Chapter 37: Gaucher Disease and Related Lysosomal Storage Diseases

GLYCOLIPID STORAGE DISEASES

• 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

Etiology and Pathogenesis

• Result of a hereditary mutation in the GBA gene leading to dysfunction of a lysosomal enzyme, β-glucocerebrosidase, resulting in an accumulation of glucocerebroside.

• Inheritance is autosomal recessive, with high gene frequency among Ashkenazi Jews.

• More than 850 different mutations of the GBA gene have been reported.

• Among those of Ashkenazi Jewish origin, the predominant mutation is N370S, which accounts for approximately 75% of mutant alleles. This mutation occurs in 30% of non-Jewish patients. It usually gives rise to mild disease in the homozygous form.

• The second most common mutation is L444P, which when homozygous accounts for most patients with neuronopathic disease and is the most prevalent mutation in Asians, Arabs, and Norrbottnians.

Clinical Features

• Three types of Gaucher disease are recognized based on absence (type 1) or presence of neurologic features (types 2 and 3) (Table 37–1).

  — Type 1 occurs in both children and adults and is primarily caused by an accumulation of glucocerebroside-laden macrophages in the 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 surgical 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).