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Page 294 Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34

severely affected ACAD9-deficient patients could be attributed to a deficiency in brain FAO. To date, no
patients with two ACAD9 null mutations have been described, suggesting that the complete absence of the
protein is lethal. Embryonic lethality was also proposed for the failure to generate homozygous knockout
[49]
ACAD9 mice .
Riboflavin supplementation resulted in alleviation of symptoms in 65% patients, and, most notably,
[51]
improved survival was observed when commenced within the first year of life . Riboflavin responsiveness
may be related to its essential function as a precursor of FAD cofactor for ACAD enzyme activity and
stability. It also increases ACAD9 protein levels and rescues Complex I assembly, while also functioning as
[49]
[49]
a chemical chaperone by improving folding of ACAD9 mutant proteins . Schiff et al. (2015) suggested
that similar specific interventions used for VLCAD defects including avoidance of fasting, medium-chain
triglycerides, or triheptanoin anaplerotic therapy could be beneficial in terms of long-term outcomes in
patients.

FAD-dependent OXidoREDuctase deficiency (FOXRED1) (OMIM #618241)
FOXRED1 has been proposed to be a dual function protein. It plays a key role as an assembly factor for
Complex I biogenesis, and, secondly, due to its oxidoreductase activity, it is hypothesized to participate in
glycine metabolism which modulates glutathione biosynthesis, an antioxidant protecting the cells from
ROS [53-55] . Co-immunoprecipitation experiments suggest that FOXRED1 facilitates Complex I assembly
by associating with the 370-kDa subcomplex and two other FAD-dependent Complex I assembly factors,
[55]
ACAD9 and probably AIFM1 .

FOXRED1 mutations have been recognized as a cause of Complex I deficiency. To date, eight patients
from six families have been described with variable clinical spectrum and severity [55-60] . Age of onset of
clinical manifestations ranged from birth to early infancy with one prenatal onset of oligohydramnios,
severe intrauterine growth retardation, and periventricular cysts . The clinical manifestations included
[60]
Leigh syndrome and infantile-onset encephalomyopathy with epilepsy, mild to severe psychomotor
retardation, and hypotonia. Non-neurological features included congenital lactic acidosis, cardiomyopathy,
hepatomegaly, kyphoscoliosis, optic atrophy, roving eye movements, strabismus, and distal renal tubular
acidosis [55-58,60] . Brain neuroimaging (MRI) findings ranged from normal to delayed myelination and
features consistent with Leigh syndrome [55-57] . Enzymatic studies supported Complex I deficiency in all
[59]
patients. Additionally, a milder decrease in Complex II was observed in one patient . The majority of
mutations identified were missense. Riboflavin supplementation was reported in only two patients [57,60] , of
whom one had prenatal onset and died at three months of age . Outcome was available in 6/8 patients: 4/6
[60]
are alive with median age of 17 years (age range: 10-22 years) and another died at eight years. In contrast to
patients with other nuclear encoded Complex I defects who typically have a severe clinical presentation and
associated early death, it has been suggested that pathogenic variants in the FOXRED1 gene result in partial
loss of function and are probably hypomorphic due to the longer survival of patients .
[61]
COQ6 deficiency (OMIM #614650)
Human Coenzyme Q10 monooxygenase 6 (COQ6) is a flavoprotein involved in the biosynthesis of
Coenzyme Q10 which operates as a redox carrier by transferring electrons from respiratory chain
[62]
Complexes I and II to Complex III. Coenzyme Q10 is also a potent antioxidant and a cofactor of
many mitochondrial dehydrogenases. It is required for pyrimidine nucleoside biosynthesis and has
been implicated in the inhibition of apoptosis by preventing the collapse of the inner mitochondrial
membrane . Studies using human cell line lacking functional COQ6 showed impaired COQ synthesis,
[63]
[64]
severe ATP deficiency, and increased production of reactive oxygen species .