Fanconi anemia (FA) is a genetic disease caused by mutations in at least 21 genes. Even if the clinical phenotype of FA patients is heterogeneous, the main clinical aspects are somatic malformations, bone marrow failure and predisposition to develop cancer, in particular acute myeloid leukemia (AML) and epithelial cancer of head and neck [1]. Regarding the molecular causes of the disease, the impairment of DNA repair has been considered the principal defect in FA cells. However, in the last few years, other contributors to DNA repair defects have emerged. They include mitochondrial function alterations and the consequent reduction of energy production and the increment of oxidative stress [2], the defects in mitophagy, the reduced ability of aldehyde detoxification, the hyperproduction and the hyper sensitivity to inflammatory cytokines [3]. This view seems to be strengthened by the recent publication in this journal about the case of a female child with a clinical and cellular phenotype largely compatible with a diagnosis of FA, consisting in failure to thrive, minor dysmorphic features and a positive chromosomal fragility test (29% of the cells showing ≥1 break/cell after exposure to DEB) [4], which is still considered the diagnostic gold standard for FA [1]. This patient did not carry mutations in any of the currently known FA genes, but displayed a mutation only in COX 4-1, a gene codifying for a mitochondrial protein involved in the oxidative phosphorylation [4].

The case of this patient suggests shifting the focus from defect of DNA repair to the energy metabolism alteration in FA. Indeed, FA cells display defects in respiratory chain, generating a decrement of energetic status and an enhancement of the oxidative stress [2], a biochemical framework very close to the one described in Abu-Libdeh paper.

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