Ataxia-Telangiectasia-Like Disorder 1

A number sign (#) is used with this entry because ataxia-telangiectasia-like disorder-1 (ATLD1) is caused by homozygous or compound heterozygous mutation in the MRE11A gene (600814) on chromosome 11q21.

Description

Ataxia-telangiectasia-like disorder-1 is an autosomal recessive disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia. Laboratory studies of patient cells showed increased susceptibility to radiation, consistent with a defect in DNA repair. The disorder shares some phenotypic features of ataxia-telangiectasia (AT; 208900), but telangiectases and immune deficiency are not present in ATLD1 (summary by Hernandez et al., 1993 and Stewart et al., 1999).

Genetic Heterogeneity of Ataxia-Telangiectasia-Like Disorder

See also ATLD2 (615919), caused by mutation in the PCNA gene (176740) on chromosome 20p12.

Clinical Features

Hernandez et al. (1993) reported a large inbred family in which 2 cousins presented with the same clinical features of ataxia-telangiectasia 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.

Delia et al. (2004) reported 2 Italian sibs with late-onset cerebellar degeneration that progressed slowly until puberty. The sibs had no telangiectasia or malignancy through their fourth decade.

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.

Chaki et al. (2012) reported 2 sibs, born of consanguineous Pakistani parents, with ataxia and cerebellar vermis hypoplasia. One patient had dysarthria and myoclonus. Although the patients studied were part of a larger group of patients with nephronophthisis (see, e.g., NPHP1, 256100) and related ciliopathies, neither sib had renal failure or retinal involvement. Chaki et al. (2012) noted that cerebellar vermis hypoplasia is a cardinal feature of NPHP-related ciliopathies.

Miyamoto et al. (2014) reported a 52-year-old woman who presented at age 9 years with progressive myoclonus of subcortical origin. She later developed tremor, and the myoclonus expanded to involve her entire body; medication was ineffective. At age 40, she developed mild walking instability consistent with ataxia. Cerebellar signs included dysmetria, dysdiadochokinesis, and dysarthria, but she did not have ocular apraxia or nystagmus, and brain imaging did not show cerebellar atrophy. Extraneurologic features were absent.

Inheritance

The transmission pattern of ATLD in the family reported by Hernandez et al. (1993) was consistent with autosomal recessive inheritance.

Molecular Genetics

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 the English family with ataxia-telangiectasia-like disorder originally reported by Klein et al. (1996), Pitts et al. (2001) identified a second mutation in the MRE11A gene (600814.0003).

In 2 Italian sibs with ATLD, Delia et al. (2004) identified compound heterozygosity for MRE11A mutations (600814.0003 and 600814.0004).

In 2 Pakistani sibs with ataxia and cerebellar vermis hypoplasia, Chaki et al. (2012) identified a homozygous mutation in the MRE11A gene (600814.0001). The mutation was found by homozygosity mapping and whole-exome sequencing. The report linked the pathogenesis of NPHP and ciliopathy to defects in DNA damage response signaling.

In a 52-year-old Japanese woman, born of consanguineous parents, with a relatively mild form of ATLD1 presenting as progressive myoclonic ataxia, Miyamoto et al. (2014) identified a homozygous missense mutation in the MRE11A gene (A47V; 600814.0006). The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. Western blot analysis of patient cells showed mildly decreased levels of MRE11A, RAD50 (604040), and NBS1 (NBN; 602667) that likely did not fully disrupt the MRN complex.