TANGO2-deficiency disorder (TDD) is a rare autosomal recessive condition characterised by neurodevelopmental delay, TANGO2 spells, life-threatening metabolic crises, and cardiac arrhythmias. Genotype–phenotype correlations remain poorly defined and the neurobehavioural profile of affected individuals is largely unexplored. We conducted a retrospective multicentre study of five Italian patients with genetically confirmed TDD, identified between June 2023 and May 2025. Clinical, neurophysiological, neuroimaging, genetic, and neurodevelopmental data were collected. Adaptive functioning, cognitive ability, and behavioural profiles were assessed using standardised instruments. All five patients carried biallelic TANGO2 mutations, including two previously unreported variants. Clinical severity ranged from an asymptomatic individual under preventive therapy to a fatal early-onset metabolic crisis. Marked intrafamilial variability was observed in two siblings sharing the same genotype. Systematic neurodevelopmental assessment revealed a spectrum of cognitive and adaptive outcomes, with attentional difficulties identified as a recurrent feature. No metabolic crises or TANGO2 spells were documented following initiation of B-vitamin and cofactor supplementation in surviving patients. This cohort expands the mutational and phenotypic spectrum of TDD and highlights the diagnostic value of TANGO2 testing in patients with neurodevelopmental delay or paroxysmal neurological episodes, even in the absence of metabolic crises. Early supplementation therapy may contribute to clinical stability, though prospective controlled studies are needed.
Turco et al. (Thu,) studied this question.