Mucopolysaccharidosis type IIIC (MPS IIIC) is a rare lysosomal storage disorder caused by biallelic pathogenic variants in the HGSNAT gene, encoding heparan-α-glucosaminide N-acetyltransferase. Deficient enzymatic activity leads to heparan sulfate accumulation, resulting in progressive central nervous system involvement and multisystem disease. Clinical features typically include developmental delay, intellectual disability, behavioral disturbances, coarse facial features, hypertrichosis, and hearing loss. This report describes the oldest documented siblings with MPS IIIC: a male diagnosed at 46 years (currently 50 years) and his sister diagnosed at 38 years (currently 42 years). Both presented with bilateral sensorineural hearing loss, retinitis pigmentosa, intellectual disability, mildly coarse facial features, and hypertrichosis. Molecular analysis identified two novel HGSNAT variants: c.1205T>C; p.(Leu402Pro) and c.1565C>A; p.(Thr522Lys). Functional studies demonstrated markedly reduced heparan-α-glucosaminide N-acetyltransferase activity and elevated urinary heparan sulfate excretion, providing biochemical evidence supporting variant pathogenicity and confirming the diagnosis. These cases expand both the phenotypic and genotypic spectrum of MPS IIIC and underscore the importance of considering this disorder in adults with multisystem involvement. Functional characterization proved essential for establishing a definitive diagnosis when molecular findings alone were inconclusive.
Yu et al. (Wed,) studied this question.