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.

Epidemiology and clinical presentation

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

Pathology

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 hepatomegaly, splenomegaly, 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; hepatomegaly, splenomegaly, is also present (usually evident by 6 months of age)
• type III: type I with neurological involvement

Radiographic features

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:

• osteopaenia
• osteonecrosis
• pathological/crush fractures
• endosteal scalloping
• Erlenmeyer flask deformities
• H-shaped vertebrae 
• paranasal sinus obliteration due to medullary expansion ⁹

MRI

• spleen
  • massive splenomegaly
  • splenic nodules (30%) ¹
  • splenic infarcts (33%)
• 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

Treatment and prognosis

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 

History and etymology

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