Question

What is the appropriate stepwise approach for diagnosing Mucopolysaccharidosis (MPS)?

• A. Clinical suspicion $\rightarrow$ Urinary GAGs $\rightarrow$ Enzyme assay $\rightarrow$ Genetic testing
• B. Clinical suspicion $\rightarrow$ Enzyme assay $\rightarrow$ Urinary GAGs $\rightarrow$ Genetic testing
• C. Clinical suspicion $\rightarrow$ Genetic testing $\rightarrow$ Enzyme assay $\rightarrow$ Urinary GAGs
• D. Clinical suspicion $\rightarrow$ Urinary GAGs $\rightarrow$ Genetic testing $\rightarrow$ Enzyme assay

Hint:

Standard Metabolic Workup Hierarchy:
Clinical Suspicion $\rightarrow$ Metabolic Screening (Urine GAGs) $\rightarrow$ Definitive Biochemical Assay (Enzyme Activity) $\rightarrow$ Molecular Confirmation (Genetic Analysis).

Answer 1

The Correct Option is A

Concept:
Mucopolysaccharidoses (MPS) are a heterogeneous group of rare inherited lysosomal storage disorders caused by deficiencies of specific lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAGs, previously termed mucopolysaccharides).
Explanation:
• The diagnostic algorithm for suspected inborn errors of metabolism like MPS follows a standardized, logical tiered approach:
1. Clinical Suspicion: Identifying phenotypic features such as coarse facial features, dysostosis multiplex, hepatosplenomegaly, corneal clouding, joint stiffness, and neuroregression.
2. Screening Test (Urinary GAGs): Quantitative and qualitative estimation of urinary glycosaminoglycans (dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate) serves as a rapid, sensitive, non-invasive initial screening test.
3. Confirmatory Biochemical Test (Specific Enzyme Assay): Fluorometric or radiometric measurement of specific lysosomal enzyme activity in leukocytes, plasma, or cultured fibroblasts to definitively identify the defective enzyme and establish the MPS subtype (e.g., alpha-L-iduronidase in MPS I, iduronate-2-sulfatase in MPS II).
4. Molecular Genetic Testing: Targeted gene sequencing to detect specific pathogenic variants for genotype-phenotype correlation, family screening, carrier detection, and prenatal counseling.

• Skipping directly to molecular testing or performing enzyme assays before urinary GAG screening is cost-ineffective and clinically inefficient.
Final Answer:
The correct stepwise diagnostic approach for MPS is: Clinical suspicion $\rightarrow$ Urinary GAGs $\rightarrow$ Specific Enzyme assay $\rightarrow$ Confirmatory Genetic testing.