15q26.3 deletions

Inspired by a patient

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

Abstract

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

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

Abstract

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

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

Abstract

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

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

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

Abstract

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

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

Abstract

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

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

Infantile spasms--therapeutic thoughts

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

Abstract

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

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

Abstract

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

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

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

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

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

Abstract

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

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

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

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

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

Abstract

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

SETD1A mutations

Inspired by a patient

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

Abstract

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

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

Abstract

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

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

Abstract

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

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

Abstract

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

PRRT2 mutations

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

Abstract

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

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

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

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

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

Abstract

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

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

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

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

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

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

Abstract

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

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

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

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

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

Abstract

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

FLNA mutations

Inspired by a patient

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

Abstract

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

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

Abstract

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

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

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

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

Abstract

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

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

Abstract

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

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

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

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

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/