Mucopolysaccharidosis Type IIID / Sanfilippo Syndrome D via the GNS 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 IIID is caused by deficiency of the lysosomal N-acetylglucosamine 6-sulfatase.

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 IIID is the rarest subtype. Only 26 families with the history of MPS IIID have been reported to date (Valstar et al. 2010).

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 IIID is inherited with an autosomal recessive manner; it is caused by pathogenic variants in the GNS gene (Beesley et al. 2003; Mok et al. 2003). A total of about 25 pathogenic variants are reported in patients from various ethnic and geographical populations. Most variants are predicted to result in protein truncation and include nonsense, splicing, small insertions or deletions and large deletions. Only three missense variants are reported to date. They occur within the sulphatase domain and affect highly conserved amino acids (Valstar et al. 2010; Human Mutation Gene Database).

As in the case of the other MP III subtypes, there are no clear genotype-phenotype correlations 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 GNS causative mutations (Valstar et al. 2010). Genetic and environmental modifying factors, including intrauterine environment, are suspected to contribute to the phenotypic presentation (Jansen et al. 2007).

The GNS gene encodes N-acetylglucosamine-6-sulfatase, one of four lysosomal enzymes involved in the stepwise degradation of heparan sulfate.

Using Sanger sequencing, pathogenic variants in the GNS gene were identified in about 85% of the alleles in patients with clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of N-acetylglucosamine-6-sulfatase in leukocytes or cultured skin fibroblasts. Large deletions were identified in all the remaining alleles (Valstar et al. 2010).

Large pathogenic deletions were found in about 15% of the mutated alleles (Valstar et al. 2010). They represent about 18 % of the known GNS causative variants (Human Gene Mutation Database).

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