Abstract
Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α‐L‐iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler‐Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype‐phenotype correlation in large MPS I cohorts have been performed. Understanding genotype‐phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.
Highlights
Mucopolysaccharidosis type I (MPS I) is a rare recessive lysosomal storage disorder caused by pathogenic α-L-iduronidase (IDUA) gene variants which lead to deficiency of the lysosomal enzyme IDUA, EC 3.2.1.76.1 Historically, MPS I patients have been classified into three phenotypic disease categories; Hurler, Hurler-Scheie and Scheie syndrome.[2]
This nosology was based on age of symptom onset and presence of progressive intellectual disability; with Hurler syndrome representing the most severely affected individuals, characterized by onset of symptoms in early infancy with evidence of early progressive intellectual decline and when untreated, death within the first decade
The recent initiation of newborn screening for MPS I as well as other programs to identify individuals with MPS I at an age when central nervous system (CNS) and somatic involvement may be minimal, highlight the need for accurate delineation of patients so effective therapies can be initiated early. 7-12 no currently available biochemical assessments allow for accurate classification of patients as either severe or attenuated
Summary
Mucopolysaccharidosis type I (MPS I) is a rare recessive lysosomal storage disorder caused by pathogenic α-L-iduronidase (IDUA) gene variants which lead to deficiency of the lysosomal enzyme IDUA, EC 3.2.1.76.1 Historically, MPS I patients have been classified into three phenotypic disease categories; Hurler, Hurler-Scheie and Scheie syndrome.[2]. From the practical perspective of disease management, a binary classification of patients into the categories of severe disease (Hurler syndrome) or attenuated disease (Hurler-Scheie and Scheie syndromes) is most useful This classification facilitates management decisions based on the currently approved treatments for MPS I: hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) with laronidase.[3] ERT has been shown to alter somatic disease symptoms and progression but as current recombinant enzyme does not cross the bloodbrain barrier this treatment approach does not address the progressive central nervous system (CNS) disease characteristic of Hurler patients.[4] HSCT when initiated early, has been shown to preserve cognition and lead to improved developmental outcomes and is considered the standard of care for patients with severe MPS I.5,6. Over 200 pathogenic IDUA variants have been reported to underlie MPS I and a genotype-phenotype association is emerging whereby patients who are either homozygous or compound heterozygous for the common nonsense mutations W402X or Q70X consistently have severe disease.[14,15,16,17,18,19] The large number of patients enrolled in the MPS I Registry offers a unique resource for further elaboration of genotype/phenotype relationships for this rare disease.[20,21,22]
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