Ataxia-telangiectasia

Abstract

ObjectiveAtaxia-telangiectasia (AT) is a rare, severe, and ineluctably progressive multisystemic neurodegenerative disease. Variant AT phenotypes have been described in patients with mild- and late-onset neurologic deterioration and atypical features (dystonia and myoclonus). We report on the clinical characteristics and transcriptome profile of patients with a typical AT presentation and genotype who experienced an unexpected favorable course.MethodsA 24-year-old woman developed, by the age of 3 years, all the classic symptoms of AT associated with increased alpha-fetoprotein levels, a compound AT-mutated (ATM) genotype with an inframe deletion c.2250G>A (p.Glu709_Lys750del42) and a missense mutation c.8122G>A (p.Asp2708Gln), and no residual ATM protein expression. By the age of 12 years, ataxia slowly disappeared, and a very mild choreic disorder was the only neurologic feature in adulthood. Brain MRI was normal. The blood transcriptome profile was assessed and compared with that of healthy controls and patients with the classic AT phenotype.ResultsThe atypical clinical course of the patient was associated with a transitional transcriptome profile: while 90% of transcripts were expressed as in patients with the classic AT presentation, 10% of transcripts were expressed as in healthy controls.ConclusionsThe unexpected mild clinical outcome and transcriptome profile of this patient with AT suggest the existence of individual resilience to the altered ATM synthesis. Because of their possible prognostic and therapeutic implications, the identification of modifier factors affecting the phenotype would deserve further studies.

Mild Neurological Phenotype Associated with Hypomorphic Variants in the Ataxia‐Telangiectasia Mutated Gene

“…In other cases, there is a similarly mild phenotype even though all A‐T cellular biomarkers are present (ie, radiosensitivity, chromosomal rearrangements, undetectable ATM protein, and kinase activity) (Table S1). In a girl with an apparent classic presentation associated with typical A‐T biological markers, a remitting form was described 5 . These aspects highlight the occurrence of other modifying factors that may influence clinical outcome.…”

“…In a girl with an apparent classic presentation associated with typical A-T biological markers, a remitting form was described. 5 These aspects highlight the occurrence of other modifying factors that may influence clinical outcome.…”

Novel genetic variants of inborn errors of immunity

“…Another example is the six known pathogenic variants of ataxia telangiectasia (AT) in our community; one of these is novel and reported here. This entity is characterized by genomic instability due to defects in DNA repair [ 16 ]. Homozygous and double heterozygous affected individuals have immune derangements (e.g., thymic involution) and central nervous system degeneration.…”

Transcriptomic profile of ataxia telangiectasia cells treated for 30 days with a low dose of dexamethasone

“…Nevertheless, several studies and clinical trials have shown that glucocorticoid administration in AT patients can improve their clinical outcome and quality of life (Buoni et al 2006;Broccoletti et al 2008;Zannolli et al 2012;Chessa et al 2014;Leuzzi et al 2015). However, the mechanism of action of glucocorticoids in AT patients has only been partially elucidated; therefore, we have focused our research on investigating the effects of dexamethasone (dex) in both cellular models (Menotta et al 2012;Menotta, Biagiotti, Bartolini, et al 2017;Ricci et al 2020) and patients (Menotta, Biagiotti, Spapperi, et al 2017;Leuzzi et al 2018;Menotta, Biagiotti, et al 2018). We had the opportunity to test whole blood gene expression variation in patients treated with autologous dexamethasone loaded RBCs (Chessa et al 2014).…”