Mitochondrial encephalomyopathy presenting with deafness, mutism, ataxia and late onset external ophthalmoplegia caused by a mutation in the X-linked gene AIFM1
Case Report: In 2010, two male siblings were described with a severe mitochondrial encephalomyopathy associated with a mutation in the gene coding for the apoptosis-inducing factor (AIF). AIF functions under normal circumstances as a FAD-dependent NADH oxidase. Upon apoptotic stimulation, it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. In 2011, a second family with mutations in this gene was described with 3 affected boys who presented with a more severe phenotype including prenatal ventriculomegaly. Here, we describe a male patient with ataxia, deafness, secondary mutism, progressive myopathy, and external ophthalmoplegia. Muscle biopsy showed an unspecific dystrophic pattern and decreased complex I activity. Cranial MRI showed periventricular leukodystrophy and cerebellar atrophy. By next generation sequencing of a panel of genes involved in mitochondrial disorders, a hemizygous missense mutation in the AIFM1 gene was detected and confirmed by sanger sequencing. The mutation, that was also present in the asymptomatic mother, is a highly conserved residue located in the FAD-binding domain. In comparison with the previously described patients, onset of symptoms was later and progression slower. The patient, now age 11 years, is able to communicate by sign language. In summary, we describe the third mutation detected in the AIFM1 gene so far. The phenotype we describe expands the clinical spectrum of clinical phenotypes associated with such mutations.