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Page 296 Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34
[78]
functional defect was shown to recover by adding extra FAD . Hence, riboflavin supplementation in
patients with GFER mutations may potentially have clinical benefit, but this is speculative.

FDXR deficiency (OMIM #617717)
FDXR (Ferredoxin Reductase) has one FAD/NAD(P)-binding domain and two NAD(P)-binding domains.
It is the sole ferredoxin reductase in humans and has important roles in iron-sulfur (Fe-S) cluster biogenesis
[82]
and heme synthesis . Mitochondrial membrane associated FDXR reduces the ferredoxins, FDX1 and
FDX2, and transfers electrons from NADPH to the mitochondrial cytochrome P450 system, thus initiating
[83]
the mitochondrial electron transport chain reaction . Studies using patient derived fibroblasts showed
loss of FDXR function led to decreased enzyme activity, reduced functions of Complexes I-III, significant
increase in reactive oxygen species production, and mitochondrial iron overload [84,85] .

There are 27 patients in 19 families with mutations in the FDXR gene reported in the literature [84-86] . A
cohort of eight patients presented predominantly with auditory neuropathy and optic atrophy with onset
[84]
in childhood or adolescence . There were no other clinical features except for mild language delay in one
and retinitis pigmentosa, ophthalmoplegia, and lower limbs hypoallesthesia in another patient . However,
[84]
clinical variability was present in another cohort of patients who presented with neurological features
[85]
of early onset, i.e., infancy to childhood . Apart from visual problems, i.e., retinitis pigmentosa and/or
optic atrophy, and hearing loss, this cohort of 13 unrelated patients also had other clinical features such
as hypotonia, global developmental delay, axonal sensorimotor polyneuropathy, regression after febrile
[85]
illness, ataxia, failure to thrive, progressive microcephaly, and encephalopathy . Respiratory chain enzyme
activities, when reported, showed normal activities or combined deficiencies. Post-mortem findings of
one FDXR patient showed neuronal loss and vacuoles in the cerebral cortex and increased biomarkers for
gliosis, astrocyte activation, and neurodegeneration . These findings were also observed in a homozygous
[86]
p. R389Q mouse model, suggesting that inflammation could be a major component of the pathology in the
neurodegeneration of FDXR mutations
[86]
NDUFV1 deficiency (OMIM # 618225)
NADH: ubiquinone oxireductase flavoprotein 1 (NDUFV1) is a 51-kDa highly conserved nuclear encoded
subunit comprising the electron input (N) functional module of Complex I ). It contains NADH-, FMN-,
[87]
[88]
and Fe-S-binding sites .
Mutations in the NDUFV1 gene causing Complex I deficiency have been identified in 41 patients in 33
families [56,88-110] . The median age of onset of clinical manifestations was 8.0 months (range: birth to 6 years).
The most common clinical features were motor delay or neurodevelopmental regression usually
precipitated by an illness, hypotonia, dystonia, seizures, spasticity, and cognitive impairment. Oculomotor
impairment including ptosis, strabismus, and ophthalmoplegia was also frequently observed. Typical Leigh
syndrome [88,107] and late-onset Leigh syndrome have been reported [95,103] . The clinical course was variable
with some patients having slower progression of neurological manifestations [90,91,103] . Brain MRI and MRS
findings included features of typical Leigh syndrome, white matter changes, basal ganglia changes, elevated
[97]
lactate peak, infantile striatal necrosis , and cavitating leukoencephalopathy [109] . Outcome was available
in 34 patients; ten died at a median age of six months (range: three days to three years). The median age
among surviving patients was seven years (range: 1-15 years) and severity of neurocognitive outcome
varied from mild learning disability [91,96] to significant impairment [101,103] . Riboflavin supplementation was
only reported in seven patients [94,97,98,101] and was given with other supplements such as thiamine, Coenzyme
Q10, creatine, and alpha lipoic.

NDUFV2 deficiency (OMIM #618229)
Human NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), a 24-kDa binuclear [2Fe-2S] cluster
containing protein, is highly conserved and one of the nuclear encoded subunits of Complex I which is