Thursday, October 30, 2025

A Mark Scher potpourri


Pardo AC, Agarwal S, Vollmer B, Venkatesan C, Scelsa B, Lemmon ME, Mulkey SB, Scher M, Hart AR, Gano D, Tarui T. Fetal Callosal Anomalies: A Narrative Review and Practical Recommendations for Pediatric Neurologists. Pediatr Neurol. 2025 Apr;165:117-127. doi: 10.1016/j.pediatrneurol.2025.01.022. Epub 2025 Feb 10. PMID: 40020510.

Abstract

Agenesis of the corpus callosum is a common indication for fetal neurology consultation, increasingly identified through advances in fetal sonography and fetal magnetic resonance imaging. Despite improvements in diagnostic accuracy, prognostic counseling is challenging due to highly variable neurodevelopmental outcomes. Several factors contribute to neurodevelopmental outcome variability, including associated anomalies and etiologic considerations such as genetic, acquired, and environmental factors. This narrative review discusses existing literature on prenatal findings, postnatal outcomes, and comorbidities to provide practical guidelines for prenatal diagnosis, counseling, and postnatal management. Additionally, practice and research gaps are identified to advocate for guidelines to improve counseling, management, and optimization of outcomes for affected children and families.

Venkatesan C, Gano D, Scelsa B, Vollmer B, Lemmon ME, Pardo AC, Mulkey SB, Tarui T, Scher M, Hart AR, Agarwal S. Prenatally Diagnosed Absent Septum Pellucidum and Septo-Optic Dysplasia: A Narrative Review and Practical Recommendations for Pediatric Neurologists. Pediatr Neurol. 2025 Mar;164:17-24. doi: 10.1016/j.pediatrneurol.2024.12.014. Epub 2024 Dec 30. PMID: 39827528.

Abstract

Evaluation of the cavum septum pellucidum is required in standard second-trimester screening fetal anatomy ultrasound scans. The absence of septum pellucidum triggers further evaluation and referral for subspecialty counseling. Absence of septum pellucidum is linked to other midline anomalies including septo-optic dysplasia. The purpose of this narrative review on absent septum pellucidum and septo-optic dysplasia is to discuss the literature, including pre- and postnatal management and neurodevelopmental outcome, provide practical recommendations, and outline research gaps to advance this nascent field.

Scelsa B, Gano D, Hart AR, Vollmer B, Lemmon ME, Tarui T, Mulkey SB, Scher M, Pardo AC, Agarwal S, Venkatesan C. Prenatally Diagnosed Holoprosencephaly: Review of the Literature and Practical Recommendations for Pediatric Neurologists. Pediatr Neurol. 2025 Jan;162:87-96. doi: 10.1016/j.pediatrneurol.2024.10.014. Epub 2024 Oct 26. PMID: 39577233.

Abstract

Holoprosencephaly (HPE) is one of the most common malformations in embryonic development. HPE represents a continuum spectrum that involves the midline cleavage of forebrain structures. Facial malformations of varying degrees of severity are also observed. It is probable that HPE results from a combination of genetic mutations and environmental influences during the initial weeks of pregnancy. Some patients with HPE experience early death, whereas others go on to experience neurodevelopmental impairment. Accurate fetal imaging can facilitate diagnosis and prenatal counseling, although more subtle brain abnormalities can be difficult to diagnose prenatally. Fetal counseling can be complex, given that the etiopathogenesis remains unclear and variable penetrance is prevalent in inherited genetic mutations. The aim of this narrative review is to examine the literature on HPE and to offer recommendations for pediatric neurologists for fetal counseling and postnatal care.

Friday, October 24, 2025

A rare form of Charcot-Marie-Tooth disease.

Isabelle Tate, born and raised in Nashville and a Middle Tennessee State University graduate, is remembered for her love of music, animal shelters, and friends. (Image: McCray Agency/Instagram)((Image: McCray Agency/Instagram))

Isabelle Adora Tate, a 23-year-old actress on "9-1-1: Nashville," died on Sunday. She was 23.

Her agent told Fox News Digital that "Isabelle ‘Izzy’ Tate had a rare form of Charcot-Marie-Tooth disease. She passed away peacefully on the 19th of October."

"The family requests privacy as they deal with this sudden and shocking loss," the agent reportedly said. Tate is survived by her mother, stepfather, father and sister.

What is Charcot-Marie-Tooth disease?

According to Mayo Clinic, Charcot-Marie-Tooth disease is a group of inherited conditions (passed down through families) that cause nerve damage. Charcot-Marie-Tooth disease is also called hereditary motor and sensory neuropathy.

Meanwhile, the National Institutes of Health described it as a genetic conditions that affect the nerves connecting the brain and spinal cord to the rest of the body.

Charcot-Marie-Tooth disease causes smaller, weaker muscles. It may also cause trouble walking and loss of feeling in the legs and feet, according to the Mayo Clinic.

Foot issues such as hammertoes and high arches are also common. Symptoms most often begin in the feet and legs. But in time, they may affect the hands and arms.

People with Charcot-Marie-Tooth disease most often get symptoms in the teen years or early adulthood. But symptoms also may start in midlife or in the toddler years.

What to know about Charcot-Marie-Tooth disease

Symptoms: Symptoms of Charcot-Marie-Tooth disease may include weakness in the legs, ankles and feet, muscle shrinking, high foot arches, curled toes (hammertoes), trouble walking, running, lifting the foot at the ankle; tripping or falling often and loss of feeling in the legs and feet. Other symptoms may include curved spine (scoliosis), nerve pain, hip displacement abd muscle cramps.

As per Mayo Clinic, these gene changes most often pass down through families. But new gene changes can happen when there's no family history of changed genes. Sometimes, these gene changes damage the nerve.

Prevention: Since Charcot-Marie-Tooth disease is a hereditary disease, there's no way to prevent it. If you have the condition, genetic testing may help you with family planning.

Who is more likely to get Charcot-Marie-Tooth disease? Those with a family history of Charcot-Marie-Tooth disease are more likely to develop it. However, if a person has CMT, that doesn’t mean their children will have it, but it does increase the risk, the NIH said.

Isabelle Tate diagnosed with Charcot-Marie-Tooth disease at 13

Isabelle Tate was in a wheelchair due to a rare neuromuscular disease, which she opened up about on her Instagram in 2022.

"When I was 13, I got diagnosed with a progressive neuromuscular disease that weakens my leg muscles over time. When I was first diagnosed, I couldn’t fully understand what it was or grasp what it could be," she wrote at the time.

She said, “Recently, it’s really progressed and I’ve come to terms that if I want to live my life to the fullest I need to use a wheelchair at time.”

"This has been a difficult journey for me because having to accept help and surrender to the progression of this condition has been extremely hard. While I was trying to come to terms with this, I really did find that I lost myself in certain ways," she said.

"I hated that it was not only breaking me down physically, but I was allowing it to also break down my spirit," she added.

Akriti Anand

https://www.livemint.com/us/hollywood/isabelle-tates-cause-of-death-confirmed-what-is-charcot-marie-tooth-disease-11761263483669.html

Thursday, October 23, 2025

Grayson's syndrome

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

PCDH19 epilepsy

Inspired by a patient

Tobiasz A, Hager M, Dębowska J, Jaunich A, Paprocka J. Tough to treat: What we know about managing PCDH19-related epilepsy - Systematic review. Seizure. 2025 Aug 26;132:98-109. doi: 10.1016/j.seizure.2025.08.030. Epub ahead of print. PMID: 40934839.

Abstract

Background: PCDH19-related epilepsy is a rare, X-linked developmental and epileptic encephalopathy that primarily affects heterozygous females. It is caused by pathogenic variants in the PCDH19 gene, encoding protocadherin-19, a calcium-dependent adhesion protein involved in neurodevelopment. The disorder's hallmark is cellular interference, leading to brain mosaicism and clinical features including early-onset clustered focal seizures, cognitive impairment, and frequent comorbidity with autism.

Objective: This review synthesizes current evidence on treatment approaches for PCDH19-related epilepsy, covering conventional anti-seizure medications, adjunctive therapies, and non-pharmacological interventions, while highlighting emerging strategies and research gaps.

Methods: A systematic literature search was conducted in PubMed and Scopus (January 2008 - April 2025).

Results: 27 studies were included, involving patients with genetically or clinically confirmed PCDH19-related epilepsy and reported treatment outcomes. The condition is often pharmacoresistant, with highly variable responses. Levetiracetam, especially when initiated early, showed the most consistent seizure reduction, followed by clobazam and potassium bromide. Topiramate and stiripentol showed potential in isolated reports. Carbamazepine was often ineffective or worsened seizures. Adjunctive agents - including corticosteroids, ganaxolone - had variable efficacy; ganaxolone showed promise in recent trials. Non-pharmacological interventions, like vagus nerve stimulation, ketogenic diet, and temporal lobectomy, reduced seizures in some cases but lacked standardized evidence.

Conclusions: Treatment remains challenging due to clinical heterogeneity and limited high-quality data. Early, individualized, multimodal approaches appear most beneficial. There is a need for genotype-informed, multicenter trials and standardized outcome measures to guide evidence-based care.

Hu W, Zhao F, Ren Y, Zhang H, Li X. Abdominal pain as a novel manifestation in children with PCDH19-related epilepsy: A case report. Medicine (Baltimore). 2025 Jan 10;104(2):e41211. doi: 10.1097/MD.0000000000041211. PMID: 39792735; PMCID: PMC11730840.

Abstract

Rationale: PCDH19-related epilepsy manifested various clinical features, including febrile epilepsy, with or without intellectual disability, and psych-behavioral disorders. However, there are few studies demonstrating abdominal pain as the first symptom.

Patient concerns: A 3-year-old Chinese girl presented with clustered seizures of fever sensitivity accompanied by abdominal pain.

Diagnoses: After ultrasonography ruled out abdominal organic lesions, electroencephalographic (EEG) identified abdominal pain was a seizure feature. Trio whole-exome sequence demonstrated a de novo and heterozygous PCDH19 missense mutation (NM_001184880: c.824A>G, P.Y275C), which was confirmed by Sanger sequence. The final diagnosis were "PCDH19-related epilepsy; abdominal pain."

Interventions: At first, she was treated ineffectively by levetiracetam and valproate. Finally, she was provided with topiramate (TPM).

Outcomes: The patient had gained seizure-free, and the follow-up EEG discharges were reduced.

Lessons: Abdominal pain is a rare autonomic symptom in the setting of seizures. This report describes abdominal pain as a novel manifestation of PCDH19-related epilepsy and might expand its phenotypes spectrum. It also alerts us to perceive the abdominal pain characterized by seizures and early conduct EEG examination to clarify the nature of abdominal pain.

Feng W, Wang Z, Wang X, Chen S, Chen X, Chen C, Deng J, Zhuo X, Wang J. Phenotypic and genotypic characteristics of children with PCDH19 clustering epilepsy in China. Seizure. 2024 Oct;121:95-104. doi: 10.1016/j.seizure.2024.07.023. Epub 2024 Jul 31. PMID: 39146709.

Abstract

Purpose: PCDH19 gene variants, termed PCDH19 clustering epilepsy, represent a distinct etiology of epilepsy. This study aimed to elucidate the clinical manifestations and explore the genotypes and phenotypes of children affected by PCDH19 clustering epilepsy.

Methods: This retrospective study included medical history, magnetic resonance imaging, video-electroencephalography, and genetic analysis of patients diagnosed with PCDH19 Clustering Epilepsy at the Neurology Department of Beijing Children's Hospital from 2015 to 2023. Chi-square tests and logistic regression analyses were conducted to study the factors associated with developmental delay in patients.

Results: The age at seizure onset ranged from 5 to 61 months among all 30 patients (median 14 months; IQR 9.25-22.5 months). Among the 30 patients, 29 were female and 1 was male. Clusters of seizures and fever-triggered seizures were observed, with the most prevalent seizure types being focal to bilateral tonic-clonic seizures (FBTCS). Seizures were successfully controlled in 15 patients. Unfortunately, one patient experienced a sudden unexpected death in epilepsy (SUDEP). Additionally, 14 patients had hereditary mutations, 14 had de novo mutations, 1 had both hereditary and de novo mutations, and 1 male patient had a mosaic component mutation of 0.64 due to a somatic mutation. Developmental delays were identified in 17 patients (56.7 %), and 6 patients (20 %) were diagnosed with autism spectrum disorder (ASD). Among the 17 patients, 9 experienced developmental delays before the onset of epilepsy, while 8 were initially normal but later developed developmental delays during disease progression. Statistical analysis revealed that the presence of drug-resistant epilepsy was an independent risk factor for the occurrence of developmental delays (P = 0.020, OR = 9.758, 95 % CI (1.440-66.111)).

Conclusion: In this study, 13 new potential rare pathogenic variations in PCDH19 clustering epilepsy were identified. The clinical features observed in patients are consistent with known phenotypic features, and we found that patients with drug-resistant epilepsy are more likely to have developmental delays. The severity of the phenotype in patients with PCDH19 variants ranged from drug-responsive seizures to refractory epilepsy.

Kowkabi S, Yavarian M, Kaboodkhani R, Mohammadi M, Shervin Badv R. PCDH19-clustering epilepsy, pathophysiology and clinical significance. Epilepsy Behav. 2024 May;154:109730. doi: 10.1016/j.yebeh.2024.109730. Epub 2024 Mar 22. PMID: 38521028.

Abstract

PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability (ID) and behavioral disturbances, which is caused by PCDH19 gene variants. PCDH19 pathogenic variant leads to epilepsy in heterozygous females, not in hemizygous males and the inheritance pattern is unusual. The hypothesis of cellular interference was described as a key pathogenic mechanism. According to that, males do not develop the disease because of the uniform expression of PCDH19 (variant or wild type) unless they have a somatic variation. We conducted a literature review on PCDH19-CE pathophysiology and concluded that other significant mechanisms could contribute to pathogenesis including: asymmetric cell division and heterochrony, female-related allopregnanolone deficiency, altered steroid gene expression, decreased Gamma-aminobutyric acid receptor A (GABAA) function, and blood-brain barrier (BBB) dysfunction. Being aware of these mechanisms helps us when we should decide which therapeutic option is more suitable for which patient.

Wednesday, October 22, 2025

Influenza-associated acute necrotizing encephalopathy

Influenza-Associated Acute Necrotizing Encephalopathy (IA-ANE) Working Group; Silverman A, Walsh R, Santoro JD, Thomas K, Ballinger E, Fisher KS, Thomas AX, Appavu B, Kruer MC, Neilson D, Knoll J, Sharp AN, Edelman HE, Otallah S, Morgan A, Grzezulkowska A, Nguyen J, Rao LM, Hecht SM, Catalano L, Daigle H, Kronfol C, Wharton J, Adams D, Kalawi AZ, Kung M, Arellano JL, Smith L, Segal D, Feja K, Broomall E, Jayakar A, Arnold SR, Retallack H, Press CA, Gombolay G, McLaughlin MH, Kannan V, Thakkar K, Rezwan T, Hulfish E, Eid D, Meylor J, Peng D, Hurtado R, Nickerson T, Mandell I, Carbonell AU, Kerner-Rossi M, Jayaraman D, Davis M, Olivero R, Shah N, Osborne CM, Zhang B, Cortina C, Randolph AG, Rao S, LaRocca T, Van Haren KP, Wilson-Murphy M. Influenza-Associated Acute Necrotizing Encephalopathy in US Children. JAMA. 2025 Aug 26;334(8):692-701. doi: 10.1001/jama.2025.11534. PMID: 40736730; PMCID: PMC12311823.

Abstract

Importance: Acute necrotizing encephalopathy (ANE) is a rare, but severe, neurologic condition for which epidemiologic and management data remain limited. During the 2024-2025 US influenza season, clinicians at large pediatric centers anecdotally reported an increased number of children with influenza-associated ANE, prompting this national investigation.

Objective: To understand the clinical presentation, interventions, and outcomes among US children diagnosed with influenza-associated ANE.

Design, setting, and participants: This study was a multicenter case series of children diagnosed with ANE with longitudinal follow-up. A call for cases was issued via academic societies, public health agencies, and by directly contacting pediatric specialists at 76 US academic centers, requesting cases between October 1, 2023, and May 30, 2025. Inclusion criteria required acute encephalopathy with radiologic evidence of acute thalamic injury and laboratory confirmation of influenza infection in individuals aged 21 years or younger.

Exposure: Influenza-associated ANE.

Main outcomes and measures: Presenting symptoms, vaccination history, laboratory and genetic findings, interventions, and clinical outcomes, including modified Rankin Scale score (0: no symptoms; 1-2: mild disability; 3-5: moderate to severe disability; 6: death), length of stay, and functional outcomes.

Results: Of 58 submitted cases, 41 cases (23 females; median age, 5 years [IQR, 2-8]) from 23 US hospitals met inclusion criteria. Thirty-one cases (76%) had no significant medical history; 5 (12%) were medically complex. Clinical presentation included fever in 38 patients (93%), encephalopathy in 41 (100%), and seizures in 28 (68%). Thirty-nine patients (95%) had influenza A (14 with A/H1pdm/2009, 7 with A/H3N2, and 18 with no subtype) and 2 had influenza B. Laboratory deviations included elevated liver enzymes (78%), thrombocytopenia (63%), and elevated cerebrospinal fluid protein (63%). Among 32 patients (78%) with genetic testing, 15 (47%) had genetic risk alleles potentially related to risk of ANE including 11 (34%) with RANBP2 variants. Among 38 patients with available vaccination history, only 6 (16%) had received age-appropriate seasonal influenza vaccination. Most patients received multiple immunomodulatory treatments, including methylprednisolone (95%), intravenous immunoglobulin (66%), tocilizumab (51%), plasmapheresis (32%), anakinra (5%), and intrathecal methylprednisolone (5%). Median intensive care unit and hospital lengths of stay were 11 days (IQR, 4-19) and 22 days (IQR, 7-36), respectively. Eleven patients (27%) died a median of 3 days (IQR, 2-4) from symptom onset, primarily from cerebral herniation (91%). Among the 27 survivors with 90-day follow-up, 63% had at least moderate disability (modified Rankin Scale score ≥3).

Conclusions and relevance: In this case series of children with influenza-associated ANE from the 2 most recent influenza seasons in the US, the condition was associated with high morbidity and mortality in this cohort of predominantly young and previously healthy children. The findings emphasize the need for prevention, early recognition, intensive treatment, and standardized management protocols.

Fazal A, Harker EJ, Neelam V, Olson SM, Rolfes MA, Reinhart K, Kniss K, Frutos A, Leonard J, Reed C, Dugan VG, Safi H, Dulski TM, Stanley-Downs A, Bhatti A, Armistead I, Rao S, Torres-Diaz C, Thomas A, Weigel A, Patten M, Sinner M, Nims D, Mattingly C, Gosack V, Voris A, Redkey J, Scaggs Huang FA, DeCesaris D, Tuggle C, Betters KA, Hand J, Krueger A, Potter DZ, Kim C, Park R, Hong S, Edelman HE, Kim S, Henderson J, McMahon M, Sanders J, Hunstad DA, Doran EL, Harbi K, Julian D, Ball H, Dreisig J, Thomas D, Faybusovich J, Shaw YP, Eisenberg N, Chaturvedi R, Faulstich A, Wester RE, Gowie DL, Fisher N, Sutton M, Boktor SW, Long JM, Marshall P, Berns AL, McAda L, Winders S, Gomez Pinedo P, Murray J, Westbrook T, Unutzer A, Lindquist S, Haupt TE, Baum K, Wilson-Murphy M, Glaser C, Harriman K, Antoon JW, Van Haren KP, Randolph AG, Silverman A, de St Maurice A, Ellington S, Uyeki TM, Garg S; CDC Influenza-Associated Encephalopathy Collaborators. Pediatric Influenza-Associated Encephalopathy and Acute Necrotizing Encephalopathy - United States, 2024-25 Influenza Season. MMWR Morb Mortal Wkly Rep. 2025 Sep 25;74(36):556-564. doi: 10.15585/mmwr.mm7436a1. PMID: 40996921; PMCID: PMC12463191.

Abstract

In January 2025, CDC received several reports of deaths among children aged <18 years with a severe form of influenza-associated encephalopathy (IAE) termed acute necrotizing encephalopathy (ANE). Because no national surveillance for IAE currently exists, CDC requested notification of U.S. pediatric IAE cases from clinicians and health departments during the 2024-25 influenza season, a high-severity season with a record number of pediatric influenza-associated deaths. Among 192 reports of suspected IAE submitted to CDC, 109 (57%) were categorized as IAE, 37 (34%) of which were subcategorized as ANE, and 72 (66%) as other IAE; 82 reports did not meet IAE criteria and were categorized as other influenza-associated neurologic disease. The median age of children with IAE was 5 years and 55% were previously healthy, 74% were admitted to an intensive care unit, and 19% died; 41% of children with ANE died. Only 16% of children with IAE who were vaccination-eligible had received the 2024-25 influenza vaccine. Health care providers should consider IAE in children with encephalopathy or altered level of consciousness and a recent or current febrile illness when influenza viruses are circulating. Annual influenza vaccination is recommended for all children aged ≥6 months to prevent influenza and associated complications, potentially including severe neurologic disease such as IAE and ANE.

Silverman A, Sasaki M, Espíndola Lima JE, Cheronis C, Lin GL, Johnson A, Dahmoush H, Archer E, Grekov K, LaRocca TJ, Van Haren K. Child Neurology: Remarkable Recovery From Severe Acute Necrotizing Encephalopathy. Neurology. 2024 Oct 22;103(8):e209877. doi: 10.1212/WNL.0000000000209877. Epub 2024 Sep 19. PMID: 39298704.

Abstract

A previously healthy 6-year-old girl presented with several days of fever before a generalized seizure. Laboratory investigation revealed elevated liver enzymes, normal ammonia, and positive influenza A through respiratory PCR. Brain MRI demonstrated extensive, bilateral lesions in the cerebral and cerebellar white matter, thalami, basal ganglia, and brainstem. She was diagnosed with acute necrotizing encephalopathy, a rare parainfectious encephalitis commonly associated with influenza. Genetic variants have been implicated (e.g., RANBP2 and RNH1), but our patient's rapid genome was nondiagnostic. Her 1-month hospitalization was complicated by prolonged encephalopathy and intracranial pressure crises requiring hyperosmolar therapy, sedation, intermittent paralysis, and hypothermia. Concomitantly, she received pulse corticosteroids, plasmapheresis, and oseltamivir. Three months after illness onset, she achieved a remarkable recovery with a normal neurologic examination. Although prognosis may comprise considerable morbidity and mortality, prompt recognition, immunotherapy, and intensive care can achieve positive neurodevelopmental outcomes. Our discussion concludes with a focus on the intrinsic uncertainties of neuroprognostication in the pediatric intensive care unit.

Monday, October 20, 2025

TRAPPC4-related neurodevelopmental disorder

Forno A, Oliveira J, Amorim MZ, Conceição C, Sousa PR. Child Neurology: TRAPPC4-Related Neurodevelopmental Disorder. Neurology. 2025 May 13;104(9):e213538. doi: 10.1212/WNL.0000000000213538. Epub 2025 Apr 2. PMID: 40173375.

Abstract

Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, first described in 2020, is associated with autosomal recessive inheritance of pathogenic variant in the TRAPPC4 gene. Given a relatively high carrier frequency, it is crucial to recognize and consider this diagnosis. We report 2 sisters with pathogenic homozygous variants (c.454+3A>G) in the TRAPPC4 gene, diagnosed after an extensive and time-consuming clinical investigation. This report reviews the phenotypic spectrum of TRAPPC4-related neurodevelopmental disorder, particularly homozygous pathogenic variant c.454+3A>G in TRAPPC4, to raise awareness of this diagnosis.

Ghosh SG, Scala M, Beetz C, Helman G, Stanley V, Yang X, Breuss MW, Mazaheri N, Selim L, Hadipour F, Pais L, Stutterd CA, Karageorgou V, Begtrup A, Crunk A, Juusola J, Willaert R, Flore LA, Kennelly K, Spencer C, Brown M, Trapane P, Hurst ACE, Lane Rutledge S, Goodloe DH, McDonald MT, Shashi V, Schoch K; Undiagnosed Diseases Network; Tomoum H, Zaitoun R, Hadipour Z, Galehdari H, Pagnamenta AT, Mojarrad M, Sedaghat A, Dias P, Quintas S, Eslahi A, Shariati G, Bauer P, Simons C, Houlden H, Issa MY, Zaki MS, Maroofian R, Gleeson JG. A relatively common homozygous TRAPPC4 splicing variant is associated with an early-infantile neurodegenerative syndrome. Eur J Hum Genet. 2021 Feb;29(2):271-279. doi: 10.1038/s41431-020-00717-5. Epub 2020 Sep 8. PMID: 32901138; PMCID: PMC7868361.

Abstract

Trafficking protein particle (TRAPP) complexes, which include the TRAPPC4 protein, regulate membrane trafficking between lipid organelles in a process termed vesicular tethering. TRAPPC4 was recently implicated in a recessive neurodevelopmental condition in four unrelated families due to a shared c.454+3A>G splice variant. Here, we report 23 patients from 17 independent families with an early-infantile-onset neurodegenerative presentation, where we also identified the homozygous variant hg38:11:119020256 A>G (NM_016146.5:c.454+3A>G) in TRAPPC4 through exome or genome sequencing. No other clinically relevant TRAPPC4 variants were identified among any of over 10,000 patients with neurodevelopmental conditions. We found the carrier frequency of TRAPPC4 c.454+3A>G was 2.4-5.4 per 10,000 healthy individuals. Affected individuals with the homozygous TRAPPC4 c.454+3A>G variant showed profound psychomotor delay, developmental regression, early-onset epilepsy, microcephaly and progressive spastic tetraplegia. Based upon RNA sequencing, the variant resulted in partial exon 3 skipping and generation of an aberrant transcript owing to use of a downstream cryptic splice donor site, predicting a premature stop codon and nonsense mediated decay. These data confirm the pathogenicity of the TRAPPC4 c.454+3A>G variant, and refine the clinical presentation of TRAPPC4-related encephalopathy.

Van Bergen NJ, Guo Y, Al-Deri N, Lipatova Z, Stanga D, Zhao S, Murtazina R, Gyurkovska V, Pehlivan D, Mitani T, Gezdirici A, Antony J, Collins F, Willis MJH, Coban Akdemir ZH, Liu P, Punetha J, Hunter JV, Jhangiani SN, Fatih JM, Rosenfeld JA, Posey JE, Gibbs RA, Karaca E, Massey S, Ranasinghe TG, Sleiman P, Troedson C, Lupski JR, Sacher M, Segev N, Hakonarson H, Christodoulou J. Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability. Brain. 2020 Jan 1;143(1):112-130. doi: 10.1093/brain/awz374. Erratum in: Brain. 2020 Mar 1;143(3):e24. doi: 10.1093/brain/awaa007. PMID: 31794024; PMCID: PMC6935753.

Abstract

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.

Child’s rare neurodegenerative disease fuels therapy innovation

A family’s journey navigating an 8-year-old boy’s rare neurodegenerative CLCN6 mutation highlights diagnostic challenges and hope through emerging gene therapy research.

For families of children with life-threatening neurologic conditions, a diagnosis marks the beginning of an urgent and uncertain medical journey. This is especially true in cases of rare diseases where therapeutic options are limited, clinical trials are scarce, and research is still catching up to the need.

The parents of Paxton Purdy, an 8-year-old boy from Southern California, learned this firsthand when their son was diagnosed with a mutation on the CLCN6 gene in January 2024. This gene “encodes a member of the voltage-dependent chloride channel protein family”; CLCN6 mutations have been linked to severe early-onset neurodegeneration.

While the diagnosis explained his symptoms that were initially attributed to autism spectrum disorder (ASD), it also heightened fears for Paxton’s future and launched a quest for a cure with the help of experts at UMass Chan Medical School in Worcester, Massachusetts. Paxton’s parents founded Cure CLCN6, Inc., a 501(c)(3) organization aimed at raising funds for Paxton’s experimental gene therapy at the University of Massachusetts and to connect with others affected by CLCN6 gene mutations.

In this patient perspective, we spoke with Paxton’s father, Paul Purdy, about the family’s experience, their ongoing collaboration with clinicians and scientists, and the urgent need for progress in treating CLCN6-related disease.

Instead of our days being filled with dread and despair, we have hope and optimism, and this drives us to keep fighting for our son and the other children with CLCN6 mutations that we are finding on this journey.

How would you describe your family’s experience with the health care system — from Paxton’s first symptoms to diagnosis and now, as you await treatment?

Purdy: Paxton was suspected of [having autism] when he turned 1 and began early intervention services, specifically applied behavior analysis (ABA) therapy, speech therapy, and occupational therapy. All of his challenges at that time were attributed to autism — global developmental delay, apraxia of speech, poor motor planning, hypotonia, and intellectual disability.

When Paxton was 5, he began having seizures. He had undergone microarray testing when he was 2, looking for markers to explain autism or intellectual disability. He then underwent more genetic testing looking for markers to explain epilepsy, and nothing came up. The CLCN6 mutation was not discovered until an epileptologist ordered testing for him since the epilepsy was refractory. The health care we received was appropriate based on the autism diagnosis, and the medical providers and therapists we interacted with were great.

Purdy: It wasn’t until we received the CLCN6 mutation diagnosis that things became discouraging. The genetic counselor can only go on the information available and what current treatments are available. However, I do find it frustrating as a parent to know that the technology and ability to create gene therapies for genetic mutations is possible, but we were given zero direction on what to do or who to contact [to pursue these options]. We were left in shock and in the cycle of grief to navigate this new rare disease world.

The other families that have reached out to us at Cure CLCN6, Inc. have reported similar stories. They were told their child has this mutation, but it has only recently been diagnosed, so not much is known about it except that it is neurodegenerative and 2 of the 4 children reported in the literature have passed away. The families we’ve been in contact with are in the United States, Mexico, and Scotland. 

Can you share how the collaboration with UMass Chan Medical School was initiated and what it has meant for your family’s care journey?

Purdy: [Upon receiving his diagnosis] I relentlessly looked for doctors, researchers, hospitals, and universities that may be able to work with us. There were some phone calls with researchers, but the research hospitals and universities we reached out to did not respond to our inquiries. One night I came across a news article about a family in Oregon who had a son with an ultra-rare mutation, and they were working with UMass Chan Medical School to develop a gene therapy. I thought, ‘That’s what I want for Paxton!’ I reached out to the UMass Chan Medical School Horae Gene Therapy Center, and they responded right away to set up a call with us.

It has been a rollercoaster of emotions, as all I wanted when we received the diagnosis was for someone to say they can help us. But as I am learning on this journey, genetics is incredibly complex, and it takes years to develop a gene therapy. Also, there are things that can go wrong in the development process, and the procedure itself has risks. There is also the fact that there are limitations to what gene therapies can do right now — not to mention the overwhelming price tag of $1.5 million that this project has.

Overall, we are incredibly grateful and fortunate to be in this position and to have this opportunity. Instead of our days being filled with dread and despair, we have hope and optimism, and this drives us to keep fighting for our son and the other children with CLCN6 mutations that we are finding on this journey.

In what ways could this research and investigational treatment help inform future approaches to developing therapies for other rare diseases?

Purdy: Gene therapy as a field is still in its infancy, so researchers are still learning with each project and study that is being done. One of the biggest challenges with treating mutations affecting the central nervous system (CNS) is crossing the blood brain barrier. With this project, they may use some newer capsids that can bind more effectively to the transferrin, which means that many more of the cells can be treated. If this delivery method is found to be safe and efficient and is ultimately used, it would provide real-time evidence on its effectiveness, and this would have major ramifications on more effectively delivering therapeutics to cells in the brain. 

What should health care providers understand about the needs and challenges faced by families navigating a rare disease diagnosis and treatment?

Purdy: I remember when we received the diagnosis and were told that this mutation is neurodegenerative and that there is no treatment and no cure. [Clinicians] told me that they would learn more about this mutation by studying Paxton, but my only thought was, ‘What can I do to help my son?’ I would have felt some relief and had more direction if the genetics team had told me that while there is currently no treatment and no cure, the technology and ability to develop a treatment — and 1 day, even a cure — exists, and that there are research hospitals and scientists who may be willing to work with us if we can fund the project.

I understand that this is considered experimental and there are likely liability concerns with suggesting this to patients, but I would have felt a lot better knowing that something could be done, despite the price tag, and having some leads or recommendations on who to contact would have alleviated a lot of grief and anxiety. 

How can clinicians best support and advocate for patients and families throughout the diagnostic and treatment journey for rare diseases?

Purdy: The journey from initial symptoms to diagnosis can take months, if not years for most patients with rare diseases. After learning more about rare diseases, especially ones that impact the CNS, there is a consensus that if a child is exhibiting 2 or more challenges in neuromuscular areas, then whole exome testing should be done. This could be a combination of autism (especially when nonverbal), intellectual disability, poor motor planning, hypotonia or hypertonia, feeding difficulties, seizures, digestive issues, or sleep disturbance.

Many children will have these traits without a genetic mutation, but we are learning that many of these mutations present very similarly with these neurologic challenges. So, if clinicians are seeing patients with 2 or more of these symptoms, they should refer them to a geneticist and order whole exome sequencing.

In many cases, like with Paxton’s, a mutation can be neurodegenerative, so time is critical. When that diagnosis is made, I understand that doctors are only going to use US Food and Drug Administration (FDA)-approved treatments, but many parents, like me and my wife Kristin, are willing to pursue these opportunities and fundraise to develop novel treatments. When it comes to ultra-rare diseases, if the families of the affected children don’t take the lead, then the research and development is not going to happen.

I would want clinicians to at least let these families know that these opportunities are out there and to form relationships with research hospitals that may be willing and able to work with these families on novel treatments. I would also want them to refer families to patient advocacy groups for the respective disease, so collectively we can show a need for funding the research and development into treatments for our respective diseases and mutations. 

What additional reflections from your experience might be valuable for clinicians to hear?

Purdy: Having a child with special needs is incredibly challenging on all levels, especially in terms of the emotional and mental toll it takes on parents. When a child has a rare disease diagnosis that can lead to death, we are not only grieving the childhood and life we envisioned for them before they were born, but we are now struggling with the reality that our child may pass away before us. This is a devastating experience for us, and it is not a transitory one. Please be patient with us, we are doing the best we can despite the circumstances.

Tori Rodriguez, MA, LPC, AHC

https://www.neurologyadvisor.com/features/rare-neurodegenerative-disease-diagnosis-child/

Rasmussen syndrome without seizures

Morgan LE, Eschbach K, Gilani A, Kammeyer R. Child Neurology: A Case of Rasmussen Syndrome Without Seizures. Neurology. 2025 Jul;105(1):e213800. doi: 10.1212/WNL.0000000000213800. Epub 2025 Jun 5. PMID: 40472308.

Abstract

Rasmussen syndrome (RS) is a neuroimmune disease typically characterized by refractory focal epilepsy, epilepsia partialis continua, progressive focal neurologic deficits, and cognitive impairment. Seizures are often a presenting and prominent symptom, but RS may be diagnosed in the absence of seizures when a patient has 2 of the 3 Part B Bien criteria: (1) consistent histopathologic findings, (2) progression in unilateral cortical deficits, or (3) progression in focal cortical atrophy. We describe a patient who presented with hemiparesis and unihemispheric atrophy, meeting Bien criteria through progressive clinical changes and consistent histopathology on a brain biopsy. She did not have progression in focal cortical atrophy on imaging at the time of diagnosis. The patient has not developed seizures in the 4.5 years of monitoring after symptom onset. Our case illustrates that the underlying pathophysiology of RS is an immune-driven, progressive neurodegenerative disorder, which frequently-but not always-causes seizures.

A ribosomopathy masquerading as cerebral palsy.

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

Abstract

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

Sunday, October 19, 2025

Life is worth living, even when we are dying

In the spring of 2022, Canadian teenager Markus Schouten’s dying wish was that no child should be forced to choose between life and death.

Markus had just learned he was about to die. His oncologist broke the news to him and his family on the eighth floor cancer ward at British Columbia Children's Hospital in Vancouver, Canada. They held each other, weeping.

Weeks later, lying on his family’s living room sofa, Markus dictated a letter to the Canadian Parliament’s Special Joint Committee on Medical Assistance in Dying, established to set guidelines on a federal law that allowed "assisted suicide" in Canada in 2016.




Markus opposed lobbying efforts to expand the law to children under the age of 18.

"That’s because life is worth living and we should always work to alleviate suffering without eliminating the sufferer," read the final letter, which was signed by his parents.

The letter closed, "Life is worth living, even when we are dying."

A month later, Markus died, surrounded by his family and friends, telling them, "See you in paradise."

Three years later, his parents, Mike and Jennifer Schouten, are carrying the torch for Markus in a mission to block efforts to allow "mature minors" the right to choose to die through assisted suicide. They now work alongside a global network of like-minded advocates, including disability rights groups, who argue the assisted-suicide industry targets vulnerable people who would benefit from assisted living services. Already, in Canada, the law is expected to expand to patients with severe psychiatric disorders, as early as 2027.

But they are up against a powerful, well-funded machine. A Fox Digital investigation reveals the Schoutens and other opponents of euthanasia face a multimillion-dollar global lobby that could be called Assisted Suicide Inc., a sprawling network changing laws worldwide, developing euthanasia services for funeral parlors, selling "suicide pods," promoting "suicide tourism" and even training "doulas for death."

"As we continue to expand the euthanasia regime, all the safeguards and windows have gone out the window," said Mike Schouten. "And it becomes open season for anyone to choose death, including children."

What began as a limited effort to provide adults with terminal illnesses the ability to end pain and suffering has now grown into an international industry. According to a database compiled by the Pearl Project, a nonprofit journalism initiative, at least 96 organizations worldwide are now part of this movement.

The global lobby cloaks assisted suicide in the language of civil rights and human rights, using euphemisms in their names, such as "assisted dying," "medical assistance in dying," "dying with dignity," "choice," "end of life," "completed life," "final exit," "free exit" and the "right to die."

These groups have a presence on every continent, but are predominately found in the West, which also faces alarmingly low birth rates. There are 41 groups in Europe; 31 groups in North America, with 25 of them in the United States, four in Canada and two in Mexico; 13 in Oceania, with most in Australia and one in New Zealand; and only five in Asia, two in Africa, and three in South America.

While most of their work has focused on adults, with Robert Munsch, the Canadian author of the best-selling children’s book, "Love You Forever," the latest high-profile person to recently announce he was approved for assisted suicide after being diagnosed with dementia. "Hello, Doc — come kill me!" he joked, sharing the news.

The boundaries are shifting. Behind the push to extend these laws to children lies a legal Trojan horse: the "mature minor doctrine."

This concept, first established in a 1967 Washington Supreme Court case, Smith v. Seibly, once allowed limited medical discretion for minors. But over decades, it has metastasized into a sweeping jurisdiction for granting children autonomy – and secrecy – over their medical decisions. Today, it lets minors make choices without parental involvement on gender pronouns, gender transitions, contraception and abortion. In 13 U.S. states and the District of Columbia, minors can even obtain abortions without parental knowledge.

Now, advocates are leveraging that same doctrine to argue that children should have the "medical autonomy" to choose death. The "National Youth Rights Association," a 501(c)(3) nonprofit based in Hyattsville, Md., uses the "mature minors" to die by physician-assisted suicide.

Euthanasia is already legal for adults in Australia, Belgium, Colombia, the Netherlands, New Zealand, Spain and 11 U.S. states. But three countries – the Netherlands, Belgium and Colombia – have gone further, allowing "mature minors" to die by physician-assisted suicide.

In February 2023, despite the pleas of Marcus and his parents, Canada’s Special Joint Committee on Medical Assistance in Dying recommended extending the right to some youth, declaring that parents should be "consulted" but that the "will of a minor" with decision-making capacity "ultimately takes priority."

The same debate has now reached the United Kingdom, where a bill to allow adult euthanasia is moving through the British Parliament. Earlier this year, the British House of Commons narrowly voted 259 to 216 to bar physicians from discussing assisted suicide with youth, meaning nearly half of lawmakers supported discussing assisted suicide for youth.

Katharine Birbalsingh, a British educator known as "Britain’s Strictest Headmistress," believes it’s only a matter of time before youth are included.

"Assisted suicide will spread, full stop," she told Fox Digital. "And the people allowed to do assisted suicide will grow, making it younger and younger."

Birbalsingh argues that Western societies have fallen for the dangerous illusion that "the child must lead," leading to thinking such as "Oh, he wants to change his gender, or he wants to commit suicide."

"Once upon a time," she said, "adults used to say, ‘No, the child is not capable of leading, because he is a child.‘ In the West, we have forgotten that we’re meant to be in charge as adults."

"There 's just a million reasons why young people would want to choose death," said Birbalsingh, the founder of the Michaela Community School in London. "You know, young people are compulsive, they make whimsical decisions. They make irresponsible decisions. They're young. That's sort of the definition of a child."

"That's why they need looking after," Birbalsingh added. "That's why we need to look after them as adults. That's our job. It's our role in life, to keep and protect them, sometimes from themselves. The people making these decisions just don't understand young people." Lawmakers there was a "very real risk" that proposed assisted suicide legislation, called the "Terminally Ill Adults (End of Life) Bill," would be expanded to include children if they didn’t vote for her amendment.

British Labour Party MP Meg Hillier voiced similar concerns during parliamentary debate, warning that teen brains make them particularly "susceptible to being influenced, including into dangerous and risky behavior."

She said, "In a number of countries, assisted dying laws have been expanded to allow children and young people to end their lives. We need to be alert to that very real risk."

Another MP, Sorcha Eastwood, cited social media’s toll on youth brain health, saying, "If we throw this into the mix, it has the potential to do untold damage."

So far, pro-euthanasia groups in the U.S. have remained quiet about extending assisted suicide to minors, but critics fear it’s only a matter of time.

The British Children’s Commissioner, Dame Rachel de Souza, warned that the proposed changes would allow doctors to discuss assisted dying with 17-year-olds "deemed competent," preparing them for the choice upon turning 18. In a May report, she said that she had convened a panel of youth to discuss the issue.

In Canada, the euphemism "MAID," or "Medical Assistance In Dying," has softened the conversation. But the statistics are stark. In 2023, about 15,000 Canadians died through "MAID," about one in every 20 deaths nationwide, a 16% increase from 2022, making assisted suicide the fifth leading cause of death.

The movement is also big business. Dying with Dignity Canada, based in Toronto, reported $3 billion in expenses in 2024, including $803,555 for advertising and promotions. It publicly argues that "mature minors should be allowed the right to choose MAID," calling it "unfair" to deny a 17-year-old what a 70-year-old is granted.

The British Columbia Humanist Association, the Canada chapter of Humanists International Inc., a 501(c)(3) nonprofit based in New York City, likewise demands MAID access for "mature minors" and "those whose sole underlying condition is a mental illness," It insisting there is "no moral or ethical distinction between a mature minor and a young adult." It argues: "Ensure Dignity in Death." The "high priestess" of euthanisia, Dr. Ellen Wiebe, also supports extending assisted suicide to children.

The Netherlands offers a preview of what comes next. Legal since 2002, Dutch euthanasia laws permit doctors to end lives of children as young as one, including newborns "suffering unbearably with no prospects of improvement."

By 2024, euthanasia accounted for 9,958 deaths in 2024, or 5.8% of the country’s deaths.

A recent study published in the International Journal of Psychiatry found that among Dutch euthanasia applicants, 73% were young women with psychiatric diagnoses including major depression, autism, eating disorder, trauma-related disorders and a "history of suicidality." The researchers acknowledged there is an "urgent need" to study "persistent death wishes" in this "high-risk group."

In one chilling case, a boy with autism, aged 16 to 18, ended his life after describing it as "joyless" and "lonely," according to the 2024 annual report of the Regional Euthanasia Review Committees, which approves medical-assisted suicides. His doctor "had no doubt about his decisional competence."

Last year, 14 Dutch psychiatrists urged prosecutors to investigate a case involving a 17-year-old girl, Milou, who died by euthanasia after years of depression, anxiety and suicidal ideation, following childhood sexual abuse. They warned against the "widespread promotion of euthanasia" leading to "unnecessary deaths." The Royal Dutch Medical Association scolded the psychiatrists, and prosecutors declined to act.

In 2014, Belgium became the second country in the world to allow child euthanasia, requiring parental consent.The Belgian Federal Euthanasia Review and Evaluation Committee says that six youth have requested euthanasia between 2014 and 2024. Last year, one young person made the request.

The industry has faced allegedly criminal revelations. In Australia, one alleged "euthanasia ring kingpin," Brett Daniel Taylor, faces prison for selling vulnerable people lethal veterinary drugs nicknamed "the Green Dream."

Back in Canada, Mike and Jennifer Schouten remain committed to fulfilling their son’s wish.

Michael remembers Markus lying on the sofa, dictating the words that became his son’s final message to lawmakers.

One day, in his final days, Markus said to his parents, "I can see what you are doing with your work is connected to what we’re going through. If we can share our story, we should."

Now, Michael says, "I feel he is blessing our work."

Asra Q. Nomani

https://www.foxnews.com/world/untold-damage-global-assisted-suicide-movement-targets-children

Saturday, October 11, 2025

MIT scientists have found a way to make gene editing far safer and more accurate

Summary:

MIT scientists have found a way to make gene editing far safer and more accurate — a breakthrough that could reshape how we treat hundreds of genetic diseases. By fine-tuning the tiny molecular “tools” that rewrite DNA, they’ve created a new system that makes 60 times fewer mistakes than before.

Scientists Push Gene Editing to Record Precision

A gene-editing approach called prime editing could one day help treat many illnesses by turning faulty genes into healthy ones. However, the technique sometimes introduces small mistakes into DNA, which can occasionally be harmful.

Researchers at MIT have now discovered a way to significantly reduce these errors by altering the key proteins that drive the editing process. They believe this improvement could make gene therapy safer and more practical for treating a wide range of diseases.

"This paper outlines a new approach to doing gene editing that doesn't complicate the delivery system and doesn't add additional steps, but results in a much more precise edit with fewer unwanted mutations," says Phillip Sharp, an MIT Institute Professor Emeritus, a member of MIT's Koch Institute for Integrative Cancer Research, and one of the senior authors of the new study.

Using their refined method, the MIT team lowered the rate of mistakes in prime editing from roughly one in seven edits to about one in 101 for the most common editing type. In a more precise editing mode, the improvement went from one in 122 to one in 543.

"For any drug, what you want is something that is effective, but with as few side effects as possible," says Robert Langer, the David H. Koch Institute Professor at MIT, a member of the Koch Institute, and one of the senior authors of the new study. "For any disease where you might do genome editing, I would think this would ultimately be a safer, better way of doing it."

Koch Institute research scientist Vikash Chauhan led the study, which was recently published in Nature.

The potential for error

In the 1990s, early gene therapy efforts relied on inserting new genes into cells using modified viruses. Later, scientists developed techniques that used enzymes like zinc finger nucleases to directly repair genes. These enzymes worked but were difficult to reengineer for new DNA targets, making them slow and cumbersome to use.

The discovery of the CRISPR system in bacteria changed everything. CRISPR uses an enzyme called Cas9, guided by a piece of RNA, to cut DNA at a specific location. Researchers adapted it to remove faulty DNA sequences or insert corrected ones using an RNA-based template, making gene editing faster and more flexible.

In 2019, scientists at the Broad Institute of MIT and Harvard introduced prime editing, a new version of CRISPR that is even more precise and less likely to affect unintended areas of the genome. More recently, prime editing was used successfully to treat a patient with chronic granulomatous disease (CGD), a rare disorder that weakens white blood cells.

"In principle, this technology could eventually be used to address many hundreds of genetic diseases by correcting small mutations directly in cells and tissues," Chauhan says.

One of the advantages of prime editing is that it doesn't require making a double-stranded cut in the target DNA. Instead, it uses a modified version of Cas9 that cuts just one of the complementary strands, opening up a flap where a new sequence can be inserted. A guide RNA delivered along with the prime editor serves as the template for the new sequence.

One reason prime editing is considered safer is that it doesn’t cut both strands of DNA. Instead, it makes a gentler, single-strand cut using a modified Cas9 enzyme. This opens a small flap in the DNA where a new, corrected sequence can be inserted, guided by an RNA template.

Once the corrected sequence is added, it must replace the original DNA strand. If the old strand reattaches instead, the new fragment can sometimes end up in the wrong spot, leading to unintended errors.

Most of these mistakes are harmless, but in rare cases they could contribute to tumor growth or other health issues. In current prime editing systems, the error rate can vary from about one in seven edits to one in 121, depending on the editing mode.

"The technologies we have now are really a lot better than earlier gene therapy tools, but there's always a chance for these unintended consequences," Chauhan says.

Precise editing

To reduce those error rates, the MIT team decided to take advantage of a phenomenon they had observed in a 2023 study. In that paper, they found that while Cas9 usually cuts in the same DNA location every time, some mutated versions of the protein show a relaxation of those constraints. Instead of always cutting the same location, those Cas9 proteins would sometimes make their cut one or two bases further along the DNA sequence.

This relaxation, the researchers discovered, makes the old DNA strands less stable, so they get degraded, making it easier for the new strands to be incorporated without introducing any errors.

In the new study, the researchers were able to identify Cas9 mutations that dropped the error rate to 1/20th its original value. Then, by combining pairs of those mutations, they created a Cas9 editor that lowered the error rate even further, to 1/36th the original amount.

To make the editors even more accurate, the researchers incorporated their new Cas9 proteins into a prime editing system that has an RNA binding protein that stabilizes the ends of the RNA template more efficiently. This final editor, which the researchers call vPE, had an error rate just 1/60th of the original, ranging from one in 101 edits to one in 543 edits for different editing modes. These tests were performed in mouse and human cells.

The MIT team is now working on further improving the efficiency of prime editors, through further modifications of Cas9 and the RNA template. They are also working on ways to deliver the editors to specific tissues of the body, which is a longstanding challenge in gene therapy.

They also hope that other labs will begin using the new prime editing approach in their research studies. Prime editors are commonly used to explore many different questions, including how tissues develop, how populations of cancer cells evolve, and how cells respond to drug treatment.

"Genome editors are used extensively in research labs," Chauhan says. "So the therapeutic aspect is exciting, but we are really excited to see how people start to integrate our editors into their research workflows."

The research was funded by the Life Sciences Research Foundation, the National Institute of Biomedical Imaging and Bioengineering, the National Cancer Institute, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Vikash P. Chauhan, Phillip A. Sharp, Robert Langer. Engineered prime editors with minimal genomic errors. Nature, 2025; DOI: 10.1038/s41586-025-09537-3

Abstract

Prime editors make programmed genome modifications by writing new sequences into extensions of nicked DNA 3′ ends1. These edited 3′ new strands must displace competing 5′ strands to install edits, yet a bias towards retaining the competing 5′ strands hinders efficiency and can cause indel errors2. Here we discover that nicked end degradation, consistent with competing 5′ strand destabilization, can be promoted by Cas9-nickase mutations that relax nick positioning. We exploit this mechanism to engineer efficient prime editors with strikingly low indel errors. Combining this error-suppressing strategy with the latest efficiency-boosting architecture, we design a next-generation prime editor (vPE). Compared with previous editors, vPE features comparable efficiency yet up to 60-fold lower indel errors, enabling edit:indel ratios as high as 543:1.




Hypothalamic hamartoma potpourri

Cohen NT, Cross JH, Arzimanoglou A, Berkovic SF, Kerrigan JF, Miller IP, Webster E, Soeby L, Cukiert A, Hesdorffer DK, Kroner BL, Saper CB, Schulze-Bonhage A, Gaillard WD; Hypothalamic Hamartoma Writing Group. Hypothalamic Hamartomas: Evolving Understanding and Management. Neurology. 2021 Nov 2;97(18):864-873. doi: 10.1212/WNL.0000000000012773. Epub 2021 Oct 4. PMID: 34607926; PMCID: PMC8610628.

Abstract

Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3 and other patterning genes are involved in HH pathogenesis. About 50%-80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.

Hinojosa J, Candela-Cantó S, Becerra V, Muchart J, Gómez-Chiari M, Rumia J, Aparicio J. Multimodal Approach for the Treatment of Complex Hypothalamic Hamartomas. Adv Tech Stand Neurosurg. 2024;50:119-145. doi: 10.1007/978-3-031-53578-9_4. PMID: 38592529.

Abstract

Hypothalamic hamartomas (HHs) are rare congenital lesions formed by heterotopic neuronal and glial cells attached to the mammillary bodies, tuber cinereum, and hypothalamus.They often present with an intractable epilepsy typically characterized by gelastic seizures but commonly associated with other types of refractory seizures. The clinical course is progressive in most of the cases, starting with gelastic seizures in infancy and deteriorating into complex seizure disorders that result in catastrophic epilepsy associated with cognitive decline and behavioral disturbances.Hamartomas are known to be intrinsically epileptogenic and the site of origin for the gelastic seizures. As antiepileptic drugs are typically ineffective in controlling HH-related epilepsy, different surgical options have been proposed as a treatment to achieve seizure control. Resection or complete disconnection of the hamartoma from the mammillothalamic tract has proved to achieve a long-lasting control of the epileptic syndrome.Usually, symptoms and their severity are typically related to the size, localization, and type of attachment. Precocious puberty appears mostly in the pedunculated type, while epileptic syndrome and behavioral decline are frequently related to the sessile type. For this reason, different classifications of HHs have been developed based on their size, extension, and type of attachment to the hypothalamus.The bigger and more complex hypothalamic hamartomas typically present with severe refractory epilepsy, behavioral disturbances, and progressive cognitive decline posing a formidable challenge for the control of these symptoms.We present here our experience with the multimodal treatment for complex hypothalamic hamartomas. After an in-depth review of the literature, we systematize our approach for the different types of hypothalamic hamartomas.

Eguchi S, Aihara Y, Chiba K, Kawamata T. Selective surgical mamillo-thalamic tract disconnection in hypothalamic hamartoma results in complete disappearance of gelastic seizures. Childs Nerv Syst. 2023 May;39(5):1303-1307. doi: 10.1007/s00381-023-05921-4. Epub 2023 Mar 21. PMID: 36941482.

Abstract

Hypothalamic hamartoma is a less common condition characterized by the several types of epileptic seizures including the gelastic type. It is reported that gelastic seizures are resistant to medical treatment with anticonvulsants, while stereotactic thermocoagulation or Gamma Knife radiosurgery are effective for seizure control. Here, we report an individual case where direct surgical resection disconnecting hypothalamic hamartoma from mammillothalamic tract resulted in complete disappearance of gelastic seizures without deterioration of cognitive function. A 6-year-old boy developed gelastic seizures at the age of 2 and suffered from precocious puberty. Anticonvulsants including carbamazepine and zonisamide failed to control seizures. The patient underwent direct division of the mammillothalmic tract by removal of hypothalamic hamartoma partially via anterior interhemispheric approach. It was observed that gelastic seizures disappeared completely after the surgical treatment without any endocrine and cognitive dysfunction for a follow-up period of 14 years. The mammillothalamic tract which connects anterior nucleus of thalamus and mammillary bodies plays a key role in gelastic seizures related to hypothalamic hamartoma. In this case, we disconnected the hamartoma specifically from the mammillary bodies and not from the rest of hypothalamus. Effectively, it enabled permanent control of seizures. This result shows that fibers connecting other hypothalamic structures and the dorsomedial nucleus of thalamus are not involved in gelastic seizure propagation from the hypothalamic hamartoma. When surgical treatment of hypothalamic hamartomas is performed it has high morbidity associated with hypothalamic disorders. Therefore, disconnection between hypothalamic hamartoma and mammillary bodies presents a possibility of reducing hypothalamic damage. Surgical disconnection between hamartoma and mammillothalamic tract carries minimal hypothalamic injury risk and our results suggest that it has the potential of seizure control for intractable gelastic seizures with less complications.

Bourdillon P, Ferrand-Sorbet S, Apra C, Chipaux M, Raffo E, Rosenberg S, Bulteau C, Dorison N, Bekaert O, Dinkelacker V, Le Guérinel C, Fohlen M, Dorfmüller G. Surgical treatment of hypothalamic hamartomas. Neurosurg Rev. 2021 Apr;44(2):753-762. doi: 10.1007/s10143-020-01298-z. Epub 2020 Apr 21. PMID: 32318922.

Abstract

Hypothalamic hamartomas are aberrant masses, composed of abnormally distributed neurons and glia. Along endocrine and cognitive symptoms, they may cause epileptic seizures, including the specific gelastic and dacrystic seizures. Surgery is the treatment of drug-resistant hamartoma epilepsy, with associated positive results on endocrine, psychiatric, and cognitive symptoms. Recently, alternatives to open microsurgical treatment have been proposed. We review these techniques and compare their efficacy and safety. Open resection or disconnection of the hamartoma, either through pterional, transcallosal, or transventricular approach, leads to good epileptological control, but its high complication rate, up to 30%, limits its indications. The purely cisternal peduncular forms remain the only indication of open, pterional approach, while other strategies have been developed to overcome the neurological, endocrine, behavioral, or cognitive complications. Laser and radiofrequency thermocoagulation-based disconnection through robot-guided stereo-endoscopy has been proposed as an alternative to open microsurgical resection and stereotactic destruction. The goal is to allow safe and complete disconnection of a possibly complex attachment zone, through a single intraparenchymal trajectory which allows multiple laser or radiofrequency probe trajectory inside the ventricle. The efficacy was high, with 78% of favorable outcome, and the overall complication rate was 8%. It was especially effective in patients with isolated gelastic seizures and pure intraventricular hamartomas. Stereotactic radiosurgery has proved as efficacious and safer than open microsurgery, with around 60% of seizure control and a very low complication rate. Multiple stereotactic thermocoagulation showed very interesting results with 71% of seizure freedom and 2% of permanent complications. Stereotactic laser interstitial thermotherapy (LiTT) seems as effective as open microsurgery (from 76 to 81% of seizure freedom) but causes up to 20% of permanent complications. This technique has however been highly improved by targeting only the epileptogenic onset zone in the hamartoma, as shown on preoperative functional MRI, leading to an improvement of epilepsy control by 45% (92% of seizure freedom) with no postoperative morbidity. All these results suggest that the impact of the surgical procedure does not depend on purely technical matters (laser vs radiofrequency thermocoagulation or stereotactic vs robot-guided stereo-endoscopy) but relies on the understanding of the epileptic network, including inside the hamartoma, the aim being to plan an effective disconnection or lesion of the epileptogenic part while sparing the adjacent functional structures.

Eladocagene exuparvovec-tneq to treat aromatic l-amino acid decarboxylase (AADC) deficiency

Texas Children’s Provides New Breakthrough Treatment for Patient with Rare Neurological Disorder

Texas Children's Hospital

October 01, 2025

Texas Children’s is pleased to announce that a three-year-old girl has been successfully treated with the first-ever FDA-approved gene therapy treatment for AADC deficiency.

Aromatic l-amino acid decarboxylase (AADC) deficiency is an extremely rare, inherited neurological disorder that prevents the brain from producing dopamine and serotonin — essential chemicals for controlling movement, mood and basic nervous system functions. The literature reports approximately 350 people with this condition worldwide. Historically, there was no cure or approved treatment for AADC, and the shortened life expectancy was estimated between five and seven years of age.

“Texas Children’s was the largest contributor to the clinical trial in the U.S. that led to this drug’s approval,” said Dr. Daniel J. Curry, who performed the six-hour surgery. Dr. Curry is Director of Functional Neurosurgery and Epilepsy Surgery at Texas Children’s Hospital and Professor of Neurological Surgery at Baylor College of Medicine. “Before now, AADC deficiency was a hopeless diagnosis. With this treatment, we’ve entered a whole new era where we can deliver solutions to formerly untreatable genetic problems. This is the first step in hopefully many future strides toward the molecular correction of inborn deficits for which there used to be no cure.”

Kebilidi (eladocagene exuparvovec-tneq) was approved on November 13, 2024, after a clinical trial involving Texas Children’s Hospital and two other testing sites. It is a modified adeno-associated virus serotype 2 (AAV2) vector-based gene therapy administered by a neurosurgeon directly into the brain’s putamen area, which is involved in learning and motor control. The procedure is a minimally invasive stereotactic neurosurgery that includes four infusions during one surgical session.

The Texas Children’s patient who received the treatment, a 3-year-old girl, first showed signs of developmental delay when she was 7 months old. She had poor muscle control and difficulty holding up her head — one of the common symptoms of AADC deficiency, along with muscle weakness, movement disorders and seizures. Genetic testing confirmed her diagnosis when she was 18 months old, and her local care team has managed her condition with medication and physical therapy until this breakthrough treatment at Texas Children’s became available.

“The treatment was successfully administered with no complications,” said Dr. Curry. “After a two-week stay in the hospital for follow-up care and monitoring, she and her family are now back home and feeling very optimistic. The therapy is expected to take 2-6 months to show measurable impact, but she is already showing signs of increased energy and happiness.”

Dr. Curry helped develop the Texas Children’s Intracerebral Gene Therapy Program with investigations into intraputamenal gene therapy for AADC deficiency, as well as investigations into gene therapy for Rett syndrome and NGLY-1 deficiency. Dr. Curry is also Director of the Neuroinfusion Service at Texas Children’s, conducting intracerebral enzyme replacement therapy in Batten’s disease and other neurodegenerative diseases.

“With these exciting advancements in gene delivery and surgical precision, we can not only treat the root cause of diseases in the brain, but hopefully reverse them,” said Dr. Curry. “This will make a life-changing difference for so many patients.”

https://www.texaschildrens.org/content/news-release/texas-childrens-provides-new-breakthrough-treatment-for-patient-with-rare

Tai CH, Lee NC, Chien YH, Byrne BJ, Muramatsu SI, Tseng SH, Hwu WL. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022 Feb 2;30(2):509-518. doi: 10.1016/j.ymthe.2021.11.005. Epub 2021 Nov 8. PMID: 34763085; PMCID: PMC8822132.

Abstract

Aromatic L-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adeno-associated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

Keam SJ. Eladocagene Exuparvovec: First Approval. Drugs. 2022 Sep;82(13):1427-1432. doi: 10.1007/s40265-022-01775-3. PMID: 36103022.

Abstract

Eladocagene exuparvovec (Upstaza™) is a gene therapy developed by PTC Therapeutics for the treatment of human aromatic L-amino acid decarboxylase (AADC) deficiency. Eladocagene exuparvovec comprises an adeno-associated virus vector that delivers the dopa decarboxylase (DDC) gene, the gene for human AADC. Eladocagene exuparvovec was approved in July 2022 in the EU for the treatment of patients aged 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of AADC deficiency with a severe phenotype (i.e. patients who cannot sit, stand or walk). This article summarizes the milestones in the development of eladocagene exuparvovec leading to this first approval for the treatment of patients aged 18 months and older with AADC deficiency.

See: https://childnervoussystem.blogspot.com/2024/11/eladocagene-exuparvovec-for-aromatic-l.html

Monday, October 6, 2025

Earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles.

Zhang, X., Grove, J., Gu, Y. et al. Polygenic and developmental profiles of autism differ by age at diagnosis. Nature (2025). https://doi.org/10.1038/s41586-025-09542-6

Abstract

Although autism has historically been conceptualized as a condition that emerges in early childhood many autistic people are diagnosed later in life. It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated (rg = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism.

_________________________________________________________________________

Autism diagnosed in early childhood differs genetically and developmentally from autism identified later in an individual’s development, challenging the notion that it is a single, uniform disorder, new research suggests.

Investigators found that children diagnosed early in childhood are more likely to exhibit social and behavioral challenges during infancy and early childhood, whereas those identified later have higher rates of conditions such as attention-deficit/hyperactivity disorder (ADHD) and depression. The two subtypes also exhibit distinct genetic profiles.

“We found that, on average, individuals diagnosed with autism earlier and later in life follow different developmental pathways, and surprisingly have different underlying genetic profiles,” study investigator Xinhe Zhang, PhD student, Department of Psychiatry, University of Cambridge, UK, said in a news release.

“Understanding how the features of autism emerge not just in early childhood but later in childhood and adolescence could help us recognize, diagnose, and support autistic people of all ages,” added senior author Varun Warrier, PhD, also with Cambridge University Department of Psychiatry.

The study was published online on October 1 in Nature.

No Single Known Cause

Autism is a complex neurodevelopmental condition with no single known cause. Although it has traditionally been recognized as emerging in early childhood, many individuals are diagnosed later in life. Whether autism identified in early vs later stages of life follows different developmental trajectories or exhibits distinct genetic profiles remains unclear.

To explore how autism diagnosed early in life may differ from cases identified later in life, the investigators analyzed longitudinal data from four birth cohorts, each including 89-188 autistic individuals, alongside genetic data from over 45,000 individuals across multiple international cohorts.

They found that those diagnosed with the disorder before age 7 had significantly higher rates of global developmental delay and intellectual disability, with pronounced deficits in motor and language milestones.

In contrast, individuals diagnosed later in childhood or beyond often showed typical early development but developed more subtle cognitive and behavioral difficulties over time. They were also more likely to have comorbidities, including ADHD and depression.

The genetic analyses revealed that the early-diagnosed group was enriched for rare, deleterious variants in constrained genes, while the later-diagnosed group had elevated polygenic risk scores for educational attainment and other complex traits.

The researchers have not yet identified the specific genetic variants that are associated with each of these profiles.

Notably, the researchers observed that the average genetic profile of later-diagnosed autism more closely resembled those of ADHD, depression, and posttraumatic stress disorder (PTSD) than that of autism diagnosed in early childhood.

“An important next step will be to understand the complex interaction between genetics and social factors that lead to poorer mental health outcomes among later-diagnosed autistic individuals,” Warrier said.

The researchers cautioned against overgeneralizing the study’s findings, emphasizing that age at diagnosis is shaped by social, cultural, and healthcare factors as well as biology. They noted that some children diagnosed later may have exhibited early signs that went unrecognized.

Distinct Types

In an accompanying Nature News & Views article, Elliot Tucker-Drob, PhD, professor, Department of Psychology, University of Texas at Austin, said this study provides evidence that the “developmental timing of autism diagnosis is not simply an artefact of the challenges of identifying milder cases at early ages, but rather a primary feature that distinguishes distinct forms of autism.”

“The developmental timing of first diagnosis is just one possible axis along which autism subtypes can be differentiated, and it is possible — if not probable — that other mechanistically separable subtypes of autism exist that have yet to be identified,” Tucker-Drob said.

In a statement from the UK nonprofit Science Media Centre, experts weighed in on the findings.

Uta Frith, PhD, emeritus professor of cognitive development, University College London, said the findings make her “hopeful that even more subgroups will come to light, and each will find an appropriate diagnostic label.”

“It is time to realize that ‘autism’ has become a ragbag of different conditions. If there is talk about an ‘autism epidemic,’ a ‘cause of autism,’ or a ‘treatment for autism,’ the immediate question must be, which kind of autism?” said Frith.

Michael Absoud, PhD, with King’s College London, said this study “confirms that not only is autism highly heritable and a spectrum of conditions, but the age at diagnosis of autism is also heritable.”

Absoud also noted that the behavioral profiles were derived from the Strengths and Difficulties Questionnaire (SDQ), “a general behavioral screening tool that does not capture detailed autistic and mental health traits and relies on caregiver reports rather than clinical assessments which limits the precision of the developmental trajectories described.

“Research in more diverse populations is needed to replicate the findings, with more detailed quality of life, everyday functioning, and direct assessment measures,” Absoud concluded.

This study was supported by the Wellcome Trust, the UKRI, Horizon Europe, and the Simons Foundation Autism Research Initiative. Zhang, Warrier, Tucker-Drob, Frith, and Absoud had no relevant disclosures.

Megan Brooks  

https://www.medscape.com/viewarticle/autism-not-one-disorder-new-data-show-2025a1000qmm

Sunday, October 5, 2025

Sepsis infection is the leading cause of death in children

Globally, sepsis infection is the leading cause of death in children, taking more than 3.4 million lives per year, according to the Sepsis Alliance — and 85% of these deaths occur before age 5.

Sepsis among children is a very difficult and elusive problem for physicians to diagnose and treat, with almost 10% of cases being missed in the emergency room.

When children are admitted with the infection, the average length of stay is more than a month, per the above source.

Many people don’t know much about sepsis, according to Professor Elliot Long, team leader in clinical sciences and emergency research at the Murdoch Children’s Research Institute in Melbourne, Australia.

With sepsis, the immune system has an abnormal response to an infection — either too exuberant or too minimal.

"The immune response can be underactive, which leads to severe, overwhelming infection, or it can be overactive and the immune response itself causes damage to the body's organs, which can be life-threatening," Long told Fox News Digital during an on-camera interview.

The professor, who received a $5 million National Critical Research Infrastructure Initiative grant this year to test potential sepsis treatments across Australia and New Zealand, noted that sepsis is easily missed because parents don’t have a good understanding of how common or severe it is. 

The symptoms are often subtle — "and they overlap with the same symptoms you’d get for self-limited viral infections that are really common in kids," Long said.

"The paradox is that sepsis in its late stages is very easy to pick up, but the treatments aren’t very effective," he added. "And sepsis in its early stages is very tricky to pick up — but that’s when the treatments are most likely to be effective."

Sepsis symptoms and treatments

The Sepsis Alliance uses the acronym T.I.M.E. to help people remember the primary warning signs, as follows.

T = Temperature: higher or lower than normal (fever or hypothermia)

I = Infection: signs of an infection (e.g. a cut, pneumonia, UTI)

M = Mental decline: confusion, sleepiness, difficulty awakening or arousing

E = Extremely ill: severe pain or discomfort, shortness of breath, feeling like you might die

Other warning signs may include shortness of breath, confusion, extreme pain, low blood pressure, fever, organ dysfunction, and clammy or sweaty skin.

Early detection and treatment of sepsis is essential to preventing life-threatening complications that damage the kidney, heart, liver, brain and other organs, according to Long. Sometimes, preventing this damage involves what seems like overtreatment with antibiotics. 

Treatments for sepsis are evolving and a work in progress. Currently, all treatments are supportive, meaning the child is treated with antibiotics while doctors deal with the abnormal immune responses and wait for the return of normal function.  

"We have a lot of work to do to try and develop treatments that help improve outcomes for kids with sepsis."

"Those supportive treatments include simple things like receiving oxygen and fluids, and if kids need help with their breathing, if their oxygen levels are too low or their conscious state is impaired, then they get put on a ventilator," Long said.

"We have a lot of work to do to try and develop treatments that help improve outcomes for kids with sepsis that are not just supportive treatments, but help to modify the immune response."

Despite children’s resilience, sepsis can have a long-term impact. Long and his colleagues are on the lookout for long-term problems with cognition, emotions and motor abilities. 

"The impact isn’t just on the children, it's on the parents as well, because they've had an extremely stressful life event," Long said. "And sometimes that has meant that they've had to contemplate the possibility of their child dying … so parents and families are left with this kind of burden of survivorship."

Listening to parents

Because early sepsis is so easy to miss, Long emphasized how important it is for doctors to listen closely to parents. 

If parents say, ‘this is a very abnormal response for my child to an infection or this is the sickest I've ever seen them,’ these are important red flags that this may be something more than just a minor infection," he said.

Long told Fox News Digital that the most common age for sepsis patients is younger than 5 — and within that group, it's especially prevalent for kids who are less than a year old.

"They're often pre-verbal or can't describe the signs or symptoms, so we're relying a lot on the parents to go through what they think is going on or what they've observed in their child," the doctor added.

"Martha’s Rule" is a universal principle that allows parents to advocate for their sick child, which is especially important with sepsis, where a young life may be easily lost. 

"So if parents notice their child is getting worse or deteriorating over time, Martha's Rule has been put in place to allow them to bypass local escalation procedures and get an independent opinion," Long said. "[This allows them to] provide the appropriate level of care for their child in the event of deterioration."

Marc Siegel, M.D. 

https://www.foxnews.com/health/hidden-infection-kills-millions-children-each-year-doctors-warn-overlooked-symptoms


Friday, October 3, 2025

NVG-291 for spinal cord injury

An experimental drug could help to improve movement for patients with spinal cord injuries.

NVG-291, an injectable peptide, has been tested in a phase 2 trial with eligible patients — some of whom noted remarkable outcomes.

Larry Williams, a trial participant based in Philadelphia, Pennsylvania, shared with Fox News Digital that he’s been able to walk again after an accident that caused paralysis.

Williams, 58, was mountain-biking on a small trail when he struck a tree. Although he was wearing a helmet, he "instantly broke" his C4 to C6 vertebrate (specific bones in the cervical spine).

He underwent spinal surgery, but was paralyzed for two weeks until his body began to "wake up" and regained some movement after starting therapy.

Williams was able to walk "a little bit" with the assistance of a walker, but still had complications with mobility in areas like his hands. He also lost 40 pounds after the accident.

After some research, he discovered the NVG-291 trial and was considered a viable candidate, he told Fox News Digital.

For three months, starting in April 2024, Williams received a daily injection of the drug followed by one hour of physical therapy, which included hand exercises and walking with a harness on a flat track or treadmill.

Williams also underwent blood tests and electrophysiological testing to measure the electrical activity of his nerves and muscles, as well as physical testing once a month.

At the end of the trial, Williams reported that he was able to walk 10 meters (32.8 feet), balanced with a walker, in 15 seconds, an improvement over 45 seconds.

Although he has not received the drug since July 2024, Williams continues to see physical improvements over a year later.

"I'm not working out really hard. I'm currently not in therapy," he told Fox News Digital. "But just a couple of days ago, I stood up and tried to free-stand, balance and lift one foot off the ground. I was able to do it for 30 seconds."

"I hadn't been practicing this. I can't explain how it happened," he added. "There are small improvements that continue to happen."

Williams said he had tried the same maneuver six months earlier and couldn’t hold his foot off the ground for even three seconds.

"There are small improvements that continue to happen."

Since the trial, Williams has continued to improve his walking ability, and can even swim laps in the pool.

"I reach out to other people with the same injury as me, and it seems like a lot of them, after years and years of therapy, get to where I am," he said. "And it kind of seems like I've been given a shortcut … I would love to get to the life that I had before, being fully independent."

After taking the experimental drug, Williams said he has been able to perform physical tasks "easily and quickly."

"The movement in my legs seems to be a little bit smoother and less restricted as the time passed by," he said. "I'm not going to give up. I'm going to keep pushing and trying."

How the drug works

In a separate interview with Fox News Digital, lead researcher Dr. Monica Perez, scientific chair at the Shirley Ryan AbilityLab in Chicago and professor of physical medicine and rehabilitation at Northwestern University, said the drug was first tested on animals, which displayed improved locomotor function (movement).

The researchers then conducted a randomized clinical trial in humans, in which half of the participants received the NVG-291 drug, which contained a repair molecule to improve nervous system function.

The drug is a peptide, which is a small protein that works like a roadblock remover. After a spinal cord injury, the body sends out signals that tell nerve fibers to stop growing. This drug blocks those signals, so the nerves have a better chance to regrow.

"This peptide can block those inhibitory signals," Ryan said. "There is a little bit of evidence in animals that it can actually enhance the growth of neurons."

Although GLP-1 receptor agonists, best known for weight loss and diabetes treatment, are a peptide, Perez said this spinal cord injury treatment works differently.

"It has a specific mechanism, and it's more related to repair, to try to enhance the growth of neurons that are affected by central nervous system injury," she said.

Spinal cord injuries are typically approached with cell therapies, like stem cells and bone marrow stromal cells, Perez noted.

This peptide approach, in contrast, is "easy to administer," can be done at home, achieves a "similar goal" and is "extremely safe," she added.

Perez said more research is necessary to determine how long the effects of this drug will last.

"We observed strong electrophysiological changes in the group that received the medication compared to the placebo group, but we don't have follow-up measurements," she said. "There's no way for us to understand the real duration of these treatments."

As there is not currently an FDA-approved treatment for spinal cord injuries, Perez said that those involved with this research are "very devoted" to advancing this science.

While each patient may react differently, Williams said he would recommend this treatment to other people with spinal cord injuries.

"It could really change things for people with injuries like mine," he said. "I'm just praying that everybody out there is able to have an opportunity to gain back their life."

Angelica Stabile

https://www.foxnews.com/health/paralyzed-man-walks-again-after-experimental-drug-trial-triggers-remarkable-recovery

Daniel Mikol, Judy Toews, Steven Mulcahy, Marc DePaul, Nana Collett, James Guest, Monica Perez. NVG-291 Phase 1 Results and Phase 1b/2a Study Design in Individuals with Spinal Cord Injury, Archives of Physical Medicine and Rehabilitation, Volume 105, Issue 4, 2024, Page e18, ISSN 0003-9993, https://doi.org/10.1016/j.apmr.2024.02.049.

Research Objectives
To provide an update on the development of NVG-291 for spinal cord injury (SCI). There is a high unmet need for treatments to repair damage after SCI. A Phase 1 safety trial of NVG-291 (a receptor protein tyrosine phosphatase sigma peptide mimetic) in 70 healthy subjects supports a Phase 1b/2a efficacy/safety trial in individuals with SCI. Doses tested overlap with and exceed equivalent efficacious doses in animal models of acute/chronic SCI.

Design
The 16-week Phase 1b/2a randomized, double-blind, placebo-controlled trial (12-week treatment period, 4-week noninterventional period) will assess individuals with chronic and subacute traumatic SCI.

Setting
The trial will be conducted at a single center, Shirley Ryan AbilityLab (Chicago, IL). We will conduct longitudinal electrophysiological assessments to enable precise measurement of descending motor connectivity following treatment.

Participants
Approximately 40 subjects will be enrolled. ∼20 cervical motor incomplete SCI subjects per cohort will be enrolled: cohort 1 chronic (1 – 10 years post-injury); cohort 2 subacute (10 – 49 days post-injury). All subjects will undergo regular exercise.

Interventions
Randomization (1:1) to NVG-291 or placebo (daily subcutaneous injection) for 12 weeks.

Main Outcome Measures
The primary objective is to evaluate the change in motor evoked potential amplitudes (an index of corticospinal excitability) in predefined muscle groups. Other electrophysiological measures will also be assessed. Key clinical outcome measures include 10mWT, 9-HPT, GRASSP, pinch dynamometry, and motor scores.

Results
NVG-291 was safe and well tolerated in the Phase 1 trial and showed good pharmacokinetic characteristics. The most common AE was injection site related, more common in the NVG-291 group.

Conclusions
Phase 1 results support advancing investigation of NVG-291 to individuals with SCI. The Phase 1b/2a trial in SCI, which initiates in mid-2023, will assess change in electrophysiological and clinical measures following treatment of individuals with subacute or chronic SCI.