Biochemical and molecular analysis in mucopolysaccharidoses: what a paediatrician must know

Abstract

Mucopolysaccharidoses (MPS) are rare inherited disorders caused by a deficit of the lysosomal hydrolases involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). They are all monogenic defects, transmitted in an autosomal recessive way, except for MPS type II which is X-linked. The enzymatic deficit causes a pathologic accumulation of undegraded or partially degraded substrates inside lysosomes as well as in the extracellular compartment. MPS generally present with recognizable signs and symptoms to raise a clinical suspicion. However, although they have individual peculiarities, often signs and symptoms may overlap between different MPS types. Therefore, a deeper evaluation of specific disease biomarkers becomes necessary to reach an appropriate diagnosis. This paper stresses the central role of the laboratory in completing and confirming the clinical suspicion of MPS according to a standardized procedure: first, a biochemical evaluation of the patient samples, including qualitative/quantitative urinary GAG analysis and a determination of enzyme activities, and then the molecular diagnosis. We also encourage a constant and close communication between clinicians and laboratory personnel to address a correct and early MPS diagnosis.

Keywords: Genetic counselling; Genotype-phenotype relationship; Glycosaminoglycans; Laboratory tests; Lysosomal storage disorders; Molecular analysis; Mucopolysaccharides; Pseudodeficiency.

Fig. 1

Stepwise degradation of the main glycosaminoglycan chains, heparan sulphate (HS), dermatan sulphate (DS), and keratan sulphate (KS). The enzymes involved in the pathway are shown in black. Defective enzyme activity leading to the different types of mucopolysaccharidosis (MPS) is indicated in blue. Note that the degradation pathway of chondroitin sulphates, being similar to that of DS, is not shown

Fig. 2

Diagnostic flow chart for mucopolysaccharidoses (MPS). The diagnosis of the MPS can be performed starting with a screening of the urine followed by quantitative assay of urinary glycosaminoglycans (GAGs) and, if available, by qualitative evaluation of the GAGs accumulated that can steer the enzymatic assay. Once the enzymatic defect has been determined, the molecular analysis will serve to identify the causative genomic variant. Note that keratan sulphate (KS) does not form a reaction product with any of the routinely methods reported here; hence, quantitative GAG assessment in Morquio syndrome (MPS IV) requires other techniques or the two enzymatic assays. Differential laboratory diagnosis includes multiple sulphatase deficiency and mucolipidosis II and III, in which GAGs accumulate because of their primitive defect involving some of the enzymes of the GAG degradation pathway. HS heparan sulphate, DS dermatan sulphate