Philippe Charles Ernest Gaucher (go-shay) was the first to describe in France, 1882, the clinical syndrome which liver and spleen were enlarged with anemia and bone pain in a woman patient.
Gaucher Disease is the commonest inherited (genetic) Lysossomal Storage Disease. A defect in the enzyme called Glucocerebrosidase is the key point for disease.
Gaucher disease is transmitted as an autossomal recessive disorder. Although more than 50 different mutations have been already identified, just 4 specific mutations are responsible for 50% of cases. In addition, this disease is very heterogeneous. Patients with the same mutations can have different symptomatology or even a different type of disease (see below). As an autossomal disorder, males and females have the same chances for it.
The prevalence of type I Gaucher Disease in general population is 1/60.000 to 1/120.000 births. In the Ashkenazi Jewish population (jews of eastern european ancestry) the prevalence rise to 1/500 births with a rate for heterozygous about 1 in 10 jews. Type II Gaucher Disease has a prevalence lower than 1/100.000 births and type III lower than 1/50.000 births. Both seem to be pan-ethnic, Although descriptions of a subtype of type III disease are being made in Nerbottniam, Swedden.
Glucocerebroside is a lipid ( a by product) resulting from the normal recycling of red blood cells. Glucocerebrosidase is the enzyme which catalyzes his breakdown in glucose and ceramide into macrophages. A defect in this enzyme leads to the accumulation of glucocerebroside in the lysossomes of resident macrophages of tissues. These macrophages become lipid-engorged and dilated cells with eccentric nucleus. These modified macrophages are known as Gaucher’s Cells (Fig 1).
Gaucher’s cells can be found in the spleen, liver , bone marrow, lymphonodes, tonsils, thymus and peyer patches. The accumulation of Gaucher’s cells in bone marrow leads to an impairment of its function and replacement of the healthy cells causing bone pain and lesions, osteopenia, osteonecrosis, avascular necrosis and pathological fractures. The accumulation of GC in liver and spleen can lead to hepatosplenomegaly.
Type I - It is the most frenquent type found, mainly in Jews. It is also called Non-neuropathic or Adult form. The onset is most likely during adulthood, although it could be found in childhood. Painless splenomegaly is the most frequent early sign of disease and it is almost always present in all patients. Secondary pancytopenia and trombocytopenia are frequent. Anemia, easy bruising and bleeding can occur. Hepatomegaly often occurs beside splenomegaly and loose of hepatic function is not rare. Spleen volume increases up to 20 times the normal and liver volume up to 9 times the normal. Bone crises including pain, lesons, osteopenia, osteonecrosis, avascular necrosis, and pathological fractures are the most debilitating symptoms, however they are often unrecognized manifestations of Gaucher Disease. Primary Central Nervous System disease is absent . The lifespan range 6 to 80 years.
Type II - It is also known as Infant or Acute Neuropathic form. It is characterized by CNS complications. The onset of CNS problems occurs too early and it is usually fatal before the third year of life. Normally , did not have enough time for development of hepatosplenomegaly, but it is possible. Skeletal disease is absent.
Type III- It is also known as Sub Acute Neuropathic form. It is the intermediate form between Type I and Type II. The onset of symptoms is during childhood . Hepatomegaly, splenomegaly, and skeletal disease are present likely in Type I, but CNS symptoms are less severe than Type II. The lifespan range 2 to 60 years.The neurological symptoms are incoordination, mental deterioration, and myoclonic seizures.
The diagnosis of Gaucher Disease is confirmed by laboratorial tests. There are three methods of diagnosis that can be used:
Bone Marrow Biopsy- This a rapid and traditional procedure although invasive. The presence of Gaucher’s cells is indicative of disease. False negatives can occurs because Gaucher’s cells are sparsely distributed. Heterozygous can not be identified by this test.
Leukocyte and Beta-glucerebrosidase Enzyme Assay- This is the most important test that should be done. 30% lower of beta glucocerebrosidase activity at pH 4.0 compared with normal is diagnosis of Gaucher Disease. This test is important because it can identify patient enzyme activity , which is necessary to introduce an appropriated therapy ( to determinate the enzyme replacement dose).This test is not good for heterozygous detection.
DNA-Based Mutation Analysis- DNA analysis is of great value for all individuals with glucocerebrosidadse deficiency to confirm diagnosis, but is not predictive of clinical course. Hemorrhaging for the N370S mutations appears to preclude neuropathic involvement. This is the only test accurate to identify heterozygous.
Because the fundamental defect resides in mononuclear phagocyte cells originated from marrow stem cells, bone marrow transplantation was considered the best intervention for type I disease in any age. It still is the best choice for very severe disease.
Enzyme Replacement therapy is a relatively new treatment that can stop and reverse the symptoms of Gaucher Disease and improves quality of life. How it is a all life therapy, it becomes a very expensive procedure which the great majority of patients can’td afford whit it, however it is the best treatment until now.Good results in neurological symptoms of Type II disease after enzyme replacement are not recognized.
Splenectomies are now not commonly performed . It is usually reserved for certain situations such as when a patient with symptoms is unable to obtain enzyme replacement therapy or in those with extremely low platelet counts. These patients can have some relief of symptoms.
bibliography
1- Beutler E. Diagnosis and treatment of Gaucher’s Disease . AJDC. 1993; 147:1778
2- Borton N, et al. Replacement therapy for inherited enzyme deficiency - macrophage targeted glucocerebrosidase for Gaucher disease. NEJM. 1991; 324:1464-1470.
3- Beutler E, Kuhl W. The diagnosis of the adult type of Gaucher disease and its carrier state by demonstration of beta-glucosidase activity im peripheral blood leukocytes. J Lab Clin Med. 1970; 76: 747-755
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