Mucopolysaccharidosis Type III Panel

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. The different subtypes are caused by deficiency of: N-sulfoglucosamine sulfohydrolase, also known as sulfaminidase (MPS IIIA); α-N-acetylglucosaminidase (MPS IIIB); heparan acetyl CoA: α-glucosaminide N-acetylglucosaminidase (MPS IIIC); or N-acetylglucosamine 6-sulfatase (MPS IIID). A putative fifth subtype, MPS IIIE, has been proposed to be caused by deficiency of N-glucosamine 3-O-sulfatase, although to date this subtype has only been observed in dog and animal models, with no human cases reported (Fedele 2015). 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 intellectual disability. 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; Fedele 2015). There is currently no treatment for MPS III (Fedele 2015). MPS III occurs in diverse ethnic and geographical populations with an estimated prevalence of 1-9:100,000 live births (www.orpha.net; Fedele 2015).

MPS III is inherited in an autosomal recessive manner and is caused by pathogenic variants in one of four genes: SGSH (MPS IIIA; N-sulfoglucosamine sulfohydrolase or sulfaminidase); NAGLU (MPS IIIB; α-N-acetylglucosaminidase); HGSNAT (MPS IIIC; heparan acetyl CoA: α-glucosaminide N-acetylglucosaminidase) or GNS (MGS IIID; N-acetylglucosamine 6-sulfatase) (Fedele, 2015). Pathogenic variants are most common in SGSH and NAGLU with over 100 disease-causing variants in each gene reported in patients from various ethnic and geographical populations, while variants in HGSNAT and GNS have been reported in 66 and 23 patients, respectively. In SGSH, NAGLU, and HGSNAT, most reported variants are missense, although nonsense, splicing, small insertions or deletions and large deletions have been reported. In GNS, the reported variants are evenly distributed across the different variant types (Human Gene Mutation Database; Fedele 2015).

Several studies have reported genotype-phenotype correlations in some subtypes of MPS III. In particular, the following SGSH variants have been associated with a severe phenotype: p.Arg245His; p.Gln380Arg; p.Ser66Trp; c.1080delC (p.Val361Serfs*52); and p.Arg74Cys, while p.Ser298Pro has been associated with an attenuated phenotype (Bodamer et al. 2014; Fedele 2015). In NAGLU, p.Arg297Ter has been associated with a severe phenotype while p.Arg643Cys has been associated in an attenuated phenotype (Bodamer et al. 2014).

See individual gene test descriptions for information on molecular biology of gene products.

Pathogenic variants were identified in SGSH in >98% of the alleles in patients diagnosed with MPS IIIA based on deficient N-sulfoglucosamine sulfohydrolase activity (Valstar et al. 2010a). Pathogenic variants in NAGLU were identified in 94% to 100% of the alleles in patients diagnosed with MPS IIIB based on clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of alpha-N-acetyl-glucosaminidase activity (Zhao et al. 1998; Beesley et al. 2005). Pathogenic variants in the HGSNAT gene were identified in 98% of the alleles in patients diagnosed with MPS IIIC based on clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of acetyl-CoA:α-glucosaminide N-acetyltransferase (Ruijter et al. 2008). Finally, pathogenic variants in the GNS gene were identified in approximately 85% of the alleles in patients diagnosed with MPS IIID based on clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of N-acetylglucosamine-6-sulfatase. Large deletions were identified in all of the remaining alleles (Valstar et al. 2010b).

Although rare, large pathogenic deletions have been reported in all four of the genes associated with Mucopolysaccharidosis Type III (SGSH, NAGLU, HGSNAT, and GNS) (Fedele 2015; Human Gene Mutation Database).

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.