An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Population
2.1.1. Ethics Approval and Consent to Participate
2.1.2. Consent for Publication
2.2. First-Line Biochemistry Examinations and the Confirmative Methods
2.2.1. DMB Method
2.2.2. 2-D EP Method
2.2.3. LC-MS/MS of DS, HS, and KS
2.2.4. Enzyme Activity Measurements
2.3. Normal Reference Values of Urinary GAGs
2.4. Clinical Characteristics of Patients with a Confirmative Diagnosis of MPS
2.5. Statistical Analysis
3. Results
4. Discussion
5. Limitations
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
MPS | Mucopolysaccharidosis |
GAGs | Glycosaminoglycans |
DS | Dermatan sulfate |
HS | Heparan sulfate |
KS | Keratan sulfate |
CS | Chondroitin sulfate |
2-D EP | Two-dimensional electrophoresis |
DMB | Dimethylmethylene blue |
LC-MS/MS | Liquid chromatography/tandem mass spectrometry |
ERT | Enzyme replacement therapy |
HSCT | Hematopoietic stem cell transplantation |
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Organs and Systems | Signs and Symptoms |
---|---|
Musculoskeletal system | Skeletal malformations, joint stiffness or hypermobility, short stature, kyphoscoliosis, carpal tunnel syndrome |
Neurological system | Psychomotor delay, cognitive delay, behavioral disorders |
Face | Coarse facial features |
Connective tissue | Hernias |
Heart | Valvulopathy, myocardiopathy |
Visceromegaly | Hepatomegaly, splenomegaly |
Respiratory system | Recurrent respiratory infection, noisy breath sounds |
Otorhinolaryngological system | Recurrent otitis media, hearing impairment, recurrent sinusitis, obstructive sleep apnea syndrome |
Ophthalmological system | Cornea clouding, retinopathy |
Specialist | Number | Percentage |
---|---|---|
Pediatric endocrinologist | 40 | 26% |
Pediatric neurologist | 39 | 25% |
General pediatrician | 34 | 22% |
Geneticist | 17 | 11% |
Pediatric rheumatologist | 6 | 4% |
Neonatologist | 6 | 4% |
Pediatric orthopedist | 5 | 3% |
Pediatric cardiologist | 5 | 3% |
Pediatric surgeon | 1 | 1% |
Total | 153 | 100% |
Signs and Symptoms by Different Systems | Number | Percentage |
---|---|---|
Musculoskeletal system | 84 | 55% |
Neurological system | 69 | 45% |
Face | 59 | 39% |
Hernias | 13 | 8% |
Heart | 10 | 7% |
Visceromegalies | 9 | 6% |
Respiratory system | 7 | 5% |
Hearing system | 5 | 3% |
Ophthalmological system | 4 | 3% |
Otorhinolaryngological system | 4 | 3% |
Family history of MPS | 3 | 2% |
Total | 267 |
No. | MPS type | Gender | Age at Diagnosis (years) | DS (μg/mL) | HS (μg/mL) | KS (μg/mL) | DMB Ratio (mg/mmol creatinine) | *DMB Reference Range (mg/mmol creatinine) | Enzyme | Enzymatic Activity | Gene | Genotype |
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | I | F | 0.6 | 322.1 | 5.0 | 3 | 113.62 | <69.15 | Alpha-iduronidase | 0.3 nmol/mg protein/h | IDUA | c.590-7G > A/c.1861C > T |
2 | I | F | 0.7 | 174 | 3.9 | 2.79 | 159.51 | <69.15 | Alpha-iduronidase | 0.39 nmol/mg protein/h | IDUA | c.1192_1194delGAG/c.1634delA, c.1634_1635insGGG |
3 | I | F | 2.9 | 147.66 | 21.71 | 0.7 | 49.78 | <58.82 | Alpha-iduronidase | 0.87 nmol/mg protein/h | IDUA | c.95T > G |
4 | II | M | 0.9 | 78.69 | 176.3 | 0 | 185.43 | <69.15 | Iduronate-2-sulfatase | 0.1 nmol/mg protein/ 4h | IDS | c.137A > C (hemizygous) |
5 | II | M | 3.8 | 127.69 | 109.75 | 6.31 | 61.29 | <58.82 | Iduronate-2-sulfatase | 0.4 nmol/mg protein/ 4h | IDS | c.1122C > T (hemizygous) |
6 | II | M | 6.3 | 51.8 | 0 | 1.51 | 37.60 | <18.20 | Iduronate-2-sulfatase | 0.2 nmol/mg protein/ 4h | IDS | c.1600A > C (hemizygous) |
7 | II | M | 10.9 | 91.93 | 384.03 | 0.22 | 27.03 | <16.81 | Iduronate-2-sulfatase | 0.86 nmol/mg protein/ 4h | IDS | c.1006 + 5G > C (hemizygous) |
8 | IIIB | M | 1.3 | 0 | 92.43 | 3.59 | 55.35 | <58.82 | N-acetyl-glucosaminidase | 0.05 nmol/mg protein/h | NAGLU | c.383 + 1G > T/c.1693C > T |
9 | IIIB | M | 1.8 | 0.3 | 179.2 | 0.36 | 65.23 | <58.82 | N-acetyl-glucosaminidase | 0.06 nmol/mg protein/h | NAGLU | c.252_253ins19/c.1493T > C |
10 | IIIB | M | 3.4 | 0 | 48.59 | 2.68 | 47.20 | <58.82 | N-acetyl-glucosaminidase | 0.07 nmol/mg protein/h | NAGLU | c.383 + 1G > T/c.1693C > T |
11 | IIIB | M | 4.7 | 0.9 | 58.1 | 0.06 | 22.52 | <18.20 | N-acetyl-glucosaminidase | 0.04 nmol/mg protein/h | NAGLU | c.926A > G/c.1241A > G |
12 | IIIB | F | 5.0 | 0.14 | 11.54 | 0.01 | 55.85 | <18.20 | N-acetyl-glucosaminidase | 0.2 nmol/mg protein/h | NAGLU | c.1693C > A/c.1693C > A (homozygous) |
13 | IVA | M | 1.5 | 0.04 | 0.01 | 90.28 | 45.27 | <58.82 | Galactose-6-sulfate sulfatase | 0.3 nmol/mg protein/h | GALNS | c.953T > G/c.1567T > G |
No. | MPS type | Gender | Age at Diagnosis (years) | Referring Specialist | Musculoskeletal System | Ophthalmological System | Heart | Neurological System | Hernias | Visceromegaly | Face | Respiratory System | Otorhinolaryngological System | Hearing System | Family History of MPS | Surgeries before a Confirmative Diagnosis |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | I | F | 0.6 | Neonatologist | Y | N | N | N | Y | N | Y | Y | Y | N | M | Herniorrhaphy, supraglottoplasty for laryngomalacia, tracheostomy |
2 | I | F | 0.7 | Pediatric orthopedist | Y | N | N | N | N | N | Y | N | N | N | N | None |
3 | I | F | 2.9 | Pediatric cardiologist | Y | N | Y | N | N | Y | Y | Y | N | N | N | None |
4 | II | M | 0.9 | Geneticist | Y | N | N | N | Y | Y | Y | N | N | N | N | Surgery for spina bifida, herinorrhaphy |
5 | II | M | 3.8 | Pediatric orthopedist | Y | N | N | N | Y | N | Y | N | N | N | N | Herinorrhaphy |
6 | II | M | 6.3 | Pediatric neurologist | Y | N | N | N | Y | N | N | Y | Y | Y | N | Ventilation tube insertion, tonsillectomy, adenoidectomy, herniorrhaphy |
7 | II | M | 10.9 | Pediatric neurologist | Y | N | Y | N | Y | Y | Y | N | Y | N | N | Herinorrhaphy |
8 | IIIB | M | 1.3 | Pediatric neurologist | Y | N | N | Y | N | Y | Y | N | Y | Y | Y | None |
9 | IIIB | M | 1.8 | General pediatrician | Y | N | N | Y | N | N | Y | N | N | N | N | None |
10 | IIIB | M | 3.4 | Pediatric neurologist | Y | N | N | Y | N | Y | Y | N | Y | N | Y | None |
11 | IIIB | M | 4.7 | Pediatric neurologist | Y | N | Y | Y | N | N | Y | Y | Y | N | N | Ventilation tube insertion |
12 | IIIB | F | 5.0 | Pediatric neurologist | Y | N | N | Y | N | N | Y | N | Y | Y | N | Ventilation tube insertion |
13 | IVA | M | 1.5 | Pediatric orthopedist | Y | N | N | N | N | N | N | N | N | N | N | None |
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Lin, H.-Y.; Lee, C.-L.; Lo, Y.-T.; Tu, R.-Y.; Chang, Y.-H.; Chang, C.-Y.; Chiu, P.C.; Chang, T.-M.; Tsai, W.-H.; Niu, D.-M.; et al. An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan. Diagnostics 2019, 9, 140. https://doi.org/10.3390/diagnostics9040140
Lin H-Y, Lee C-L, Lo Y-T, Tu R-Y, Chang Y-H, Chang C-Y, Chiu PC, Chang T-M, Tsai W-H, Niu D-M, et al. An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan. Diagnostics. 2019; 9(4):140. https://doi.org/10.3390/diagnostics9040140
Chicago/Turabian StyleLin, Hsiang-Yu, Chung-Lin Lee, Yun-Ting Lo, Ru-Yi Tu, Ya-Hui Chang, Chia-Ying Chang, Pao Chin Chiu, Tung-Ming Chang, Wen-Hui Tsai, Dau-Ming Niu, and et al. 2019. "An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan" Diagnostics 9, no. 4: 140. https://doi.org/10.3390/diagnostics9040140
APA StyleLin, H.-Y., Lee, C.-L., Lo, Y.-T., Tu, R.-Y., Chang, Y.-H., Chang, C.-Y., Chiu, P. C., Chang, T.-M., Tsai, W.-H., Niu, D.-M., Chuang, C.-K., & Lin, S.-P. (2019). An At-Risk Population Screening Program for Mucopolysaccharidoses by Measuring Urinary Glycosaminoglycans in Taiwan. Diagnostics, 9(4), 140. https://doi.org/10.3390/diagnostics9040140