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TANGO2‐deficiency disorder (TDD) is an autosomal recessive condition arising from pathogenic biallelic variants in the TANGO2 gene. TDD is characterized by symptoms typically beginning in late infancy including delayed developmental milestones, cognitive impairment, dysarthria, expressive language deficits, and gait abnormalities. There is wide phenotypic variability where some are severely affected while others have mild symptoms. This variability has been documented even among sibling pairs who share the same genotype, but reasons for this variability have not been well understood. Emerging data suggest a potential link between B‐complex or multivitamin supplementation and decreased metabolic crises in TDD. In this report, we describe two sibling pairs from unreladiagnosed with TDD with marked differences in symptoms. In both families, the older siblings suffered multiple metabolic crises and are clinically more affected than their younger siblings who have very mild to no symptoms; they are the least impaired among 70 other patients in our ongoing international natural history study. Unlike their older siblings, the two younger siblings started taking B‐complex vitamins early between 9 and 16 months. This report delineates the mildest presentation of TDD in two families. These data may support a role for early diagnosis and initiation of vitamin supplementation to not only prevent metabolic crises but also improve neurologic outcomes in this life‐threatening disorder.

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