Ataxia-telangiectasia-like disorder-2 is an autosomal recessive syndrome resulting from defects in DNA excision repair. Affected individuals have a neurodegenera...
Ataxia-telangiectasia-like disorder-2 is an autosomal recessive syndrome resulting from defects in DNA excision repair. Affected individuals have a neurodegenerative phenotype characterized by developmental delay, ataxia, and sensorineural hearing loss. Other features include short stature, cutaneous and ocular telangiectasia, and photosensitivity (summary by Baple et al., 2014).
For a discussion of genetic heterogeneity of ATLD, see ATLD1 (604391).
▼ Clinical Features
Baple et al. (2014) reported 4 patients between 11 and 31 years of age from an extended Ohio Amish family with a neurodegenerative syndrome. The main features included delayed development or learning difficulties, prelingual sensorineural hearing loss, progressive gait instability and ataxia, progressive muscle weakness, dysarthria, dysphagia, and cognitive decline with age. All patients had short stature (-3.8 to -5.2 SD), and the 2 oldest patients never underwent a pubertal growth spurt. Other features included cutaneous and conjunctival telangiectasia, photophobia, and photosensitivity, with evidence of predisposition to sun-induced malignancy in 1 patient. Another patient showed premature aging. Brain MRI of 1 patient revealed cerebellar atrophy. The features were reminiscent of syndromes caused by DNA repair defects, such as xeroderma pigmentosum (see, e.g., XPA; 278700), Cockayne syndrome (see, e.g., CSA; 216400), and ataxia-telangiectasia (AT; 208900). None of the patients reported by Baple et al. (2014) had evidence of immunodeficiency.
The transmission pattern of ATLD2 in the family reported by Baple et al. (2014) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 4 members of an extended Ohio Amish pedigree with ATLD2, Baple et al. (2014) identified a homozygous missense mutation in the PCNA gene (S228I; 176740.0001). The mutation was found by homozygosity mapping followed by candidate gene sequencing. In vitro studies as well as studies of patient cells showed that the mutation caused a defect in nucleotide excision repair.