Glycosaminoglycan levels in dried blood spots of patients with mucopolysaccharidoses and mucolipidoses

Kubaski, Francyne; Suzuki, Yasuyuki; Orii, Kenji E.; Giugliani, Roberto; Church, Heather J.; Mason, Robert W.; Dũng, Vũ Chí; Ngọc, Cấn Thị Bích; Yamaguchi, Seiji; Kobayashi, Hironori; Girisha, Katta M.; Fukao, Toshiyuki; Orii, Tadao; Tomatsu, Shunji

doi:10.1016/j.ymgme.2016.12.010

Cited by 36 publications

(35 citation statements)

References 74 publications

(80 reference statements)

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“…The use of glycosaminoglycans (GAGs) as biomarkers for the diagnosis of neonatal MPS has been recently proposed by Kubaski as a first tier test [39]. Retrospective analysis of GAGs DBS levels in our study showed elevated levels of heparan and dermatan sulphates in the two patients carry pathogenic mutations and normal in all patients with pseudodeficiency alleles.…”

Section: Discussionsupporting

confidence: 48%

Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy

Burlina

Polo

Rubert

et al. 2019

IJNS

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The increasing availability of treatments and the importance of early intervention have stimulated interest in newborn screening for lysosomal storage diseases. Since 2015, 112,446 newborns in North Eastern Italy have been screened for four lysosomal disorders—mucopolysaccharidosis type I and Pompe, Fabry and Gaucher diseases—using a multiplexed tandem mass spectrometry (MS/MS) assay system. We recalled 138 neonates (0.12%) for collection of a second dried blood spot. Low activity was confirmed in 62 (0.06%), who underwent confirmatory testing. Twenty-five neonates (0.02%) were true positive: eight with Pompe disease; seven with Gaucher disease; eight with Fabry disease; and two with Mucopolysaccharidosis type I. The combined incidence of the four disorders was 1 in 4497 births. Except for Pompe disease, a second-tier test was implemented. We conclude that newborn screening for multiple lysosomal storage diseases combined with a second-tier test can largely eliminate false-positives and achieve rapid diagnosis.

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Section: Discussionsupporting

confidence: 48%

Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy

Burlina

Polo

Rubert

et al. 2019

IJNS

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“…GAGs can be quantified in: urine [34,[49][50][51][52][53][54], serum/plasma [34,48,[54][55][56], dried blood spots [57][58][59] (Figure 3), amniotic fluid [60], cerebrospinal fluid [34,61], cultured cells [34], and tissues [62]. Some of these assays can be used for newborn screening of MPSs [57,63] or even to allow the discrimination of specific disease subtypes [53]. Another biomarker that can be used is dipeptidyl peptidase (DDP) IV (CD26).…”

Section: Biomarkersmentioning

confidence: 99%

Diagnosis of Mucopolysaccharidoses

et al. 2020

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The mucopolysaccharidoses (MPSs) include 11 different conditions caused by specific enzyme deficiencies in the degradation pathway of glycosaminoglycans (GAGs). Although most MPS types present increased levels of GAGs in tissues, including blood and urine, diagnosis is challenging as specific enzyme assays are needed for the correct diagnosis. Enzyme assays are usually performed in blood, with some samples (as leukocytes) providing a final diagnosis, while others (such as dried blood spots) still being considered as screening methods. The identification of variants in the specific genes that encode each MPS-related enzyme is helpful for diagnosis confirmation (when needed), carrier detection, genetic counseling, prenatal diagnosis (preferably in combination with enzyme assays) and phenotype prediction. Although the usual diagnostic flow in high-risk patients starts with the measurement of urinary GAGs, it continues with specific enzyme assays and is completed with mutation identification; there is a growing trend to have genotype-based investigations performed at the beginning of the investigation. In such cases, confirmation of pathogenicity of the variants identified should be confirmed by measurement of enzyme activity and/or identification and/or quantification of GAG species. As there is a growing number of countries performing newborn screening for MPS diseases, the investigation of a low enzyme activity by the measurement of GAG species concentration and identification of gene mutations in the same DBS sample is recommended before the suspicion of MPS is taken to the family. With specific therapies already available for most MPS patients, and with clinical trials in progress for many conditions, the specific diagnosis of MPS as early as possible is becoming increasingly necessary. In this review, we describe traditional and the most up to date diagnostic methods for mucopolysaccharidoses.

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“…However, it should be noted that MPS patients with attenuated phenotypes may have false-negative results due to lower GAG levels [9]. The determination of GAGs in dried blood spot (DBS) is a rather complicated method, which is not carried out in all laboratories [10].…”

Section: Introductionmentioning

confidence: 99%

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

et al. 2020

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Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders associated with impaired glycosaminoglycans (GAGs) catabolism. In MPS I, II, III, and VII, heparan sulfate (HS) cannot be degraded because of the lack of sufficient activity of the respective enzymes, and its accumulation in the brain causes neurological symptoms. Globotriaosylsphingosine (LysoGb3), the deacylated form of globotriaosylceramide (Gb3), is described as a highly sensitive biomarker for another lysosomal storage disease-Fabry disease. The connection between MPSs and LysoGb3 has not yet been established. This study included 36-MPS I, 15-MPS II, 25-MPS III, 26-MPS IV, and 14-MPS VI patients who were diagnosed by biochemical and molecular methods and a control group of 250 males and 250 females. The concentration of lysosphingolipids (LysoSLs) was measured in dried blood spots by high pressure liquid chromatography-tandem mass spectrometry. We have demonstrated that LysoGb3 concentration was significantly elevated (p < 0.0001) in untreated MPS I (3.07 + 1.55 ng/mL), MPS II (5.24 + 2.13 ng/mL), and MPS III (6.82 + 3.69 ng/mL) patients, compared to the control group (0.87 + 0.55 ng/mL). LysoGb3 level was normal in MPS VI and MPS IVA (1.26 + 0.39 and 0.99 + 0.38 ng/mL, respectively). Activity of α-galactosidase A (α-Gal A), an enzyme deficient in Fabry disease, was not, however, inhibited by heparan sulfate in vitro, indicating that an increase of LysoGb3 level in MPS I, MPS II, and MPS III is an indirect effect of stored MPSs rather than a direct result of impairment of degradation of this compound by HS. Our findings indicate some association of elevated LysoGb3 concentration with the neuronopathic forms of MPSs. The pathological mechanism of which is still to be studied.

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Glycosaminoglycan levels in dried blood spots of patients with mucopolysaccharidoses and mucolipidoses

Cited by 36 publications

References 74 publications

Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy

Implementation of Second-Tier Tests in Newborn Screening for Lysosomal Disorders in North Eastern Italy

Diagnosis of Mucopolysaccharidoses

Elevated LysoGb3 Concentration in the Neuronopathic Forms of Mucopolysaccharidoses

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