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Page 298 Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34

Secondary mitochondrial dysfunction
Multiple Acyl-CoA Dehydrogenase Deficiency (OMIM# 231680)
Multiple acyl-coenzyme A dehydrogenase deficiency, also known as glutaric aciduria Type II (GAII), is an
autosomal recessive disorder that affects the oxidation of fatty acids, BCAA, lysine, tryptophan, and choline.
MADD is caused by deficiency of one of the two electron-transfer flavoproteins which transfer electrons
from acyl-CoA dehydrogenases to Coenzyme Q in the respiratory chain: Electron Transfer Flavoprotein
(ETF), encoded by ETFA and ETFB genes, and electron-transfer flavoprotein dehydrogenase (ETFDH),
encoded by ETFDH [136] . Metabolic defects resulting from impaired beta-oxidation include decreased ATP
biosynthesis, excessive lipid accumulation in various organs, and insufficient gluconeogenesis [137] .

The clinical phenotype is variable and has been classified into neonatal onset forms, with the most
severely affected patients presenting with congenital anomalies (Type I) or without anomalies (Type II),
and mild and/or later onset (Type III) [138] . Severely affected patients present in the first few days of life
with non-ketotic hypoglycemia, hyperammonemia, and metabolic acidosis accompanied by hypotonia,
encephalopathy, hepatomegaly, cardiomyopathy, and poor prognosis. An odor of sweaty feet similar to
that in isovaleric acidemia may be observed [139] . Some patients have congenital anomalies (including large
cystic kidneys, hypospadias, and neuronal migration defects that can be prenatally detected by fetal MRI
and facial dysmorphism (low set ears, high forehead, and midfacial hypoplasia) [139] . The most frequent
clinical presentation is the milder myopathic Type III form, which manifests with fluctuating proximal and
axial myopathy with exercise intolerance and occasionally respiratory insufficiency [138] or rhabdomyolysis,
although often with hepatomegaly, encephalopathy, and episodic lethargy, as well as vomiting and
hypoglycemia often triggered by metabolic stress, episodes of which have been lethal in 5% of patients [140] .
Although most decompensations occur in childhood, severe metabolic crises have also been reported in
adulthood [138] . The majority of the 350 cases of late-onset MADD described in the literature carry mutations
in the ETFDH gene (93%), while mutations in the ETFA (5%) and ETFB (2%) genes are less frequent [138] .

Laboratory parameters include increased creatine kinase and lactate levels, with low carnitine. Diagnostic
confirmation is made by the increase of short-, medium-, and long-chain acyl-carnitines on acylcarnitine
analysis and characteristic urinary organic acid pattern comprising elevated levels of glutaric, ethylmalonic,
3-hydroxyisovaleric, 2-hydroxyglutaric, 5-hydroxyhexanoic, and relevant ketonuria, particularly glycine
conjugates of C4 and C5 acids [137,138] . Muscle biopsies usually reveal lipid storage myopathy and secondary
mitochondrial dysfunction with decreased Complexes I and II + III, attributable to deficiency of Coenzyme
Q, which has been associated with increased ROS generation due to electron leak from misfolded variant
ETFDH proteins and impaired Q10 binding affinity [138] .

A clear genotype-phenotype correlation has been reported with the heterogenous subtypes of MADD. Type
I disease is usually associated with homozygosity for null mutations. Even minor amounts of residual ETF/
ETFDH activity suffices to prevent embryonic development of congenital anomalies observed in Type II
disease, whereas higher residual activity is found in the late-onset form/ Type III disease. The genotype-
phenotype correlation within Type III patients is however poor, as exogenous stressors including febrile
infections may modulate the residual activity [138] .

Riboflavin supplementation has successfully ameliorated clinical symptoms and metabolic abnormalities in
almost all patients (98%) with late-onset MADD, the majority of whom have ETFDH mutations (93%) [138] .
High levels of FAD and FMN due to riboflavin supplementation promote folding and stability of
flavoproteins, particularly at fever simulating temperatures (40 °C), permitting certain mutant flavoenzymes
[7]
to reach a folding efficiency and stability that attenuates the enzyme deficiency . Combined treatment of
riboflavin and Coenzyme Q10 has been advocated for use in riboflavin-responsive MADD based on studies