SETD1A mutations

Inspired by a patient

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

Abstract

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

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

Abstract

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

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

Abstract

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

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

Abstract

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

PRRT2 mutations

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

Abstract

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

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

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

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

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

Abstract

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

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

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

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

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

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

Abstract

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

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

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

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

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

Abstract

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

FLNA mutations

Inspired by a patient

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

Abstract

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

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

Abstract

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

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

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

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

Abstract

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

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

Abstract

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

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

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

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

Treatment of TUBB4A-related leukodystrophy with antisense oligonucleotide

Connor Gooley is the first patient ever treated with an n-Lorem ASO for TUBB4A-Related Leukodystrophy, a condition that severely disrupts his nervous system, slows nerve impulses, and impairs his fine motor skills. As a result, Connor cannot speak, walk, sit up on his own, or chew well. Still, he manages to army crawl, propel himself in his wheelchair, and use a gait trainer. He’s also remarkably resilient—rarely crying or complaining despite the daily challenges he faces. In this episode of the Patient Empowerment Program, Connor’s parents, Diana and Mike, share their family’s journey from diagnosis to treatment and reflect on their observations of Connor after more than six months on an n-Lorem discovered and developed treatment. This episode is proudly sponsored by Hongene Biotech.

On This Episode We Discuss:
1:33 Shaking eyes were the first sign of Connor’s rare disease
4:10 An MRI revealed little to no myelin, leading to whole genome sequencing and an eventual TUBB4A genetic mutation diagnosis
7:10 Connecting with another family with the same mutation 10:00 Finding n-Lorem through a ‘seeking patient candidates’ advertisement in a Global Genes annual report
12:26 Contextualizing Connor’s TUBB4A mutation in simple terms
21:19 How rare diseases affect families and creating a new normal
27:41 Receiving treatment in Boston and contemplating the decision to agree to an experimental treatment for their son
32:00 Observations after 6 months on treatment
35:45 n-Lorem has given the Gooley family hope for a better future for Connor

https://www.nlorem.org/connor-gooleys-story-a-first-for-tubb4a-treatment/

Sase S, Hacker JL, Napit PR, Bhagavatula A, Woidill S, D'Alessandro A, Jeffries MA, Almad A, Takanohashi A, Padiath QS, Grinspan JB, Marsh ED, Vanderver A. Therapeutic suppression of Tubb4a rescues H-ABC leukodystrophy. Mol Ther. 2026 May 6;34(5):2923-2943. doi: 10.1016/j.ymthe.2026.01.016. Epub 2026 Jan 20. PMID: 41566774; PMCID: PMC13154311.

Abstract

Hypomyelination and atrophy of basal ganglia and cerebellum (H-ABC) is a rare leukodystrophy associated with causal variants in β-tubulin 4A (TUBB4A). The recurring variant p.Asp249Asn (D249N) presents in infancy with dystonia, communication deficits, and loss of ambulation during the first decade of life. In this study, we characterized a genetic murine series (Tubb4aKO/KO, Tubb4aD249N/+, Tubb4aD249N/KO, and Tubb4aD249N/D249N) to demonstrate that disease severity correlates with the expression of mutant Tubb4a and relative preservation of wild-type tubulin. To further evaluate the translational potential of Tubb4a suppression as a therapy in H-ABC, we identified a well-tolerated Tubb4a-targeted antisense oligonucleotide (ASO) candidate that selectively reduces Tubb4a. Notably, single intracerebroventricular administration of ASO in postnatal Tubb4aD249N/KO mice drastically extends its lifespan, improves motor phenotypes, and reduces seizures. Neuropathologically, treating ASO Tubb4aD249N/KO mice prevents myelin and oligodendrocyte (OL) loss and recovers visual evoked potential latencies in vivo. Furthermore, the microtubule function of Mbp mRNA transport from the OL soma to the myelin sheath is retained. A major limitation we noted is that ASOs fail to target cerebellar granule neurons even with multiple routes of administration in the brain. This is the first preclinical proof-of-concept for Tubb4a suppression via ASO as a disease-modifying therapy for H-ABC.

When a child needs neurology care, fear is not the whole story

In child neurology, there is a moment when a parent’s face changes.

They have just heard that their child may be having seizures, or that something may be affecting the brain, and suddenly an appointment becomes a fear about the future. Parents imagine what a diagnosis could mean for independence, friendships, school and family life before they understand what is known, what remains uncertain, and what kinds of care and support may be available.

This is not a rare experience in Rochester. At Golisano Children’s Hospital, the Division of Child Neurology serves nearly 13,000 patients each year from across Upstate New York. Some children come with seizures or headaches. Others come with movement concerns, muscle weakness, developmental questions, immune-related neurologic conditions, or rare genetic disorders.

But a referral to child neurology does not always mean the worst. All concerns are evaluated step by step, often beginning with pediatricians who know what to watch for and when a specialist should become involved. Some symptoms turn out to be common or manageable. Others require a closer look. Part of our work is helping families understand what is routine, what is uncertain, and what may be more complicated.

Child neurology has a wealth of tools to help make those distinctions. We begin by listening carefully to what families have noticed about a child’s symptoms, development, and daily life. A neurologic examination, imaging, genetic testing, EEG monitoring, blood work, developmental assessment, and ongoing follow-up can then help us better understand what is happening. When we know something may be serious, or when the answer is not yet clear, specialized child neurology care becomes especially important.

The goal is not only to treat a condition, but to help a child and family live as fully as possible. For one family, that may mean learning what to do if a seizure happens at school. For another, it may mean finding a medication plan that helps a child sleep through the night and feel more like themselves during the day. For another, it may mean understanding why a child tires easily, struggles with movement, or needs support that teachers and classmates cannot always see.

Families also need help with ordinary questions that become urgent when a child has a neurologic condition: What is safe? What should school know? When should we worry? How do we help our child keep learning, growing, and belonging?

A diagnosis can be an important turning point, but for many families, the medical plan becomes real in daily life. A diagnosis gives a name to symptoms a family has been watching for months or years. It can point toward treatment, therapies, school supports, genetic counseling, or what to watch for next. A diagnosis can help them to identify a community for guidance, support, and sharing of goals. But a diagnosis is a beginning, not an ending.

Child neurology is rarely limited to one appointment or decision. A child’s condition is lived out over time, often in places far from the exam room: at school, at home, with friends, in sports and activities, and later in the push toward independence. Good care has to follow the child into those settings, not simply name the condition and stop there.

That is why pediatric neurology is team-based. A child’s care may involve a physician adjusting medication, a neuropsychologist helping a family understand learning needs, a dietitian supporting dietary therapy for epilepsy, or a surgeon evaluating whether a procedure could help. Others may need coordination across school, therapy, genetics, and developmental services.

Rochester has a long history of leadership in neurology, clinical research, and care for rare neurological diseases. At University of Rochester Medicine, child neurology works closely with neurosurgery, developmental and behavioral pediatrics, behavioral health, genetics, and other specialties to support children whose needs do not fit neatly into one category. That kind of collaboration matters because families rarely experience a child’s condition in isolated pieces. They experience it as part of daily life.

The field is also changing rapidly. Research in rare diseases, neurogenetics, epilepsy, and gene-targeted therapies is opening new possibilities for diagnosis and treatment, especially for conditions where earlier recognition can change what options are available. These advances are promising, but they also make public understanding, research participation, and community support more important.

Families who participate in research help expand what we know about common and rare neurologic conditions and contribute to better diagnostic and treatment options for children in the future. But participation in research is only one way families and communities move this work forward. Advocacy, education, philanthropy, and broader public understanding all help support the mission of helping children with neurologic conditions live as fully as possible.

That engagement matters because child neurology does not happen only inside the clinic. It depends on families who share what they are seeing, pediatricians who know when to refer, schools that understand a child’s needs, researchers who ask better questions, and communities willing to support children whose challenges are not always visible.

A neurologic diagnosis should never define the whole of a child’s life. With the right diagnosis, support, treatment, and understanding, many children continue to learn, play, build friendships, and live lives marked not only by medical complexity, but by joy, growth, and possibility.

For families, the first referral to child neurology may begin with fear. Our responsibility as a community is to help ensure it does not end there.

Inna Hughes M.D.

https://rochesterbeacon.com/2026/07/28/when-a-child-needs-neurology-care-fear-is-not-the-whole-story/

"Can you prescribe leucovorin for my child?"

When the White House announced it was exploring leucovorin as a treatment for autism, the calls from families started pouring in: "Can you prescribe leucovorin for my child?"

We experience versions of this frequently: an unproven treatment gains momentum on social media, and we as physicians must become informed enough to counsel families who are counting on us for answers. Not surprisingly, a recent analysis published in The Lancet showed a 71% increase in outpatient leucovorin prescriptions for a few months after the White House suggested the drug as a potential autism treatment.

The White House's promotion of leucovorin suggested that millions of people with autism have an ultra-rare condition called cerebral folate deficiency (CFD). The Lancet report captures exactly what concerned me when I heard the announcement: that physicians would feel compelled to prescribe an unproven treatment, predicated on an underlying diagnosis that most children with autism almost certainly do not have.

In reality, FOLR1-CFD -- for which leucovorin is an appropriate off-label treatment -- is so rare that less than 100 cases total have been reported worldwide. For people with this condition, mutations in the folate transporter gene FOLR1 prevent folate from being transported into the brain. Low cerebral folate levels cause people with untreated CFD to have more than just autism. They also have severe cognitive impairments, developmental regression, epilepsy, and movement disorders. This kind of CFD can be treated with leucovorin, a folate derivative that enters the brain through a different mechanism that doesn't require the FOLR1 transporter. The diagnosis of FOLR1-CFD is confirmed with a combination of genetic testing and a spinal tap to measure folate levels in the brain.

In addition to asking about leucovorin, families are also inquiring about testing their children for autoantibodies against the folate transporter. The premise is that autoantibodies inhibit the FOLR1 transporter, which leads to CFD and autism. This is an interesting idea, but that doesn't make it true. The blood test, which is only available from one commercial lab, has a cute name (Folate Receptor Autoantibody Test or FRAT), costs hundreds of dollars, and is not covered by insurance. Not only does the test have a high false positive rate, but the presence of an autoantibody alone does not equate to having an autoimmune disease. Using a positive folate receptor antibody test to diagnose a child with CFD would be like using a positive antinuclear antibody (ANA) test to diagnose lupus.

In the months since the White House announcement, one of the largest randomized, placebo-controlled studies on the use of leucovorin to treat autism was retracted for data inconsistencies. In addition, the American Academy of Pediatrics, the Society for Developmental and Behavioral Pediatrics, and the Child Neurology Society released guidelines recommending against leucovorin for autism treatment and recommending against folate receptor autoantibody testing for people with autism. And even though the White House reversed its stance on leucovorin for autism and acknowledged that there is insufficient evidence of its efficacy, the damage was already done.

What Do We Tell Families?

When I step back, it's clear that families are asking about leucovorin the same way they inquire about gluten-free diets, stem-cell tourism, and broccoli extract. I take every one of these conversations seriously, because the underlying question -- is there something treatable? -- is the one I'm also asking.

I educate families that profound autism is a symptom of 1,000 rare neurogenetic diseases. I now routinely offer genome sequencing to families to understand if their child has one of these conditions. It's a noninvasive test (just a cheek swab) -- no lumbar puncture required. I tell families that doing a "spellcheck on the DNA" is the first step in their diagnostic and treatment journey.

Identifying the cause of each child's disability is becoming increasingly important because we are entering the era of precision medicine for neurodevelopmental disorders. A growing number of autism-associated conditions already have treatments available or treatments being tested in clinical trials.

I tell families that getting the right diagnosis is what puts their child in line for when treatments become available for their condition. If testing reveals a treatable cause for their child's disability, we can act on it immediately. If their condition isn't treatable today, rapid advances in precision medicine mean it may be tomorrow. And if current testing does not provide an answer, we can retest in a few years once technology and our understanding of neurogenetics have advanced.

For families who aren't able to obtain genetic testing clinically, I recommend they enroll in a study to obtain testing on a research basis.

Families of autistic children are navigating long wait times with a limited number of neurodevelopmental specialists and real gaps in treatment for core features of autism. They deserve the best that science and medicine have to offer. That doesn't include prescribing drugs without scientific evidence, which are unlikely to help and could even cause harm.

Audrey C. Brumback, MD, PhD, is a pediatric neurologist specializing in autism spectrum disorder at Dell Medical School at The University of Texas at Austin.

https://www.medpagetoday.com/opinion/second-opinions/120530

Overlooked form of adversity can reveal hidden mental health risks

For years, pediatricians have relied on a widely used checklist to identify children who have experienced traumatic events such as abuse, neglect or household violence. But a new UC Irvine-led study suggests that another, less visible form of adversity may be shaping children’s mental health, and it often goes undetected.

Researchers found that growing up in an unpredictable environment, where daily life lacks consistency and children are unsure what comes next, is strongly associated with depression, anxiety, sleep disorders and other mental health challenges. The findings, published in Nature Mental Health, are based on nearly 30,000 children receiving care through Rady Children’s Health pediatric clinics in Orange County.

The study also shows that asking children and families a handful of questions about unpredictability can identify many at-risk young people who would not have been recognized through traditional Adverse Childhood Experiences, or ACEs, screenings alone.

The work represents years of neuroscience research translated into a practical tool that could help pediatricians identify vulnerable children earlier and give families opportunities to intervene before problems become more severe.

From the neuroscience lab to the doctor’s office

The project brings together neuroscientists, psychologists, pediatricians and data scientists from UC Irvine, Chapman University and Rady Children’s Health, demonstrating how discoveries about the developing brain can move beyond the laboratory and into everyday clinical care.

At the center of the research is Dr. Tallie Z. Baram, UC Irvine Donald Bren Professor and Distinguished Professor of pediatrics, neurology, and anatomy and neurobiology, as well as Danette Shepard Chair in Neurological Studies. For decades, Baram has studied how early-life experiences influence brain development.

Her laboratory research revealed that developing brains rely on predictable patterns to build healthy neural connections – findings that now appear to extend to children’s everyday lives.

“What we discovered in the laboratory mice is that optimal development of the brain depends on consistent patterns, which enable the maturation of brain connections,” said Baram, the study’s senior author and co-corresponding author. “Like mice, children’s brain connections involved in happiness, threat and safety benefit from repeated, predictable experiences. This study shows that those principles matter not only in neuroscience research but also in the lives of children and families from a broad range of wealth and backgrounds.”

Looking beyond traditional measures of adversity

Traditional ACEs screenings focus on experiences such as abuse, neglect and family dysfunction. While those tools have transformed the understanding of childhood trauma, they do not capture every child who may be struggling.

The new study evaluated whether adding a simple five-question measure of childhood unpredictability could improve screening.

Researchers found that both traditional adversity and unpredictability were linked to higher rates of depression, anxiety, behavioral concerns, sleep disorders and physical symptoms including headaches and abdominal pain.

But unpredictability revealed something more.

Children who reported highly unpredictable lives – even when they had no traditional ACEs – were substantially more likely to experience depression than children who scored low on both measures. The screening also proved especially useful in identifying children at risk for sleep disorders.

When researchers combined both screening methods, the relationship to mental health outcomes was often stronger than either tool alone.

“Traditional ACEs screening has helped our understanding of childhood adversity, but it fails to identify many children who are at risk for mental health problems,” said Laura M. Glynn, Ph.D., professor of psychology at Chapman University and co-corresponding author of the study. “Our findings suggest that unpredictability is a distinct and meaningful form of adversity that contributes to risk in ways that existing screening tools do not detect, thus increasing our ability to target individual children.”

A statewide effort with national implications

The study grew out of a $2.9 million grant awarded in 2021 by the California Initiative to Advance Precision Medicine. Between 2021 and 2024, researchers incorporated the unpredictability questionnaire into routine pediatric visits at 19 Rady-affiliated clinics across Orange County.

California’s statewide ACEs screening initiative – already the first publicly supported program of its kind in the nation, created a unique opportunity to test whether expanding childhood adversity screenings could improve care for families from diverse socioeconomic, ethnic and cultural backgrounds.

Nearly 30,000 children under age 18 participated, making the project one of the largest real-world studies examining how different forms of adversity affect children’s mental health.

Small routines can make a difference

Unlike many forms of childhood adversity, unpredictability is often something families and communities can influence.

Consistent bedtime routines, reliable caregiving, predictable schedules and stable daily patterns may all help create environments that support healthy brain development. Previous research by members of the team also found that predictable home environments helped buffer children from stress during the COVID-19 pandemic.

Baram emphasizes that the findings are not about perfection.

“For parents, this isn’t about creating a perfect home,” Baram said. “It’s about recognizing that consistency matters. Small routines and predictable patterns in daily life can support healthy development.”

As pediatricians increasingly look for ways to identify children before mental health problems escalate, the researchers say measuring unpredictability could become an important addition to routine care – providing families with another opportunity to support healthy development during the years when the brain is growing fastest.

https://news.uci.edu/2026/07/21/when-childhood-feels-unpredictable-the-brain-remembers/

Glynn, L.M., Liu, S.R., Golden, C. et al. Unpredictability is a childhood adversity that contributes to mental health problems. Nat. Mental Health (2026). https://doi.org/10.1038/s44220-026-00681-x

Abstract

Although adverse childhood experiences (ACEs) increase risk for mental illness at the population level, existing ACEs screens are less helpful in forecasting individual outcomes, suggesting they may not capture significant elements of childhood adversity. We have previously identified unpredictable parental and household experiences as an ACE that portends poorer cognitive and mental health. However, the contribution of unpredictability to established ACEs in real-world settings is unknown. Here, leveraging existing ACEs screening in California, we added the five-item Questionnaire on Unpredictability in Childhood (QUIC-5) in 19 pediatric clinics spanning broad sociodemographic constituencies and compared in ~30,000 children the link of each screen with mental health diagnoses. Scores on either the ACEs or QUIC-5 associated with probabilities of depression, externalizing symptoms, sleep disorders, anxiety and somatic symptoms. Each screen provided unique contributions and combining them often doubled the strength of associations. For depression and sleep disorders, the QUIC-5 identified vulnerable individuals missed by ACEs screen, improving risk detection and facilitating future interventions.