Abstract
Purpose: Pathogenic UNC13A variants are increasingly recognized in pediatric neurodevelopmental disorders, but epilepsy phenotypes and antiseizure medication (ASM) responses remain poorly characterized. This study aimed to define the epileptic spectrum of UNC13A-related disorders in children and identify effective ASM strategies.
Methods: We retrospectively analyzed 10 children with pathogenic/likely pathogenic UNC13A variants. Clinical data, seizure phenotypes, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and ASM outcomes were systematically evaluated.
Results: We identified 10 patients, including eight with de novo heterozygous variants and two with biallelic variants. Most missense variants were localized within the critical hinge regions of Munc13-1, with p.Pro814Leu identified as a recurrent variant in three individuals. Six patients (60%) presented with developmental and epileptic encephalopathy, with a median seizure onset of 19 months (range: 5 months-7 years). Focal seizures were the predominant seizure type, and all affected patients experienced status epilepticus. Febrile seizures occurred in half of these patients. While seizures were largely refractory, levetiracetam (LEV) was observed effective in three out of four treated patients. Genotype-phenotype analysis revealed distinct clinical trajectories: biallelic variants resulted in catastrophic early-onset symptoms and early mortality, whereas heterozygous variants were characterized by drug-resistant epilepsy, tremor and ataxia.
Conclusions: UNC13A variants represent an underrecognized cause of developmental and epileptic encephalopathy in children, characterized by refractory seizures, a high incidence of status epilepticus, and increased susceptibility to febrile seizures. Preliminary observations noted favorable clinical outcomes in a small subset of patients treated with LEV.
Asadollahi R, Ahmad A, Boonsawat P, Shahanoor Hinzen J, Lohse M, Bouazza-Arostegui B, Sun S, Utesch T, Sommer JD, Ilic D, Padmanarayana M, Fischermanns K, Ranjan M, Boll M, Ka C, Piton A, Mattioli F, Isidor B, Õunap K, Reinson K, Wojcik MH, Marshall CR, Mercimek-Andrews S, Matsumoto N, Miyake N, Stephan BO, Honjo RS, Bertola DR, Kim CA, Yusupov R, Mefford HC, Christodoulou J, Lee J, Heath O, Brown NJ, Baker N, Stark Z, Delatycki M, Lake NJ, Zeidler S, Zuurbier L, Maas SM, de Kruiff CC, Rajabi F, Rodan LH, Coury SA, Platzer K, Oppermann H, Abou Jamra R, Beblo S, Maxton C, Śmigiel R, Underhill H, Dubbs H, Rosen A, Helbig KL, Helbig I, Ruggiero SM, Fitzgerald MP, Kraemer D, Prada CE, Tenney J, Jayakar P, Redon S, Lefranc J, Uguen K, Race S, Efthymiou S, Maroofian R, Houlden H, Coppens S, Deconinck N, Ashokkumar B, Varalakshmi P, Gowda K VR, Eghbal F, Ghayoor Karimiani E, Heidari M, Neidhardt J, Owczarek-Lipska M, Korenke GC, Bamshad MJ, Campeau PM, Lehman A, Hendon LG, Wentzensen IM, Monaghan KG, Chen Y, Szuto A, Cohn RD, Au PYB, Hübner C, Boschann F, Manickam K, Koboldt DC, Rad A, Oprea G, Bachman KK, Seeley AH, Agolini E, Terracciano A, Carmelo P, Bupp C, Grysko B, Rein-Rothschild A, Ben Zeev B, Margolin A, Morrison J, Dagli A, Stolerman E, Louie RJ, Washington C, Stevens SJC, Heijligers M, Alkuraya FS, Lisfeld J, Neu A, Paoli Monteiro F, Santos Pessoa AL, Camelo-Filho AE, Kok F, Koeberl D, Riley K, Burglen L, Doummar D, Héron B, Mignot C, Keren B, Charles P, Nava C, Bernhard FP, Kühn AA, Thoms S, Morrie RD, Mekhoubad S, Green EM, Barmada SJ, Gitler AD, Jahn O, Rhee JS, Rosenmund C, Mitkovski M, Sticht H, Sun H, Le Gac G, Taschenberger H, Brose N, Dittman JS, Rauch A, Lipstein N. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet. 2025 Nov;57(11):2691-2704. doi: 10.1038/s41588-025-02361-5. Epub 2025 Oct 22. PMID: 41125872; PMCID: PMC12597829.
Abstract
The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype-phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A-C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.
Ohno K, Ito M, Ohkawara B. Review of 40 genes causing congenital myasthenic syndromes. J Hum Genet. 2025 Jun 18. doi: 10.1038/s10038-025-01355-9. Epub ahead of print. PMID: 40533459.
Abstract
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by compromised neuromuscular signal transmission due to pathogenic germline variants in genes expressed at the neuromuscular junction (NMJ). A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DES, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MACF1, MUSK, MYO9A, PLEC, PREPL, PTPN11, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TEFM, TOR1AIP1, UNC13A, UNC50 and VAMP1). The 40 genes are putatively classified into 13 subtypes by pathomechanical, clinical, and therapeutic features. A unique feature shared by recently identified genes is that CMS is concomitantly recognized in other mostly severer diseases. For example, four recently identified genes exhibit the following phenotypes: PURA-CMS, developmental delay; TEFM-CMS, mitochondrial disease; PTPN11-CMS, Noonan syndrome/Leopard syndrome; and DES-CMS, desmin myopathy. Conversely, these diseases are not always associated with CMS, although genetic and/or environmental factors that determine the involvement of the NMJ remain to be identified. In this review, particular emphasis will be placed on five recently identified genes (MACF1, TEFM, PTPN11, DES and UNC50).
See: https://childnervoussystem.blogspot.com/2024/05/unc13a-mutation-and-congenital.html
https://childnervoussystem.blogspot.com/2023/12/unc13a-mutation-as-cause-of-congenital.html
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