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Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34 Page 291

Ethylmalonic ETHE1 602473 Encephalopathy, Vasculopathy Increase in Limited data (n = 4) [152]
encephalopathy (petechial purpura, orthostatic ethylmalonic, C4 and
acrocyanosis, chronic C5 acylcarnitines.
hemorrhagic diarrhoea) Complex IV
deficiency
Combined oxidative AIFMI 300816 Encephalomyopathy Combined Limited data (n = 2)
phosphorylation respiratory chain for ataxia [160] and
deficiency 6 deficiencies neurological condition
(n = 1, gross, fine motor
and communication) [155]
Cowchock syndrome AIFMI 310490 X-linked Charcot-Marie-Tooth
disease (CMTX4) with axonal
sensorimotor neuropathy,
deafness and cognitive
Impairment
Deafness, X-linked 5 AIFMI 300614 Auditory neuropathy with
peripheral neuropathy
Spondyloepimetaphyseal AIFMI 300232 Spondyloepimetaphyseal
dysplasia, X-linked, dysplasia with hypomyelination
with hypomyelinating
leukodystrophy

Haploinsufficiency of the SLC52A1 (OMIM#615026) due to maternal microdeletion and heterozygous
intronic variant has been reported to cause a transient riboflavin responsive neonatal multiple acyl-CoA
dehydrogenase deficiency that resolved with oral supplementation of riboflavin [27-29] .

Disorders of Flavocoenzyme Transport
Mitochondrial FAD transporter deficiency (OMIM #616839)
SLC25A32 encoding the mitochondrial FAD transporter has been described in two patients with biallelic
mutations to date [30,31] . The first, a 14-year-old girl presented with riboflavin-responsive recurrent exercise
[30]
intolerance and biochemical findings of MADD . The second, a 51-year-old Dutch patient with a severe
neuromuscular phenotype had initially presented aged three years with muscle weakness post- influenza
infection. He subsequently developed impaired motor skills, progressive exercise intolerance in childhood,
[31]
early-onset ataxia, myoclonus, dysarthria, and dysphagia . Muscle biopsy in both patients demonstrated
ragged-red fibers, lipid storage, and decreased staining for succinate dehydrogenase (SDH, FAD-dependent
mitochondrial respiratory chain Complex II) and COX (mitochondrial respiratory chain Complex IV).
Complex II deficiency was revealed in cultured skin fibroblasts and muscle from the first and second
patients, respectively [30,31] . Dramatic improvements in exercise tolerance and endurance and biochemical
abnormalities were reported in both patients following oral riboflavin supplementation [30,31] .

SLC25A32 has recently been revealed to be a novel regulator of cancer cell proliferation and mitochondrial
FAD metabolism. SLC25A32 knock-down in sensitive tumor cells resulted in inhibition of the FAD-
[32]
dependent Complex II, increased succinate levels, and reduced oxygen consumption rate . These findings
corroborate evidence of decreased Complex II protein levels and OXPHOS activity, which is a marker
for mitochondrial FAD in muscle of patients with severe neuromuscular phenotype and novel variants
in SLC25A32 [30,31] . Reduction of mitochondrial FAD concentrations by inhibition of SLC25A32 is anti-
proliferative in a subset of tumor cell lines and has potential clinical applications as a novel cancer target by
increasing oxidative stress and reducing tumor growth .
[32]

Disorders of Flavocoenzyme Metabolism
Flavin adenine dinucleotide synthase (FAD) synthase deficiency (OMIM # 255100)
The FLAD1 gene encodes FAD synthase (EC 2.7.7.2), which catalyzes the adenylation of FMN into the
redox cofactor FAD. Human FADS has previously been shown to be a bifunctional enzyme with both FAD
synthase and hydrolase activity . The enzyme contains an N-terminal molybdopterin binding (MPTb)
[33]
domain, which has FAD hydrolase activity, and a C-terminal 3’-phosphoadenosine-5’-phosphosulfate