ATAXIA-TELANGIECTASIA - LINKAGE ANALYSIS IN HIGHLY INBRED ARAB AND DRUZE FAMILIES AND DIFFERENTIATION FROM AN ATAXIA-MICROCEPHALY-CATARACT SYNDROME

Ataxia-telangiectasia (A-T) is a progressive autosomal recessive disea se featuring neurodegeneration, immunodeficiency, chromosomal instabil ity, radiation sensitivity and a highly increased proneness to cancer. A-T is ethnically widespread and genetically heterogeneous, as indica ted by the existence of four complementation groups in this disease. S everal "A-T-like" genetic diseases share various clinical and cellular characteristics with A-T. By using linkage analysis to study North Am erican and Turkish A-T families, the ATA (A-T, complementation group A ) gene has been mapped to chromosome 11q23. A number of Israeli Arab A -T patients coming from large, highly inbred families were assigned to group A. In one of these families, an additional autosomal recessive disease was identified, characterized by ataxia, hypotonia, microcepha ly and bilateral congenital cataracts. In two patients with this syndr ome, normal levels of serum immunoglobulins and alpha-fetoprotein, chr omosomal stability in peripheral blood lymphocytes and skin fibroblast s, and normal cellular response to treatments with X-rays and the radi omimetic drug neocarzinostatin indicated that this disease does not sh are, with A-T, any additional features other than ataxia. These tests also showed that another patient in this family, who is also mentally retarded, is affected with both disorders. This conclusion was further supported by linkage analysis with 11q23 markers. Lod scores between A-T and these markers, cumulated over three large Arab families, were significant and confirmed the localization of the ATA gene to 11q23. H owever, another Druze family unassigned to a specific complementation group, showed several recombinants between A-T and the same markers, l eaving the localization of the A-T gene in this family open.