Intrafamilial Variability in 2 Siblings With TANGO2-Related Disorder.

Abstract

BackgroundTANGO2-related disorder (TDD) is a rare autosomal recessive condition characterized by episodic metabolic crises, rhabdomyolysis, encephalopathy, and life-threatening cardiac arrhythmias, with marked phenotypic variability that often contributes to delayed diagnosis.Case presentationWe report 2 sisters homozygous for the recurrent TANGO2 variant c.460G>A (p.Gly154Arg), identified in a family of Hispanic/Latino ancestry, who exhibited divergent clinical presentations. The older sibling presented with developmental delay and recurrent fasting-induced hypoglycemia associated with hyperCKemia and episodic weakness, whereas the younger sibling showed early hypotonia, ataxia, behavioral dysregulation, and subclinical hypothyroidism without initial metabolic crises. Brain magnetic resonance imaging studies were normal in both patients. In both cases, routine metabolic testing was largely unremarkable between episodes, and early manifestations were interpreted within isolated subspecialty frameworks, delaying diagnostic integration.ConclusionThese cases highlight intrafamilial variability within the recognized TDD spectrum and underscore the importance of early recognition of neurologic and endocrine features as potential red flags. Prompt molecular diagnosis is essential to guide anticipatory management and reduce morbidity and mortality.