Here, we present a novel association between a novel likely pathogenic hemizygous c.617A>G/p.(Gln206Arg) variant in AIFM1 and a teen age onset slowly progressive pure motor neuron disease, thus expanding the spectrum of AIFM1-related phenotypes.

The AIFM1 gene encodes for the apoptosis-inducing factor mitochondrion-associated 1 which is a mitochondrial intermembrane space flavoprotein with diverse functions in cellular physiology. Pathogenic variants in AIFM1 have been linked to diverse range of disorders, including Charcot-Marie-Tooth disease-4, with or without cerebellar ataxia (CMT4X) and mitochondrial encephalopathy. AIFM1 is now also identified as a rare cause of infantile SMA like motor neuron disease.

Four patients from two unrelated families, diagnosed with AIFM1 related motor neuron disease, who carried likely pathogenic variants in AIFM1, were included to the study. We obtained signed informed consent from all patients, who then received riboflavin 400 mg per day and underwent motor assessment using manual muscle testing, 6MWT and ALSFRS-R at baseline and every six months for two years. Comet assay was used to detect DNA damage.

All patients were male and their mean age of onset was 16 age of years. Each presented with slowly progressive weakness in lower extremities. Deep tendon reflexes were brisk. Sensory exam was normal. EMG showed lower motor involvement in distal muscle. Exome sequencing identified the AIFM1 (NM_004208.4):c.617A>G/ p.(Gln206Arg) variant in two index patients, and this variant was  segregated among affected family members. The p.(Gln206Arg) occurred at highly conserved residue in FAD-Dependent oxidoreductase domain of the AIFM1 peptide. The alteration of a glutamine to arginine at position 206 would disrupt the hydrophobic interactions which participates in NAD binding. Mean 6MWT was 420 mt at baseline and 453 At 12^th month and 510 at 24^th month after the treatment.

This new riboflavin responsive of slowly progressive motor neuron disease expands

the phenotypic spectrum of AIFM1 mutations.