IDUA Mutational Profiling of a Cohort of 102 European Patients with Mucopolysaccharidosis Type I: Identification and Characterization of 35 Novel alpha-L-iduronidase (IDUA) Alleles

Consortium for Human Molecular Genetics, Milano Bicocca University, Monza, Italy.
Human Mutation (Impact Factor: 5.14). 06/2011; 32(6):E2189-210. DOI: 10.1002/humu.21479
Source: PubMed


Mutational analysis of the IDUA gene was performed in a cohort of 102 European patients with mucopolysaccharidosis type I. A total of 54 distinct mutant IDUA alleles were identified, 34 of which were novel including 12 missense mutations, 2 nonsense mutations, 12 splicing mutations, 5 micro-deletions, 1 micro-duplication 1 translational initiation site mutation, and 1 'no-stop' change (p.X654RextX62). Evidence for the pathological significance of all novel mutations identified was sought by means of a range of methodological approaches, including the assessment of evolutionary conservation, RT-PCR/in vitro splicing analysis, MutPred analysis and visual inspection of the 3D-model of the IDUA protein. Taken together, these data not only demonstrate the remarkable mutational heterogeneity characterizing type 1 mucopolysaccharidosis but also illustrate our increasing ability to make deductions pertaining to the genotype-phenotype relationship in disorders manifesting a high degree of allelic heterogeneity.

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    • "Based on the literature [10,27,33-41], a list of 25 mutations, which have been shown to reliably predict a Hurler phenotype when patients are homozygous or compound heterozygous for these mutations, was constructed (Table 3). In our cohort, the association of these mutations with MPS I-H could be confirmed for the mutations p.Q70X, p.W402X, p.L218P and c.134del12. "
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    ABSTRACT: Mucopolysaccharidosis type I (MPS I) is a progressive multisystem lysosomal storage disease caused by deficiency of the enzyme alpha-L-iduronidase (IDUA). Patients present with a continuous spectrum of disease severity, and the most severely affected patients (Hurler phenotype; MPS I-H) develop progressive cognitive impairment. The treatment of choice for MPS I-H patients is haematopoietic stem cell transplantation, while patients with the more attenuated phenotypes benefit from enzyme replacement therapy.The potential of newborn screening (NBS) for MPS I is currently studied in many countries. NBS for MPS I, however, necessitates early assessment of the phenotype, in order to decide on the appropriate treatment. In this study, we developed an algorithm to predict phenotypic severity in newborn MPS I patients. Thirty patients were included in this study. Genotypes were collected from all patients and all patients were phenotypically categorized at an age of > 18 months based on the clinical course of the disease. In 18 patients, IDUA activity in fibroblast cultures was measured using an optimized IDUA assay. Clinical characteristics from the first month of life were collected from 23 patients. Homozygosity or compound heterozygosity for specific mutations which are associated with MPS I-H, discriminated a subset of patients with MPS I-H from patients with more attenuated phenotypes (specificity 100%, sensitivity 82%). Next, we found that enzymatic analysis of IDUA activity in fibroblasts allowed identification of patients affected by MPS I-H. Therefore, residual IDUA activity in fibroblasts was introduced as second step in the algorithm. Patients with an IDUA activity of <0.32 nmol x mg-1 x hr-1 invariably were MPS I-H patients, while an IDUA activity of >0.66 nmol x mg-1 x hr-1 was only observed in more attenuated patients. Patients with an intermediate IDUA activity could be further classified by the presence of differentiating clinical characteristics, resulting in a model with 100% sensitivity and specificity for this cohort of patients. Using genetic, biochemical and clinical characteristics, all potentially available in the newborn period, an algorithm was developed to predict the MPS I phenotype, allowing timely initiation of the optimal treatment strategy after introduction of NBS.
    Full-text · Article · Jul 2013 · Orphanet Journal of Rare Diseases
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    • "Because clinical signs and symptoms appear to be insufficiently reliable to assess phenotypic severity at diagnosis, other methods should be vigorously investigated. Combined genotyping and biomarker analysis in plasma and/or urine, such as the recently reported plasma heparin cofactor II-thrombin (HCII-T) complex and the urinary dermatan sulfate:chondroitin sulfate (DS:CS) ratio, promises to be a good strategy for determining disease severity in newly diagnosed MPS I patients [2,3,29,30] "
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    ABSTRACT: Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed. A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity. Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'. Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis.
    Full-text · Article · Apr 2012 · Orphanet Journal of Rare Diseases
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    • "Genotype-phenotype correlations are still limited in MPS I, except for a small number of mutations which invariably result in MPS I-H if present in homozygous or compound heterozygous combination [4], and few mutations which reliably predict MPS I-S [24]. However, new reports [25] and accumulating (unpublished) data from the MPS I Registry, an observational program designed to collect data of MPS I patients with the primary purpose to study the clinical onset, symptoms, and outcomes of these patients [5], show that the predictive value of the genotype in MPS I may increase substantially in the (near) future (expert consensus). This will help in forming the decision on the optimal strategy in individual patients, and may eventually become indispensable for future introduction of newborn screening for MPS I (expert consensus). "
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    ABSTRACT: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies. A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus. Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT. This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.
    Full-text · Article · Aug 2011 · Orphanet Journal of Rare Diseases
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