Abstract
Germline ATM gene variations result in phenotypic heterogeneity characterized by a variable degree of disease severity. We retrospectively collected clinical, genetic, and immunological data of 26 cases with A-T. Clinical manifestations included oculocutaneous telangiectasia (100%), ataxia (100%), fever, loose stools or infection (67%), cerebellar atrophy (50%), nystagmus (8%), dysarthria (15.38%), and visual impairment (8%). Genetic analysis confirmed ATM gene variations in 16 unrelated cases. The most common type of variation was stopgain variants (56%). Immunoglobulin profile indicated reduced IgA, IgG, and IgM in 94%, 50%, and 20% cases, respectively. T cell lymphopenia was observed in 80% of cases among those investigated. Unusual presentations included an EBV-associated smooth muscle tumour located in the liver in one case and Hyper IgM syndrome-like presentation in two cases. Increased immunosenescence was observed in T-cell subsets (CD4+CD57+ and CD8+CD57+). T-cell receptor excision circles (TRECs) were reduced in 3/8 (37.50%) cases.
Highlights
Ataxia-telangiectasia (A-T) is an early-onset autosomal recessive inborn error of immunity (IEI) characterized by a constellation of symptoms including progressive debilitating neuro-degeneration, cerebellar ataxia, oculocutaneous telangiectasia, recurrent sino-pulmonary infections, radiation sensitivity, insulin-resistant diabetes, and a high risk of lymphoid malignancies
Clinical data were collated from records of patients who were diagnosed as A-T in the Pediatric immunodeficiency clinic and/or Pediatric Neurodevelopmental clinic of the Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Hyper IgM syndrome (HIGM) is associated with severe immunological manifestations including autoimmunity, lymphoproliferation and poor o utcomes[12]
Summary
Ataxia-telangiectasia (A-T) is an early-onset autosomal recessive inborn error of immunity (IEI) characterized by a constellation of symptoms including progressive debilitating neuro-degeneration, cerebellar ataxia, oculocutaneous telangiectasia, recurrent sino-pulmonary infections, radiation sensitivity, insulin-resistant diabetes, and a high risk of lymphoid malignancies. Genetic analysis in 5 A-T cases was performed at the National Defense Medical College, Japan using a targeted NGS gene panel containing 29 genes implicated in severe combined immunodeficiency and all coding exons of the ATM gene with ion semiconductor sequencing and multiplex PCR amplicons. ATM gene variants were found in 16 out of 25 clinically diagnosed unrelated A-T cases (including a sibling pair).
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