AUTOPHAGIC MYOPATHIES / MYOFIBRILLAR MYOPATHIES / DISTAL MYOPATHIES / POMPE DISEASE: P.10 Distal myopathy associated with two novel variants in SPTAN1

Abstract

The phenotypic spectrum associated with autosomal dominant SPTAN1 variants has evolved since the initial 2008 description of infantile epileptic encephalopathy due to non-truncating mutations. Loss of function variants were reported in association with a central nervous system phenotype without epilepsy in 2018, and with a juvenile onset hereditary motor neuropathy in 2019. Here we report novel SPTAN1 variants in two patients seen in our clinic. The first presented at 9 years old with a history of mild motor and cognitive delays, dysmorphic features and abnormal gait. Examination showed distal leg muscle atrophy and weakness most significant in the ankles. Serum CK was normal; limited EMG was unremarkable but showed no evidence for neuropathy. His family history was non-contributory, and standard genetic testing was non-diagnostic. Whole exome sequencing (WES) at age 11 identified a SPTAN1 variant (c.6657delC/p.Asn2220ThrfsTer44) that was not maternally inherited (father unavailable to test). The second presented to our clinic at age 15, with reported first symptoms of abnormal standing posture and delayed motor milestones noted at 20 months. Based on symptoms of bilateral distal atrophy, pes cavus and foot drop, he was thought to have a distal motor neuropathy. An EMG at age 15 years showed evidence of distal myopathy without evidence of neuropathy; serum CK was normal. There was no family history of similar symptoms, and genetic testing including MYH7 sequencing, FSHD testing and a neuromuscular gene panel, was all negative. Examination at age 22 showed distal weakness with preserved EDB bulk, and WES identified a de novo pathogenic truncating SPTAN1 variant (c.2613delG; p.Lys871AsnfsTer5). Additional follow-up studies (including more extensive EMG and muscle biopsy) are planned, and will be reported. These patients suggest that SPTAN1 variants may be associated with a distal myopathy, expanding the clinical heterogeneity associated with mutations in this gene.