Screening patients referred to a metabolic clinic for lysosomal storage disorders

Fuller, Maria; Tucker, Justin N.; Lang, Debbie; Dean, Caroline J.; Fietz, Michael; Meikle, Peter J.; Hopwood, John J.

doi:10.1136/jmg.2010.088096

Cited by 44 publications

(32 citation statements)

References 25 publications

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“…Indeed, in ML II or III, the mannose-6-phosphate tag on the lysosomal enzymeswhich ensures sorting to the lysosome -is missing, leading to the excretion of the enzymes into the plasma. This yields elevated in vitro plasma enzyme activities, which can also be found in DBS (Gusina and Tsukerman 1988;Fuller et al 2011;Wood et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The advantage of using DBS for enzymatic diagnosis of MPS and ML II/III has been demonstrated (Chamoles et al 2001b;Chamoles et al 2001a). In the past years, fluorometric methods, immunocapture enzyme assays and even high-throughput tandem mass spectrometry assays have been developed and optimised to allow (large-scale) screening for LSDs (Blanchard et al 2008;Dean et al 2006;Duffey et al 2010a;Duffey et al 2010b;Fuller et al 2011;Reuser et al 2011;Wang et al 2007;Wolfe et al 2011). However, all studies using DBS were feasibility studies, including only patients with a confirmed diagnosis of MPS.…”

Section: Discussionmentioning

confidence: 99%

“…So far, several studies have shown the feasibility of the enzymatic diagnosis of MPS I, II or VI using DBS (Blanchard et al 2008;Chamoles et al 2001a;Chamoles et al 2001b;Dean et al 2006;Duffey et al 2010a;Duffey et al 2010b;Fuller et al 2011;Wang et al 2007;Wolfe et al 2011). However, none of these studies had a prospective design, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Dried Blood Spots Allow Targeted Screening to Diagnose Mucopolysaccharidosis and Mucolipidosis

Cobos¹,

Steglich²,

Santer³

et al. 2014

JIMD Reports

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Background: As patients with different types of mucopolysaccharidosis (MPS) and mucolipidosis (ML) may present with overlapping clinical features -including coarse face, hepatosplenomegaly, bone dysplasia and claw-hand deformities, collectively also called 'MPS-like phenotype', enzymatic and/or molecular genetic analyses are indispensable for accurate diagnosis and applying specific therapy. In this prospective study, we screened patients with symptoms compatible with MPS for MPS I, II (males) and VI.Methods: Dried blood spots/specimens (DBS) were collected from 200 patients with an MPS-like phenotype and analysed for activities of a-iduronidase (IDUA), iduronate-2-sulphatase (IDS), and arylsulphatase B (ARSB), the enzymes deficient in mucopolysaccharidosis (MPS) type I, II and VI, respectively. For the samples with pathologic enzyme activity, mutational analysis was carried out using the same DBS.Results: Based on enzymatic analysis of 200 DBS samples, a total of 45 (22.5%) showed low activity; 17 for MPS I (8.5%), 11 for MPS II (5.5%) and 9 for MPS VI (4.5%). Enzyme activities were suggestive for ML II/III in 8 (4.0%) cases. For 41 (91.1%) samples, DNA could be extracted from the filter paper. Mutations were identified in 11 (64.7%), 11 (100%), 9 (100%) and 5 (62.5%) patients putatively diagnosed biochemically with MPS I, II, VI, and ML II/III, respectively.Conclusions: DBS enzymatic analysis can be used to diagnose MPS/ML. Initial results should be confirmed by a second enzyme assay and/or by molecular genetic testing. Given the advantages of DBS over other sample types in terms of ease of collection, storage and transportation, DBS are particularly useful for screening patients with an MPS-like phenotype in regions lacking specialised laboratories. In order to ascertain the diagnosis in a large number of cases, patients should be assessed in parallel for at least MPS I, II and VI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dried Blood Spots Allow Targeted Screening to Diagnose Mucopolysaccharidosis and Mucolipidosis

Cobos¹,

Steglich²,

Santer³

et al. 2014

JIMD Reports

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“…Early diagnosis will thus be essential and can only be achieved by increasing awareness for MPS III and, probably best, by NBS. Earlier studies showed that NBS for MPS IIIA is feasible, for example, by measuring HS concentrations or lysosomal protein concentrations in dried blood spots 22, 31, 32. Early diagnosis, especially through NBS, will make reliable assessment of the phenotype crucial, either by genotyping or, if that is inconclusive, by other methods such as the method reported here.…”

Section: Discussionmentioning

confidence: 87%

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Knottnerus

Nijmeijer

IJlst

et al. 2017

Annals of Neurology

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ObjectiveMucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype–phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease‐modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course.MethodsFifty‐three patients were included for whom skin fibroblasts and data on disease course and mutation analysis were available. Patients were phenotypically characterized on clinical data as rapidly progressing or slowly progressing. Sulfamidase activity was measured in fibroblasts cultured at 37 °C and at 30 °C.ResultsSulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a combination of known severe mutations remained below the limit of quantification under both culture conditions. In contrast, sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a known mild mutation increased above the limit of quantification when cultured at 30 °C. With division on the basis of the patients' phenotype, fibroblasts from slowly progressing patients could be separated from rapidly progressing patients by increase in sulfamidase activity when cultured at 30 °C (p < 0.001, sensitivity = 96%, specificity = 93%).InterpretationPhenotypic severity strongly correlates with the potential to increase sulfamidase activity in fibroblasts cultured at 30 °C, allowing reliable distinction between patients with rapidly progressing or slowly progressing phenotypes. This method may provide an essential tool for assessment of treatment effects and for health care and life planning decisions. Ann Neurol 2017;82:686–696

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“…The availability of the multiplex technology has facilitated the technical aspect of testing, making it easier to identify LSDs. Pilot studies of newborn screening for specific LSDs (Fabry, Pompe, Gaucher and MPS-I) carried out so far in some countries have indicated a much greater prevalence than the prevalence estimated by clinical diagnosis (18,19). This increase in prevalence is primarily due to recognition of later-onset forms of LSDs.…”

Section: Diagnostic Strategy For Lsdsimperative For Early Detectionmentioning

confidence: 99%

Integrative Algorithms in the Diagnostics of Lysosomal Storage Diseases / INTEGRATIVNI ALGORITMI U DIJAGNOSTICI POREMEĆAJA U SKLADIŠTENJU LIZOZOMA

Fumić¹,

Bilić²,

Rogić³

2014

Journal of Medical Biochemistry

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SummaryLysosomal storage disorders (LSDs) are a clinically heterogeneous group of more than 50 disorders which still represent a challenge in modern medicine. The efficacy of many current and proposed therapies relies heavily upon early detection and treatment prior to the onset of irreversible pathology. Although there are multiple paths and algorithms to a final diagnosis, the diagnostic strategy for LSDs still mostly relies on initial clinical suspicion followed by adequate specialist and laboratory management -a selective screening approach. Despite the fact that the technology of tandem mass spectrometry enables newborn screening, such screening is generally acceptable only for a population at high risk for a certain LSD. As diagnostic testing for these disorders may be difficult, communication between the clinician who has established clinical suspicion and laboratory personnel will help complete this process.Keywords: lysosomal storage disorders, diagnostic strategy, a selective screening approach Kratak sadr`ajPoreme}aji u skladi{tenju lizozoma u klini~kom smislu ~ine heterogenu grupu vi{e od 50 poreme}aja koji jo{ pred stavljaju izazov za modernu medicinu. Efikasnost mnogih postoje}ih i predlo`enih terapija u velikoj meri zavisi od rane detekcije i primene terapije pre nego {to do|e do razvoja neizle ~ive patologije. Iako postoje brojni putevi i algoritmi za kona~nu dijagnozu, dijagnosti~ka strategija za poreme}aje u skladi{tenju lizozoma i dalje se uglavnom oslanja na po~etnu klini~ku sumnju posle koje sledi adekvatan specijalisti~ki tretman i laboratorijski rad -pristup selektivnog skrininga. Uprkos ~injenici da tehnologija tandem masene spektrometrije omogu}ava skrining novoro|en~adi, takav skrining je generalno prihvatljiv samo za populacije sa visokim rizikom za odre |eni poreme}aj u skladi{tenju lizozoma. Kako dijagnosti~ko testiranje za ove poreme}aje mo`e biti te{ko, komunikacija izme|u klini~ara koji je ustanovio klini~ku sumnju i osoblja u laboratoriji doprine}e uspe{nom okon~anju ovog procesa.

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Screening patients referred to a metabolic clinic for lysosomal storage disorders

Abstract: This study demonstrates the sensitivity and specificity of this technology to accurately identify 99% of LSD patients, with the exception of one MPS II false negative.

Cited by 44 publications

References 25 publications

Dried Blood Spots Allow Targeted Screening to Diagnose Mucopolysaccharidosis and Mucolipidosis

Dried Blood Spots Allow Targeted Screening to Diagnose Mucopolysaccharidosis and Mucolipidosis

Prediction of phenotypic severity in mucopolysaccharidosis type IIIA

Integrative Algorithms in the Diagnostics of Lysosomal Storage Diseases / INTEGRATIVNI ALGORITMI U DIJAGNOSTICI POREMEĆAJA U SKLADIŠTENJU LIZOZOMA

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