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An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life.

ABSTRACT: INTRODUCTION: Mucopolysaccharidosis type I (MPS I) is a progressive multisystem lysosomal storage disease caused by deficiency of the enzyme ?-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. METHODS: 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. RESULTS: 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 ?0.66 nmol × mg(-1) × 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. CONCLUSION: 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.

SUBMITTER: Kingma SD

PROVIDER: S-EPMC3710214 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life.

Kingma Sandra D K SD Langereis Eveline J EJ de Klerk Clasine M CM Zoetekouw Lida L Wagemans Tom T Ĳlst Lodewijk L Wanders Ronald J A RJ Wijburg Frits A FA van Vlies Naomi N

Orphanet journal of rare diseases 20130709

<h4>Introduction</h4>Mucopolysaccharidosis type I (MPS I) is a progressive multisystem lysosomal storage disease caused by deficiency of the enzyme α-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 ...[more]

PMID: 23837464

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Project description:BackgroundThere have been few longitudinal studies assessing the effect of preoperative phenotypic severity on long-term esthetic outcomes in metopic craniosynostosis. This study evaluates the relationship between metopic severity and long-term esthetic outcomes using interfrontal angle (IFA) and CranioRate, a novel metopic synostosis severity measure.MethodsPatients with metopic craniosynostosis who underwent bifrontal orbital advancement and remodeling between 2012 and 2017 were reviewed. Preoperative computed tomography head scans were analyzed for IFA and CranioRate, a machine learning algorithm which generates quantitative severity ratings including metopic severity score (MSS) and cranial morphology deviation (CMD). Long-term esthetic outcomes were assessed by craniofacial surgeons using blinded 3-rater esthetic grading of clinical photos. Raters assessed Whitaker score and the presence of temporal hollowing, lateral orbital retrusion, frontal bone irregularities and/or "any visible irregularities."ResultsPreoperative scans were performed at a mean age of 7.7±3.4 months, with average MSS of 6/10, CMD of 200/300, and IFA of 116.8±13.8 degrees. Patients underwent bifrontal orbital advancement and remodeling at mean 9.9±3.1 months. The average time from operation to esthetic assessment was 5.4±1.0 years. Pearson correlation revealed a significant negative correlation between MSS and age at computed tomography ( r =-0.451, P =0.004) and IFA ( r =-0.371, P =0.034) and between IFA and age at surgery ( r =-0.383, P =0.018). In multinomial logistic regression, preoperative MSS was the only independent predictor of visible irregularities (odds ratio=2.18, B =0.780, P =0.024) and preoperative IFA alone significantly predicted Whitaker score, with more acute IFA predicting worse Whitaker score (odds ratio=0.928, B =-0.074, P =0.928).ConclusionsMore severe preoperative phenotypes of metopic craniosynostosis were associated with worse esthetic dysmorphology. Objective measures of preoperative metopic severity predicted long-term esthetic outcomes.

Dataset Information

An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life.

Publications

An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life.

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