Mucopolysaccharidosis type IIIA and IIIC phenotypic progression: A case series

Mucopolysaccharidosis type III (MPS III), or Sanfilippo syndrome, is a group of rare autosomal recessive lysosomal storage disorders caused by deficiency of enzymes involved in heparan sulfate degradation, encoded by SGSH (type A), NAGLU (type B), HGSNAT (type C), or GNS (type D). Progressive lysosomal accumulation leads to neurodegeneration, cognitive decline, behavioral disturbances, and premature death. Despite a global pooled birth prevalence of ∼0.76 per 100,000 live births, MPS III remains substantially underdiagnosed in Latin America. To date, only a single MPS IIIB case has been molecularly confirmed in Mexico, with no reported cases of MPS IIIA or IIIC.

Two adolescent patients with progressive neurodevelopmental deterioration were evaluated at a tertiary genetics center in Yucatán, Mexico. Assessment included structured clinical history, neuroimaging, conventional karyotyping, and whole-exome sequencing (WES), with variants classified per ACMG/AMP guidelines.

Case 1 (MPS IIIC): a 15-year-old male presented with speech delay, progressive loss of ambulation and self-feeding, sleep disturbances, and hyperactivity. WES identified a homozygous pathogenic HGSNAT variant (NM_152419.3): c.234 + 1G > A, a previously described Iberian-associated allele. Case 2 (MPS IIIA): a 15-year-old female presented with neurological regression from age 4, refractory generalized seizures, and profound intellectual disability. WES identified two compound heterozygous SGSH variants (NM_000199.5): c.233 T > G (p.Leu78Arg) and c.368 A > G (p.Lys123Arg), both classified as likely pathogenic and, to our knowledge, not previously reported in the literature or genomic databases.

These cases are consistent with the first reported diagnoses of MPS IIIA and MPS IIIC in Mexico, supported by concordant clinical and molecular findings and indicating the presence of at least three MPS III subtypes in the country. The two SGSH variants represent candidate novel alleles, with enzymatic and functional confirmation pending. The identification of these variants and of a recurrent Iberian-associated HGSNAT allele in non-consanguineous patients underscores the likely underdiagnosis of MPS III in Mexico and the diagnostic value of WES in resource-limited settings.