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Page 292 Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34

(PAPS) reductase domain, which is sufficient to catalyze FAD synthesis and has thus been renamed
the FADS domain [33,34] . Multiple FADS isoforms generated due to alternative splicing of the encoding
FLAD1 gene result in distribution within different subcellular localizations [34-36] .Two isoforms, the more
[33]
abundant cytosolic (FADS2) and the mitochondrial (FADS1), have been described in detail . Human
FADS1, FADS2, and FADS3 possess both catalytic domains and are bifunctional, while FADS4 and FADS5
[37]
present the sole mMPTb domain and are monofunctional enzymes . A novel cytosolic FADS6 isoform
recently characterized contains only the PAPS domain with considerable FAD synthesis activity, which
[37]
allows survival of affected patients with biallelic FLAD1 frameshift variants .The FADS6 isoform has
approximately 70% of the FAD-synthesizing capacity of human FADS2. Its catalytic efficiency (kcat/Km) is
[38]
however higher due to a lower Km for FMN and ATP compared to FADS2 .
The recently described clinical spectrum for FAD synthase deficiency has ranged from neonatal-onset, a
lethal disease with metabolic myopathy, cardiomyopathy, swallowing, speech difficulties, and respiratory
insufficiency, to later-onset, a potentially treatable neuromuscular disorder with lipid storage myopathy,
[34]
MADD-like metabolic aberrations, and combined respiratory-chain deficiency . To date, sixteen
patients have been reported with age of onset ranging from birth to 44 years [34,39-45] . Most patients (92%)
have however presented in infancy, with five out of thirteen dying within the first twelve months of life.
[39]
The first patient described by Taylor et al. , a Turkish male infant of consanguineous parents, presented
at age four months with respiratory insufficiency, lipid myopathy, decreased activities of mitochondrial
respiratory chain Complexes I and IV, and early death at eight months of age. A homozygous 4-bp
deletion (c.397_400delTTCT) in the FLAD1 gene was identified, resulting in a frameshift and premature
termination (Phe134CysfsTer8). Functional studies were not performed; however, in silico predictions of
the deleterious effect of the mutations supported a causal association.

A further 15 patients from 13 unrelated families affected by MADD and/or multiple respiratory-chain
deficiency and lipid storage myopathy were diagnosed with FLAD1 deficiency. Apart from one patient,
[3]
all were identified by whole-exome sequencing or through candidate gene panels . Characteristic clinical
manifestations included early infantile onset hypotonia, swallowing, speech difficulties, respiratory
insufficiencies, and a fatal course (seven died within the first year of life and one at age 16 years).
Cardiorespiratory collapse was the cause of death for a neonate who presented at 32 h of age and died
at three days. One patient died of multiorgan failure at seven months due to recurrent episodes of
sudden cardiac arrest necessitating a pacemaker. Another infant with cardiomyopathy and recurrent
supraventricular tachycardias who required implantable cardioverter defibrillator placement showed a
dramatic response to riboflavin supplementation and was still alive at 22 years. Interestingly, the acute
metabolic decompensations observed in the neonatal forms of MADD caused by ETFA, ETFB, and ETFDH
defects, including hypoglycemia, metabolic acidosis, and hyperammonemia have not been reported
[41]
in early-onset FADS deficiency . The adult onset presentations at 20 and 44 years included exercise
intolerance and progressive muscle weakness, with gait difficulties, bilateral foot drop, and arm weakness in
the older patient. These individuals were alive at 44 and 56 years, respectively [34,40] .

Metabolic findings in FADS deficiency are typical of riboflavin deficiency or MADD, with increased
acylcarnitines (C4-C14 even chain acylcarnitines; C5 and C5-DC; and C10:1, C14:1, C16:1, C18:1, and
C18:2) and urinary organic acids (increased urinary excretion of ethylmalonic, adipic, suberic, glutaric
[3]
and methylsuccinic acids, hexanoylglycine, and tiglylglycine) . Characteristic muscle pathology with
pronounced lipid storage and global decrease of COX and/or SDH histochemical staining has been
reported . Multiple respiratory chain enzyme deficiencies involving Complexes I-III were described in
[39]
skeletal muscle biopsies in seven of eight cases tested [34,39,41] .

A possible genotype-phenotype correlation has been proposed with homozygous carriers of frameshift
variants affecting the MPTb domain displaying a more severe clinical course than that observed in