ABSTRACT Aims To characterize the clinical, electrophysiological, and genetic spectrum of pediatric CMS and evaluate genotype‐informed outcomes using an integrated phenotype–electrophysiology–genomics approach. Methods We retrospectively reviewed 36 pediatric CMS patients evaluated at a single center between 2015 and 2025. Clinical features, RNS, targeted NGS/WES variants, ventilator use, treatments, ACMG/AMP classifications, and MG‐ADL outcomes were analyzed. Results Of 36 patients, 28 (77.8%) developed symptoms in the neonatal period or infancy. Biallelic variants involved 17 CMS genes; postsynaptic CMS was most common (55.6%, 20/36). COLQ and CHRNE were the most frequent genes (13.9%, 5/36 each), followed by CHAT (11.1%, 4/36). VUS were detected in 19 patients (52.8%, 19/36), including 8 with biallelic VUS supported by phenotype, neuromuscular transmission findings, treatment response, and follow‐up. RNS showed a ≥ 10% decrement in 16/21 tested patients (76.2%). CHAT‐CMS was associated with higher ventilator use (3/4 vs. 6/32; p = 0.041) and early mortality (3/4 vs. 1/32; p = 0.002). Median MG‐ADL improved from 5 to 3 after genotype‐informed therapy. Conclusion Pediatric CMS shows marked genetic heterogeneity and frequent VUS‐related uncertainty. Integrating phenotype, electrophysiology, and genomics supports diagnosis and mechanism‐guided therapy. CHAT‐CMS is high risk for early respiratory failure and mortality.
Li-Ya Cui, Kai-Yue Ma, Xiao-Na Fu et al.· CNS Neuroscience & Therapeut...· 0 citations
OBJECTIVE
This study was undertaken to characterize the clinical and genetic spectrum of RHOBTB2-related disorders (RHOBTB2-RDs) in a Chinese population, explore genotype-phenotype correlations, and develop a refined clinical framework to improve diagnosis and management.
METHODS
We conducted a comprehensive analysis by integrating data from 12 Chinese patients (five retrospective, seven from literature) with 79 international cases from published studies. Genetic analysis focused on variant classification and hotspot identification. Standardized phenotypic data extraction was performed, followed by systematic classification and correlation analyses.
RESULTS
In the Chinese cohort, all variants were de novo missense mutations, with 75% in the Broad-complex, Tramtrack, and Bric-à-brac (BTB) domain and conserved hotspots (e.g., p.Arg483His). Across the combined cohort (N = 91), RHOBTB2-RDs presented a broad phenotypic spectrum. As an exploratory proposal, we introduce paroxysmal encephalopathy with weakness (PEW) as a potential novel clinical phenotypic cluster, strongly associated with BTB domain variants. A practical subtyping framework was proposed: the BTB subtype (severe developmental and epileptic encephalopathy [DEE] with prominent paroxysmal features, often necessitating aggressive seizure management), the truncating/splicing subtype (primarily intellectual disability/developmental delay and movement disorders with epilepsy, requiring focused neurodevelopmental support), the guanosine triphosphatase subtype (a mixed phenotype with a generally more favorable neurodevelopmental course), and the interdomain subtype (frequently associated with PEW alongside DEE or paroxysmal movement disorders).
SIGNIFICANCE
This study systematically characterizes RHOBTB2-RDs in Chinese patients, confirming conserved pathogenic hotspots across ethnicities and identifying population-specific features. The proposed clinical subtyping framework and PEW diagnostic criteria provide valuable tools for improving diagnostic accuracy and guiding personalized management of RHOBTB2-RDs.
Ming Liu, Xiao-Juan Tian, Yu-Pin Ma et al.· Epilepsia· 0 citations
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