Mucopolysaccharidosis Type IIIC / Sanfilippo Syndrome C via the HGSNAT 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 IIIC is caused by deficiency of the lysosomal acetyl-CoA:alpha-glucosaminide acetyltransferase.

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 IIIC is inherited in an autosomal recessive manner and is caused by mutations in the HGSNAT gene (Hrebicek et al. 2006; Fan et al. 2006). To date, about 65 pathogenic variants have been reported in patients from various ethnic and geographical populations. All major types of variants have been reported including two large deletions (Human Mutation Gene Database and Leiden Open Variation Database).

There are no clear genotype-phenotype correlations in any of the four MPS III because most pathogenic variants are private or occur with low frequencies (Yogalingam and Hopwood 2001). In addition, severity and clinical course vary even among sibs with HGSNAT causative mutations. Nonetheless, patients with two nonsense variants usually develop a severe MPS III (Ruijter et al. 2008; Feldhammer et al. 2009).

The HGSNAT gene encodes acetyl-CoA:alpha-glucosaminide acetyltransferase, one of four lysosomal enzymes involved in the stepwise degradation of heparan sulfate.

Using Sanger sequencing, pathogenic variants in the HGSNAT gene were identified in 98% of the mutated alleles in patients with clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of acetyl-CoA:alpha-glucosaminide N-acetyltransferase in leukocytes or cultured skin fibroblasts (Ruijter et al. 2008).

Although rare, large pathogenic deletions in HGSNAT have been reported (Human Gene Mutation Database).

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