AIFM1 – Charcot-Marie-Tooth disease X-linked recessive 4

Charcot-Marie-Tooth disease X-linked recessive 4 (CMTX4) is a slowly progressive axonal neuropathy characterized by sensorineural hearing loss, cognitive impairment, and motor-sensory deficits. The condition maps to Xq24-q26 and is caused by hemizygous variants in the apoptosis-inducing factor mitochondrion-associated 1 gene AIFM1 in male patients, with carrier females typically asymptomatic or mildly affected (PMID:23217327).

Genetic studies have described four unrelated male probands from four families harboring distinct missense AIFM1 variants, all showing X-linked recessive inheritance and complete cosegregation with CMTX4 features (4 probands; PMID:23217327, PMID:28888069, PMID:30031633, PMID:36907087). In each pedigree, multiple affected male relatives carried the variant, while obligate carrier females were unaffected, confirming an X-linked recessive mode and providing robust segregation evidence (affected relatives ≥5).

The variant spectrum in CMTX4 comprises missense changes that perturb AIF enzymatic or mitochondrial functions. The original Cowchock family harbors c.1478A>T (p.Glu493Val), which alters a conserved residue in the FAD-binding domain and co-segregates with disease in a multigenerational pedigree (PMID:23217327). Subsequent reports identified c.630C>G (p.Phe210Leu) in an isolated late-onset axonal neuropathy without central involvement (PMID:28888069), c.513G>A (p.Met171Ile) in a Chinese family with childhood-onset motor-sensory neuropathy (PMID:30031633), and c.1369C>T (p.His457Tyr) in two brothers treated with deep brain stimulation for refractory tremor (PMID:36907087).

Functional assays in patient-derived cells demonstrate that p.Glu493Val alters AIF redox properties and increases caspase-independent apoptosis without affecting respiratory chain complex activities, whereas p.Phe210Leu impairs assembly of mitochondrial complexes I and III, linking biochemical defects to peripheral axonal degeneration (PMID:23217327, PMID:28888069). These concordant findings validate a pathogenic mechanism of haploinsufficiency and impaired mitochondrial oxidative phosphorylation in CMTX4.

Overall, the association between AIFM1 variants and CMTX4 meets ClinGen Strong clinical validity: multiple unrelated probands, consistent segregation, and functional concordance. Genetic evidence is Strong, with four families and robust segregation. Functional evidence is Moderate, supported by in vitro assays recapitulating mitochondrial and apoptotic defects.

Key Take-home: Hemizygous missense variants in AIFM1 cause X-linked CMTX4 by disrupting mitochondrial redox and OXPHOS assembly, providing a clear molecular target for diagnosis, genetic counseling, and potential therapeutic interventions.

References

• American journal of human genetics • 2012 • Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. PMID:23217327
• European journal of neurology • 2017 • A novel missense mutation in AIFM1 results in axonal polyneuropathy and misassembly of OXPHOS complexes. PMID:28888069
• Neuromuscular disorders : NMD • 2018 • A novel AIFM1 mutation in a Chinese family with X-linked Charcot-Marie-Tooth disease type 4. PMID:30031633
• Pediatric neurology • 2023 • Deep Brain Stimulation for the Management of AIFM1-Related Disabling Tremor: A Case Series. PMID:36907087

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