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Diagnosis of severe Type 1 Gaucher’s disease before irreversible damage occurs : is HDL cholesterol the answer?

Type 1 Gaucher disease is a pan ethnic condition but has a gene frequency of 1:17 in the Ashkenazi Jewish population [Horowitz et al, 1998]. The severity of type 1 Gaucher disease is variable. Most patients homozygous for the GBA N370S mutation have a milder disease, whereas many double heterozygotes show a more severe phenotype. Although many cases are asymptomatic there is a need for a test to diagnose cases that would benefit from enzyme replacement therapy before irreversible damage occurs, such as destruction of femoral heads, compression fractures of vertebrae, significant bleeding or fractures following bone crises. After receiving permission from local and national ethics committees we reviewed the high density lipoprotein (HDL) cholesterol blood levels in 60 of our Askenazi Jewish patients and found that all 34 patients with the more severe genotypes of the GBA gene (N370S/84GG, N370S/L444P, N370S/IV2+1 and N370S/V394L) had reduced HDL cholesterol levels below 1Æ0 mmol/l (Fig 1). They ranged between 0Æ34 and 0Æ98 mmol/l (13Æ4 and 38 mg/dl))(levels are considered reduced when <1Æ03mmol/l (40 mg/dl) in men and <1Æ30 mmol/l (50 mg/dl) in women) [Ashen & Blumenthal, 2005; ]. The levels of the 26 patients with the homozygous N370S/N370S genotype varied considerably, but 6 who had phenotypes severe enough to require enzyme replacement therapy had HDL cholesterol levels below 1Æ0 mmol/l. LDL and total cholesterol levels did not clearly delineate the high risk group. The association of low cholesterol levels and Gaucher disease has been noted [Ginsberg et al, 1984; Pocovi et al, 1998] but without mention of any correlation between cholesterol levels and genotype. Only physicians with experience in treating Gaucher disease seem to be aware that HDL cholesterol levels may be low in Gaucher patients. We hope that the knowledge of the significance of a low HDL cholesterol level in a patient with a clinical picture compatible with type 1 Gaucher disease will result in a referral for definitive testing to enable the diagnosis and treatment of Gaucher disease before irreversible complications occur.