Page 149 - Read Online

Page 300 Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34

AIFM1 deficiency (OMIM#300816, OMIM#310490, OMIM#300614, OMIM#300232)
The X-linked AIFM1 gene encodes the apoptosis-inducing factor (AIF), a mitochondrial flavoprotein
with a dual role, first as a FAD-dependent NADH oxidoreductase and second as a caspase-independent
death effector which regulates apoptosis [153,154] . AIFM1 mutations have been associated with wide spectrum
of clinical phenotypes with X-linked recessive inheritance including a severe, early-onset mitochondrial
encephalomyopathy with combined oxidative phosphorylation deficiency [155] , prenatal ventriculomegaly [156] ,
the Cowchock syndrome, an X-linked Charcot-Marie-Tooth disease (CMTX4) with axonal sensorimotor
neuropathy, deafness and cognitive impairment [157] , auditory neuropathy spectrum disorder [158] ,
spondyloepimetaphyseal dysplasia with mental retardation [159] , and, more recently, cerebellar ataxia partially
responsive to riboflavin [160] .

The AIFM1 protein is highly expressed in hairy cells and spiral ganglion within the inner ear, consistent
with its crucial role in maintaining normal auditory function [158] . Hence, the predominant phenotypes
described with AIFM1 mutations are either mitochondrial encephalomyopathies or sensorineural hearing
loss and auditory neuropathy as transmission from the inner ear to the auditory nerve and brain stem is
distorted [160] . Cerebellar ataxia, with or without vermian atrophy, was described only recently in relation to
AIFM1 mutations, and has further widened the symptomatology [160] .

Supplementation with riboflavin was reported to temporarily slow the disease progression in a patient
with the severe encephalomyopathy [155] . A clear improvement of ataxia by 44% and 20% was observed in
two patients, respectively, as measured by the ICARS score, an objective assessment that quantifies the
magnitude of improvement in progressive ataxias, with a score of 5%-20% considered as substantial in
providing a clinical impact. Prompt diagnosis through early recognition of constellation of symptoms
including ataxia with sensorineural hearing loss especially auditory neuropathy would be important since
the symptoms may be partially amenable to riboflavin treatment [160] .

CONCLUSION
Defects of riboflavin metabolism present with a heterogeneous clinical spectrum and variable severity,
ranging from severe, early-onset neurodegenerative disorders to adult-onset myopathy. Riboflavin has
been used as a potential therapeutic agent in the “mitochondrial cocktail”, particularly in Complex I- and
II-related primary mitochondrial disease to ameliorate oxidative stress. There is growing evidence of the
beneficial role of riboflavin in treating defects of riboflavin metabolism. Riboflavin supplementation has
dramatically led to clinical improvements in riboflavin transporter deficiencies (RTD2 and RTD3), which
encompasses BVVL and FL syndromes and mitochondrial FAD transporter deficiency. It has also been
proven efficacious in FAD synthase deficiency, late-onset MADD due to ETFDH mutations and deficiencies
in ACAD9, dihydrolipoamide dehydrogenase (E3), and AIFM1. In view of the promising therapeutic
effects of riboflavin in these disorders, early recognition and treatment including trial of riboflavin
supplementation is imperative.

DECLARATIONS
Authors’ contributions
Made equal contributions to writing and critically revising the manuscript: Balasubramaniam S, Yaplito-
Lee J

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.