One variant, type 1, also called the chronic nonneuronopathic form, accounts for 99% of cases of Gaucher disease. It is characterized by clinical or radiographic bone involvement (osteopenia, focal lytic lesions, and osteonecrosis) in 70% to 100% of cases. Additional features are hepatosplenomegaly and the absence of CNS involvement. The spleen often enlarges to massive proportions, filling the entire abdomen. Gaucher cells are found in the liver, spleen, lymph nodes, and bone marrow. Marrow replacement and cortical erosion may produce radiographically visible skeletal lesions, and peripheral blood cytopenias. It is believed that bone changes are caused by the aforementioned macrophage-derived cytokines. Type 1 is most common in Ashkenazi Jews; unlike other variants, it is compatible with long life. Neurologic signs and symptoms characterize types 2 and 3 variants. In type 2, these manifestations appear during infancy (acute infantile neuronopathic form) and are more severe, whereas in type 3, they emerge later and are milder (chronic neuronopathic form). Although the liver and spleen also are involved, the clinical features in types 2 and 3 are dominated by neurologic disturbances, including convulsions and progressive mental deterioration. As mentioned earlier mutation of the glucocerebroside gene is a very important risk factor for Parkinson disease. Patients with Gaucher disease have a 20 fold higher risk of developing Parkinson disease (compared to controls) and 5–10% of patients with Parkinson disease have mutations in the gene encoding glucocerebrosidase.
There is a reciprocal relationship between the level of this enzyme and alpha synuclein. The latter is involved in the pathogenesis of Parkinson disease (Chapter 24). The level of glucocerebrosides in leukocytes or cultured fibroblasts is helpful in diagnosis and in the detection of heterozygote carriers. DNA testing is also available in select populations.
Currently, there are two approved therapies for type I Gaucher disease. The first is lifelong enzyme replacement therapy via infusion of recombinant glucocerebrosidase. The second, known as substrate reduction therapy, involves oral intake of an inhibitor of the enzyme glucosylceramide synthase. This leads to reduced systemic levels of glucocerebroside, the substrate for the defective enzyme in Gaucher disease. Clinical trials have confirmed that substrate reduction therapy leads to reduced spleen and liver sizes, improved blood counts, and enhanced skeletal function. Other emerging treatments include gene therapy through transplant of hematopoietic stem cells containing the corrected enzyme.
Mucopolysaccharidoses (MPSs) are characterized by defective degradation and excessive storage of mucopolysaccharides in various tissues. Recall that mucopolysaccharides are part of the extracellular matrix and are synthesized by connective tissue fibroblasts. Most mucopolysaccharide is secreted, but a certain fraction is degraded within lysosome through a catabolic pathway involving multiple enzymes. 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 in this pathway. The mucopolysaccharides that accumulate within the tissues include dermatan sulfate, heparan sulfate, keratan sulfate, and (in some cases) chondroitin sulfate.
Hepatosplenomegaly, skeletal deformities, lesions of heart valves, subendothelial arterial deposits, particularly in the coronary arteries, and lesions in the brain, are features that are seen in all of the MPSs. 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. Most cases are associated