Mutations in Apoptosis-inducing factor mitochondrion-associated-1 (AIFM1) cause X-linked peripheral neuropathy (Cowchock syndrome, CMT4X); however, more recently a cerebellar presentation has been described.
We describe a large family with seven affected males. They presented with variable age of onset, 18 months-39 years of age. All developed variably present sensorineural deafness, peripheral neuropathy, cerebellar ataxia and pyramidal involvement. Scale for the Assessment and Rating of Ataxia (SARA) ranged 2–23/40, while Charcot-Marie-Tooth neuropathy score 2 varied between 7–13/36. In addition, three had colour vision deficiency.
All individuals had normal cognitive assessment.
Neurophysiology demonstrated length-dependent large-fibre sensorimotor axonal neuropathy, with particular involvement of superficial radial sensory responses. Brain imaging, performed in four, revealed varying extent of cerebellar atrophy, and white-matter changes in one. Optical coherence tomography was abnormal in one, who had unrelated eye pathology. Two obligate female carriers were assessed clinically and neurophysiologically and were unaffected.
Whole genome sequencing demonstrated a previously reported hemizygous AIFM1 mutation. Analysis for mutations in other genes associated with colour deficiency was negative.
AIFM1-associated phenotype in this family demonstrated significant variability, including previously unreported phenotypic features. Superficial radial nerve was particularly affected neurophysiologically, which may be a phenotypic clue towards this specific genetic diagnosis.
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