone RT, Ahmed Y, Ali S, Arjona S, Choe J, Colantuoni C, Cortes-Gutierrez M, Herb BR, Humphries EM, Mocci E, O'Hara-Payne R, Kuehner R, Damcott C, Sampath H, Shaub S, Woelfel K, Wolford C, Ahn K, Detera-Wadleigh S, Markx S, Gogos JA, Kochunov P, Pollin TI, Postolache T, Shuldiner AR, McMahon FJ, Hong LE, Mitchell BD, Ament SA. Clinical, cellular, and genomic consequences of a population-enriched SETD1A missense variant. Res Sq [Preprint]. 2026 Jul 13:rs.3.rs-9900286. doi: 10.21203/rs.3.rs-9900286/v1. PMID: 42523465; PMCID: PMC13405502.

Abstract

Rare variants in SETD1A, encoding a histone H3K4 methyltransferase, are among the strongest genetic risk factors for schizophrenia. Exome sequencing (n=3,736) revealed a population-enriched SETD1A missense variant (P596L) in the Lancaster Old Order Amish founder population, presenting a unique opportunity to elucidate variant-specific, multi-scale mechanisms. Psychiatric and cognitive phenotyping revealed nearly two-fold increased risk for bipolar disorder, accompanied by allele dose-dependent cognitive deficits in adulthood. Induced pluripotent stem cells (iPSCs) from homozygous carriers exhibited signatures of SETD1A hypofunction, including reduced proliferation and heightened susceptibility to replication stress and DNA double-strand breaks. During forebrain-directed differentiation, homozygous mutant cells displayed premature activation of neurodevelopmental transcriptional programs but impaired neural rosette formation, reduced neurite complexity, and early progenitor senescence. Multi-omic profiling revealed dysregulation of gene modules converging on replication stress pathways and neuronal regulatory networks enriched for autism and psychiatric risk genes. Pharmacologic inhibition of the H3K4 demethylase KDM5 partially rescued replication stress and neurite deficits, supporting an epigenetic mechanism and suggesting therapeutic tractability. Together, these findings link a population-enriched missense variant to disrupted chromatin regulation, genome stability, and neurodevelopmental timing, bridging human genetic risk with cellular pathophysiology.

Lee S, Menzies L, Hay E, Ochoa E, Docquier F, Rodger F, Deshpande C, Foulds NC, Jacquemont S, Jizi K, Kiep H, Kraus A, Löhner K, Morrison PJ, Popp B, Richardson R, van Haeringen A, Martin E, Toribio A, Li F, Jones WD, Sansbury FH, Maher ER. Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders. Hum Mol Genet. 2023 Nov 3;32(22):3123-3134. doi: 10.1093/hmg/ddad079. PMID: 37166351; PMCID: PMC10630252.

Abstract

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

Eising E, Vino A, Mabie HL, Campbell TF, Shriberg LD, Fisher SE. Genome Sequencing of Idiopathic Speech Delay. Hum Mutat. 2024 Mar 28;2024:9692863. doi: 10.1155/2024/9692863. PMID: 40225914; PMCID: PMC11918988.

Abstract

Genetic investigations of people with speech and language disorders can provide windows into key aspects of human biology. Most genomic research into impaired speech development has so far focused on childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of FOXP2 provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of de novo variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in SETD1A, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic SETD1A variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of SPTBN1 and ARF3. Overall, this study expands the phenotype spectrum associated with pathogenic SETD1A variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.

PRRT2 mutations

Sun X, Geng L, Chen X. Distinct phenotypes differentiate paroxysmal kinesigenic dyskinesia from epilepsy in children with PRRT2 variants. Epileptic Disord. 2026 Jun 1. doi: 10.1002/epd2.70274. Epub ahead of print. PMID: 42223384.

Abstract

Objective: PRRT2 gene variations are commonly associated with paroxysmal kinesigenic dyskinesia (PKD) and epilepsy (EP). This study compares the clinical phenotypes of PKD and EP in relation to PRRT2, focusing on the association of the hotspot mutation c.649dupC (p.Arg217Profs*8).

Methods: We retrospectively analyzed PRRT2 cases from our hospital (2017-2025) and reviewed literature from major databases up to 2025. Pediatric patients (≤ 18 years) with either PKD or EP were included and categorized into sporadic and familial groups. Data on gender, onset age, and c.649dupC mutation prevalence were analyzed.

Results: In our cohort (41 patients), EP onset typically occurred in infancy (0.3-2.6 years), while PKD onset was during school age (8-13 years). The c.649dupC mutation rate was numerically higher in the PKD group (57%) than in the EP group (44%), but it was not statistically significant. From literature data (95 sporadic, 436 familial cases), EP was more frequent than PKD. The c.649dupC mutation rate was higher in PKD patients (77%) than in EP patients (66%) overall. This difference reached statistical significance in familial cases (84% vs. 71%, p < 0.05) but not in sporadic cases.

Significance: Among children with PRRT2 variations, EP is more common than PKD. The onset of EP is concentrated in early childhood, whereas PKD typically begins at school age, indicating age-dependent expression. The c.649dupC mutation shows a stronger association with the PKD phenotype in familial cases.

Sampath R, Somanna P, Gowda VK, Kolandaswamy A, K M, Kukkle PL. Genetic analysis of self-limiting familial infantile epilepsy caused by PRRT2 variants in Indian patients. Seizure. 2026 Aug;140:112-117. doi: 10.1016/j.seizure.2026.05.025. Epub 2026 May 25. PMID: 42269415.

Abstract

Introduction: Self-limiting familial infantile epilepsy (SeLFIE) is an epilepsy syndrome characterized by recurrent focal motor seizures. It follows an autosomal dominant inheritance pattern. Phenotypic and genetic heterogeneity of SeLFIE are associated with the PRRT2 gene, with the most common mutation being the frameshift variant c.649dupC. This study broadens the mutation spectrum of PRRT2 associated with SeLFIE.

Objective: To analyze the genotypic and phenotypic spectrum of SeLFIE in relation to PRRT2 gene variants.

Methodology: A cohort of fifteen pediatric probands diagnosed with SeLFIE was clinically evaluated and genetically screened for PRRT2 mutations using Sanger sequencing. Pathogenicity of the variants was classified according to American College of Medical Genetics and Genomics (ACMG) guidelines.

Results: Twelve out of fifteen patients (80%) harbored the common hotspot frameshift mutation c.649dupC (p.Arg217Profs*8) in the PRRT2 gene. Three exhibited different PRRT2 gene variants, including a frameshift c.649delC (p.Arg217Glufs*12), a missense c.696C>G (p.His232Gln), and a nonsense variant c.649C>T (p.Arg217*). Initially, all patients were treated with either sodium channel blockers or in combination with other antiseizure medications like levetiracetam/sodium valproate. Later, changed to sodium channel blockers (oxcarbazepine, phenytoin or carbamazepine) in all cases and achieved seizure-free status in all the patients.

Conclusion: Our study findings broaden the variant spectrum of PRRT2 in SeLFIE, while oxcarbazepine remains highly effective treatment for seizure control. Early-stage genetic analysis plays a crucial role in minimizing unnecessary diagnostic procedures and in guiding more effective disease management in SeLFIE patients.

Sun Y, Cao H, Wang X. Paroxysmal kinesigenic dyskinesia: clinical report of 10 cases from three pedigrees with literature review. Neurol Sci. 2026 May 22;47(6):510. doi: 10.1007/s10072-026-09099-w. PMID: 42168455.

Abstract

Objective: To characterize the clinical and genetic features of 10 paroxysmal kinesigenic dyskinesia (PKD) patients from three Chinese pedigrees, with emphasis on intrafamilial phenotypic variability and the broader PRRT2-associated disease spectrum.

Methods: Clinical data were collected from PKD patients attending the Department of Neurology, Second Hospital of Hebei Medical University (January 2023 - December 2024). Targeted next-generation sequencing of PKD-associated genes (PRRT2, TMEM151A, SCN8A, KCNA1, etc.) was performed for probands, followed by Sanger sequencing validation and family segregation analysis in available family members. Clinical features were analyzed in conjunction with literature review.

Results: Ten PKD cases from three families were identified. All patients exhibited exercise-induced dystonia, chorea, or athetosis without impaired consciousness; each episode lasted < 1 min. Interictal EEG and brain MRI were normal. Inheritance was autosomal dominant. Pathogenic variants were identified in PRRT2 (chromosome 16), including frameshift mutations c.649dup (p.Arg217ProfsTer8) and c.641delC (p.Arg217Glufs*12). Intrafamilial phenotypic variability was notable: the same c.649dup mutation produced clinically silent carriage in one father but severe daily attacks with secondary depression in another family member. In family 3, cold exposure was identified as a novel trigger.

Conclusion: This study expands the mutational spectrum of PRRT2-associated PKD in the Chinese population by documenting a relatively rare c.641delC variant. The marked intrafamilial variability observed supports the role of additional modifiers influencing clinical expression beyond the primary PRRT2 mutation.

Li M, Tan D, Zhu Y, Xiong Y, Zhu M, Zhou M, Hong D, Qiu Y. Clinical and Genetic Characteristics of Paroxysmal Kinesigenic Dyskinesia: A Single-Center Study and Literature Review. FASEB J. 2026 Jan 31;40(2):e71479. doi: 10.1096/fj.202502596R. PMID: 41553070.

Abstract

Paroxysmal kinesigenic dyskinesia (PKD) is a genetically heterogeneous movement disorder primarily associated with PRRT2 variants. Recently, TMEM151A and KCNJ10 have emerged as additional PKD-associated genes. However, genotype-phenotype correlations remain poorly defined. In this study, we retrospectively analyzed 41 PKD patients from a single center in Southeastern China. All patients underwent comprehensive clinical evaluation and whole-exome sequencing (WES), with variant classification based on ACMG guidelines. Additionally, we conducted a literature review of PKD cohorts published since 2021 to compare the clinical characteristics of patients carrying PRRT2, TMEM151A, KCNJ10 variants, and those without identified mutations. A genetic diagnosis was achieved in 19/41 patients (46.3%), with PRRT2 being the most frequent. We identified five novel variants, including two in KCNJ10, two in TMEM151A, and one in PNKD. Compared to other groups, PRRT2-positive patients had the earliest onset and highest treatment response. TMEM151A-positive patients tended to exhibit more frequent attacks and a lower response to carbamazepine. KCNJ10-positive patients presented with later onset and ultra-brief attacks. Genetically negative cases displayed distinct features, including fewer auras and more unilateral, ultra-brief episodes, yet responded well to carbamazepine. PKD exhibits significant genotype-dependent clinical heterogeneity. Novel variants in TMEM151A and KCNJ10 expand the mutational spectrum and suggest emerging genotype-specific phenotypic trends. Systematic genetic and phenotypic profiling may guide more precise diagnosis and management of PKD.

FLNA mutations

Inspired by a patient

Pai V, Shinar S, Krishnan P, Shannon P, Chitayat D, Fisher Y, Blaser S, Miller E. Periventricular Nodular Heterotopia, Cerebellar Hypodysgenesis, and Mesial Temporal Malformation Detected on Fetal MRI: An Underrecognized Association. AJNR Am J Neuroradiol. 2026 Jul 1;47(7):1953-1959. doi: 10.3174/ajnr.A9173. PMID: 41565358; PMCID: PMC13322346.

Abstract

Periventricular nodular heterotopia (PNH) is a neuronal migrational anomaly frequently associated with filamin-A (FLNA) gene variants. However, in the absence of a pathogenic FLNA gene or in the context of other genetic mutations, PNH may demonstrate a distinct pattern of distribution, often accompanied by a variety of brain abnormalities. PNH associated with cerebellar hypodysgenesis (CHD) and malformation of cortical development (MCD) involving the mesial temporal lobes, without detectable FLNA variants, is a known but under-reported association. PNH in this context demonstrates a phenotypically distinct distribution (ie, along the infrasylvian lateral ventricles). In this review, we report the prenatal MRI finding of this unusual association and provide key insights into this abnormality.

Yang L, Wu G, Yin H, Pan M, Zhu Y. Periventricular nodular heterotopias is associated with mutation at the FLNA locus-a case history and a literature review. BMC Pediatr. 2023 Jul 8;23(1):346. doi: 10.1186/s12887-023-04161-4. PMID: 37422633; PMCID: PMC10329368.

Abstract

Background: Periventricular nodular heterotopia (PNH), associated with FLNA mutations, is a rare clinical condition potentially associated with multiple systemic conditions, including cardiac, pulmonary, skeletal, and cutaneous diseases. However, due to a paucity of information in the literature, accurate prognostic advice cannot be provided to patients with the disease.

Case presentation: We report a 2-year-old female whose PNH was associated with a nonsense mutation in the q28 region of the X chromosome, in exon 31 of FLNA (c.5159dupA). The patient is currently seizure-free and has no congenital heart disease, lung disease or skeletal or joint issues, and her development is normal.

Conclusions: FLNA-associated PNH is a genetically-heterogeneous disease, and the FLNA mutation, c.5159dupA (p.Tyr1720*) is a newly identified pathogenic variant. FLNA characterization will help the clinical diagnosis and treatment of PNH and provide individualized genetic counseling for patients.

Loft Nagel J, Jønch AE, Nguyen NTTN, Bygum A. Phenotypic manifestations in FLNA-related periventricular nodular heterotopia: a case report and review of the literature. BMJ Case Rep. 2022 Apr 12;15(4):e247268. doi: 10.1136/bcr-2021-247268. PMID: 35414575; PMCID: PMC9006829.

Abstract

Periventricular nodular heterotopia (PVNH) is an X-linked disease caused by loss-of-function variants in the filamin A (FLNA) gene. FLNA-PVNH is a heterogeneous disorder, and the phenotype is associated with neurological and non-neurological features including cardiovascular, gastrointestinal, pulmonary, haematological, cutaneous and skeletal manifestations. No clear definition of the FLNA-PVNH phenotype has been established, but the patients are predominantly females with seizures, cardiovascular manifestations, and normal intelligence or mild intellectual disability. Herein, we describe a PVNH patient diagnosed with a novel heterozygous missense variant in FLNA after an atypical presentation of deep vein thrombosis and thrombocytopenia. Clinical evaluation found hypermobility, cardiovascular and skin manifestations. Moreover, we conducted a literature review of 186 FLNA-PVNH patients to describe the phenotypic spectrum. In conclusion, our patient highlights the importance of thorough clinical evaluation to identify manifestations in this very heterogeneous disorder. The phenotypic review may guide clinicians in the assessment and follow-up of FLNA-PVNH patients.

Lu YT, Hsu CY, Liu YT, Chan CK, Chuang YC, Lin CH, Chang KP, Ho CJ, Ng CC, Lim KS, Tsai MH. The clinical and imaging features of FLNA positive and negative periventricular nodular heterotopia. Biomed J. 2022 Jun;45(3):542-548. doi: 10.1016/j.bj.2021.05.003. Epub 2021 May 20. PMID: 35660364; PMCID: PMC9421925.

Abstract

Background: Periventricular nodular heterotopia (PVNH) is caused by abnormal neuronal migration, resulting in the neurons accumulate as nodules along the surface of the lateral ventricles. PVNH often cause epilepsy, psychomotor development or cognition problem. Mutations in FLNA (Filamin A) is the most common underlying genetic etiology. Our purpose is to delineate the clinical and imaging spectrum that differentiates FLNA-positive and FLNA-negative PVNH patients.

Methods: We included 21 patients with confirmed PVNH. The detailed clinical information, electroencephalography, and other clinical findings were recorded. Detailed brain MR imaging was assessed. Mutation analysis of the FLNA gene was used Sanger sequencing or a next generation sequencing based assay.

Results: FLNA mutations were identified in 9 patients (7 females and 2 males), including two nonsense, two splice site, three frameshift, and two missense mutations. In FLNA-positive group, 8 patients had anterior predominant bilateral symmetric presentation and only one had asymmetrical distribution and dilated ventricles. Extra-cerebral features were more often observed in FLNA-positive group than FLNA-negative group.

Conclusion: Genetics of PVNH is heterogenous, and mutations in FLNA gene account for less than half of the patients in our cohort. Our finding between FLNA-positive and FLNA-negative patients could guide the clinicians to select relevant genetic testing.