Gaucher's disease

Gaucher's disease
Synonyms	Glucocerebrosidase deficiency, Gaucher disease
Pronounce	or
Field	Medical genetics, Hematology
Symptoms	Hepatosplenomegaly, anemia, thrombocytopenia, bone pain, fatigue, growth retardation, easy bruising
Complications	Bone crises, osteonecrosis, lung disease, Parkinson's disease, liver dysfunction
Onset	Typically childhood to early adulthood, varies by type
Duration	Lifelong
Types	Type 1 (non-neuronopathic), Type 2 (acute neuronopathic), Type 3 (chronic neuronopathic)
Causes	Mutation in GBA gene → deficiency of glucocerebrosidase
Risks	Ashkenazi Jewish ancestry, family history
Diagnosis	Enzyme assay, genetic testing, bone marrow biopsy, imaging for organomegaly
Differential diagnosis	Niemann–Pick disease, multiple myeloma, leukemia, lymphoma
Prevention	None; genetic counseling available for at-risk individuals
Treatment	Enzyme replacement therapy, substrate reduction therapy, supportive care
Medication	Imiglucerase, velaglucerase alfa, taliglucerase alfa, eliglustat, miglustat
Prognosis	Varies by type; Type 1 has good prognosis with treatment, Types 2 and 3 more severe
Frequency	~1 in 50,000 to 100,000 globally; 1 in 850 in Ashkenazi Jews (carrier frequency ~1 in 15)
Deaths	Rare in Type 1; more common in Types 2 and 3 if untreated

Sphingolipidoses

Gaucher disease - very high magnification

Gaucher's disease (GD) is a hereditary genetic disorder resulting in the accumulation of glucocerebroside in cells and various organs. This accumulation leads to a range of symptoms and complications, including bruising, fatigue, and organ enlargement.

Definition

Gaucher's disease is characterized by an abnormal buildup of glucocerebroside in cells due to a hereditary deficiency of the enzyme glucocerebrosidase. The enzyme's defect results in glucocerebroside accumulation, notably in white blood cells, particularly macrophages (mononuclear leukocytes), leading to organ complications and other health issues.

Clinical Presentation

Affected individuals may experience:

• Enlarged spleen and liver
• Liver malfunction
• Skeletal disorders or bone lesions causing pain
• Neurological complications
• Swelling of lymph nodes and adjacent joints
• Brownish skin pigmentation
• Anemia, and low blood platelet count
• Yellow fatty deposits on the white of the eye (sclera)
• Increased susceptibility to infections

Treatment

While the disease is hereditary, some forms can be treated using enzyme replacement therapy, offering hope for symptom alleviation and quality of life improvement.

Genetic Factors

The root cause of Gaucher's disease is a recessive mutation in the GBA gene on chromosome 1. This mutation affects both males and females indiscriminately. Among Ashkenazi Jews, the carrier rate is significantly higher than in the general population.

Epidemiology

Gaucher's disease is recognized as the predominant lysosomal storage disease, with dysfunctional sphingolipid metabolism playing a crucial role.

History

The disease derives its name from the French physician Philippe Gaucher, who first detailed the condition in 1882.

Types and Symptoms

The disease can be classified into three primary types, each exhibiting unique symptoms:

• Type I: Impaired olfaction and cognition.
• Type II: Presents severe neurological symptoms in children, including convulsions, hypertonia, intellectual disability, and apnea.
• Type III: Symptoms include muscle twitches, convulsions, dementia, and ocular muscle apraxia.

Moreover, studies have shown a higher prevalence of Parkinson's disease in patients with Gaucher's disease and their carrier relatives.

Genetics

The disease's inheritance pattern is autosomal recessive. For a child to be affected, both parents need to be carriers. If this is the case, there's a 25% likelihood with each pregnancy for the child to be affected. Genetic counseling and testing are paramount for potential carriers.

Pathophysiology

The disease stems from a defect in the housekeeping gene for lysosomal glucocerebrosidase located on the first chromosome. The defective enzyme cannot breakdown glucocerebroside, causing it to accumulate. As a result, macrophages, which usually clear these cells, turn into 'Gaucher cells' that under light microscopy resemble crumpled paper.

See also

• Niemann–Pick disease
• Fabry disease
• Tay–Sachs disease
• Krabbe disease
• Metachromatic leukodystrophy
• Medical genetics of Ashkenazi Jews
• List of radiographic findings associated with cutaneous conditions

External links

• Gaucher Disease at NINDS

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