SGSH – Mucopolysaccharidosis Type III (Sanfilippo Syndrome)

1. The SGSH gene encodes N-sulfoglucosamine sulfohydrolase (sulfamidase), a lysosomal enzyme required for heparan sulfate (HS) degradation. Deficiency of SGSH causes mucopolysaccharidosis type 3 (MPS III), characterized by progressive neurocognitive decline and mild somatic involvement.

2. MPS III exhibits autosomal recessive inheritance with biallelic SGSH variants leading to enzyme loss. Over 274 unrelated MPS IIIA probands have been described with homozygous or compound heterozygous SGSH mutations across cohorts in France, the UK, and Greece ([PMID:21204211]).

3. Case reports include a patient homozygous for c.617G>C (p.Arg206Pro) presenting with attenuated mental retardation and stable phenotype ([PMID:15637719]), and the first MPS IIID case with a c.1169delA frameshift causing premature truncation and early-onset neurological regression ([PMID:12624138]).

4. The SGSH variant spectrum encompasses >100 unique missense changes (e.g., p.Leu146Pro, p.Ser298Pro), multiple frameshift and nonsense alleles (e.g., c.1080del (p.Val361fs)), and occasional population-specific founder variants. The p.Ser298Pro substitution correlates with a milder phenotype in compound heterozygotes.

5. Functional studies in heterologous systems show most missense and truncating SGSH alleles abolish enzymatic activity and impair protein stability ([PMID:15542396]). Structural and computational analyses reveal misfolding mechanisms ([PMID:24816101]). In vivo, SGSH-deficient mice recapitulate CNS pathology and support therapeutic gene-delivery strategies ([PMID:37891179], [PMID:29503202]).

6. Collectively, robust genetic and experimental concordance definitively establishes SGSH deficiency as the cause of MPS III. Early molecular diagnosis enables carrier detection, informed genetic counseling, and enrollment in emerging gene or enzyme replacement trials. Key take-home: SGSH testing is essential in children with unexplained neurodevelopmental regression and mild somatic features.

References

• Journal of Medical Genetics • 2003 • Sanfilippo syndrome type D: identification of the first mutation in the N-acetylglucosamine-6-sulphatase gene. PMID:12624138
• American Journal of Medical Genetics Part A • 2005 • An adult Sanfilippo type A patient with homozygous mutation R206P in the sulfamidase gene. PMID:15637719
• American Journal of Medical Genetics Part A • 2011 • Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. PMID:21204211
• Molecular Genetics and Metabolism • 2004 • Expression and functional characterization of human mutant sulfamidase in insect cells. PMID:15542396
• Acta Crystallographica Section D • 2014 • Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA. PMID:24816101
• Scientific Reports • 2023 • An immune deficient mouse model for mucopolysaccharidosis IIIA (Sanfilippo syndrome). PMID:37891179
• Molecular Therapy • 2018 • Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy. PMID:29503202

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