Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management

Clarke, Lorne A.; Atherton, Andrea M.; Burton, Barbara K.; Day‐Salvatore, Debra; Kaplan, Paige; Leslie, Nancy; Scott, C. Ronald; Stockton, David W.; Thomas, Janet A.; Muenzer, Joseph

doi:10.1016/j.jpeds.2016.11.036

Cited by 66 publications

(68 citation statements)

References 49 publications

(54 reference statements)

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“…Among LSDs, it is well-known that there are some examples of pseudodeficiency alleles found in several disorders including Pompe disease [22]. For example, in mucopolysaccharidosis type I, four pseudodeficiency IDUA alleles were recently identified (p.A79T, p.H82Q, p.D223N, and p.V322E) in newborn screening in Missouri [23]. In Fabry disease, an earlier study reported that p.D313Y is a GLA pseudodeficiency mutant with minimal alteration of enzyme structure [24].…”

Section: Discussionmentioning

confidence: 99%

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Mashima

Okuyama

2017

Molecular Genetics and Metabolism Reports

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Lysosomal storage disorders (LSDs) are caused by defective enzyme activities in lysosomes, characterized by the accumulation of sphingolipids, glycolipids, oligosaccharides, mucopolysaccharides, the oxidation products of cholesterol, and other biological substances. A growing number of clinical studies have suggested the enhanced efficacy of existing therapies, including enzyme replacement therapy, which is effective when it is initiated during the presymptomatic period. Thus, the identification of disease-affected individuals by newborn screening has been considered an effective platform. Previous studies have suggested that the discrimination of infantile-onset Pompe disease (IOPD) requires multi-step examination of GAA enzyme activity using the fluorometric technique. In sharp contrast, the MS/MS-based technique can identify the population of IOPD and the pseudodeficiency alleles of the GAA enzyme [Liao HC et al. Clin Chem (2017) in press; doi: http://dx.doi.org/10.1373/clinchem.2016.269027]. To determine whether MS/MS-based assay can identify these two populations in Japanese neonates, we first performed a validation study of this assay using flow-injection analysis (FIA)-MS/MS and liquid chromatography (LC)-MS/MS followed by examination of GAA enzyme activity in our population. By minimizing the effect of substrate-derived in-source decomposition products, the activities of 6 LSD enzymes were quantified in FIA-MS/MS and LC-MS/MS. The mean value of GAA activity with IOPD, pseudodeficiency alleles, and healthy controls by FIA-MS/MS were 1.0 ± 0.3 μmol/h/L (max, 1.3; min, 0.7; median, 1.2; n = 3), 2.7 ± 0.7 μmol/h/L (max, 4.5; min, 1.5; median, 2.5; n = 19), and 12.9 ± 5.4 μmol/h/L (max, 29.6; min, 2.5; median, 11.0; n = 83), respectively. These results suggest that the population of GAA with pseudodeficiency alleles has approximately 20% of GAA enzyme activity compared to controls, providing the preliminary evidence to estimate the cut-off values in the Japanese population using this technique.

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Section: Discussionmentioning

confidence: 99%

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Mashima

Okuyama

2017

Molecular Genetics and Metabolism Reports

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“… Unfortunately, no currently available biochemical assessments allow for accurate classification of patients as either severe or attenuated. Published diagnosis and management guidelines suggest a role for IDUA genotype in management decision making . 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 .…”

Section: Introductionmentioning

confidence: 99%

“…5,6 The recent initiation of newborn screening for MPS I as well as other programs to identify individuals with MPS I at an age when CNS and somatic involvement may be minimal, highlight the need for accurate delineation of patients so effective therapies can be initiated early. [7][8][9][10][11][12] Unfortunately, no currently available biochemical assessments allow for accurate classification of patients as either severe or attenuated. 13 Published diagnosis and management guidelines suggest a role for IDUA genotype in management decision making.…”

Section: Introductionmentioning

confidence: 99%

“…13 Published diagnosis and management guidelines suggest a role for IDUA genotype in management decision making. 7 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.…”

Section: Introductionmentioning

confidence: 99%

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Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

et al. 2019

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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.

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“…Although effective newborn screening techniques are now available to facilitate early diagnosis, newborn screening is not yet widely available and there are no biomarkers that can predict phenotypic severity in those newborn infants identified by screening 4, 5, 6. In some cases, the clinical phenotype could be predicted by the genotype, based on mutations of the human alpha‐L‐iduronidase gene.…”

Section: Introductionmentioning

confidence: 99%

Easy‐to‐use algorithm would provide faster diagnoses for mucopolysaccharidosis type I and enable patients to receive earlier treatment

Tylki‐Szymańska

Meırleır²,

Rocco

et al. 2018

Acta Paediatrica

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AimThe aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I).MethodsAn international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real‐world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested.ResultsAn algorithm was developed. In patients under two years of age, kyphosis or gibbus deformity were the key symptoms that raised clinical suspicion of MPS I and in those over two years they were kyphosis or gibbus deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler–Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) – 16 Hurler, nine Hurler–Scheie and seven Scheie patients – would have been referred earlier if the algorithm had been used.ConclusionThe expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment.

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Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management

Cited by 66 publications

References 49 publications

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Genotype‐phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

Easy‐to‐use algorithm would provide faster diagnoses for mucopolysaccharidosis type I and enable patients to receive earlier treatment

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