Chapter 82 Mucopolysaccharidoses
Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (acid mucopolysaccharides). Glycosaminoglycan (GAG) is a long-chain complex carbohydrate composed of uronic acids, amino sugars, and neutral sugars. The major GAGs are chondroitin-4-sulfate, chondroitin-6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. These substances are synthesized and, with the exception of hyaluronan, linked to proteins to form proteoglycans, major constituents of the ground substance of connective tissue, as well as nuclear and cell membranes. Degradation of proteoglycans starts with the proteolytic removal of the protein core followed by the stepwise degradation of the GAG moiety. Failure of this degradation due to absent or grossly reduced activity of mutated lysosomal enzymes results in the intralysosomal accumulation of GAG fragments (Fig. 82-1). Distended lysosomes accumulate in the cell, interfere with cell function, and lead to a characteristic pattern of clinical, radiologic, and biochemical abnormalities (Table 82-1, Fig. 82-2). Within this pattern, specific diseases can be recognized that evolve from the intracellular accumulation of different degradation products (Table 82-2). As a general rule, the impaired degradation of heparan sulfate is more closely associated with mental deficiency and the impaired degradation of dermatan sulfate, chondroitin sulfates, and keratan sulfate with mesenchymal abnormalities. Variable expression within a given entity results from allelic mutations and varying residual activity of mutated enzymes. Allelic mutations of the gene encoding L-iduronidase may result in severe Hurler disease with early death or in mild Scheie disease manifesting only with limited joint mobility, mild skeletal abnormalities, and corneal opacities. Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease, which is X-linked recessive. Their overall frequency is between 3.5/100,000 and 4.5/100,000. The most common subtype is MPS-III, followed by MPS-I and MPS-II.
Clinical Entities
Mucopolysaccharidosis I
the MPS-I alleles in the white population. The mutations introduce stop codons with ensuing absence of functional enzyme (null alleles); homozygosity or compound heterozygosity gives rise to Hurler disease. Other mutations occur in only one or a few individuals.Hurler Disease
This form of MPS I (MPS I-H) is a severe, progressive disorder with multiple organ and tissue involvement that results in premature death, usually by 10 yr of age. An infant with Hurler syndrome appears normal at birth, but inguinal hernias are often present. Diagnosis is usually made between 6 and 24 mo of age with evidence of hepatosplenomegaly, coarse facial features, corneal clouding, large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia (see Fig. 82-2). Acute cardiomyopathy has been found in some infants <1 yr of age. Most patients have recurrent upper respiratory tract and ear infections, noisy breathing, and persistent copious nasal discharge. Valvular heart disease with incompetence, notably of the mitral and aortic valves, regularly develops, as does coronary artery narrowing. Obstructive airway disease, notably during sleep, may necessitate tracheotomy. Obstructive airway disease, respiratory infection, and cardiac complications are the common causes of death.
Most children with Hurler syndrome acquire social but only limited language skills because of developmental delay, combined conductive and neurosensory hearing loss, and an enlarged tongue. Progressive ventricular enlargement with increased intracranial pressure caused by communicating hydrocephalus may be responsible for headache and sleep disturbance. Corneal clouding, glaucoma, and retinal degeneration are common. Radiographs show a characteristic skeletal dysplasia known as dysostosis multiplex (Figs. 82-3 and 82-4). The earliest radiographic signs are thick ribs and ovoid vertebral bodies. Skeletal abnormalities in addition to those shown in the figures include enlarged, coarsely trabeculated diaphyses of the long bones with irregular metaphyses and epiphyses. With progression of the disease, macrocephaly develops, with thickened calvarium, premature closure of lambdoid and sagittal sutures, shallow orbits, enlarged J-shaped sella, and abnormal spacing of teeth with dentigenous cysts.
Mucopolysaccharidosis II
Hunter disease (MPS II) is an X-linked disorder caused by the deficiency of iduronate-2-sulfatase (IDS). The gene encoding IDS is mapped to Xq28. Point mutations of the IDS gene have been detected in about 80% of patients with MPS II. Major deletions or rearrangements of the IDS gene have been found in the rest; these are usually associated with a more severe clinical phenotype (see Fig. 82-2). Hunter disease manifests almost exclusively in males; it has been observed in a few females and this is explained by skewed inactivation of the X chromosome carrying the normal gene.
