Diagnosing Lysosomal Storage Disorders: Mucopolysaccharidosis Type I

Abstract

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to deficiency of alpha iduronidase (IDUA). Progressive storage of dermatan and heparan sulfate throughout the body lead to a multiorgan presentation including short stature, dysostosis multiplex, corneal clouding, hearing loss, coarse facies, hepatosplenomegaly, and intellectual disability. Diagnosis of MPS I is based on IDUA enzyme analysis in leukocytes or dried blood spots (DBS) followed by molecular confirmation of the IDUA gene mutations in individuals with low enzyme activity. The advent of mass spectrometry methods for enzyme analysis in DBS has enabled high-throughput screening for MPS I in symptomatic individuals and newborn infants. The following unit provides the detailed analytical protocol for measurement of IDUA activity in DBS using tandem mass spectrometry.

Case Report: Cerebral Revascularization in a Child With Mucopolysaccharidosis Type I

“…At 9 months, the patient developed dysostosis multiplex, kyphosis, macrocephaly, and coarse facial features. Enzyme analysis revealing abnormally low alpha-L-iduronidase activity and elevated GAG levels confirmed the diagnosis of MPS I (Hurler syndrome) (14). The patient commenced the recommended treatment for MPS I with 8 weeks of ERT followed by HSCT (5,6).…”

Chiari I malformation and syringomyelia in mucopolysaccharidosis type I (Hurler syndrome) treated with posterior fossa decompression: Case report and review of the literature

“…MPSI is an autosomal recessive lysosomal storage disease caused by mutation in the IDUA gene located on chromosome 4p16.3,[ 12 ] resulting in deficient or absent activity of the IDUA , which catalyzes the degradation of the glycosaminoglycans (i.e., dermatan and heparan sulfates). [ 25 ] These molecules can be found in free form in the extracellular matrix or as part of the structure of different types of proteoglycans, with important functions both in the structure of tissues and intercellular communication.…”

“…Intralysosomal accumulation of these substrates results in pathological processes that produce a progressive dysfunction resulting in multiorgan deterioration that includes hepatosplenomegaly, dysostosis multiplex, short stature, coarse facial features, corneal clouding, joint contractures, umbilical hernias, failure to thrive, intellectual disability, and developmental delay. [ 5 12 ] The extensive storage of these glycosaminoglycans is also known to cause meningeal thickening. [ 4 ] Intraoperatively, our patient was noted to have thickened arachnoid membrane, which was biopsied and sent for pathological assessment.…”

“…[ 2 ] Diagnosis of MPSI is based on IDUA enzyme analysis in leukocytes or dried blood spots followed by molecular confirmation of the IDUA gene mutations in individuals with low enzyme activity. [ 12 ]…”

International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome

“…These include quantitative and qualitative urinary glycosaminoglycan assessments, enzyme assays to evaluate α ‐L‐iduronidase activity and genetic and molecular testing to determine disease severity and the appropriate treatment approach . Testing enzyme activity and genotype using the dried blood spot test provides a valuable fast approach to the diagnosis of MPS I , but the results must always be confirmed by traditional laboratory methods. Critically, earlier diagnosis leads to earlier treatment and better outcomes .…”