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

Abstract

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.

Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985–2019)

“…Since MPS is a rare, progressive, multisystemic disease with insidious initial signs and symptoms, making an early diagnosis can be challenging for first-line general practitioners [ 35 ]. Newborn screening programs could help provide an early diagnosis for MPS at an asymptomatic age, thus allowing for more timely and appropriate treatment for these patients.…”

Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

“…This type of analytical tool allows more extensive studies to detect KS in different biological specimens (blood, urine, dried blood spots, tissues, etc.) and applies to newborn screening with high sensitivity and specificity, which makes it feasible to reduce the false positive and negative in the diagnosis [63][64][65][66][67][68][69]. Although the determination for the KS in urine and blood leads to precise diagnosis in MPS IVA, more biomarkers, including pro-inflammatory factors, are required for the prognosis, therapeutic efficacy, and clarification of pathogenesis with the development of advanced therapies [70,71].…”

Cardiac Evaluation Using Two-Dimensional Speckle-Tracking Echocardiography and Conventional Echocardiography in Taiwanese Patients with Mucopolysaccharidoses

“…However, due to the progressive nature of MPS, starting the ERT before the occurrence of irreversible cardiac damage may contribute to a better clinical outcome. As such, it is essential to make an early diagnosis via screening programs for high-risk populations or newborns [45][46][47][48].…”