SGSH – Sanfilippo Syndrome Type A (Mucopolysaccharidosis IIIA)

Sanfilippo syndrome type A (MPS IIIA) is a rare autosomal recessive neurodegenerative lysosomal storage disorder caused by pathogenic variants in the SGSH gene, encoding N-sulfoglucosamine sulfohydrolase. Affected individuals present in early childhood with developmental regression, progressive dementia, seizures, sleep disturbances, behavioral abnormalities, and hepatosplenomegaly, often leading to death in the second decade of life. The disorder has been observed worldwide, with certain populations exhibiting founder mutations.

A founder effect for the recurrent c.734G>A (p.Arg245His) variant was established in the Cayman Islands, where carrier frequency reaches 1/7–1/10 and all affected individuals in one pedigree were homozygous for the mutation ([PMID:12490062]). Segregation analysis in this family and in a consanguineous Israeli pedigree (homozygous c.416C>T (p.Thr139Met)) confirms autosomal recessive transmission and supports carrier testing in at-risk populations.

Genetic studies across multiple cohorts have described over 100 SGSH mutations, including missense, nonsense, frameshift, and splice-site variants. In a survey of 109 MPS IIIA patients from diverse regions, 16 novel likely pathogenic variants were identified, with R245H accounting for 31%–58% of alleles in certain populations ([PMID:9285796]). Additional cohorts have expanded the variant spectrum to include deep-intronic and large deletion alleles, with recurrent and population-specific mutations facilitating molecular diagnosis.

Functional assays of mutant SGSH proteins expressed in cell models demonstrate dramatically reduced or absent enzymatic activity for variants such as c.220C>T (p.Arg74Cys) and c.318C>A (p.Ser106Arg), with studies showing misfolding, rapid ER-associated degradation, and impaired lysosomal targeting ([PMID:15146460]). Structural analysis of recombinant SGSH at 2 Å resolution further elucidates the molecular consequences of pathogenic substitutions and informs potential structure-guided therapies ([PMID:24816101]).

Preclinical models of MPS IIIA, including Sgsh null mice, recapitulate key features such as retinal degeneration and microglial activation, and have been instrumental in evaluating enzyme replacement and gene therapy strategies. A variant SGSH optimized for secretion improved CSF enzyme levels and cognitive function in AAV-treated mice, highlighting translational potential ([PMID:32195255]).

Integration of robust genetic evidence, consistent autosomal recessive segregation, and concordant functional and structural data supports a Definitive gene–disease validity classification. SGSH variant analysis is critical for early diagnosis, carrier screening, and guiding emerging therapies in Sanfilippo syndrome type A.

Key Take-home: Biallelic SGSH pathogenic variants cause MPS IIIA with a consistent clinical presentation; molecular diagnosis enables timely management and informs novel therapeutic development.

References

• Genetic testing • 2002 • Founder mutation R245H of Sanfilippo syndrome type A in the Cayman Islands PMID:12490062
• Human molecular genetics • 1997 • Novel mutations in Sanfilippo A syndrome: implications for enzyme function PMID:9285796
• Human mutation • 2004 • Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A PMID:15146460
• Acta crystallographica Section D • 2014 • Structure of sulfamidase provides insight into the molecular pathology of mucopolysaccharidosis IIIA PMID:24816101
• Frontiers in cell and developmental biology • 2020 • Retinal Degeneration in MPS-IIIA Mouse Model PMID:32195255

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