Chapter 38: Lipid Storage Disease

In Gaucher and Niemann-Pick diseases, major clinical manifestations result from accumulation of glucocerebroside and sphingomyelin, respectively, in macrophages, leading to their massive expansion in tissues (see Fig. 38–1).

Etiology and Pathogenesis

• Glucocerebroside accumulates because of a deficiency of glucocerebrosidase (β-glucosidase).

• Very rarely a neuropathic form may be caused by a deficiency of saposin, a β-glucosidase cofactor.

• Inherited as an autosomal recessive disorder, with high gene frequency among Ashkenazi Jews.

• More than 100 different mutations have been reported, but the 5 mutations most common in Ashkenazi Jews account for more than 95 percent 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:

  — 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.

• Type 1 may be asymptomatic, or symptoms may range from minimal to severe:

  — Chronic fatigue is common.

  — Hepatic and/or splenic enlargement may cause significant (mechanical) problems.

  — Thrombocytopenia is a common presenting finding.

  — Skeletal lesions are often painful. "Erlenmeyer flask" deformity of the femur is common. Aseptic necrosis of femoral head and vertebral collapse may occur.

Laboratory Features

• Blood count may be normal, but normocytic, normochromic anemia with modest reticulocytosis is often found. Thrombocytopenia is common, particularly in patients with significant splenomegaly and may be severe.

• Leukocytes are deficient in acid β-glucosidase activity.

• 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.

• Serum acid phosphatase, chitotriosidase, ferritin, and hexosaminidase activities are commonly increased.

• Biochemical abnormalities as a consequence of liver involvement may be found.

• Serum monoclonal Ig spikes have an increased incidence in Gaucher disease patients over the age of 50 years.

• Acquired coagulation factor deficiencies (isolated coagulation factors) have been reported.

Diagnosis

• Established by demonstrating β-glucosidase deficiency in leukocytes or cultured fibroblasts.

• The most widely used biomarker is chitotriosidase, which is elevated, often several thousand-fold, in patients with Gaucher disease. Deficiency of chitotriosidase occurs in 6 percent of the population.

• It is not necessary or desirable to perform a marrow examination or liver biopsy to demonstrate the presence of Gaucher cells. Cells indistinguishable from Gaucher cells are seen in other diseases, including chronic myeloproliferative disorders, Hodgkin lymphoma, myeloma, and AIDS.

• Demonstration of specific DNA abnormalities will establish the diagnosis, but negative studies do not rule it out unless the entire coding region is sequenced.

• Prenatal diagnosis can be made by examination of cells obtained by amniocentesis or chorionic villus biopsy.

• Heterozygosity may be assumed by assay of acid β-glucosidase activity in leukocytes or fibroblasts, but DNA analysis is the only reliable method.

Therapy

• Enzyme replacement therapy with recombinant human β-glucosidase (imiglucerase) has been successful. It is very expensive. New enzymes will come to the market soon.

• Notwithstanding the manufacturer's recommendations, the enzyme should not be given to asymptomatic adults to "prevent progression" because progression rarely occurs.

• The enzyme is usually infused at bi-weekly intervals, but weekly or monthly infusions can be effective as well.

• The total dose is usually 30 to 120 U/kg per month for type 1 patients. Higher doses relate to quicker responses, but are not needed for the majority of patients. Maintenance dose can be as low as 15 to 30 U/kg per month.

• Type 3 patients are treated with 60 to 120 U/kg per month. Enzyme replacement therapy does not affect neurologic disease. Type 2 should not be treated with enzyme replacement therapy.

• The response normally requires 6 months or more. The response can be monitored by an (impressive) reduction in liver and spleen size, and improvement or correction of cytopenias. The bone response is slower and less predictable.

• Chitotriosidase measurement is useful for monitoring both untreated patients, to assess stability versus deterioration, and treated patients, to assess response to therapy. A change in chitotriosidase levels rather than absolute values is used for monitoring.

• Escalation of doses to attempt to achieve a more rapid response is commonly recommended, but has not been demonstrated to be useful.

• In patients who are not suitable for enzyme replacement therapy, oral substrate reduction therapy using 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 endoplasmatic reticulum to the lysosome.

• Splenectomy (since introduction of enzyme replacement treatment less often performed) generally corrects anemia and thrombocytopenia caused by hypersplenism but may cause more rapid deposition of lipid in liver and marrow.

• 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 and 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.

Etiology and Pathogenesis

• Inherited as an autosomal recessive disorder.

• 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.

Clinical Features

• Type A disease has onset in infancy with poor growth and neurologic manifestations.

• Type B disease usually presents with hepatosplenomegaly ordinarily 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

Niemann-Pick Types A and B

• Mild anemia may be present.

• Blood lymphocytes typically contain small, lipid-filled vacuoles.

• Leukocytes 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 94 percent of individuals with NPC.

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.

• Most patients with type B disease reach adult life.

• Type C patients either die during infancy or have a protracted course with neurologic deterioration.