From ventriculomegaly to severe muscular atrophy: expansion of the clinical spectrum related to mutations in AIFM1

Mitochondrion. 2015 Mar;21:12-8. doi: 10.1016/j.mito.2015.01.001. Epub 2015 Jan 10.


The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1, a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5 years he developed hearing loss and severe ataxia and at age 10 years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G>T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5 years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent.

Keywords: AIFM1; External ophthalmoplegia; Leukodystrophy; Muscle wasting; X-chromosomal mitochondriopathy.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Adolescent
  • Adult
  • Apoptosis Inducing Factor / genetics*
  • Apoptosis Inducing Factor / metabolism*
  • Ataxia / genetics
  • Ataxia / pathology
  • Child
  • Child, Preschool
  • Family Health
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / pathology*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / pathology*
  • Muscular Diseases / genetics
  • Muscular Diseases / pathology
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation, Missense
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / pathology
  • Young Adult


  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • Mutant Proteins