Gaucher's Disease

Synonyms; glucocerebrosidase deficiency; acid beta-glucosidase deficiency

Gaucher’s disease is the most common lysosomal storage disease and is caused by insufficient activity of the lysosomal enzyme acid beta glucosidase (glucocerebrosidase) leading to the deposition of glucocerebroside in cells of the macrophage-monocyte system.¹

• Deficiency of a specific lysosomal hydrolase, acid beta-glucocerebrosidase, causes widespread accumulation of glucosylceramide-laden macrophages.
• Glucosylceramide accumulation is widespread, including in the bone marrow, liver, spleen and lungs. Central nervous system involvement only occurs in patients with disease type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) Gaucher’s disease.² There are three clinical subtypes:
  • Type 1: adult or non-neuronopathic form.
    • Often presents in childhood with hepatosplenomegaly, pancytopenia, and skeletal disease.
    • The severity of type 1 Gaucher’s disease is extremely variable, such that some patients present in childhood with virtually all the complications of Gaucher’s disease, while others are asymptomatic into the eighth decade.
    • Patients diagnosed in the first 5 years of life are frequently non-Jewish and typically have a more malignant disease course.²
  • Type 2 (rare): Infantile form (acute neuronopathic). Causes rapidly progressive neurovisceral storage disease and death during infancy.³
  • Type 3: Juvenile or Norrbottnian form (chronic or subacute neuronopathic). Less rapidly progressive neurovisceral storage disease, causing death in childhood or early adulthood.⁴

• All 3 subtypes are inherited as autosomal recessive traits.
• The overall frequency of Gaucher’s disease variants is about 1 in 40,000 to 1 in 50,000 live births.¹
• Type 1 Gaucher’s disease is frequent among Jewish people of Eastern European origin; the carrier frequency in these individuals is approximately 1 in 15, whereas the disease frequency is 1 in 8555.
• Many Type 1 affected individuals never come to medical attention, contributing to an underestimation of frequency.
• Neuronopathic forms (Types 2 and 3) are the rarest variants of Gaucher’s disease, with an estimated incidence of fewer than 1 in 100,000 live births.⁵

Type 1 Gaucher’s disease

• May present with chronic fatigue, hepatomegaly, splenomegaly (may become massive), bone involvement (bone pain due to bone infarcts or pathological fractures due to osteopenia) and may bruise easily or present with nose bleeds, bruising and petechiae (because of thrombocytopenia).
• Short stature and wasting occasionally are found in patients with massive organomegaly.
• Occasionally present with pulmonary infiltration or portal hypertension.

Type 2 Gaucher’s disease

• Presents in infancy, with increased tone, strabismus, and organomegaly. Failure to thrive and stridor (due to laryngospasm) are also common.
• Rapid neurodegenerative course with extensive visceral involvement and death (usually caused by respiratory problems) within the first 2 years of life.

Type 3 Gaucher’s disease

• Presents in infancy or childhood. In addition to organomegaly and bony involvement, neurological involvement is present, including developmental delay and abnormal neurological findings, e.g. increased tendon reflexes.
• Has been further classified as type 3a (with progressive myotonia and dementia) and 3b (with isolated supranuclear gaze palsy) based on the extent of neurological involvement.

• Any other cause of hepatosplenomegaly, thrombocytopenia, bone pain and osteopenia (Type 1).
• Any other cause of neurodevelopmental delay (Types 2 and 3).

General assessment

• Full blood count and differential (assess the degree of pancytopenia), liver function tests (minor elevations of liver enzymes are common but jaundice is a poor prognostic indicator).
• Skeletal radiography can detect and evaluate skeletal manifestations of Gaucher’s disease. Chest x-ray to evaluate pulmonary manifestations.
• Ultrasonography of the abdomen: determine extent of organomegaly.
• MRI is more accurate in determining organ size and involvement.
• Patients with neuronopathic forms also need MRI scan of the brain, EEG and diagnostic brain stem evoked responses.⁵
• Dual-energy x-ray absorptiometry (DEXA) scanning: evaluation of osteopenia.

Diagnosis

• Acid beta-glucosidase activity: diagnosis can be confirmed by measurement of acid beta-glucosidase activity in peripheral blood leucocytes or cultured skin fibroblasts.¹ Heterozygotes have half-normal enzyme activity, but there is an overlap with non-affected controls.
• Acid beta-glucosidase genotyping: molecular diagnosis can be helpful, especially in Ashkenazi patients, in whom 4 mutations (N370S, 84GG, L444P, IVS 2 1) in the acid beta-glucosidase gene account for nearly 97% of disease alleles.
• Bone marrow aspiration: diagnosis may be suggested by the finding of classic glycolipid-laden macrophages (Gaucher cells). Not now the initial diagnostic test, as the blood enzyme test is sensitive, specific, and much less invasive.⁶

Prenatal diagnosis

• There is carrier-screening for individuals of Ashkenazi Jewish descent to identify couples at risk of having a child affected with Gaucher’s disease.

• Enzyme replacement therapy (ERT) with macrophage-targeted recombinant human glucocerebrosidase (imiglucerase) is administered as enzyme replacement therapy for non-neurological manifestations of type I or type III Gaucher’s disease.⁵
• ERT is very effective in reversing the visceral and haematological manifestations of Gaucher’s disease, but skeletal disease is slow to respond. In patients with established acute neuronopathic disease, enzyme replacement therapy has had little effect on the progressively downhill course.
• Miglustat, an inhibitor of glucosylceramide synthase, is licensed for the treatment of mild to moderate type I Gaucher’s disease in patients for whom imiglucerase is unsuitable. It has been shown to help with the symptoms of mild to moderate Type 1 Gaucher’s disease.⁷
• Responses to miglustat are slower and less robust than those observed with ERT, and miglustat may produce significant side effects. Miglustat is currently in trials in combination with ERT to assess whether it will help to reduce some of the neurological deterioration in Type 3 Gaucher’s Disease.⁸
• Bone marrow transplantation may be an effective treatment for neurological progression in this disorder. However, there is significant morbidity and mortality, and therefore not currently recommended in the current management of neuronopathic Gaucher’s disease.⁹
• Gene therapy may offer the possibility of definitive therapy in the future.^1,10
• Supportive treatment for specific organ involvement.
• There is evidence that, in neuronopathic Gaucher’s disease, complete or partial splenectomy is associated with increased severity and rate of progression of neurological and bone involvement and increased risk of infection.⁵

• Bone: Avascular necrosis of the hip, bone crises (secondary to infarcts).
• Splenic rupture (from trauma).
• Cirrhosis is rare.
• Rarely, pulmonary infiltration by Gaucher cells may lead to overt lung disease.
• Haematologic abnormalities (e.g. anaemia, thrombocytopenia, and leucopenia) are common.
• Immunological abnormalities (e.g. hypergammaglobulinaemia, T-lymphocyte deficiency in the spleen and impaired neutrophil chemotaxis) are also common.

• Type 1: very variable disease severity.
• Type 2 (acute neuronopathic): rapidly progressive with death during infancy.
• Type 3 (subacute neuronopathic): less rapidly progressive neurovisceral involvement, causing death in childhood or early adulthood.