Which of the following is correct regarding mucopolysaccharidosis (MPS)?
ExplanationThe patient in question has Hunter’s syndrome, which is inherited in an X-linked fashion. In mucopolysaccharidosis (MPS) type III or Sanfilippo’s syndrome, there is accumulation of heparan sulfate but not dermatan sulfate. Mucopolysaccharidoses are caused by impaired lysosomal degradation of glucosaminoglycans (not n-acetylaspartic acid, which accumulates in Canava disease which are long unbranched molecules of repeating disaccharides. Various enzymatic defects lead to the accumulation of glucosaminoglycans in lysosomes and the extracellular matrix. The MPS are all autosomal recessive except for Hunter’s disease, which is X-linked. In general, MPS are a group of progressive multisystemic disorders that affect the cornea, cartilage, bone, connective tissue, reticuloendothelial system, and nervous system. Hurler’s syndrome is MPS type I and is caused by α-Liduronidase deficiency. The gene is localized to chromosome 4, and there is accumulation of both dermatan and heparan sulfate. These patients are normal at birth, but within the first 2 years of life, they will develop coarsening of facial features, with progressive skeletal dysplasia with dysostosis multiplex and growth impairment (dwarfism). These patients have restricted range of motion of the joints, hearing loss, corneal clouding, macroglossia, hernias, visceromegaly, valvular heart disease, and prominent intellectual disability. Mild MPS type I is also known as Scheie’s syndrome, and the intermediate form is known as Hurler–Scheie syndrome. Most recently, MPS type I has been classified as severe MPS type I and attenuated MPS type I. The diagnosis of MPS type I is based on elevated urinary excretion of dermatan and heparan sulfate and confirmed with enzyme analysis in leukocytes and fibroblasts. Pathologically, there are cells with vacuolated appearance, expansion of perivascular spaces in the CNS, and neuronal lipidosis. Electron microscopy (not light microscopy) demonstrates reticulogranular material in epithelial and mesenchymal cells, and lamellar material in neurons, some of which adopt a layered appearance and are called zebra bodies. Enzyme replacement therapy can be used to treat non-CNS manifestations of the disease. Stem cell transplantation can be potentially helpful. Hunter’s syndrome or MPS type II is caused by a defect in iduronate sulfatase, with accumulation of dermatan sulfate and heparan sulfate. These patients have the Hurler phenotype but lack the corneal clouding and have characteristic nodular ivory-colored lesions on the back, shoulders, and upper arms. These children have short stature, macrocephaly, macroglossia, hoarse voice, hearing loss, visceromegaly, dysostosis multiplex, joint contractures, entrapment neuropathies such as carpal tunnel syndrome, and intellectual disability. The diagnosis is based on mucopolysacchariduria and confirmed with analysis of the enzyme activity. Treatment is symptomatic. Other MPS include types III, IV, VI, VII, and IX as follows: • MPS type III or Sanfilippo’s syndrome has several subtypes (A, B, C, and D) and is associated with accumulation of heparan sulfate only. The main manifestation is intellectual disability. • MPS type IV or Morquio’s syndrome has two subtypes (A and B, see question 87), and they manifest with corneal clouding, dysostosis multiplex, and heart disease, with normal intelligence. • MPS type VI is also known as Maroteaux–Lamy syndrome and manifests with normal intelligence, dysostosis multiplex, corneal clouding, heart disease, and other features similar to Hurler’s syndrome. • MPS type VII is also known as Sly’s syndrome, and these patients have hydrops fetalis, intellectual disability, dysostosis multiplex, corneal clouding, and other features of Hurler’s syndrome. • MPS type IX is also known as Natowicz’s syndrome and is caused by deficiency of hyaluronidase with accumulation of hyaluronan.
