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Gaucher's Disease

Gaucher's disease (GD) is a genetic disorder marked by the accumulation of glucocerebroside, a type of sphingolipid, in various organs and cells due to a deficiency of the enzyme glucocerebrosidase. This condition predominantly affects macrophages, leading to their transformation into 'Gaucher cells,' which are characterised by a crumpled paper-like appearance under light microscopy.

Acid beta-glucosidase
Acid beta-glucosidase

Signs and Symptoms

Gaucher's disease manifests in various ways, with common features including bruising, fatigue, anaemia, low blood platelet count, and organomegaly, particularly of the liver and spleen. The spleen can enlarge considerably, increasing the risk of rupture and compressing the stomach, thus impacting appetite. Bone and joint pain, especially in the hips and knees, are also frequent. Neurological symptoms vary by type:

  • Type I: Impaired olfaction and cognition.
  • Type II: Severe convulsions, hypertonia, intellectual disability, and apnoea.
  • Type III: Myoclonus, convulsions, dementia, and ocular muscle apraxia.

Other symptoms include osteoporosis, jaundice, and susceptibility to infections. Notably, patients and carriers have an elevated risk of Parkinson's disease and possibly myeloma.

Genetics

Gaucher's disease is autosomal recessive, requiring both parents to be carriers for a child to be affected. The disease is linked to mutations in the GBA gene on chromosome 1, with over 80 known mutations grouped into three types:

  • Type I (N370S homozygote): The most common, affecting Ashkenazi Jews predominantly. It is non-neuropathic with a median diagnosis age of 28 and a mildly decreased life expectancy.
  • Type II (L444P allele): Characterised by severe neurological issues in early childhood, with most affected children dying before age three.
  • Type III (L444P allele): More common in Swedish individuals from the Norrbotten region, with later onset but a shortened lifespan, usually not beyond 30 years.

Pathophysiology

The disease results from defective glucocerebrosidase, leading to glucocerebroside accumulation in macrophages. This defect causes these cells to engorge and display a crinkled paper-like appearance under microscopy.

Micrograph showing crinkled paper macrophages in the bone marrow space in a case of Gaucher disease, H&E stain.
Micrograph showing crinkled paper macrophages in the bone marrow space in a case of Gaucher disease, H&E stain.

The mechanisms leading to neurotoxicity are not fully understood but may involve glucosylsphingosine accumulation. Other suggested mechanisms include ER stress, altered lipid composition, and inflammation due to cytokine secretion.

Diagnosis

Diagnosis is based on clinical presentation and confirmed through enzyme testing, revealing glucocerebrosidase activity below 15% of normal. Genetic testing can confirm the diagnosis by identifying specific mutations. Biochemical markers such as high alkaline phosphatase, angiotensin-converting enzyme, and chitotriosidase levels are also indicative.

Classification

Gaucher's disease is classified into three main types:

  • GD Type I: Non-neuropathic, affecting the liver, spleen, and bones, with patients living into adulthood.
  • GD Type II: Acute infantile neuropathic, leading to severe brain damage and death by age two.
  • GD Type III: Chronic neuropathic, with milder and slower progression of neurological symptoms, typically leading to a lifespan into early adulthood.

Treatment

Treatment for type I and most type III cases involves enzyme replacement therapy with recombinant glucocerebrosidase, which can reduce organ size, skeletal abnormalities, and other symptoms. Approved therapies include imiglucerase, velaglucerase, and taliglucerase alfa. Substrate reduction therapy with miglustat or eliglustat is another approach, aiming to decrease the production of glucocerebroside.

Epidemiology

Gaucher's disease occurs in about 1 in 20,000 live births. The carrier frequency in the general population is about 1 in 100, while it is significantly higher among Ashkenazi Jews at 1 in 15. Type II shows no ethnic preference, whereas type III is prevalent in the northern Swedish population.

History

First described by Philippe Gaucher in 1882, the disease's inheritance pattern was identified in 1902. The biochemical basis was elucidated in the 1960s, leading to the development of effective treatments like alglucerase and its improved version, imiglucerase, approved by the FDA in 1991 and 1994, respectively.

Prominent People with Disease

  • Wallace Chapman: New Zealand radio and television personality.
  • Anne Begg: Scottish politician.
  • Adam Rose: American actor.

Self-assessment MCQs (single best answer)

What enzyme deficiency causes Gaucher's disease?



Which type of Gaucher's disease is most common among Ashkenazi Jews?



What is the inheritance pattern of Gaucher's disease?



Which organ is primarily affected and can enlarge considerably in Gaucher's disease?



Gaucher cells in Gaucher's disease are characterised by what appearance under light microscopy?



What is a common neurological symptom in Type II Gaucher's disease?



Which biochemical marker is typically elevated in Gaucher's disease?



What is the primary treatment for Type I Gaucher's disease?



What is the frequency of Gaucher's disease in the general population?



Which gene is mutated in Gaucher's disease?



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