Neurological disease progression in adults with ataxia telangiectasia: a longitudinal study.
Ataxia-telangiectasia (AT) is a rare, multisystem neurodegenerative disorder with marked clinical heterogeneity. Longitudinal data on neurological progression remain limited, restricting understanding of disease mechanisms and therapeutic trial design. We analysed longitudinal Scale for the Assessment and Rating of Ataxia (SARA) data from the largest published adult AT cohort to date (n = 82, age > 16 years). Linear mixed-effects models were used to estimate severity at the earliest available neurological evaluation (baseline) and annual progression rates (points/year) in classic and variant AT, and to examine clinical and genetic modifiers. Neurological impairment progressed with a mean SARA increase of 0.38 points/year. Adults with classic AT were more severely affected than those with variant AT, with SARA scores approximately 8-9 points higher at baseline. However, neurological progression in adulthood was similar between classic and variant AT (0.33 vs 0.41 points per year), which includes 15 individuals with the antisense oligonucleotide targetable c.5763-1050A>G variant. Although AT subtypes differ substantially in childhood and adolescence, neurological decline converges to a similar pace in adulthood, irrespective of subtype or genotype. SARA remains a useful outcome measure but may underestimate progression in advanced disease and non-cerebellar domains. These findings inform counselling, prognostication, and the design of interventional trials, including mutation-specific therapies.