Gaucher disease

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

Epidemiology

Type 1 is the most common, affecting 1:500-1,000 Ashkenazi Jews and 1:50,000-100,000 of the general population ⁷. Types 2 and 3 are considered much rarer.

Clinical presentation

Age of presentation depends on the type of Gaucher disease:

• type 1 (most common form)

  • 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 2: evident by 6 months of age, with progressive neurological deterioration resulting in death by the age of 1 or 2

• type 3: presents with mild neurological complications by late adolescence or early childhood ⁶

Pathology

Classification

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

• type 1 (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 2 (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 3: type 1 with neurological involvement

Genetics

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.

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:

• osteopenia

• 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 Gaucher disease, halting the 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 Gaucher disease who cannot receive enzyme replacement therapy ⁸.

Complications

• osteonecrosis of the hip ⁸

• pathological fracture and pyogenic osteomyelitis ¹⁰

• lung involvement ⁸

  • pulmonary infiltration by Gaucher cells (type 2)

  • parenchymal infiltration with fibrosis (type 3)

  • pulmonary hypertension ¹²

• increased frequency of multiple myeloma, Parkinson disease and Lewy body dementia ⁸ 

• Gaucheromas: rare pseudotumours comprising a mass of Gaucher cells ¹¹

History and etymology

First described by French physician Philippe CE Gaucher (1854-1918) in 1882, while still a medical student ².