Mucopolysaccharidosis Type IIIB / Sanfilippo Syndrome B via the NAGLU 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 IIIB is caused by deficiency of the alpha-N-acetyl-glucosaminidase.

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 IIIB is an autosomal recessive disease caused by pathogenic variants in the NAGLU gene (Zhao et al. 1996). About 150 pathogenic variants have been reported in patients from various ethnic and geographical populations. They include missense, nonsense, splicing, and small insertions or deletions mutations (Human Mutation Gene Database). Large deletions that cannot be detected by Sanger sequencing appear to be rare. Only one such deletion is reported (Champion et al. 2010).

There are no clear genotype-phenotype correlations because most pathogenic variants are private or occur with low frequencies (Yogalingam and Hopwood 2001; Wijburg et al. 2013). Nonetheless, it appears that most causative mutations in the NAGLU gene lead to severe MPS III (Zhao et al.1998).

The NAGLU gene encodes alpha-N-acetyl-glucosaminidase, one of four lysosomal enzymes involved in the stepwise degradation of heparan sulfate.

Using Sanger sequencing, pathogenic variants in the NAGLU gene were identified in all analyzed patients who have clinical features suggestive of MPS, elevated urinary heparan sulfate, and low levels of alpha-N-acetyl-glucosaminidase activity in the plasma (Zhao et al. 1998).

Large pathogenic deletions in NAGLU appear to be rare (Human Gene Mutation Database). Only one such deletion is reported (Champion et al. 2010).

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