INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Mucopolysaccharidoses (MPSs) are a group of 7 inherited lysosomal storage diseases caused by a deficiency in the lysosomal enzymes that degrade glycosaminoglycans (GAGs), also known as mucopolysaccharides. The deficiency in lysosomal enzymes leaves undegraded GAGs that are either stored in the lysosome or excreted in the urine. The MPSs show extensive genetic heterogeneity among and within loci.

Multiple enzymes are involved in the degradation of GAGs; a deficiency in just one of these enzymes causes the symptoms of MPS. Many clinical features are common to the different MPS disorders, and the features may be of different intensity. Excess of one or more of the GAGs results in numerous physical and mental features that may involve virtually all organ systems. Disorders may include hearing and visual defects, cardiovascular functional impairments, hepatosplenomegaly, and dysostosis multiplex. Severe mental retardation usually is associated with MPS type IH (MPS-IH), MPS type II, and MPS type III. Symptoms vary in type and severity, depending on which MPS is involved. Although, individually, the MPSs are rare, the overall incidence is approximately 1 per 25,000 population.

Diagnosis is made by enzyme assays in fibroblasts, leukocytes, or serum, and it is possible to have prenatal diagnosis by amniocentesis or chorionic villi biopsy. Measurement of enzyme activity is becoming more definitive for determining heterozygotes. Supportive treatment is used for the management of hearing loss, hydrocephaly, and pulmonary and cardiovascular complications. Treatments using exogenously supplied genes have been encouraging.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: MPS-IH is the most clinically severe type of the MPS.

• In addition to the inguinal and umbilical hernias that may be present early in life, chronic rhinitis also may be common.

• Growth is normal or even higher than normal in infancy; however, usually by age 12-14 months, patients experience a declining growth rate resulting in short stature.

• The language skills of the child do not develop because of hearing loss, enlarged tongue, and impaired vision.

• Upper respiratory infections, ear infections, loud breathing, and continuous nasal discharge are common.

• Endocardial fibroelastosis with acute cardiomyopathy may be a problem, usually in infancy. Diffuse coronary artery disease may set in early stages. Cardiac diseases and complications are major features late in the course of the disorder and are major causes of death.

• Onset of developmental delay is usually by age 1-2 years. Functional age is achieved by 2-4 years with progressive deceleration. Poor head control and an inability to walk progress rapidly. A rapid decline of muscle tone results in breathing problems.

Physical:

• The head may appear somewhat enlarged before some of the other typical facial features develop.

• A gibbus deformity of the lower spine and hepatosplenomegaly are good early indications of the syndrome. If a diagnosis of MPS-IH is suspected from either of these nonspecific features (including possible skeletal abnormalities), a biochemical assay for urinary excretion of DS and HS is helpful for confirmation.

• The most physically visible symptoms are the skeletal abnormalities known as dysostosis multiplex. Major features include an enlarged skull, enlarged but shortened bones, malformed pelvis, and other skeletal defects.

• Corneal clouding is variable, but the progressive clouding is a common feature of the syndrome and may lead to blindness.

• Hydrocephalus also may be a complication for children older than 2 years.

• Diagnosis of the disease usually is made by age 24 months, as indicated by an enlarged liver, enlarged spleen, enlarged tongue, course facial features, prominent forehead, joint stiffness, and skeletal deformities.

Causes:

• A deficiency of the lysosomal enzyme, a-L-iduronidase

• Accumulation of the undegraded mucopolysaccharides, DS and HS, occurs in tissues and organs.

• Storage of excess mucopolysaccharides leads to numerous morphological abnormalities.

• Genetic causes

• The metabolic defect in MPS-IH has an autosomal recessive mode of inheritance (as is true of the other MPSs, except for MPS-IH, Hunter syndrome, which is transmitted as a sex-linked recessive disorder).

• The a-L-iduronidase gene has been mapped to band 4p16.3.