Enfermedad de Gaucher

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 acid beta-glucocerebrosidase causes widespread accumulation of glucosylceramide-laden macrophages.

• Glucosylceramide accumulation is widespread, including the bone marrow, liver, spleen and lungs. Central nervous system (CNS) 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; 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 five years of life are frequently non-Jewish and typically have a more malignant disease course.²

  • Type 2 (rare) - infantile form (acute neuronopathic). This causes rapidly progressive neurovisceral storage disease and death during infancy.³

  • Type 3 - juvenile or Norrbottnian form (chronic or subacute neuronopathic). This is less rapidly progressive neurovisceral storage disease, causing death in childhood or early adulthood.⁴

Epidemiología

• All three 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 as high as 1 in 855.⁵

• 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.

Presentación⁶⁷

Type 1 Gaucher's disease

• May present with chronic fatigue, hepatomegaly, splenomegaly (may become massive), and bone involvement (bone pain due to bone infarcts or pathological fractures due to osteopenia) and may bruise easily or present with nosebleeds, 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 two 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 - eg, increased tendon reflexes.

• It has been further classified as type 3a (with progressive myotonia and dementia) and type 3b (with isolated supranuclear gaze palsy) based on the extent of neurological involvement.

Diagnóstico diferencial

• Any other cause of hepatosplenomegaly, thrombocytopenia, bone pain and osteopenia (type 1).

• Any other cause of neurodevelopmental delay (types 2 and 3).

Investigaciones

General assessment

• FBC and differential (assess the degree of pancytopenia); LFTs (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. CXR to evaluate pulmonary manifestations.

• Ultrasonography of the abdomen: determine extent of organomegaly.

• MRI scanning is more accurate in determining organ size and involvement.

• Patients with neuronopathic forms also need MRI scan of the brain, electroencephalogram (EEG) and diagnostic brainstem-evoked responses.

• Dual-energy X-ray absorptiometry (DEXA) scanning: evaluation of osteopenia.

Diagnóstico

• Acid beta-glucosidase activity: this can be measured in peripheral blood leukocytes or cultured skin fibroblasts to confirm diagnosis.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 four mutations (N370S, 84GG, L444P, IVS2+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). This is not now the initial diagnostic test, as the blood enzyme test is sensitive, specific, and much less invasive.

Diagnóstico prenatal

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

Manejo⁶⁸

Management options include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), although bone marrow transplantation and gene therapy have been used (in rare cases). Management also includes treatment of complications such as anaemia, thrombocytopenia, bleeding tendency, skeletal disease, liver or lung involvement and organomegaly.

Three different human recombinant enzymes are available: imiglucerase, velaglucerase alfa and taliglucerase alfa. Improvement in bone marrow and in the osseous skeleton in response to ERT occurs more slowly than the visceral and haematological responses. Increase of bone mineral density in response to ERT can take up to eight years. Pathological damage such as osteonecrosis, bone infarctions and fractures are clearly irreversible. Bisphosphonates can be effective to increase bone density and prevent complications. Supportive management for bone pains or bone crises is frequently required and orthopaedic surgery may be needed for pathological fractures or osteonecrosis.

Substrate synthesis inhibition therapy is an alternative approach, based on reduced synthesis of glucosylceramide by inhibiting the appropriate synthetic enzyme (glucosylceramide synthase). Miglustat was approved in 2002 for patients with mild-to-moderate Gaucher's disease. However, adverse effects related to the use of miglustat limited its acceptance. Eliglustat is a new agent with a better safety profile and higher potency than miglustat.

Bone marrow transplantation may be an effective treatment for neurological progression in this disorder. However, there is significant morbidity and mortality and therefore it is not currently recommended in the management of neuronopathic Gaucher's disease. Gene therapy may offer the possibility of definitive therapy in the future.¹

Complicaciones⁷⁸

• Avascular necrosis of the hip and bone crises (secondary to infarcts).

• Splenic rupture (from trauma).

• Cirrhosis - rare.

• Rarely, pulmonary infiltration by Gaucher cells may lead to overt lung disease.

• Haematological abnormalities are common - eg, anaemia, thrombocytopenia and leukopenia.

• Immunological abnormalities are also common - eg, hypergammaglobulinaemia, T-lymphocyte deficiency in the spleen and impaired neutrophil chemotaxis.

Pronóstico⁷⁸

• 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.