Gaucher's disease

In medicine (hematology), Gaucher's disease (or Gaucher disease, pronounced "Go-shay") is a genetic disorder that affects platelets, white blood cells, the spleen, bones, and in Types II and III, the brain. It is the most common lysosomal storage disease. It is named after the French doctor who originally described it in 1882.

The disease is caused by a mutation in the gene for the enzyme acid β-glucosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside, in the spleen, liver, lungs, bone marrow, and, in rare cases, the brain.

Contents

1 Signs and symptoms 2 Diagnosis 3 Pathophysiology 4 Classification and genetics 5 Epidemiology 6 Treatment 7 History 8 References 9 External links

Signs and symptoms

• Painless hepatomegaly and splenomegaly; the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml.
• Hypersplenism: increased destruction of red and white blood cells and platelets, leading to anemia, neutropenia and thrombopenia (with an increased risk of infection and bleeding)
• Cirrhosis of the liver is rare
• Neurological symptoms occur only in some types of Gaucher's (see below):
  • Type II: serious convulsions, hypertonia, mental retardation, apnea.
  • Type III: myoclonus, convulsions, dementia, ocular muscle apraxia.
• Osteoporosis: 75% develop visible bony abnormalities due to the accumulated glucosylceramide. Erlenmeyer flask deformity of the distal femur.
• Yellowish-brown skin pigmentation
• No cardiac, renal and pulmonary signs

Diagnosis

In populations with high rates of carriage (Ashkenazi Jews and Norrbottnian Swedes), some family members of the index patient may already have been diagnosed with Gaucher's. Truly sporadic cases may suffer diagnostic delay due to the protean symptoms.

Biochemical abnormalities: high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels.

The diagnosis is made with genetic testing of the β-glucosidase gene. As there are numerous different mutations, sequencing of the gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor.

Pathophysiology

The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (also known as β-glucosidase, EC 3.2.1.45, 1OGS.PDB) on the first chromosome (1q21). The enzyme is a 55.6 KD, 497 amino acids long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopy as containing crumpled-up paper.

Different mutations in the β-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype.

In the brain (type II and III), glucocerebroside accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.

Research suggests that heterozygotes for particular acid β-glucosidase mutations are at an increased risk of Parkinson's disease (Aharon-Peretz et al 2004).

Classification and genetics

There are three recognized forms; all have been linked to particular mutations. In all, there are about 80 known mutations.

• Type I (N370S homozygote, the most common, also called the "non-neuropathic" type) occurs mainly (100x the general populace) in Ashkenazi Jews. It is mainly diagnosed in late childhood or early adulthood. Life expectancy is mildly decreased; there are no neurological symptoms. Dor Yeshorim, a non-profit testing organisation, therefore only tests patients on request.
• Type II (1 or 2 alleles L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomes. Prognosis is dismal: most die before reaching the third birthday.
• Type III (also 1-2 copies of L444P, possibly delayed by protective polymorphisms) occurs in Swedish patients from the Norrbotten region. This group develops the disease somewhat later, but most die before their 30th birthday.

All three types of Gaucher's disease are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of mutations.

Diaz et al (2000) suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).

Epidemiology

• The National Gaucher Foundation states that around 1 in 100 people in the general U.S. population is a carrier for type 1 Gaucher's disease, giving a prevalence of 1 in 1000: the rate of carriers is considerably higher, at roughly 1 in 14, among Ashkenazi Jews.
• Type 2 Gaucher's disease shows no particular preference for any ethnic group.
• Type 3 Gaucher's disease is notably common in the population of the Northern Swedish region of Norrbotten where the incidence of the disease is 1 in 50,000.

Treatment

Many patients can be completely asymptomatic and never be aware of the fact that genetically they have Gaucher's disease. A large proportion, however, requires supportive treatment (antibiotics for infections, blood transfusions for anemia, antiepileptics for seizures), splenectomy, liver transplants or bone marrow transplants (which may be curative, as it introduces a monocyte population with active β-glucosidase). Symptoms can improve markedly in type 1 patients using enzyme replacement therapy with mannose-terminated recombinant glucocerebrosidase, 60 Units/kg twice a month; spleen size and activity reduces, as well as improving blood counts and decreasing bony abnormalities. This treatment is becoming the gold standard in treating Gaucher's. Due to the low incidence, this has become an orphan drug in many countries. Gene therapy may be a future step.

There is currently no effective treatment for severe brain damage that may occur in patients with types 2 and 3.

History

Philippe Gaucher described the disease in his doctoral thesis in 1882. The biochemical basis for the disease would be elucidated in 1965 by Brady et al.

References

• Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the Glucocerebrosidase Gene and Parkinson's Disease in Ashkenazi Jews. N Engl J Med 2004;351:1972-1977. PMID 15525722.
• Barranger JA, Rice EO. Gaucher disease: diagnosis, monitoring and management. Gaucher Clin Persp 1997;5:1-6.
• Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides. II. Evidence of enzymatic deficiency in Gaucher's disease. Biochem Biophys Res Commun 1965;18:221. PMID 14282020.
• Charrow J et al. Gaucher disease, recommendations on diagnosis, evaluation and monitoring. Arch Intern Med 1998;158:1754-60.
• Diaz GA, Gelb BD, Risch N, Nygaard TG, Frisch A, Cohen IJ, Miranda CS, Amaral O, Maire I, Poenaru L, Caillaud C, Weizberg M, Mistry P, Desnick RJ. Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations. Am J Hum Genet 2000;66:1821-32. PMID 10777718.
• Gaucher PCE. De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie. Academic thesis, Paris, France, 1882.
• Template:OMIM (acid β-glucosidase), Template:OMIM (type I), Template:OMIM (type II), Template:OMIM (type III)

External links

• Public domain NINDS Gaucher's Disease Information Page (http://www.ninds.nih.gov/health_and_medical/disorders/gauchers_doc.htm)
• National Gaucher Foundation: Prevalence and transmission of Gaucher disease (http://www.gaucherdisease.org/prevalence.htm)de:Morbus Gaucher

fr:Maladie de Gaucher