Mucopolysaccharidoses (MPS)

 

Epidemiology and Etiology:

·         Lysosomal storage disease

·         Heterogenous group of storage diseases in which mucopolysaccharides accumulate in lysosomes

·         One or more glycosaminoglycans may accumulate if the defective enzyme is required for their catabolism

·         Mucopolysaccharides (glycosaminoglycans):

·         Synthesized by connective tissue cells

·         Long disaccharide repeating units

·         Degradation occurs in the lysosome

·         A series of enzymes is required for the degradation of any one glycosaminoglycan

·         Autosomal recessive:

·         Hurler syndrome / Scheie syndrome (MPS-I)

·         X-linked recessive:

·         Hunter syndrome (MPS-II)

·         Onset:

·         < 18 mo. in Hurler

·         > 5 y in Scheie

·          

 

Common sites:

·          

 

Gross features:

·         “gargoylism” originally described

·         Coarse facial features

·         Hepatosplenomegaly

·         Skeletal dysplasia (dysostosis multiplex)

·         Short stature

·         Corneal clouding (not Hunter)

·         Hearing loss

·         Valvular heart disease (MPS-I)

 

Histologic features:

·          

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 

 

 

 

Molecular features:

·         IDUA mutations

·         Alpha-L-Iduronidase defect

·         108 known mutations (mostly missense)

·         IDUA sequence analysis (combination of targeted mutation analysis and mutation scanning) detects ~97%

·         Alleles that greatly impair enzyme activity – Hurler

·         Alleles that confer some residual enzyme activity – Scheie

·         Iduronate sulfatase defect

·         Hunter

 

Other features:

·         Undegraded glycosaminoglycans appear in the urine

·         Screening tests (heparan and dermatan sulphate in Hurler)

·         Alpha-L-iduronidase enzyme assay

·         Mental retardation

·         Severe in Hurler

·         Normal intelligence in Scheie

·         Variable in Hunter

·         Prognosis:

·         progressive

·         psychomotor development may be normal in early childhood

·         Slower progression in Hunter

·         Cardiorespiratory arrest in first 10 y in Hurler

·         Normal life span in Scheie

·         BMT has therapeutic benefit

·         Ability of mutant cells to take up lysosomal enzymes (secreted from donor cells) from the extracellular fluid

 

References:

·         Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine: With STUDENT CONSULT Online Access. 7th ed. Saunders; 2007.