mucopolysaccharidoses

Definition: The mucopolysaccharidoses (MPS) are a group of closely related syndromes that result from genetically determined deficiencies of lysosomal enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans).

They are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function.

Types

MPS1H	Alpha-L-iduronidase	Maladie de Hurler
-	Alpha-L-iduronidase	Maladie de Scheie
MPS2	Iduronate sulfatase	Maladie de Hunter
MPS3	-	Maladie de Sanfilippo
MPS4	-	Maladie de Morquio
MPS6	-	Maladie de Maroteaux-Lamy
MPS7	-	Maladie de Sly

Several clinical variants of MPS, classified numerically from MPS I to MPS VII, have been described, each resulting from the deficiency of one specific enzyme.

All the MPS except one are inherited as autosomal recessive traits; the exception, called Hunter syndrome, is an X-linked recessive trait.

Within a given group (e.g., MPS I, characterized by a deficiency of α-l-iduronidase), subgroups exist that result from different mutant alleles at the same genetic locus. Thus, the severity of enzyme deficiency and the clinical picture even within subgroups are often different.

In general, MPS are progressive disorders, characterized by involvement of multiple organs, including liver, spleen, heart, and blood vessels.

Most are associated with coarse facial features, clouding of the cornea, joint stiffness, and mental retardation. Urinary excretion of the accumulated mucopolysaccharides is often increased.

Pathogenesis

The accumulated mucopolysaccharides are generally found in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells, and fibroblasts throughout the body. Common sites of involvement are thus the spleen, liver, bone marrow, lymph nodes, blood vessels, and heart.
Microscopically, affected cells are distended and have apparent clearing of the cytoplasm to create so-called balloon cells.

The cleared cytoplasm can be resolved as numerous minute vacuoles, which, with the electron microscope, can be visualized as swollen lysosomes filled with a finely granular PAS-positive material that can be identified biochemically as mucopolysaccharide.

Similar lysosomal changes are found in the neurons of those syndromes characterized by central nervous system involvement.

In addition, however, some of the lysosomes in neurons are replaced by lamellated zebra bodies similar to those seen in Niemann-Pick disease. Hepatosplenomegaly, skeletal deformities, valvular lesions, and subendothelial arterial deposits, particularly in the coronary arteries, and lesions in the brain, are common threads that run through all of the MPS.

In many of the more protracted syndromes, coronary subendothelial lesions lead to myocardial ischemia. Thus, myocardial infarction and cardiac decompensation are important causes of death.

Of the seven recognized variants, only two well-characterized syndromes are described briefly here. Hurler syndrome, also called MPS I H, results from a deficiency of α-l-iduronidase. It is one of the most severe forms of MPS.

Affected children appear normal at birth but develop hepatosplenomegaly by age 6 to 24 months. Their growth is retarded, and, as in other forms of MPS, they develop coarse facial features and skeletal deformities.

Death occurs by age 6 to 10 years and is often due to cardiovascular complications. Hunter disease, also called MPS II, differs from Hurler disease in mode of inheritance (X-linked), absence of corneal clouding, and milder clinical course.

Types

MPS1H	Alpha-L-iduronidase	Maladie de Hurler
-	Alpha-L-iduronidase	Maladie de Scheie
MPS2	Iduronate sulfatase	Maladie de Hunter
MPS3	-	Maladie de Sanfilippo
MPS4	-	Maladie de Morquio
MPS6	-	Maladie de Maroteaux-Lamy
MPS7	-	Maladie de Sly