We investigated two male infant patients born from monozygotic twin sisters and unrelated fathers, suggesting an X-linked trait. Several months after birth, both patients developed severe psycho- motor regression, hypotonia and seizures associated with bilateral lesions in the striatum and brainstem. Patient #1 died at 16 months, patient #2 is now 5 years, alert but unable to communicate, tetraplegic and wheelchair-bound under permanent artificial ventila- tion. A muscle biopsy of Pt#1 showed ragged red, complex-IV negative fibers and fibrosis, with severe reduction of mitochondrial respiratory complexes cI, cIII and cIV. The muscle biopsy of Pt #2 showed massive connective and fat tissue replacement with hardly any residual muscle fiber. Fibroblasts from both patients showed reduction of cIII and cIV but not of cI. We SNP-screened the X chromosome, and found a disease-segregating haploidentical region containing a mutation in the Apoptosis Inducing Factor 1 (AIF1) gene that eliminates aminoacid R201. AIF1 is bound to the inner mitochondrial membrane (AIFmit) as an NADH oxidase flavoprotein of unknown function; under apoptogenic stimuli, a soluble form (AIFsol) is released by proteolytic cleavage of AIFmit, and migrates to the nucleus, where induces parthanatos, i.e. caspase-independent fragmentation of chromosomal DNA. We found that in vitro the R201del mutation increases the DNA binding affinity of AIF1sol and decreases the stability of both forms. Staurosporine-induced partha- natos, and galactose-induced mitochondrial fragmentation were markedly increased, whereas re-expression of AIF1wt induced recovery of cIII and cIV activities, in AIFR201del fibroblast cells. This is the first report of an AIF1 mutation in a human mitochondrial encephalomyopathy. Unlike the Harlequin mouse, a spontaneous AIF1 knockdown model, which displays partial cI deficiency, the human disease showed multiple respiratory enzyme defects asso- ciated with reduced mtDNA amount in skeletal muscle. Interestingly, riboflavin supplementation improved the neurological conditions of patient 2 for several months, suggesting that stabilization of the FAD- associated NADH oxidase activity of AIF1mit is beneficial
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