GENETICS AND BIOCHEMISTRY OF CREUTZFELDT-JAKOB-DISEASE IN LIBYAN JEWS

A focus of Creutzfeldt-Jakob disease (CJD) among Jews from Libyan orig in was identified in Israel 20 years ago. The incidence of the disease in this ethnic group is about 100 times more than in the worldwide po pulation. The consumption of lightly cooked sheep brain has been invok ed to explain the high incidence of CJD in this community. The discove ry of mutations in the PrP gene which segregates with other familial p rion diseases such as Gerstmann-Straussler syndrome (GSS) lead us to p erform a molecular genetic study and compare it to an epidemiological survey among the Libyan community. The epidemiological data suggests a very high familial incidence of CJD in this population and a molecula r genetic research elucidated that CJD segregates with a point mutatio n at codon 200 of the PrP gene resulting in the substitution of Lysine for Glutamate. This mutation was found in some 40 CJD patients of Lib yan origin and was not found in one Moroccan Jew suffering from CJD. I t was also absent in almost 100 healthy Libyan controls above the age of 60. This result strongly supports a genetic etiology for CJD pathog enesis in the Libyan Jewish community and disregards the previous culi nary hypothesis. The disease is vertically transmitted in autosomal do minant inheritance with unknown penetrance. All our patients were hete rozygote for the mutation except one homozygote patient. The course of the disease in this patient was identical to the heterozygote patient s, strongly arguing that inherited CJD displays complete phenotypic do minance. We examined the presence of PrP in cerebrospinal fluid (CSF), fibroblasts and leukocytes derived from eight CJD patients with the c odon 200 mutation. In patients' CSF, only negligible higher concentrat ion of the normal protein was found as compared to normal CSF. In cult ured fibroblasts as well as leukocytes, there was a significant increa se in PrP as judged by immunoblotting. Most of the PrP present in fibr oblasts and leukocytes could be released from the external surface by phosphatidylinositol-specific phospholipase C, a property characterist ic of PrPC. In leukocytes only, part of the protein was protease resis tant, resembling PrPCJD. The concentration of PrP mRNA was similar in fibroblast lines derived from controls and from CJD patients. These re sults suggest that in CJD patients carrying a mutation at codon 200 of the PrP gene, the metabolism of PrP, rather than PrP synthesis, is ab normal.