RPH3A – Congenital Myasthenic Syndrome

An association between RPH3A and autosomal recessive congenital myasthenic syndrome (CMS) is supported by a single unrelated case: an 11-year-old girl with muscle fatigability, tremors, cerebellar ataxia, and learning disability in whom compound heterozygous RPH3A variants were identified ([PMID:29441694]). The variants c.806G>A (p.Arg269Gln) and c.1390G>T (p.Val464Leu) segregate in trans with disease in her family, with both parents unaffected carriers ([PMID:29441694]). Functional expression studies demonstrated that p.Arg269Gln strongly impairs Rabphilin-3A binding to 14-3-3, consistent with disrupted synaptic vesicle homeostasis and a loss-of-function mechanism ([PMID:29441694]). RPH3A encodes Rabphilin-3A, a presynaptic vesicle protein critical for neurotransmitter release, and was also listed among 35 genes implicated in CMS in a comprehensive review ([PMID:36835142]). No additional affected families or conflicting reports have been reported. The current evidence places RPH3A at a Limited level of clinical validity for CMS; further case series and functional validation are required.

Key take-home: RPH3A should be included in genetic testing panels for presynaptic CMS when bi-allelic variants are detected.

References

• Molecular genetics & genomic medicine • 2018 • Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A. PMID:29441694
• International journal of molecular sciences • 2023 • Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review. PMID:36835142

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