Adult-Onset Sandhoff Disease in a Filipino Patient: Asymmetric Weakness, Whole HEXB Gene Deletion, and Coexisting MYH7 Pathogenic Variant.

Abstract

ObjectiveTo describe a Filipino patient with adult-onset Sandhoff disease manifesting with an atypical asymmetric lower motor neuron syndrome due to a novel whole HEXB deletion in trans with a pathogenic missense variant and with a coexisting MYH7 pathogenic variant.MethodsWe performed clinical, laboratory, myopathologic, and genetic evaluation with next-generation sequencing in the proband and targeted mutational analysis in an asymptomatic sibling.ResultsA 59-year-old Filipino woman presented with 15 years of slowly progressive, asymmetric, proximal-predominant, lower greater than upper extremity weakness, mildly elevated creatine kinase, and generalized cerebellar atrophy. Serum total β-hexosaminidase was significantly reduced, and hexosaminidase A percentage was increased. We identified a novel HEXB whole gene deletion in compound heterozygosity with a pathogenic missense variant (c.1513C>T, p.Arg505Trp) previously described in 1 patient with adult-onset Sandhoff disease. The patient, with a family history of cardiomyopathy, has a coexisting MYH7 pathogenic variant (c.3134G>A, p.Arg1045His), causative of cardiomyopathy but without cardiac involvement, likely due to variable penetrance. Myopathic features were absent from skeletal muscle biopsy.DiscussionThis patient expands the genotypic, phenotypic, and ethnic spectrum of Sandhoff disease and highlights challenges generated by low-penetrant pathogenic variants, especially when considering a potentially polygenic phenotype.