Gaucher's disease

Gaucher's disease (pronounced go?e?) is the most common of the lipid storage diseases. It is caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside. Fatty material can collect in the spleen, liver, kidneys, lungs, brainand bone marrow. Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disordersand bone lesions that may cause pain, severe neurologiccomplications, swelling of lymph nodesand (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood plateletsand yellow spots in the eyes. Persons affected most seriously may also be more susceptible to infection. The disease affects males and females equally. It is the most common lysosomal storage disease. It is named afterthe Frenchdoctor who originally described it in 1882.

Subtypes

Gaucher disease has three common clinical subtypes. Type 1 (or nonneuropathic type) is the most common form of the disease. It occurs most often among persons of Ashkenazi Jewishheritage. Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen, which can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. The brain is not affected, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruiseeasily and experience fatigue due to low blood platelets. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms. Type 2 (or acute infantile neuropathic Gaucher disease) typically begins within 3 months of birth. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2. Type 3 (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live to their early teen years and often into adulthood.

Signs and symptoms

• Painless hepatomegalyand splenomegaly; the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml.
• Hypersplenism: increased destruction of redand white blood cellsand platelets, leading to anemia, neutropeniaand thrombopenia(with an increased risk of infectionand bleeding)
• Cirrhosisof the liver is rare
• Neurologicalsymptoms 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 (AshkenaziJews and NorrbottnianSwedes), 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 immunoglobulinlevels.

The diagnosis is made with genetic testingof 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

Image:Acid beta glucosidase.pngThe disease is caused by a defect in the housekeeping genelysosomal gluco-cerebrosidase (also known as β-glucosidase, EC3.2.1.45, PDB1OGS) on the first chromosome(1q21). The enzymeis a 55.6 KD, 497 amino acidslong protein that catalyses the breakdown of glucocerebroside, a cell membraneconstituent of red and white blood cells. The macrophagesthat clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopyas 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 lipidsduring brain development and the formation of the myelin sheathof 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 allelesL444P) 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 Swedishpatients from the Norrbottenregion. 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 recessivefashion. 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 counselingand genetic testingis 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 Norrbottenwhere the incidence of the disease is 1 in 50,000.

Treatment

For type 1 and most type 3 patients, enzyme replacement treatmentwith mannose-terminated recombinantglucocerebrosidase, 60 Units/kg, given intravenouslyevery two weeks can dramatically decrease liverand spleensize, reduce skeletal abnormalities, and reverse other manifestations. This treatment is becoming the gold standardin treating Gaucher's. Due to the low incidence, this has become an orphan drugin many countries. Successful bone marrow transplantationcures the non-neurological manifestations of the disease, because it introduces a monocytepopulation with active β-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient?s comfort. Blood transfusionmay benefit some anemic patients. Other patients may require joint replacementsurgery to improve mobility and quality of life. Other treatment options include antibioticsfor infections, antiepilepticsfor seizures and liver transplants. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease. Gene therapymay be a future step.

Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoningsince the crystal structure of glucocerebrosidaseis known.

History

Philippe Gaucherdescribed the disease in his doctoral thesisin 1882. The biochemical basis for the disease would be elucidated in 1965by 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 Med2004;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.
• OMIM606463(acid β-glucosidase), OMIM230800(type I), OMIM230900(type II), OMIM231000(type III)

External links

• Public domain NINDS Gaucher's Disease Information Page
• National Gaucher Foundation: Prevalence and transmission of Gaucher diseasede:Morbus Gaucher

fr:Maladie de Gaucher ja:?????

This article is licensed under the GNU Free Documentation License.
It uses material from the http://en.wikipedia.org/wiki/Gaucher%27s+disease Wikipedia article Gaucher's disease.