Understanding the Early Presentation of Mucopolysaccharidoses Disorders

Clarke, Lorne; Ellaway, Carolyn; Foster, Helen; Giugliani, Roberto; Goizet, Cyril; Goring, Sarah; Hawley, Sara M.; Jurecki, Elaina; Khan, Zaeem; Lampe, Christina; Martin, Ken; McMullen, Suzanne; Mitchell, John; Mubarack, Fathima; Sivri, Hatice Serap; Villarreal, Martha Solano; Stewart, Fiona; Tylki‐Szymańska, Anna; White, Klane K.; Wijburg, Frits A.

doi:10.1177/2326409818800346

Cited by 8 publications

(8 citation statements)

References 13 publications

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“…The early identification of MPS affected newborns remains challenging since most of them do not exhibit any signs of the disease early in life [23]. However, considering that several studies demonstrated that GAGs are elevated as early as 21 weeks of gestation [9,24], we strongly believe that newborn screening will be a useful tool to identify patients before the onset of irreversible signs and symptoms associated with the disease.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysaccharidoses by UPLC-MS/MS

et al. 2019

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Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by deficiencies of enzymes involved in the catabolism of glycosaminoglycans (GAGs). Various treatments such as enzyme replacement therapy and/or hematopoietic stem cell transplant are available for MPSs. Early initiation of treatment improves the outcome and delays the onset of symptoms, highlighting the need for newborn screening for MPSs. The main objective of this project was to devise and validate a multiplex urine filter paper method for GAG analysis using a tandem mass spectrometry (MS/MS) approach to screen newborns for MPSs. Eluted urine samples from 21-day-old newborns were evaporated and a methanolysis reaction was performed. Samples were resuspended and analyzed using a UPLC-MS/MS system. A one-minute chromatographic method allowed the absolute quantification of heparan sulfate (HS), dermatan sulfate (DS), and creatinine. Method validation revealed high precision (< 9% relative standard deviation) and accuracy (< 7% bias) for all analytes. The reference values normalized to creatinine obtained by the analysis of five hundred 21-day-old newborn urine samples were 34.6 +/-6.2 mg/mmol of creatinine and 17.3 +/-3.9 mg/mmol of creatinine for HS and DS, respectively. We present a rapid and efficient method for populational newborn urine screening using MS/MS, which could also be applied to high-risk screening.

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Section: Discussionmentioning

confidence: 99%

Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysaccharidoses by UPLC-MS/MS

et al. 2019

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“…MPS are genetic disorders caused by the deficiency of 1 of 11 lysosomal enzymes involved in the metabolism of glycosaminoglycans (GAGs). Enzyme deficiencies may lead to the accumulation of the GAGs heparan sulfate (HS), dermatan sulfate (DS), keratan sulfate (KS), chondroitin sulfate (CS), or hyaluronan within the lysosomes [75]. As a result, partially catabolized GAGs accumulate in the lysosomes of several tissues and are secreted into the blood and excreted in urine [76].…”

Section: Pharmacological Chaperones For Mpsmentioning

confidence: 99%

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

Diaz

Castillo

Rodríguez-López

et al. 2019

IJMS

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The mucopolysaccharidoses (MPS) are a group of 11 lysosomal storage diseases (LSDs) produced by mutations in the enzymes involved in the lysosomal catabolism of glycosaminoglycans. Most of the mutations affecting these enzymes may lead to changes in processing, folding, glycosylation, pH stability, protein aggregation, and defective transport to the lysosomes. It this sense, it has been proposed that the use of small molecules, called pharmacological chaperones (PCs), can restore the folding, trafficking, and biological activity of mutated enzymes. PCs have the advantages of wide tissue distribution, potential oral administration, lower production cost, and fewer issues of immunogenicity than enzyme replacement therapy. In this paper, we will review the advances in the identification and characterization of PCs for the MPS. These molecules have been described for MPS II, IVA, and IVB, showing a mutation-dependent enhancement of the mutated enzymes. Although the results show the potential of this strategy, further studies should focus in the development of disease-specific cellular models that allow a proper screening and evaluation of PCs. In addition, in vivo evaluation, both pre-clinical and clinical, should be performed, before they can become a real therapeutic strategy for the treatment of MPS patients.

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“…A delayed diagnosis of MPS is often due to referrals from one physician to another. This is mainly because of the rare nature of the disorder, phenotypic heterogeneity, and the broad range of nonspecific early signs and symptoms [35]. As a consequence, in addition to medical geneticists, it is important that general health care professionals are aware of the early signs and symptoms of MPS.…”

Section: Discussionmentioning

confidence: 99%

“…Since MPS disorders are rare, multisystemic and progressive diseases with subtle signs and symptoms at the beginning of the natural course, making an early diagnosis can be a challenge for first-line health care professionals. Tracing back the medical history, the patients are usually brought to miscellaneous medical specialists due to diverse manifestations before the confirmative diagnosis of MPS [35][36][37]. In Taiwan, there is insufficient awareness of MPS, which can lead to a delay in the diagnosis or even misdiagnosis with other disorders, and thus these patients often receive inappropriate management.…”

Section: Introductionmentioning

confidence: 99%

An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan

Lin

Lee

et al. 2019

Diagnostics

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Background: The mucopolysaccharidoses (MPSs) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) and which eventually cause progressive damage to various tissues and organs. We developed a feasible MPS screening algorithm and established a cross-specialty collaboration platform between medical geneticists and other medical specialists based on at-risk criteria to allow for an earlier confirmative diagnosis of MPS. Methods: Children (<19 years of age) with clinical signs and symptoms compatible with MPS were prospectively enrolled from pediatric clinics between July 2013 and June 2018. Urine samples were collected for a non-specific total GAG analysis using the dimethylmethylene blue (DMB) spectrophotometric method, and the quantitation of three urinary GAGs (dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS)) was performed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). The subjects with elevated urinary GAG levels were recalled for leukocyte enzyme activity assay and genetic testing for confirmation. Results: Among 153 subjects enrolled in this study, 13 had a confirmative diagnosis of MPS (age range, 0.6 to 10.9 years—three with MPS I, four with MPS II, five with MPS IIIB, and one with MPS IVA). The major signs and symptoms with regards to different systems recorded by pediatricians at the time of the decision to test for MPS were the musculoskeletal system (55%), followed by the neurological system (45%) and coarse facial features (39%). For these 13 patients, the median age at the diagnosis of MPS was 2.9 years. The false negative rate of urinary DMB ratio using the dye-based method for these 13 patients was 31%, including one MPS I, two MPS IIIB, and one MPS IVA. However, there were no false negative results with urinary DS, HS and KS using the MS/MS-based method. Conclusions: We established an at-risk population screening program for MPS by measuring urinary GAG fractionation biomarkers using the LC-MS/MS method. The program included medical geneticists and other medical specialists to increase awareness and enable an early diagnosis by detecting MPS at the initial onset of clinical symptoms.

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Understanding the Early Presentation of Mucopolysaccharidoses Disorders

Cited by 8 publications

References 13 publications

Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysaccharidoses by UPLC-MS/MS

Neonatal Mass Urine Screening Approach for Early Detection of Mucopolysaccharidoses by UPLC-MS/MS

Advances in the Development of Pharmacological Chaperones for the Mucopolysaccharidoses

An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan

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