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which demonstrated improved mitochondrial dynamics with decreased ROS production and restoration of
CoQ10 levels in patient fibroblasts co-treated with CoQ10 and riboflavin [141] .

Dihydrolipoamide dehydrogenase (E3) deficiency (OMIM# 246900)
The DLD gene encodes dihydrolipoamide dehydrogenase (also known as E3), a common flavoprotein
shared by three mitochondrial α-ketoacid dehydrogenase multi-enzyme complexes: pyruvate
dehydrogenase complex (PDHC), α-ketoglutarate dehydrogenase complex, and branched-chain α-keto
acid dehydrogenase complex. It catalyzes the third stage of the reaction by re-oxidizing the reduced lipoyl
moiety of E2 and generating lipoic acid and NADH [142] . E3 is also a component of a fourth mitochondrial
multienzyme complex, the glycine cleavage system, where it functions as the L protein, a housekeeping
enzyme that, to date, has not appeared to impair the function of the system in vivo when associated with
pathogenic variants of DLD [143] . The metabolic derangements incorporate PDHC and TCA cycle defects:
increased blood lactate and pyruvate, elevated plasma alanine, BCAA, presence of allo-isoleucine in plasma,
and increased urinary lactic, pyruvic, 2-ketoglutaric, and branched-chain 2-hydroxy- and 2-ketoacid [143,144] .

The phenotypic spectrum of DLD deficiency includes: (1) classical E3 deficiency, which includes
early-onset encephalopathy with progressive hypotonia, failure to thrive, hypoglycemia, ketoacidosis,
and encephalopathy or Leigh-like encephalopathy; (2) a primarily hepatic presentation with Reye-
like syndrome, wherein patients typically have normal intellect without residual neurologic deficits
between acute metabolic episodes; and (3) a milder riboflavin responsive myopathic phenotype
with exertional fatigue, intermittent elevation of blood lactate, ketoacidosis, creatine kinase, and
mitochondrial proliferation [143,145,146] . Riboflavin supplementation led to complete resolution of muscle
weakness, improvement of metabolic abnormalities, partial restoration of the DLD protein, resolution of
mitochondrial proliferation in muscle, and reduced ROS production in fibroblasts, supporting the evidence
of a chaperone-like effect of riboflavin in promoting DLD protein stability and folding [146] .

Ethylmalonic aciduria secondary to ETHE1 dysfunction (OMIM# 602473)
Ethylmalonic encephalopathy (EE) is a rare, devastating, invariably fatal neurodegenerative disease
caused by mutations in the ETHE1 gene, which encodes a mitochondrial sulfur dioxygenase critical in
hydrogen sulfide (H S) detoxification [147] . The characteristic clinical features are hydrogen sulfide mediated
2
and include vasculopathy due to diffuse microvasculature injury responsible for multiple necrotic brain
lesions, which lead to early-onset psychomotor regression, seizures, and global neurological impairment
that subsequently evolve to severe psychomotor delay with spastic tetraparesis. Vascular lesions include
diffuse and spontaneous relapsing petechial purpura, orthostatic acrocyanosis, hemorrhagic suffusions of
mesothelial surfaces, and intestinal mucosa associated with chronic hemorrhagic diarrhea [148] .

Biochemical abnormalities resulting from accumulation of hydrogen sulfide and its derivative thiosulfate
in crucial tissues including liver, brain, and colonic mucosa leading to inhibition of both short-chain acyl-
CoA dehydrogenase with consequent elevation of ethylmalonate, C4- and C5-acylcarnitines predominantly
in muscle and brain, and cytochrome c oxidase deficiency, blocking mitochondrial respiration and
increasing lactic acid [147,148] . Urinary thiosulfate is also markedly elevated [149] .

Current treatment modalities include the off-label use of common drugs such as N-acetylcysteine and
metronidazole to lower the production and promote detoxification of toxic H2S. This combined exposure
has produced some encouraging results with amelioration of some neurological abnormalities and marked
attenuation or disappearance of the vascular lesions and diarrhea [150] , suggesting disease modification
from the invariably fatal clinical course of EE [151] . Therapeutic trial with riboflavin and/or Coenzyme Q10
resulted in decreased C4- and C5-acylcarnitines in one patient and mild improvements in chronic mucoid
diarrhea and motor and cognitive functions in three patients [152] .