Evaluation of reliability for urine mucopolysaccharidosis screening by dimethylmethylene blue and Berry spot tests

Mabe, Paulina; Valiente, A.; Soto, Vivian Vialat; Cornejo, Verónica; Raimann, Erna

doi:10.1016/j.cccn.2004.03.015

Cited by 47 publications

(14 citation statements)

References 17 publications

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“…GAG levels were quantified using the dimethylmethylene blue (DMB) colorimetric assay, [22] which is a simple, rapid, low-cost, and reliable method for quantifying urinary GAGs. [23] …”

Section: Methodsmentioning

confidence: 99%

A selective screening program for the early detection of mucopolysaccharidosis

et al. 2017

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The mucopolysaccharidoses (MPSs) are underdiagnosed but they are evaluated in few newborn screening programs, probably due to the many challenges remaining, such as the identification of late-onset phenotypes. Systematic screening at the onset of clinical symptoms could help to early identify patients who may benefit from specific treatments. The aim of this prospective study was to assess a novel selective screening program, the FIND project, targeting patients aged 0 to 16 years with clinical manifestations of MPS. The project was designed to increase awareness of these diseases among pediatricians and allow early diagnosis.From July 2014 to June 2016, glycosaminoglycan (GAG) levels normalized to creatinine levels were determined in urine-impregnated analytical paper submitted by pediatricians who had patients with clinical signs and/or symptoms compatible with MPS. When high GAG concentrations were detected, a new liquid urine sample was requested to confirm and identify the GAG present. When a specific form of MPS was suspected, enzyme activity was analyzed using blood-impregnated paper to determine MPS type (I, IIIB, IIIC, IVA, IVB, VI, or VII). Age-specific reference values for GAG were previously established using 145 urine samples from healthy children.GAG levels were normal in 147 (81.7%) of the 180 initial samples received. A liquid sample was requested for the other 33 cases (18.3%); GAG levels were normal in 13 of these and slightly elevated in 12, although the electrophoresis study showed no evidence of MPS. Elevated levels with corresponding low enzymatic activity were confirmed in 8 cases. The mean time from onset of clinical symptoms to detection of MPS was 22 months, and just 2 cases were detected at the beginning of the project were detected with 35 and 71 months of evolution of clinical symptoms. Our screening strategy for MPS had a sensitivity of 100%, a specificity of 85%, and a positive predictive value of 24%.The FIND project is a useful and cost-effective screening method for increasing awareness of MPS among pediatricians and enabling the detection of MPS at onset of clinical symptoms.

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“…GAG levels were quantified using the dimethylmethylene blue (DMB) colorimetric assay, [22] which is a simple, rapid, low-cost, and reliable method for quantifying urinary GAGs. [23] …”

Section: Methodsmentioning

confidence: 99%

A selective screening program for the early detection of mucopolysaccharidosis

et al. 2017

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“…The measurement of total GAG excretion in urine is widely used as a biomarker for MPS [65–67]. Urine GAG analysis is a useful initial screening test for MPS and may be also helpful for monitoring treatment efficacy.…”

Section: Historical Review For Gag Assaymentioning

confidence: 99%

Newborn screening and diagnosis of mucopolysaccharidoses

Tomatsu

Fujii

Fukushi

et al. 2013

Molecular Genetics and Metabolism

139

124

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Mucopolysaccharidoses (MPS) are caused by deficiency of lysosomal enzyme activities needed to degrade glycosaminoglycans (GAGs), which are long unbranched polysaccharides consisting of repeating disaccharides. GAGs include: chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS), and hyaluronan. Their catabolism may be blocked singly or in combination depending on the specific enzyme deficiency. There are 11 known enzyme deficiencies, resulting in seven distinct forms of MPS with a collective incidence of higher than 1 in 25,000 live births. Accumulation of undegraded metabolites in lysosomes gives rise to distinct clinical syndromes. Generally, the clinical conditions progress if untreated, leading to developmental delay, systemic skeletal deformities, and early death. MPS disorders are potentially treatable with enzyme replacement therapy or hematopoietic stem cell transplantation. For maximum benefit of available therapies, early detection and intervention are critical. We recently developed a novel high-throughput multiplex method to assay DS, HS, and KS simultaneously in blood samples by using high performance liquid chromatography/tandem mass spectrometry for MPS. The overall performance metrics of HS and DS values on MPS I, II, and VII patients vs. healthy controls at newborns were as follows using a given set of cut-off values: sensitivity, 100%; specificity, 98.5–99.4%; positive predictive value, 54.5–75%; false positive rate, 0.62–1.54%; and false negative rate, 0%. These findings show that the combined measurements of these three GAGs are sensitive and specific for detecting all types of MPS with acceptable false negative/positive rates. In addition, this method will also be used for monitoring therapeutic efficacy. We review the history of GAG assay and application to diagnosis for MPS.

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“…Drawbacks of the assay include low specificity due to the formation of a non-specific complex of the dye with polyanions, including nucleic acids, and inability to distinguish the kind of GAG excreted without further enzymatic or separation methods. This method exhibits few false-negative results compared to other dye-based assays, but lacks reliability for detecting attenuated forms of MPS [32–34]. The sensitivity of the dye binding methods is also low compared to other methods described below, generally restricting their use to urine samples due to the high concentration of GAGs in MPS patients and general lack of other interfering substances.…”

Section: Biomarkers Based On Total Gag Accumulationmentioning

confidence: 99%

Glycan-based biomarkers for mucopolysaccharidoses

Lawrence

Brown²,

Lorey

et al. 2014

Molecular Genetics and Metabolism

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The mucopolysaccharidoses (MPS) result from attenuation or loss of enzyme activities required for lysosomal degradation of the glycosaminoglycans, hyaluronan, heparan sulfate, chondroitin/dermatan sulfate, and keratan sulfate. This review provides a summary of glycan biomarkers that have been used to characterize animal models of MPS, for diagnosis of patients, and for monitoring therapy based on hematopoietic stem cell transplantation and enzyme replacement therapy. Recent advances have focused on the non-reducing terminus of the glycosaminoglycans that accumulate as biomarkers, using a combination of enzymatic digestion with bacterial enzymes followed by quantitative liquid chromatography/mass spectrometry. These new methods provide a simple, rapid diagnostic strategy that can be applied to samples of urine, blood, cerebrospinal fluid, cultured cells and dried blood spots from newborn infants. Analysis of the non-reducing end glycans provides a method for monitoring enzyme replacement and substrate reduction therapies and serves as a discovery tool for uncovering novel biomarkers and new forms of mucopolysaccharidoses.

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Evaluation of reliability for urine mucopolysaccharidosis screening by dimethylmethylene blue and Berry spot tests

Cited by 47 publications

References 17 publications

A selective screening program for the early detection of mucopolysaccharidosis

A selective screening program for the early detection of mucopolysaccharidosis

Newborn screening and diagnosis of mucopolysaccharidoses

Glycan-based biomarkers for mucopolysaccharidoses

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