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Mucopolysaccharidosis 1 (MPS1) (Hurler / Scheie Syndrome)

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Mucopolysaccharidosis 1 (MPS1) (Hurler / Scheie Syndrome) Mucopolysaccharidosis 1 (MPS1) (Hurler / Scheie syndrome) Contact details Introduction Regional Genetics Service MPS1 (MIM 252800) is an autosomal recessive lysosomal storage disorder, also known as Levels 4-6, Barclay House Hurler syndrome (severe) or Scheie syndrome (milder variant). The condition is caused by a 37 Queen Square deficiency of the enzyme alpha-L-iduronidase (IDUA), which is required for lysosomal degradation of the glycosaminoglycans, heparin sulphate and dermatan sulphate. Affected London, WC1N 3BH individuals have a characteristic pattern of urine metabolites and a deficiency in the IDUA T +44 (0) 20 7762 6888 enzyme activity; biochemical enzyme analysis utilises these features to confirm a clinical F +44 (0) 20 7813 8578 diagnosis. Hurler patients are usually diagnosed by the age of 2 years and characteristically have short Samples required stature, coarse facial features, developmental delay, heart defects and hepatosplenomegaly. 5ml venous blood in plastic EDTA Scheie patients can present at a later age, and have a milder course of symptoms, including joint bottles (>1ml from neonates) stiffness, corneal clouding and aortic valve disease. Other patients have an intermediate phenotype. The phenotypic heterogeneity correlates to some extent with the different nature of Prenatal testing must be arranged the pathogenic variants identified in the IDUA gene, although many novel pathogenic variants in advance, through a Clinical are known, there are ‘common’ pathogenic variants within the gene. Genetics department if possible. The IDUA gene (4p16.3) has 14 exons and pathogenic variants have been found throughout the Amniotic fluid or CV samples gene. The recurrent pathogenic variants p.(Gln70*), p.(Ala327Pro) and p.(Trp402*) account for should be sent to Cytogenetics for approx. 70% of disease alleles in the Northern European population. The p.(Trp402*) and dissecting and culturing, with p.(Gln70*) are the most common pathogenic variants seen in Hurler patients. p.(Arg89Gln) and instructions to forward the sample c.590-7G>A are generally associated with Scheie syndrome. to the Regional Molecular Genetics laboratory for analysis Referrals A completed DNA request card should accompany all samples Clinically affected patients should have their diagnosis confirmed by biochemical analysis; this should be arranged either locally or with the Enzyme Unit, Great Ormond Street Hospital (tel: 0207 4059200 ext 1785/6751). Biochemically confirmed patients can be Patient details referred for genetic analysis. If the necessary patient samples are unavailable genetic To facilitate accurate testing and testing can be undertaken in the parents of a child. reporting please provide patient demographic details (full name, date of Carrier testing can be offered to the adult relatives of affected patients once a pathogenic birth, address and ethnic origin), details variant has been identified. of any relevant family history and full contact details for the referring clinician Prenatal testing Prenatal testing is available for families in whom pathogenic variants have been identified or in whom appropriate family studies have been undertaken. This service is also offered by biochemical analysis. Please contact the laboratory to discuss. Service offered Level 1 analysis: detection of the ‘common’ pathogenic variants p.(Gln70*), p.(Ala327Pro) and p.(Trp402*) by Sanger sequence analysis. Level 2 analysis: Analysis of the GLA gene by next generation sequencing (Agilent SureSelect and Illumina NextSeq). A minimum coverage of 30 reads is required to call a variant. In-house validation attributes a minimum sensitivity of 97.5% (with 95% confidence) for regions covered >30x. This assay is not currently validated to detect large deletions / duplications. All clinically relevant variants are confirmed by Sanger sequence analysis. Known benign polymorphisms and sequence variants which are unlikely to be pathogenic are not reported. Detection of known pathogenic variants in relatives of patients with confirmed MPS1 pathogenic variants by Sanger sequencing. Target reporting time 4 weeks for routine level 1 screen in index case, 8 weeks for level 2 screen. 4 weeks for carrier testing using pathogenic variant specific tests. Please contact the laboratory for urgent cases. Version 10 .
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