Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + GLYCOLIPID STORAGE DISEASES Download Section PDF Listen +++ ++ These are hereditary disorders in which one or more tissues become engorged with specific lipids because of deficiencies of the lysosomal enzymes required for hydrolysis of one of the glycosidic bonds. The type of lipid and its tissue distribution have a characteristic pattern in each disorder. In Gaucher disease (the most common disorder) and Niemann-Pick disease, major clinical manifestations result from macrophage accumulation of glucocerebroside and sphingomyelin, respectively, leading to their massive expansion in tissues. + GAUCHER DISEASE Download Section PDF Listen +++ +++ Etiology and Pathogenesis ++ Glucocerebroside accumulates in macrophages because of a deficiency of β-glucocerebrosidase. Inheritance is autosomal recessive, with high gene frequency among Ashkenazi Jews. More than 100 different mutations have been reported, but the five mutations most common in Ashkenazi Jews account for more than 95% of mutations in that population. The most common mutation in the Jewish population is 1226G (N370S). It usually gives rise to mild disease in the homozygous form. +++ Clinical Features ++ Three types of Gaucher disease are recognized based on absence (type 1) or presence of neurological features (types 2 and 3) (see Table 37–1). — Type 1 occurs in both children and adults, and is primarily caused by an accumulation of glucocerebroside-laden macrophages in liver, spleen, and marrow. Neurologic manifestations are rare and primarily affect the peripheral nervous system. — Type 2 is exceedingly rare and is characterized by rapid neurologic deterioration and early death. — Type 3, or juvenile Gaucher disease, is a subacute neuropathic disorder with later onset of symptoms and better prognosis than type 2. Patients may be asymptomatic, or symptoms may range from minimal to severe: — Chronic fatigue is common. — Hemorrhage occurs after procedures. — Splenic enlargement may cause positional symptoms. Hepatomegaly is usually asymptomatic. — Skeletal lesions are often painful. “Erlenmeyer flask” deformity of the femur is common (Figure 37–1). ++Table Graphic Jump LocationTable 37–1CHARACTERISTICS OF THE THREE TYPES OF GAUCHER DISEASEView Table||Download (.pdf) Table 37–1 CHARACTERISTICS OF THE THREE TYPES OF GAUCHER DISEASE TYPE 1 TYPE 2 TYPE 3 Subtype Asymptomatic Symptomatic Neonatal Infantile 3a 3b 3c Common genotype N370S/N370S or two mild mutations N370S/other or two mild mutations Two null or recombinant mutations One null and one severe mutations None L444P/L444P D409H/D409H Ethnic predilection Ashkenazi Jews Ashkenazi Jews None None None Norrbottnians, Asians, Arabs Palestinian Arabs, Japanese Common presenting features None Hepatosplenomegaly, hypersplenism, bleeding, bone pains Hydrops fetalis; congenital ichthyosis SNGP, strabismus, opisthotonus, trismus SNGP; myoclonic seizures SNGP; hepatosplenomegaly growth retardation SNGP; cardiac valves’ calcifications Central nervous system involvement None None Lethal Severe SNGP; slowly progressive neurologic deterioration SNGP; gradual cognitive deterioration SNGP; brachycephalus Bone involvement None Mild to severe (variable) None None Mild Moderate to severe; kyphosis (gibbus) Minimal Lung involvement None None to (rarely) severe Severe Severe Mild to moderate Moderate to severe Minimal Life Expectancy Normal Normal/near-normal Neonatal death Death before age 3 years Death during childhood Death in mid-adulthood Death in early adulthood SNGP, supranuclear gaze palsy. Source: Williams Hematology, 9th ed, Chap. 72, Table 72–1. ++ FIGURE 37–1 Gaucher-related skeletal involvement. A. Humerus with chevron or herringbone pattern. B. “Erlenmeyer flask” deformity of the proximal femur. C. Plain radiograph of osteonecrosis of the left hip. D. Magnetic resonance image of pelvis and thighs that was performed 2 weeks after bone crisis of the right thigh. Bone edema is seen in the upper part of the femur at the level of lesser trochanter. Chronic marrow signal changes are seen in both femurs. E. Vertebral collapse. (Used with permission from Dr. Ehud Lebel, Shaare Zedek Medical Center, Jerusalem, Israel.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Laboratory Features ++ Blood counts may be normal or reflect effects of hypersplenism; normocytic, normochromic anemia with modest reticulocytosis is often found. Thrombocytopenia is common, particularly in patients with significant splenomegaly and may be severe. Gaucher cells are large cells found in marrow, spleen, and liver in varying numbers. They are characterized by small, eccentrically placed nuclei and cytoplasm with characteristic crinkles or striations. The cytoplasm stains with the periodic acid–Schiff (PAS) technique (Figure 37–2). Serum acid phosphatase, chitotriosidase, ferritin, and hexosaminidase activities are commonly increased. Serum polyclonal gammopathy is common. Monoclonal gammopathies have been found in 1% to 20% of older patients. Acquired coagulation factor deficiencies (isolated coagulation factors) have been reported. ++ FIGURE 37–2 A. “Gaucher cell” in the marrow aspirate of a patient with Gaucher disease. B. Histomicrograph of the spleen with marked infiltration of the red pulp by Gaucher cells. C. Liver infiltrated by Gaucher cells (the pale pink cells). (Marrow image used with permission from Prof. Chaim Hershko, Shaare Zedek Medical Center, Jerusalem, Israel; spleen and liver images used with permission from Prof. Gail Amir, Hadassah Medical Center, Jerusalem, Israel.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Diagnosis ++ This is established by demonstrating reduced enzymatic activity of β-glucocerebrosidase in leukocytes, cultured fibroblasts, or amniocytes (for prenatal diagnosis). Mutational analysis by whole-genome sequencing is recommended. Marrow aspiration is indicated only when other hematologic diseases must be considered. Definitive diagnosis of heterozygosity must be made by mutational analysis. +++ Treatment ++ Enzyme replacement therapy with recombinant human β-glucosidase (imiglucerase) has been successful. It is very expensive. New enzymes are in clinical trials. The enzyme is usually infused with biweekly doses between 15 and 60 U/kg. Responses (decrease in liver and spleen size and improved blood counts) usually occur within 6 months. The enzyme does not cross the blood-brain barrier and hence does not affect neuronopathic features. In patients who are not suitable for enzyme replacement therapy, oral substrate reduction therapy using oral miglustat (an inhibitor of glucocerebroside synthase) may be considered. Future pharmacologic options consist of “chaperone therapy,” stabilizing mutant (misfolded) glucocerebrosidase molecules that would otherwise be destroyed prior to their export from the endoplasmic reticulum to the lysosome. Splenectomy generally corrects anemia and thrombocytopenia caused by hypersplenism but may cause more rapid deposition of lipid in liver and marrow. Splenectomy is less often performed since the introduction of enzyme replacement therapy. Orthopedic procedures, particularly joint replacement, are useful in patients with severe joint damage. Hematopoietic stem cell transplantation is curative, but its use is limited by the risk. +++ Course and Prognosis ++ There is often great variability in expression of the disease, even among siblings. Severity of the disease changes little after childhood, and progression does not occur or is gradual. Some adults with aggressive disease will have slow progression, measured over decades with a gradual fall in platelet count and new bone lesions. Pulmonary complications include infiltration of the lungs by Gaucher cells, causing severe interstitial lung disease, usually in patients with severe liver disease and splenectomy. Pulmonary hypertension is rare, can be life-threatening, and does not respond to enzyme replacement therapy. There is an increased incidence of malignancies in patients, particularly hematologic malignancies (multiple myeloma) and hepatocellular carcinoma. The latter is seen in cases with severe liver involvement with fibrosis following splenectomy. + NIEMANN-PICK DISEASE Download Section PDF Listen +++ +++ Etiology and Pathogenesis ++ This disorder is autosomal recessive. Types A and B disease are a consequence of acid sphingomyelinase (ASM) deficiency and are an infantile disease and a disease with later onset, respectively. They are now referred to as ASM deficiency. Type C disease is not a result of sphingomyelinase deficiency but rather of mutations in a gene designated NPC1 or NPC2, which is involved in cholesterol and glycolipid transport. The predominant lipid accumulating in tissues is sphingomyelin in types A and B, and of unesterified cholesterol and several glycolipids in type C. Characteristic foam cells are found in the lymphoid organs (Figure 37–3). ++ FIGURE 37–3 Typical foam cell from the marrow of a patient with Niemann-Pick disease. (Source: Williams Hematology, 9th ed, Chap. 72, Fig. 72–6.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ Clinical Features ++ Type A disease presents in infancy with poor growth and neurologic manifestations. Type B disease usually presents with hepatosplenomegaly in the first decade of life but in mild cases not until adulthood. Neurologic findings are usually absent but pulmonary involvement is common. Type C disease is characterized by neonatal jaundice and dementia, ataxia, and psychiatric symptoms in later life. +++ Laboratory Features ++ Hemoglobin values may be normal or mild anemia may be present. Blood lymphocytes typically contain small, lipid-filled vacuoles. Marrow contains foam cells. +++ Niemann-Pick Types A and B ++ Leukocytes or cultured fibroblasts are deficient in sphingomyelinase activity. Lipid profiles are always abnormal including high triglycerides and LDL-cholesterol in combination with low HDL cholesterol. The consequences for cardiovascular disease are unknown. +++ ASM Deficiency and Niemann-Pick Type C ++ Large histiocytes containing small lipid droplets (foam cells) or sea-blue histiocytes are demonstrable in many tissues, including marrow. +++ Diagnosis ++ Types A and B disease diagnosed by demonstration that leukocytes or cultured fibroblasts are deficient in sphingomyelinase. Heterozygotes for types A and B cannot be reliably detected by measurement of sphingomyelinase activity. Genetic testing needs to be performed. Type C disease can be diagnosed by biochemical testing that demonstrates impaired cholesterol esterification and positive filipin staining in cultured fibroblasts. Biochemical testing for carrier status is unreliable. Molecular genetic testing of the NPC1 and NPC2 genes detects disease-causing mutations in approximately 95% of individuals with type C disease. +++ Treatment ++ Enzyme replacement therapy is currently being developed for the treatment of Niemann-Pick type B disease. Some studies have suggested beneficial effects of miglustat in Niemann-Pick type C disease. +++ Course and Prognosis ++ Patients with type A disease usually die before their third year of life. Patients with type B disease may survive into childhood or longer. Type C patients usually die in the second decade of life, but some with mild disease have a normal life span. ++ For a more detailed discussion, see Ari Zimran and Deborah Elstein: Gaucher Disease and Related Lysosomal Storage Diseases, Chap. 72 in Williams Hematology, 9th ed.