Gaucher disease

Gaucher disease (GD) is the most common lysosomal storage disease in humans. It is an autosomal recessive, multisystem disease arising from a deficiency of glucocerebrosidase or beta-glucosidase activity, resulting in accumulation of a glycolipid (glucocerebroside) within the lysosomes of macrophages, particularity in the bone marrow, spleen and liver.

Age of presentation depends on the type of Gaucher disease:

  • type I (most common form)
    • affects 1:500-1,000 Ashkenazi Jews and 1:50,000-100,000 of the general population 7
    • age of presentation varies widely, with the mean age of diagnosis being 21 years of age 6
    • some patients present in childhood while others remain asymptomatic throughout life
    • clinical presentation tends to be with skeletal symptoms (bone pain, pathological fractures, osteonecrosis and bone crises ) 4, hepatomegaly, splenomegaly and haematological disturbances
  • type II: evident by 6 months of age, with progressive neurological deterioration resulting in death by the age of 1 or 2
  • type III: presents with mild neurological complications by late adolescence or early childhood 6
Genetic changes

The glucosylceramide beta (GBA) gene provides instructions for making ß-glucocerebrosidase.  Mutations in the GBA gene reduce or eliminate the function of this lysosomal enzyme leading to a build up of toxic glucocerebroside and related substances in various tissues and organs 7.

Classification

Three types of Gaucher disease are described, each with different manifestations 1:

  • type I (non-neuropathic form or adult form): commoner type; progressive hepatomegalysplenomegaly, anaemia and thrombocytopenia, and marked skeletal involvement; lungs and kidneys may also be involved, but the CNS is spared
  • type II (acute neuropathic form or infantile form): severe progressive neurological involvement with death by 1 to 2 years of age; hepatomegalysplenomegaly, is also present (usually evident by 6 months of age)
  • type III: type I with neurological involvement
Plain radiograph

Skeletal involvement is seen in 70-100% of patients and primarily involves long bones (tibia, humerus, femur) as well as vertebrae. Ribs, hands and wrists, ankles and feet, and mandible may also be involved 6. Features of skeletal involvement include:

MRI
  • spleen
  • liver
    • hepatomegaly: less marked than the degree of splenomegaly
    • T2: hyperintense stellate areas representing inflammation and fibrosis 3
    • areas of hepatic ischaemia
  • skeletal system
    • long bones are most severely affected
    • reduced T1 and T2 signal from involved bone marrow (due to infiltration of Gaucher cells
    • bone marrow burden (BMB) score may be obtained from MRI images 4
    • may give a "salt and pepper pattern" due to scattered involvement
    • features of superimposed osteonecrosis
    • metaphyseal notching of humeri
    • pathological fractures
    • Erlenmeyer flask deformity

Enzyme replacement with macrophage-targeted glucocerebrosidase has been shown to be highly effective in Type 1 GD, halting progression and even reversing both bone marrow and visceral infiltration 5. Radiographically, hepatomegaly and splenomegaly respond more rapidly than skeletal changes.

Glucosylceramide synthase inhibitors are available for patients with Type 1 GD who cannot receive enzyme replacement therapy 8.

Complications
  • avascular necrosis (AVN) of the hip 8
  • lung involvement 8
    • pulmonary infiltration by Gaucher cells (type 2)
    • parenchymal infiltration with fibrosis (type 3)
  • increased frequency of multiple myeloma, Parkinson disease and Lewy body dementia 8 

First described by Philippe Gaucher (French doctor) in 1882 2.

Inborn errors of metabolism
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Article information

rID: 6574
Section: Pathology
Synonyms or Alternate Spellings:
  • Gaucher's disease
  • Gaucher disease (GD)

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Cases and figures

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    Case 1: splenomegaly
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    Case 2: with bone infarcts in pelvis
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