Validation of Liquid Chromatography-Tandem Mass Spectrometry-Based 5-Plex Assay for Mucopolysaccharidoses

Oguni, Tsubasa; Tomatsu, Shunji; Tanaka, Misa; Orii, Kenji E.; Fukao, Toshiyuki; Watanabe, Jun; Fukuda, Seiji; Notsu, Yoshitomo; Vu, Dung; Can, Thi Bich Ngoc; Nagai, Atsushi; Yamaguchi, Seiji; Taketani, Takeshi; Gelb, Michael H.; Kobayashi, Hironori

doi:10.3390/ijms21062025

Cited by 3 publications

(5 citation statements)

References 35 publications

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“…Detection of enzyme activity and GAGs levels in neonatal DBS samples by MS/MS, including two-layer screening of enzyme activity and combination of multiple GAGs, is helpful for early screening and diagnosis of MPSs [ 31 , 59 , 62 , 67 , 74 , 91 ]. Simultaneous measurement of multiple enzyme activities by MS/MS has revealed that the prevalence of diseases such as MPS I is higher than the estimates of clinical diagnosis [ 69 ].…”

Section: Biomarkersmentioning

confidence: 99%

Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses

Li,

Mao,

Chao

et al. 2024

Orphanet J Rare Dis

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Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.

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Section: Biomarkersmentioning

confidence: 99%

Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses

Li,

Mao,

Chao

et al. 2024

Orphanet J Rare Dis

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“…Determination of I2S activity can be performed using peripheral blood leukocytes, cultured skin fibroblasts, or dried blood spot samples. Since multiple sulfatase deficiency is also characterized by decreased I2S activity, it should be excluded by simultaneous measurement of other sulfatases to confirm I2S deficiency and the diagnosis of MPS II [ 20 , 21 , 22 ].…”

Section: Diagnosismentioning

confidence: 99%

Diagnosis and Management of Mucopolysaccharidosis Type II (Hunter Syndrome) in Poland

et al. 2023

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Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is a rare, inherited lysosomal storage disease. The disease is caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase (I2S) due to mutations in the IDS gene, which leads to accumulation of glycosaminoglycans (GAGs). Deficiency of I2S enzyme activity in patients with MPS II leads to progressive lysosomal storage of GAGs in the liver, spleen, heart, bones, joints, and respiratory tract. This process disturbs cellular functioning and leads to multisystemic disease manifestations. Symptoms and their time of onset differ among patients. Diagnosis of MPS II involves assessment of clinical features, biochemical parameters, and molecular characteristics. Life-long enzyme replacement therapy with idursulfase (recombinant human I2S) is the current standard of care. However, an interdisciplinary team of specialists is required to monitor and assess the patient’s condition to ensure optimal care. An increasing number of patients with this rare disease reach adulthood and old age. The transition from pediatric care to the adult healthcare system should be planned and carried out according to guidelines to ensure maximum benefit for the patient.

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“…This study was approved by the IRB at the local institutes and Nemours/AIDHC (IRB#: 281498). The method was adapted from another study from our lab [33].…”

Section: Dbs Samplesmentioning

confidence: 99%

“…Many groups, including our own, have reported a five-tier multiplex assay that can measure the enzyme activities for MPS I, II, IIIB, IVA, and VI simultaneously using tandem mass [31][32][33][34][35]. There are multiple methods for GAG analysis that have been summarized in detail by Kubaski et al and Khan et al [12,36].…”

Section: Introductionmentioning

confidence: 99%

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Diagnosis of Mucopolysaccharidoses and Mucolipidosis by Assaying Multiplex Enzymes and Glycosaminoglycans

Arunkumar

Khan

et al. 2021

Diagnostics

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Mucopolysaccharidoses (MPS) and mucolipidosis (ML II/III) are a group of lysosomal storage disorders (LSDs) that occur due to a dysfunction of the lysosomal hydrolases responsible for the catabolism of glycosaminoglycans (GAGs). However, ML is caused by a deficiency of the enzyme uridine-diphosphate N-acetylglucosamine:lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. A timely diagnosis of MPS and ML can lead to appropriate therapeutic options for patients. To improve the accuracy of diagnosis for MPS and ML in a high-risk population, we propose a combination method based on known biomarkers, enzyme activities, and specific GAGs. We measured five lysosomal enzymes (α-L-iduronidase (MPS I), iduronate-2-sulfatase (MPS II), α-N-acetylglucosaminidase (MPS IIIB), N-acetylglucosamine-6-sulfatase (MPS IVA), and N-acetylglucosamine-4-sulfatase (MPS VI)) and five GAGs (two kinds of heparan sulfate (HS), dermatan sulfate (DS), and two kinds of keratan sulfate (KS)) in dried blood samples (DBS) to diagnose suspected MPS patients by five-plex enzyme and simultaneous five GAGs assays. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) for both assays. These combined assays were tested for 43 patients with suspected MPS and 103 normal control subjects. We diagnosed two MPS I, thirteen MPS II, one MPS IIIB, three MPS IVA, two MPS VI, and six ML patients with this combined method, where enzymes, GAGs, and clinical manifestations were compatible. The remaining 16 patients were not diagnosed with MPS or ML. The five-plex enzyme assay successfully identified MPS patients from controls. Patients with MPS I, MPS II, and MPS IIIB had significantly elevated HS and DS levels in DBS. Compared to age-matched controls, patients with ML and MPS had significantly elevated mono-sulfated KS and di-sulfated KS levels. The results indicated that the combination method could distinguish these affected patients with MPS or ML from healthy controls. Overall, this study has shown that this combined method is effective and can be implemented in larger populations, including newborn screening.

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Validation of Liquid Chromatography-Tandem Mass Spectrometry-Based 5-Plex Assay for Mucopolysaccharidoses

Cited by 3 publications

References 35 publications

Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses

Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses

Diagnosis and Management of Mucopolysaccharidosis Type II (Hunter Syndrome) in Poland

Diagnosis of Mucopolysaccharidoses and Mucolipidosis by Assaying Multiplex Enzymes and Glycosaminoglycans

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