Mucopolysaccharidosis Type IIIA / Sanfilippo Syndrome A via the SGSH Gene

The mucopolysaccharidoses (MPS) are a group of inherited disorders caused by defects in lysosomal enzymes responsible for the stepwise degradation of glycosaminoglycans (GAGs). Each enzyme deficiency results in progressive storage of distinct GAGs in multiple organ systems and subsequent abnormalities. Although MPS share several symptoms, including physical and mental developmental abnormalities, they may differ even within the same enzyme deficiency. Seven clinically distinct types can be recognized (Types I, II, III, IV, VI, VII, and IX). Based on the biochemical and genetic defects, MPS III and IV are further divided in four and two subtypes, respectively. Deficiencies in eleven enzymes have been implicated in the various MPS.

Mucopolysaccharidosis Type III, also known as Sanfilippo syndrome is caused by deficiency in any of four lysosomal enzymes involved in the stepwise degradation of heparan sulfate. Enzyme deficiencies result in progressive storage of heparan sulfate primarily in the central nervous system, leading to severe neurodegeneration and developmental delay. MPSIII is classified into four subtypes (MPS IIIA to D) on the basis of the specific enzyme deficiency. MPS IIIA is caused by deficiency of the heparan N-sulfatase, also designated sulfamidase.

Clinically, MPS III is distinguished from the other MPS by a severe cognitive and neurological impairment; and mild somatic signs. The characteristic features are similar in all four subtypes, although MPS IIIA is usually associated with an earlier age of onset and a faster progression compared to the other MPS. Symptoms appear during childhood and death usually occurs by the second or third decade of life. Symptoms typically begin with episodes of hyperactivity and aggressive behavior and progress to severe behavioral and sleep disturbances, speech difficulties, hearing and visual defects, and mental retardation. Somatic involvement is variable. Symptoms include mildly coarse facial features, recurrent ear and respiratory infections, scoliosis, hip dysplasia, carpal tunnel syndrome and cardiac valve disease (Neufeld and Muenzer 2001; Wijburg et al. 2013).

MPS III occurs in diverse ethnic and geographical populations with an estimated prevalence of 0.87:100,000 per live births (www.orpha.net).

MPS IIIA is inherited in an autosomal recessive manner and is caused by pathogenic variants in the SGSH gene (Scott et al. 1995). Over 100 disease-causing variants have been reported in patients from various ethnic and geographical populations. Although most variants are missense; nonsense, splicing, small insertions or deletions and large deletions have been reported (Human Gene Mutation Database).

There are no clear genotype-phenotype correlations because most pathogenic variants are private (Yogalingam and Hopwood 2001), and because of the lack of strong correlations between specific causative mutations and residual enzyme activity (Beesley et al. 2000). In addition, modifying factors, including genetic and environmental, are suspected to contribute to the phenotypic presentation (Perkins et al. 1999).

The SGSH gene encodes for the lysosomal heparan N-sulfatase (or sulfamidase), one of four enzymes involved in the degradation of heparan sulfate.

Pathogenic variants were identified in over 98% of the alleles in patients diagnosed with MPS IIIA based on deficient heparan N-sulfatase activity (Valstar et al. 2010).

Although rare, large pathogenic deletions in SGSH have been reported (Ouesleti et al. 2011).

This test provides full coverage of all coding exons of the SGSH gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.