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Severe X-linked mitochondrial encephalomyopathy associated with a mutation in Apoptosis Inducing Factor 1

By Daniele Ghezzi⁎, Irina Sevrioukova, Federica Invernizzi, Costanza Lamperti, Marina Mora, Pio D'Adamo, Francesca Novara, Orsetta Zuffardi, Graziella Uziel and Massimo Zeviani


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

Topics: Encephalomyopathy
Year: 2011
DOI identifier: 10.1016/j.mito.2011.03.103
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