Clinical variability in ataxia-telangiectasia

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Rare Diseases

Background:

• Ataxia-telangiectasia (A-T) is an autosomal recessive disorder typically presenting with cerebellar ataxia, immunodeficiency, and increased cancer risk.
• Mutations in the ATM gene are causative for A-T, but milder or atypical phenotypes have been increasingly recognized.
• Recent studies suggest ATM mutations are associated with various forms of dystonia, expanding the clinical spectrum beyond classic A-T.

Purpose of the Study:

• To investigate the genetic basis of a variable dystonia phenotype in a Turkish family.
• To identify novel ATM gene variants and assess their pathogenicity in relation to observed clinical presentations.
• To further delineate the phenotypic spectrum associated with ATM gene mutations, particularly concerning dystonia.

Main Methods:

• Clinical evaluation of three affected siblings presenting with a range of dystonic symptoms.
• Whole exome sequencing to identify genetic variants.
• Segregation analysis of identified variants within the family and assessment of alpha-fetoprotein levels.

Main Results:

• Identification of compound heterozygous, potentially pathogenic variants (p.V2716A and p.G301VfsX19) in the ATM gene.
• Perfect segregation of these variants with the dystonia phenotypes within the affected family.
• Elevated alpha-fetoprotein levels, a known marker for ataxia-telangiectasia, were observed.

Conclusions:

• This study confirms that ATM gene mutations can cause a spectrum of dystonia phenotypes, including isolated cervical dystonia and generalized dystonia.
• The identified compound heterozygous variants are likely pathogenic and contribute to the variable intra-familial phenotypes observed.
• These findings support the expanding role of ATM gene mutations in neurological disorders beyond classic ataxia-telangiectasia.