A cohort of GFPT1 related congenital myasthenic syndrome in China: high frequency of c.331 c > t variant.

Background: Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the key enzyme initiating protein O- and N-glycosylation at the postsynaptic membrane. Variants in GFPT1 gene cause congenital myasthenic (GFPT1-CMS). However, the understanding of the phenotype and genetic spectrum of GFPT1-CMS remains limited.

Methods: A total of 24 patients with GFPT1-CMS from 22 Han Chinese families across four neuromuscular disease centers were included in this study. Clinical assessments involved detailed medical histories, muscle biopsies, and electrophysiological studies. GFPT1 variants were identified using targeted next-generation sequencing or WES. Additionally, published GFPT1-CMS case data from 2011 to 2024 were compiled and combined with this cohort for genotype-phenotype correlation analysis.

Results: In addition to the limb girdle myasthenia pattern, our cohort presented with extraocular involvement including eyelid ptosis and mild ophthalmoparesis (25.0%), facial weakness (20.8%) and a relatively high prevalence of distal weakness (62.5%). Electrophysiological testing revealed myopathic changes in 95.0% of cases and decremental CMAPs in all cases during RNS. We found that c.331 C > T is a hotspot variant in GFPT1-CMS patients and may have a founder effect in the Chinese population. Patients with homozygous null variants presented a more severe phenotype, including earlier onset and more frequent bulbar involvement.

Conclusion: We have described the clinical features and variant spectrum in a cohort of 24 Chinese GFPT1-CMS patients. Our findings update the understanding of clinical manifestation, pathological features and mutational spectrum in GFPT1-CMS patients.