Diagnosis of Mucopolysaccharidoses

Abstract

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.

Epidemiology of Mucopolysaccharidoses Update

“…MPS are inherited by autosomal recessive genes, except for MPS II, which is transmitted by the X-linked gene. Depending on the enzyme deficiency, specific GAG(s) are accumulated in different cells, tissues, and organs, which result in complicated clinical ramifications ranging from central nervous system involvement to multi organ failure [ 1 , 2 , 3 ]. GAGs are the primary storage materials that serve as diagnostic biomarkers for MPS.…”

Prenatal mucopolysaccharidosis VII: A novel pathogenic variant identified in GUSB gene

“…New technologies, such as next‐generation sequencing (NGS), are becoming more accessible and relatively affordable for the MPS diagnostic routine. 14 …”

Changes in expressions of genes involved in the regulation of cellular processes in mucopolysaccharidoses as assessed by fibroblast culture-based transcriptomic analyses

“…Due to the presence of specific mutations and enzymatic dysfunctions, undegraded GAGs accumulate in lysosomes and cause defects in cellular functions. There are 11 types and subtypes of MPS, depending on the kind of stored GAG(s) and enzymatic defect (Kubaski et al 2020 ). In 7 out of 11 types/subtypes, central nervous system (CNS) is involved, due to severe neurodegenerative processes occurring in the course of the diseases (Kobayashi 2019 ).…”