Mucopolysaccharidosis Type I via the IDUA 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 (Neufeld and Muenzer 2001). See also the National MPS Society at (www.mpssociety.org).

MPS I is a multisystemic disorder caused by deficiency in lysosomal alpha-L-iduronidase and subsequent systemic accumulation of dermatan and heparan sulfates. Historically, three major clinical subtypes are recognized on the basis of the age of onset, severity and disease course (Neufeld and Muenzer 2001; Clarke and Heppner 2011; Coutinho et al. 2012).

1) Hurler syndrome is the most severe and frequent form of MPS I. It is characterized by onset in infancy and death by the first decade of life, as the result of heart or lung failure. Symptoms include coarse facial features, corneal clouding, hydrocephalus, heart disease, respiratory difficulties, hepatosplenomegaly, joint stiffness, learning disabilities, and mental retardation.

2) Hurler-Scheie syndrome is characterized by onset in childhood and intermediate severity, progressive somatic involvement with normal intelligence and survival to adulthood.

3) Scheie syndrome is the mildest and most heterogeneous form. Symptoms appear after the age of five years and include stiff joint and heart disease. Life span is usually normal (Thomas et al. 2010).

Due to the wide range of clinical manifestations and the lack of clear delineation between the three subtypes, patients are best described as having severe and attenuated forms of MPS I disease (Neufeld and Muenzer 2001).

MPS I affects people worldwide with an estimated prevalence of 1:100,000 per live births (www.orpha.net).

MPS I is inherited in an autosomal recessive manner and results from pathogenic variants in the IDUA gene (Scott et al. 1992; Lee-Chen et al. 1999; Moskowitz et al. 1993). Over 200 causative variants have been reported in patients from various ethnic and geographical populations and include missense, nonsense, splicing, small insertions or deletions and indels. Large pathogenic deletions in the IDUA gene have not been reported (Human Mutation Gene Database).

There are no clear genotype-phenotype correlations because most pathogenic variants are private or occur with low frequencies. Nonetheless, patients with a nonsense mutation on both alleles typically develop a severe clinical phenotype (Terlato and Cox GF 2003). In addition, genetic and other modifying factors may contribute to the clinical phenotype (Clarke et al. 1994)

The IDUA gene encodes the lysosomal alpha-L-iduronidase enzyme, which hydrolyzes the terminal a-L-iduronic acid residues of dermatan sulfate and heparan sulfate.

Pathogenic variants in the IDUA gene were identified in about 97% of alleles in patients biochemically proven to have MPS I (Beesley et al. 2001).

Thus far, large pathogenic deletions in the IDUA gene have not been reported (Human Mutation Gene Database).

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