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Mucopolysaccharidosis type IIIC (Sanfilippo syndrome type C) is an autosomal recessive lysosomal storage disorder caused by deficiency of heparan-α-glucosaminide N-acetyltransferase (HGSNAT) (HGSNAT) leading to accumulation of heparan sulfate in neural and visceral tissues. Patients typically present in early childhood with progressive neurodegeneration, behavioral problems, speech deterioration, motor delay, and hepatomegaly (PMID:23301227).
Genetic analyses across diverse populations have identified biallelic HGSNAT variants in over 33 unrelated probands, including a Korean index case with c.1150C>T (p.Arg384Ter) and c.234+1G>A, two siblings with Klüver–Bucy neurobehavioral syndrome carrying c.518G>A (p.Gly173Asp), a Chinese patient bearing c.743G>A (p.Gly248Glu) and c.1030C>T (p.Arg344Cys), and a Dutch cohort of 29 patients harboring 14 distinct mutations (PMID:18024218). Segregation of homozygous or compound heterozygous variants in consanguineous families and sibships further supports pathogenicity (2 siblings in a KBS family; 2 sisters in attenuation cases).
Inheritance is autosomal recessive with high allelic heterogeneity: more than 100 unique HGSNAT variants have been catalogued, including splice-site, nonsense, frameshift, and missense changes. Recurrent alleles such as c.234+1G>A and p.Arg344Cys are observed in multiple populations, and founder effects have been documented in Dutch and Brazilian cohorts. The variant c.1150C>T (p.Arg384Ter) exemplifies a truncating allele associated with classical severe phenotype.
Functional studies demonstrate that loss of HGSNAT activity underlies disease: Hgsnat knockout mice exhibit ~50% reduction in rod photoreceptor density and retinal degeneration mirroring human ocular involvement (PMID:36858249). In vitro expression of 21 patient-derived missense mutants revealed misfolding, aberrant glycosylation, endoplasmic reticulum retention, and loss of enzymatic activity for 17 alleles; chemical chaperones partially rescued select mutants, illustrating haploinsufficiency and misfolding as key mechanisms (PMID:19823584).
No studies have refuted the HGSNAT–MPS IIIC association. The expanded phenotypic spectrum includes non-syndromic retinitis pigmentosa linked to hypomorphic alleles, but these represent allelic variation rather than conflicting disease assignments.
Collectively, multiple case reports, a large Dutch series, segregation data, and concordant animal and cellular models yield a Strong gene-disease association. Genetic evidence is rated Strong (biallelic variants in >33 probands; segregation in 4 affected relatives; reaches genetic cap). Functional evidence is rated Moderate (knockout mouse recapitulates human retinal phenotype; misfolding assays with rescue). Early molecular diagnosis of HGSNAT variants informs prognosis, enzymatic testing, and emerging chaperone therapies. Key take-home: HGSNAT pathogenic variants reliably cause autosomal recessive MPS IIIC, and comprehensive genetic and functional evaluation is essential for diagnosis and therapeutic development.
Gene–Disease AssociationStrongMultiple reports including 29 probands in a Dutch cohort, additional unrelated cases, multi-family segregation, concordant functional data Genetic EvidenceStrongBiallelic HGSNAT variants identified in >33 probands; segregation in 4 affected relatives; reached ClinGen genetic cap Functional EvidenceModerateHgsnat knockout mouse replicates retinal degeneration; misfolding and chaperone rescue assays support pathogenic mechanism |