CMTX4

AIFM1 | 2012

What Is CMTX4?

CMTX4 is a type of CMT caused by mutations in the AIFM1 gene. This gene provides instructions for producing apoptosis-inducing factor, mitochondria-associated 1, a protein involved in mitochondrial energy production and regulation of programmed cell death. Mutations in the AIFM1 gene disrupt normal mitochondrial function in peripheral nerve cells, leading to impaired axonal integrity and nerve signal transmission.

CMTX4 is X-linked recessive. This means the gene lives on the X chromosome. Individuals with one X and one Y chromosome (chromosomal males) who inherit a CMTX4-causing mutation in their single copy of the AIFM1 gene will have CMTX4. Individuals with two X chromosomes (chromosomal females) who have just one mutated copy will not have CMTX4.

CMTX4 is also called Cowchock Syndrome, named after F. Susan Cowchock, MD. Although different names, they refer to the same symptoms and AIFM1 gene mutations. Providers favor CMTX4 over Cowchock Syndrome because CMT is very non-syndromic. Some literature uses Cowchock Syndrome, and some uses CMTX4, but this does not mean you have both, as they refer to the same thing. For consistency across the Experts in CMT platform, CMTX4 is used.

Clinical Features

CMTX4 symptoms onset in infancy to early adulthood. They typically begin in the lower extremities and, over time, progress to involve the upper limbs. Severe sensorineural hearing loss from an early age is common. Some may have poor vision. Nerve conduction studies usually show somewhat slowed conduction velocities, consistent with an axonal form of CMT.

CMTX4 symptoms may include:

  • Weakness in the feet and lower legs
  • Muscle atrophy
  • Foot drop
  • A steppage-style walking pattern
  • Reduced sensation
  • Reduced or absent reflexes
  • Foot deformities, including high arches and hammertoes (clawed toes)
  • Progressive involvement of the hands and forearms
  • Difficulty with fine motor skills and manual dexterity
  • Balance difficulties
  • Sensorineural hearing loss
  • Poor vision (some patients)
  • Cognitive impairment (some patients)
  • Additional symptoms not listed here

Disease Course

CMTX4 shows wide variability in severity and progression. Some individuals are mildly affected, while others develop a more severe disease. Onset varies from infancy through early adulthood, but disease progression is generally slow, and life expectancy is not reduced.

Clinical Basics

Subtype
CMTX4

Classification
CMTX

Subtype Alias
Cowchock Syndrome

Neuropathy Type
Axonal

Inheritance Pattern
X-linked recessive

Symptoms

CMTX4 Symptoms

Genetic Context

HGNC-Approved Gene Symbol
AIFM1

Gene Full Name
apoptosis inducing factor mitochondria associated 1

HGNC Gene Alias(es)
PDCD8, NAMSD, AUNX1, AIF

Chromosome
Xq26.1

Zygosity of Responsible Variant
Hemizygous (Male)/Compound Heterozygous (Female)

Mitochondrial Involvement
Yes

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Hypomorphic

Confidence:
Medium

Prediction:
Functional work on the CMTX4 alleles predicts a loss-of-function mechanism: AIFM1 encodes apoptosis-inducing factor, a flavoprotein of the mitochondrial intermembrane space whose partnership with CHCHD4 drives import and folding of the disulfide-relay clients that build the respiratory chain. The reported missense changes destabilize AIF and weaken that interaction, lowering oxidative phosphorylation capacity in peripheral nerve. Males express only the mutant allele, so the hypomorphic protein sets the entire AIF activity of the tissue.

Rationale:
The disease alleles act on protein import rather than on apoptotic signaling: destabilized AIF binds CHCHD4 poorly and respiratory subunits fall with it, a shortfall in existing function rather than a new activity. AIF carries several mitochondrial roles, and which one dominates in nerve is unsettled, which is why the mechanism is not graded higher.

ClinVar Pathogenic Variants

View AIFM1 ClinVar Variants

CMTX4 OMIM Entry

CMTX4 OMIM

AIFM1 OMIM Entry

AIFM1 OMIM

More Info

CMTX4 Research Opportunity

CMT Natural History Study

CMTX

What is CMTX?

Original Discovery Publication

Publication Title

Cowchock Syndrome is Associated with a Mutation in Apoptosis-Inducing Factor

Authors

Rinaldi, C., Grunseich, C., Sevrioukova, I. F., Schindler, A., Horkayne-Szakaly, I., Lamperti, C., Landouré, G., Kennerson, M. L., Burnett, B. G., Bönnemann, C., Biesecker, L. G., Ghezzi, D., Zeviani, M., & Fischbeck, K. H.

Publication Date
December 7, 2012

DOI
10.1016/j.ajhg.2012.10.008

Updated: May 9, 2026 | By: K. Raymond

The Dorsal Root

More From The Dorsal Root


A Name That Does Too Much Work

Jean-Martin Charcot's name appears throughout medicine, but nowhere does it create more confusion than in the foot. Learn why the CMT foot and Charcot neuroarthropathy, also known as Charcot foot, share a name yet differ in how they develop, appear, and are managed.


When Medicine Lost Its Compass

Evidence failed not because it was wrong, but because it was weaponized. I lived the downstream effects of that failure for more than a decade. This is what happens when medicine forgets that data always ends in a human being.


Error 404: Gene Not Found

CMT genetic testing often fails to identify the cause of the disease, even when comprehensive panels are used. Here, we discuss why this happens, what genetic tests can and cannot do, and why a negative result still matters.

© 2020–2026 Experts in CMT