| #604391 | ||||||||||||||||||
| ATAXIA-TELANGIECTASIA-LIKE DISORDER; ATLD | ||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that this phenotype results from mutation in the MRE11A gene (600814). Hernandez et al. (1993) reported a large inbred family in which 2 cousins presented with the same clinical features of ataxia-telangiectasia (AT; 208900) but with a somewhat milder clinical course. Both patients were still ambulatory at ages 25 and 20 years. Cellular features of both patients were typical of AT and included increased radiosensitivity and an increased level of spontaneously occurring chromosome aberrations in peripheral blood lymphocytes. Linkage studies and haplotype analysis showed no clear evidence that the gene for AT in this family is located on 11q22-q23, suggesting further locus heterogeneity in AT. In 2 families clinically diagnosed with AT and previously reported by Hernandez et al. (1993) and Klein et al. (1996), respectively, Stewart et al. (1999) identified mutations in the MRE11A gene (600814.0001 and 600814.0002). Consistent with the clinical outcome of these mutations, cells established from the affected individuals within the 2 families exhibited many of the features characteristic of both AT and Nijmegen breakage syndrome (251260), including chromosomal instability, increased sensitivity to ionizing radiation, defective induction of stress-activated signal transduction pathways, and radioresistant DNA synthesis. The authors designated the disorder ATLD, for AT-like disorder. Because the MRE11A gene maps to 11q21 and the gene mutated in AT, ATM, maps to 11q23, Stewart et al. (1999) concluded that only a very detailed linkage analysis would separate ATLD from AT purely on the basis of genetic data. Assuming that the mutation rate is proportional to the length of the coding sequences of the 2 genes, they suggested that approximately 6% of AT cases might be expected to have MRE11A mutations. In an English family with ataxia-telangiectasia-like disorder originally reported by Klein et al. (1996), Pitts et al. (2001) identified heterozygosity for a nonsense mutation (600814.0003). In 2 Italian sibs with late-onset cerebellar degeneration that progressed slowly until puberty, absence of telangiectasia, and absence of malignancy through their fourth decade, Delia et al. (2004) identified compound heterozygosity for MRE11A mutations (600814.0003 and 600814.0004). Fernet et al. (2005) described 10 patients from 3 unrelated Saudi Arabian families with ataxia telangiectasia-like disorder. They presented with an early-onset, slowly progressive, ataxia plus ocular apraxia phenotype with an absence of tumor development, even in the oldest 37-year-old patient. Extraneurologic features, such as telangiectasia, raised alpha-fetoprotein, and reduced immunoglobulin levels, were absent. All patients were homozygous for a missense mutation (600814.0005) in the MRE11A gene. | ||||||||||||||||||
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