Gaucher disease (GD) and Niemann-Pick disease (NPD) 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 increased prevalence among Ashkenazi Jews, in whom the estimated birth occurrence is 1 in 850. Deficiency of the enzyme β-glucocerebrosidase results in the 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 GD depends on the demonstration of decreased enzymatic activity of β-glucocerebrosidase combined with the identification of mutations in the β-glucocerebrosidase gene (GBA) at the DNA level, usually with the elevation of specific biomarkers, such as glucosylsphingosine (lyso-Gb1) as ancillary confirmation and means of follow-up. Disease manifestations include hepatosplenomegaly, thrombocytopenia, anemia, osteopenia/osteoporosis with pathologic fractures and osteonecrosis, and, less commonly, pulmonary infiltration. Patients with the neuronopathic form of Gaucher disease may present between infancy and adolescence and even rarely in adulthood with the continuum of different clinical presentations. Some may present with slowed horizontal saccadic eye movements as their sole neurologic manifestation. Others may develop slowly progressive neurologic disease with generalized or myoclonic seizures, kyphosis, and mild to moderate organomegaly. Many patients, especially those homozygous for the common N370S mutation (new nomenclature c.1226A > G; p.N409S), are putatively protected against neurologic involvement, although there is evidence of a genetic risk factor for Parkinson disease. Generally, some 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 (ERT) is available. Substrate reduction therapy (SRT) is an oral modality but is associated with a more problematic safety profile. Pharmacologic chaperones (PCs) are being tested. Gene therapy and other oral modalities are in development.
Niemann-Pick disease is a heterogeneous group of autosomal recessive disorders. Types A and B result from the deficiency of the enzyme acid sphingomyelinase (ASM), whereas type C results from mutations in the NPC1 or NPC2 gene, which appear to be involved in cholesterol trafficking, 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 Europe in 2009; PC therapy is being evaluated.
Fabry disease, Wolman/cholesteryl ester storage disease, and GM1-gangliosidoses are other lipid storage diseases characterized by hepatosplenomegaly; GM2-gangliosidosis by hepatomegaly only. Patients with ...