Late‐onset mucopolysaccharidosis type IIIA mimicking Usher syndrome

Abstract Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH gene encoding N ‐sulfoglucosamine sulfohydrolase, an enzyme involved in the degradation of heparan sulfate. MPS IIIA is typically characterized by neurocognitive decline and hepatosplenomegaly with childhood onset. Here, we report on a 53‐year‐old male subject initially diagnosed with Usher syndrome for the concurrence of retinitis pigmentosa and sensorineural hearing loss. Clinical exome sequencing identified biallelic missense variants in SGSH , and biochemical assays showed complete deficiency of sulfamidase activity and increased urinary glycosaminoglycan excretion. Reverse phenotyping revealed left ventricle pseudo‐hypertrophy, hepatosplenomegaly, bilateral deep white matter hyperintensities upon brain MRI, and decreased cortical metabolic activity by PET‐CT. On neuropsychological testing, the proband presented only partial and isolated verbal memory deficits. This case illustrates the power of unbiased, comprehensive genetic testing for the diagnosis of challenging mild or atypical forms of MPS IIIA.