Biallelic TXNIP deficiency is associated with a multisystemic metabolic disease.

Biallelic loss-of-function variants in TXNIP (a regulator of glucose and lipid metabolism); cardiac, muscle and hepatic lipid accumulation.

Characterisation of six new individuals with biallelic pathogenic TXNIP variants, a regulator of glucose and lipid metabolism, bringing the number of described patients to ten. Lactic acidosis remains the main sign, and the spectrum expands to adult-onset cardiomyopathy, skeletal muscle weakness and dyslipidaemia. Cardiac, hepatic and muscle tissues showed pathological lipid accumulation, with increased fatty-acid synthesis markers and lipidome remodelling. In a preclinical model, carbohydrate restriction partially rescued cardiac lipid storage but induced dyslipidaemia.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An important clinical broadening: the potentially fatal adult-onset cardiomyopathy changes surveillance for TXNIP patients, long viewed through the lens of acute childhood metabolic disease. The multi-organ functional anchoring is convincing. The dietary lead (carbohydrate restriction) is double-edged and premature clinically, but it informs pathophysiology.

Analysis by Dr Thibaut Benquey