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individuals harboring single amino acid changes in the FADS domain that are potentially more responsive
[34]
to riboflavin therapy .

Riboflavin supplementation resulted in clinical improvements in nine of ten patients treated [34,39-42,44,45] .
All five children who presented in infancy and treated with riboflavin were alive, two at 8 years, one at
[44]
22 years, one at 15 months ), and one at 2 years 5 months . Treatment with riboflavin in two patients
[45]
carrying homozygous c.401_404delTTCT mutations in FLAD1 at age three months resulted in milder
improvements in spontaneous activity, muscle tone, vomiting, and alertness; however, it failed to prevent
[41]
disease progression and demise by six and five months, respectively . The same variant had previously
been reported in an untreated Turkish infant with multiple respiratory chain complex deficiencies who died
[34]
at six months of age . It has been proposed that the partial response to riboflavin supplementation and
residual FADS activity described in patients with biallelic frameshift mutations in exon 2 of FLAD1 may
be attributed to the existence of a FADS isoform that lacks exon 2, but has an intact and functional FADS
[34]
domain . However, the doses of riboflavin used in these patients may have been inadequate in ensuring
[41]
long-term survival .

A trial of riboflavin therapy should be offered to all FADS-deficient individuals while awaiting mutational
analysis. The benefits of early diagnosis and treatment is exemplified by the fatal outcome of the untreated
[34]
brother of an older sister who responded to riboflavin .
Riboflavin kinase deficiency (OMIM # 613010)
RFK (EC 2.7.1.26) is a ubiquitous rate-limiting enzyme that catalyzes the first step in flavocoenzyme
biosynthesis by phosphorylating riboflavin to form FMN, an obligatory step in riboflavin metabolism. FMN
[46]
is subsequently adenylated by FAD synthetase to generate FAD . Embryonic lethality demonstrated before
Day 7.5 of gestation in complete knockout mice was potentially attributable to secondary mitochondrial
dysfunction from the effect on flavocoenzyme deficiencies on the electron transport chain, which is
[47]
critically involved in energy generation . To date, there have been no reported human phenotypes of
RFK deficiency. It is possible that defects in RFK may be incompatible with life due to its critical role
noted above. Hypomorphic RFK mutations may result in clinical phenotypes that are not that dissimilar to
patients with FLAD1 mutations .
[3]
SECONDARY FLAVOPROTEOME DEFECTS ASSOCIATED WITH MITOCHONDRIAL

DYSFUNCTION
Primary Mitochondrial Disorders
Acyl-CoA dehydrogenase-9 deficiency (ACAD9) (OMIM #611126)
Acyl-CoA dehydrogenase 9 (ACAD9), a mitochondrial protein, was initially demonstrated to catalyze the
[48]
initial rate-limiting step in the beta-oxidation of long-chain fatty acids . It was subsequently proposed
to be a novel assembly factor crucial for oxidative phosphorylation Complex I biogenesis, independent of
[49]
its role in fatty acid oxidation . More recently, human ACAD9 was showed to be a bifunctional enzyme
involving primarily oxidative phosphorylation Complex I biogenesis, with an additional moonlighting
[50]
function in fatty acid oxidation (FAO) .

Major clinical presentations of ACAD9 deficiency include biventricular hypertrophic cardiomyopathy
[51]
(85%), muscle weakness (75%), exercise intolerance (72%) and lactic acidosis . Two subgroups of ACAD9
deficient patients have been described, including early-onset, often lethal cardiac involvement presenting
in infancy. Those surviving from this group performed more poorly than later-onset presentations.
Interestingly, developmental delay and severe intellectual disability were only seen with early disease
[51]
onset . ACAD9 is the only long-chain ACAD enzyme expressed in the brain and is especially abundant
during fetal life [49,52] . Hence, it has been proposed that the neurological symptoms present in the most