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5th February 2024
Disorders of glycosaminoglycan metabolism
Pathophysiology
Glycosaminoglycans, or mucopolysaccharides, are the degradation products of proteoglycans in the extracellular matrix and are proteolytic cleaved, giving origin to GAGs, which enter the lysosome for intracellular digestion. There are four different pathways:
- Dermatan sulfate
- Heparan sulfate
- Keratan sulfate
- Chondroitin sulfate
Mucopolysaccharidoses (MPs) are a group of inherited lysosomal storage disorders in which the abnormal accumulation of specific carbohydrate complexes can cause chronic and progressive symptoms with varying severity. Features can include organomegaly, dysostosis multiplex and characteristic abnormal facies. Definitive diagnosis is enzymatic assays of the defective enzyme in cultured fibroblasts, leucocytes, and serum or plasma. MPs are inherited in an autosomal recessive fashion, except MPS II (Hunter syndrome), which is X-linked.
Clinical summary
The table below shows details of common mucopolysaccharidoses that are favourites in the MRCP Part 1 exam:
| Group | Syndrome | Deficiency | Accumulation | Features |
|---|---|---|---|---|
| MPS 1-H;S;H/S | Hurler syndrome | Alpha-L-iduronidase | Dermatan sulfates
Heparan sulfates |
Most severe form
Developmental delays Recurrent urinary and respiratory tract infections, skeletal deformities, Cloudy cornea, pigmentary retinopathy |
| cheie syndrome | Alpha-L-iduronidase | Dermatan sulfate | Mildest form
Normal IQ, height and life expectancy Stiff joints, aortic regurgitation, cloudy cornea |
|
| Hurler-Scheie syndrome | Alpha-L-iduronidase | Dermatan sulfate | Severity in-between Hurler and Scheie syndrome
Coarse facial features, joint stiffness, cloudy corneas, hepatosplenomegaly, skeletal and cardiac abnormalities |
|
| MPS II | Hunter syndrome | Iduronate sulfatase | Dermatan sulfate
Heparan sulfate |
Progressive growth delays, short stature, stiff joints
Macrocephaly, hepatosplenomegaly IIA (more severe form)- reduced IQ IIB (mild form)- normal IQ Cornea is clear |
| MPS III | Sanfilippo syndrome | Heparan N-sulfatase | Heparan sulfate | Four subtypes (A, B, C, D)
Hyperactivity, sleep disorders, varying intellectual disability, seizures, unsteady gait Pigmentary retinopathy and optic atrophy |
| MPS IV | Morquio syndrome | N-acetyl-galactosamine-6-sulfatase and beta galactosidase | Keratan sulfate
Chondroitin sulfate |
Normal IQ
Skeletal dysplasia Prominent lower face, abnormally short neck, genu valgum, flat feet, kyphoscoliosis Cloudy cornea |
| MPS VI | Maroteaux-Lamy syndrome | N-acetylgalactosamine-4-sulfatase | Dermatan sulfate | Normal IQ
Coarse facial features, umbilical hernia, joint contractures, hepatosplenomegaly Cloudy cornea |
| MPS VII | Sly syndrome | Beta-glucuronidase | Dermatan sulfate
Heparan sulfate Chondroitin sulfate |
Normal IQ
Skeletal/facial dysmorphism Cloudy cornea Hydrocephalus, short stature, heart diseases Hydrops fetalis |
References
Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochemistry research international. 2012 Oct;2012.
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