Gaucher disease and Niemann-Pick disease are the two lipid storage disorders that are most likely to be encountered by the hematologist because both may cause hepatosplenomegaly and cytopenias.
Gaucher disease is a common autosomal recessive lipid storage disorder, with an increased prevalence among Ashkenazi Jews, in whom the estimated birth occurrence is 1 in 850. Deficiency of the enzyme β-glucocerebrosidase results in accumulation of the sphingolipid glucocerebroside in the cells of the macrophage-monocyte system. Patients with the most prevalent form, type 1, have no primary neuronopathic symptoms, whereas there is involvement of the central nervous system in type 2 and type 3. Diagnosis of Gaucher disease depends on demonstration of decreased enzymatic activity of β-glucocerebrosidase combined with identification of mutations in the β-glucocerebrosidase gene at the DNA level, usually with elevation of biomarkers, such as chitotriosidase as ancillary confirmation and means of followup. Disease manifestations include hepatosplenomegaly, thrombocytopenia, anemia, osteopenia/osteoporosis with pathologic fractures and osteonecrosis, and, less commonly, pulmonary infiltration. Many patients, especially those homozygous for the common N370S mutation, are putatively protected against neurologic involvement, albeit there is evidence of a genetic risk factor for Parkinson disease. Generally, many patients with type 1 may be asymptomatic or so mildly affected that they may not present until their fifth or sixth decade and do not require disease-specific therapy, whereas for those with more severe signs and symptoms, enzyme replacement therapy (currently three infusible enzymes) is available. Substrate reduction therapy is an oral modality but is associated with a more problematic safety profile. Pharmacological chaperones and oral enzyme are being tested.
Niemann-Pick disease is a heterogeneous group of autosomal recessive disorders. Type A and type B result from deficiency of the enzyme sphingomyelinase, whereas type C results from mutations in the NPC1 or NPC2 gene, which appears to be involved in cholesterol trafficking and resulting in accumulation of cholesterol as well as sphingomyelin. Type A is a lethal infantile form with marked progressive neurologic involvement. Type B is a later-onset form with no neurologic involvement but hepatosplenomegaly in many patients. Patients with type C disease manifest progressive neurologic involvement and hepatosplenomegaly, but may survive into adulthood. The marrow of these patients contains typical foam cells with small droplets in the cytoplasm and sea-blue histiocytes. Substrate reduction therapy was approved for patients with type C disease in 2008 in Europe; pharmacologic chaperone therapy is being attempted.
Fabry disease, Wolman/cholesteryl ester storage disease (CESD), and GM1-gangliosidoses are other lipid storage diseases characterized by hepatosplenomegaly; GM2-gangliosidosis by hepatomegaly only. CESD patients may result in anemia and have sea-blue histiocytes. They are usually not cared for by hematologists and will not be discussed in this chapter.
Acronyms and Abbreviations
cDNA, complementary DNA; ERT, enzyme replacement therapy; MRI, magnetic resonance imaging; PC, pharmacologic chaperone; SRT, substrate reduction therapy.
DEFINITION OF GLYCOLIPID STORAGE DISEASES
The glycolipid storage diseases are hereditary disorders ...