This articleisprotected bycopyright.Allrightsreserved. +44 (0)2074046191 Fax: E-mail: [email protected] +44 Phone: (0)2079052608 London, UnitedKingdom UCL Instituteof Ormond Great Street ChildHealth, Mitochondrial Research Group, ShamimaRahmanProfessor Corresponding author: 8 London, 7 Melbourne, VIC, Australia 6 Melbourne, VIC, Australia 5 Sydney, NSW,Australia 4 NSW,Australia 3 2 Australia 1 BalasubramaniamShanti
AcceptedMetabolic Unit, Great HospitalOrmond Street NHSTrust, London, Foundation UK U Group, Research Melbourne, Mitochondrial of University School, Medical Melbourne Paediatrics, of ArticleDepartment Institute, Research Children’s Murdoch Group, Research Genomics Neurodevelopmental Sydney, of University School, Medical Sydney Health, Adolescent & Child of Discipline Sydney, Sydney, of University School, Medical Sydney Medicine, Genetic of Discipline Kids ResearchInstitute,TheChildren’s NSW, Sydney, Westmead, at Hospital Children’s The Program, Genetics Sydney Western
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This articleisprotected bycopyright.Allrightsreserved. FAD deficiency, synthase metabolism Riboflavin Keywords: and prompt management of disorders secondary or primary of number a in beneficial be may therapy riboflavin Because flavoproteome. cellular the of disorders r provid deficiency, bio and an provide we metabolism. and review transport, absorption, riboflavin of overview this In disease. cardiovascular and development fetal abnormal lead may humans in homeostasis flavin of impairment the that surprising not is it Hence, processes. relevant physiologically other and apoptosis folding, protein remodelling, chromatin repair, DNA of functionality a play flavocoenzymes These (FAD). dinucleotide adenine flavin and (FMN) mononucleotide flavin flavocoenzymes the of biosynthesis the for responsible Tissue intake. dietary by principally met being requirements with synthesized, endogenously not is it as water a B2), (vitamin Riboflavin Abstract
Acceptediboflavin Article ing chemical features associated with biallelic with associated features chemical
and n vriw f lncl iodr ascae wt ntiinl eiiny of deficiency nutritional with associated disorders clinical of overview an
h ol kon rmr dfc i faoonye synthesis flavocoenzyme in defect primary known only the - pcfc rnpre poen drc rbfai t te i the to riboflavin direct proteins transporter specific primary defects of riboflavin transport. Finally, we give a brief overview of overview brief a give we Finally, transport. riboflavin of defects primary mliue of multitude a
o utsse dsucin nldn nuouclr iodr, anaemia, disorders, neuromuscular including dysfunction multisystem to ,
of these disorders of disorders these isimperative. riboflavin riboflavin FLAD1
lvpoen ivle i bonreis rdx homeostasis, redox bioenergetics, in involved flavoproteins - soluble vitamin, is an essential nutrient in higher organisms higher in nutrient essential an is vitamin, soluble
mutations, mutations, transport , riboflavin disorders responsive
flavocoenzyme the the FLAD1 ellr flavoproteome, cellular
mutations leading to FAD synthase synthase FAD to leading mutations ,
We then We lvpoen flavoproteome, flavoprotein, vital taellr machinery ntracellular
focus on the clinical the on focus role in ensuring the the ensuring in role al recognition early . , in addition to to addition in ,
This articleisprotected bycopyright.Allrightsreserved. AcceptedAll of Details Article Key three
messages deficiencies, early hence of recognition disorders these isimperative. primary both in beneficial be may therapy Riboflavin organicurinary acids biochemical secondary and primary Both dihydrolipoamide dehydrogenase dehydr CoA of flavoproteome S b) reported). have been (i involving a) P synthesized and must supplied through dietary intake be Riboflavin econdary rimary defects . authors
e disorders disorders of riboflavin defects in the synthesis o synthesis the in defects the Contributions of Individualthe of Authors Contributions .
FAD synthase deficiency synthase FAD :
contributed towriting and
s n seta ntin in nutrient essential an is flavocoenzyme
feature enzymes in the synthetic pathway of pathway synthetic the in enzymes gns dfcec ( deficiency ogenase , i , of . e .
flavocoenzyme cofactor de cofactor s
.
including characteristic elevations of plasma acylcarnitines and acylcarnitines plasma of elevations characteristic including
or flavocoenzyme
def r transport of transport r flavocoenzyme ; t ; ects ects pendent reactions which do not do which reactions pendent o date, no cases of human riboflavin kinase deficiency deficiency kinase riboflavin human of cases no date, o
deficiency
metabolism ee t the to refer critically critically revis ihr organisms higher MADD
cofactors
transport. transport. .
deficiencies deficiencies
)
includ ,
ucinl irpin f h cellular the of disruption functional g ing essential cofactors FMN and FAD and FMN cofactors essential uai aiui tp 1 type aciduria lutaric . Examples include include Examples . e
the manuscript.the genetically inherited disorders: and .
since may present with present may
secondary secondary
t s o endogenously not is it arise
as a direct result direct a as
flavocoenzyme multiple acyl multiple abnormal , and -
This articleisprotected bycopyright.Allrightsreserved. reproductiv and age on depending variations with women, for mg/day 1.1 and men ( allowance daily recommended The and riboflavin of synthesis Endogenous bacteria. Accepted and fungi plants, organisms higher as Riboflavin, 2. pyridoxine(folate, Q coenzyme biosynthes 2007) al et (Joosten apoptosis and These Article cycle, chain, transport electron in players key them one cofactor a as FMN enzymes dependent reactions enzymatic numerous (FMN) mononucleotide pathways, metabolic of range wide a Riboflavin 1. Introduction Dietary Dietary - GTP) electron
flavoproteins nitric oxide synthases oxide nitric by
is or regulation of other essential cofactors and hormones, such as coenzyme A, A, coenzyme as such hormones, and cofactors essential other of regulation or is sources ofriboflavin (7,8 10 and bacteria , with -
dimethyl h
aem
two / have lost the ability to synthesize this molecule molecule this synthesize to ability the lost have pyridoxal 5 ( other water other are also important in important also are Joosten 2007 Joosten which
, nme of number a - in the large intestine may contribute to contribute may intestine large the in electron steroids steroids
mitochondrial and peroxisomal and mitochondrial - 10 and
con for account - , ribityl
redox homeostasis redox ’
- lvn dnn dinucleo adenine flavin - . transfer
phosphate and soluble B vitamins, must be obtained through obtained be must vitamins, B soluble
T , . e ua faorti hs a has flavoprotein human he Lienhart et al 2013) al et Lienhart - critical isoalloxazine) F thyroxine because it is a precursor of precursor a is it because RDA inally, f inally,
reactions 4 o hmn flavoproteins human of 84%
chromatin remodechromatin
) of ) and niacin) eaoi processes metabolic lavoenzymes
, riboflavin s el as well as
and , also known as vitamin B2 vitamin as known also , in oxidation branched ( . Lienhart
Flav ie (FAD) tide
fatty acid fatty on average is 1.3 mg/day for adult adult for mg/day 1.3 is average on
also play an important role in the in role important an play also l eaoim f te B vitamins B other of metabolism ling, DNA repair, protein foldingprotein repair, DNA ling, o some c - – oenzymes chain amino acid catabolism acid amino chain
euto processes reduction et 2013 al the includ fo ribulose (from
β
la ba twrs FAD towards bias clear extent ( extent - essential
oxidation, which whilst , s poe to opposed as ing
are able to catalyse catalyse to able are ;
Kennedy 2016) Barile the the , cofactors r uiie in utilised are
plays a role in role a plays ny 6 use 16% only the the mitochondrial the the - 5
et al et - diet phosphate citric acid citric making ,
e status e various various
, 2016
flavin since .
). - .
This articleisprotected bycopyright.Allrightsreserved. ( occurs 1989 McCormick which AcceptedRFVT3 2016). al et specificit tissue and locations subcellular different have SLC52A2 encoded (hRFT2), RFVT3 and (hRFT3) RFVT2 hRFT1), (previously RFVT1 hum Three in the pyrophosphatase FMN/FAD stomach proteins carrier Articleto tend foods other flavoproteins in ingested Riboflavin 3 conditions in prevalent isolated sources, food of variety wide a in riboflavin of availability adequate school in 35% of sources 2016). al et (Barile lactation and pregnancy including . R iboflavin iboflavin
small alintestine (Henriques et 2013). is reported to be linear up to approximately 30 mg riboflavin per meal ( meal per riboflavin mg 30 approximately to up linear be to reported is
Zempleni 1996; etal ad subsequent and , Ynzw ad ni 2013) Inui and (Yonezawa
and and (Pinto andZempleni 2016). an plasma membrane riboflavin transporters have been characterised been have transporters riboflavin membrane plasma an iolvn in riboflavin Free riboflavin is transported into enterocytes via via enterocytes into transported is riboflavin Free the the containing transport transport
SLC52A3
children, o hc te ae bound. are they which to ; Powers 2003 Powers ; eea population general predominantly the
and the the 27% in adults, and 36% and adults, in 27% A ad FMN. and FAD epciey Ynzw ad ni 2013). Inui and (Yonezawa respectively
diet s
hydroly etr de, aig up making diet, Western Powers 2003). metabolism in
) exist the brush the ,
and beyond and contain sis a , s ,
either as either
apart apart aual tasot pro transport saturable o re riboflavin free to
border of the ile the of border
FAD and FMN and FAD M hs s civd by achieved is This
l ad eggs and ilk rm ae eei dfcs n malabsorptive and defects genetic rare from
which
re riboflavin free in the elderly the in little
M
1 o itk i pecol children, preschool in intake of 51% ies ilk and dairy products dairy and ilk
, additional absorption of riboflavin riboflavin of absorption additional
al
oti fe riboflavin free contain
( which must be must which Yonezawa and Inui 2013 Inui and Yonezawa
y laie hshtss and phosphatases alkaline by enterocyte
cess or
rti denaturation protein carrier (Powers 2003). (Powers its its
hs tre transporters three These t h aia membrane apical the at protein bound form bound protein , allowing , - eitd uptake mediated released from released
deficienc
are the largest the are by
(Figure 1a) (Figure
Levy 1966; 1966; Levy
Due to the the to Due , absor SLC52A1 u most but ; y
Barile in the the in is ption
not the the
by as as : ,
This articleisprotected bycopyright.Allrightsreserved. cytosolic the i.e. isoforms, these of abundant most The 2016). al et Olsen 2016; al et Barile of splicing alternative by of isoforms FAD oxidase of NADPH in FAD of incorporation oxidase NADPH to TNFR1 couples ( factor necrosis ADP and riboflavin RFK human of FAD by adenylated subsequently phosphor by biosynthesis . to be leukocyte albumin enterocytes of membrane RFVT2 and RFTV1 by transported being after into released be may Riboflavin ( enzymes: two of action the by cofactors active catalytically its into transformed quickly is riboflavin uptake, cellular After
Accepted Article FADS RFK S 10.5, 6.6 al and74nmol/L(Hustad et 2002;Barile2016
) aaye te dnlto o FN o FAD to FMN of adenylation the catalyses
s a is E 2772 wih aaye M ad A pouto respectively production FAD and FMN catalyse which 2.7.7.2) (EC or s. M s.
this enzyme this immunoglobulins edian plasma concentrations concentrations plasma edian bqios rate ubiquitous revealed TNF
(
Yazdanpanah 2009) et al ) ( atiea e a 2003 al et Karthikeyan receptor
to
a
are are ylating riboflavin to form FMN FMN form to riboflavin ylating (
Barile six the the NADPH oxidase, which is critical for the assembly the for critical is which oxidase, NADPH distributed in different in distributed -
- stranded antiparallel beta antiparallel stranded limiting FLAD1 or - (TNFR1) 1 the portal the r
S et al al et bfai kinase iboflavin s ovre it is onye forms coenzyme its into converted is
to generate FAD generate to TF truh h atvto o RFK of activation the through TNF, . 2016
ee Trhti t l 00 Gacseo t l 2013; al et Giancaspero 2010; al et (Torchetti gene lvkns ta ctlss h frt tp in step first the catalyses that flavokinase ). for riboflavin, FMN and FAD have been reported been have FAD and FMN riboflavin, for blood - idn poen ht hscly n functionally and physically that protein binding
. Circulating plasma riboflavin is bound to bound is riboflavin plasmaCirculating )
. RFK which are are which and to the liver the to and
(
RFK Bii e a 2006) al et (Brizio (Brizio subcellular compartments subcellular a as be shown been also has - barrel core that that core barrel )
( ( Karthikeyan et al 2003 al et Karthikeyan C 2.7.1.26 EC
medd ihn h basolateral the within embedded et al 2006) al et ).
in its in . . free f free and ) complexes with both both with complexes The crystal structure crystal The In humans, distinct distinct humans, In
in erythrocytes or or erythrocytes in
orm or as FMN as or orm o be to
A synthase FAD and activation activation and a enhanc
nd Fgr 1b) (Figure ), which is which ),
generated generated a tumour es either either FAD
the the .
This articleisprotected bycopyright.Allrightsreserved. mitochondrialFAD membrane the across mitochondrial oforthologue theyeast mitochondrial FADtransporterFLX1 2005). (Spaan et al Accepted transporter folate ( and manyFAD mitochondriainto SLC25A32 2018). al of direction peptide targeting mitochondrial the FADS2 to compared ATP and FMN however, Articleactivity variants frameshift enzyme 2018) domain 2016). al et Olsen synthesis FAD catalyse 3 C a and activity, hydrolase FAD has which domain (MPTb) binding molybdopterin al et (Giancaspero activity hydrolase and isoform or enzyme ’ - phosphoadenosine the the .
F
fatty beta oxidation acid spiral. was discovered discovered was that that f FADS6 of
ntoa characteris unctional
its -
is an is dependent dependent mitochondrial enzymes, includingcomponents ofthe respiratory chain transport transport
provid aayi efcec (kcat/Km) efficiency catalytic translocator
inner mitochondrialinner that membraneimports carrier FADfrom th
(mitochondrial FAD Very Titus andMoran2000
es , 2, has been show been has 2, is -
thus cytosolic by 5 ’
approximately recently and - in patients in phosphosul ensur
FLX1 loig uvvl of survival allowing so ation ing
has been renamed the the renamed been has FAD synthesizing FADsynthesizing ,
a novel a cataly
FAD import FAD
, harbouring frameshift mutations of mutations frameshift harbouring ph suggested
. n n might and FADS6 - t (AS reductase (PAPS) ate 70% SLC25A32 s to be a bifunctional enzyme with both FAD synthase synthase FAD both with enzyme bifunctional a be to
transporter es ),
FADS6 ( Giancaspero etal 2014) before was it the the
ht f ua FADS2 human of that is
2015). bidirectional
is expected to expected is ht FADS6 that to facilitate facilitate to to due higher
euae the regulate isoform affected capacity
; was initially
Figure 1b)
FADS The demonstrat
con
in the presenceof the in patients enzyme flavoprotein biogenesis flavoprotein movement cofactor oftheredox domain may taining only theonly taining iohnra FAD mitochondrial domain be only be , whereitisneededfor the a
identified mitochondrialas a lower . ersn an represent
ed . The possibilitythat ( otis n N an contains T wih s ufcet to sufficient is which ,
Giancaspero et al 2015 al et Giancaspero ( to be cytosolic cytosolic Torchetti
he FAD synthesizing synthesizing FAD he FADS6 FLAD1
the humanthe biallelic biallelic PAPS reductase reductase PAPS
since
“ Km The t l 2011) al et ( e cytosol e cytosol emergency
Leone et al al et Leone transporter transporter
(Leone et et (Leone
- - o both for terminal terminal
FLAD1 it lacks lacks ” ; ;
This articleisprotected bycopyright.Allrightsreserved. generally is ariboflavinosis of prevention to 10 estimated an with recognised currently than widespread more potentially is Accepted it however restriction, dietary to attributed been usually has and vitamins other of deficiencies with association in occurs disease heart congenital of Garg to confined rashes skin scaly glossitis, neuropa peripheral migraines, retardation, known imperative. is intake r Since 4 4 Article doses 2016 10 riboflavin, urine the in eliminated is reabsorption, renal stored not hydroly rapidly are flavins Unbound confirmedneither SLC25A32 FAD regulates matrixthe frommitochondrial been efflux the to cytosolhas .1 . Riboflavi absor Nutritional ).
2017). ( Barile al et 2016 iboflavin is not is iboflavin This means that means This a b a s
or in the body, hence any intake in excess of tissue requirements or requirements tissue of excess in intake any hence body, the in n disorders n disorders in humans Low intakeduring pregnancy riboflavin with mayassociated anincreased risk be
riboflavinosis utili - yrxehllvn n lmfai (hsan n McCormick and (Chastain lumiflavin and hydroxyethylflavin
riboflavin deficiency – 15% of 15% e riboflavin se n or excluded C endogenously
linical ). riboflavin
the the ,
include Set e a 2008). al et (Smedts global population population global problems
Kney 06 Mrsl e a 2017). al et Marashly 2016; (Kennedy in human ce
has a relatively low toxicity even at at even toxicity low relatively a has
s
synthesized or synthesized ed to free riboflavin and excreted in urine. urine. in excreted and riboflavin free to ed night blindness, cataracts, fatigue, anaemia, growth growth anaemia, fatigue, cataracts, blindness, night
the the associated with dietary deficiency of riboflavin, of deficiency dietary with associated
not necessary not scrotum and vulva, and chapped lips) (Smith lips) chapped and vulva, and scrotum lls thy as .
having
riboflavin and
Symptomatic stored
dermatologic
an inherited an as
adequate amounts of amounts adequate in human in or its catabolites 7 catabolites its or
iolvn deficiency riboflavin al rest
tissue
supra symptoms (cheilosis, (cheilosis, symptoms riction in their ability ability their in riction upeetto for Supplementation s , - pharmacological adequate dietary dietary adequate which - alpha
riboflavin 1987 R iboflavin iboflavin surpasses - hydroxy ; Barile Barile ; often also also and are is
This articleisprotected bycopyright.Allrightsreserved. 4.2.2 Accepted MetabolicDisease Inherited transport supplemen acyl multiple resembling maternal with associated SLC52A1 syndrome T disease disorder known also Articleneuronopathy deficiency transporter riboflavin 1 SLC52A3 of Deficiency 4.2.1 4 phenobarbitol and phenothiazine including of consequence a as present. healthy a in available .2 p 2 iolvn rnpre dfcec nuooah, r Brown or neuronopathy, deficiency transporter riboflavin 2 ype Disorders riboflavintransport of Mitochondrial FAD transporter Brown ,
a disorder similar to BVVLS to similar disorder a Riboflavindeficiency ih ubr as ad esrnua dans (re e a 21) or 2010), al et (Green deafness sensorineural and palsy bulbar with are discussed in detail in the accompanying review accompanying the in detail in discussed are -
(BVVLS2 2 tation of riboflavin of tation ( iolvn transporter riboflavin
OMIM - as Brown as Vialetto the plasma membrane riboflavin transporters transporters riboflavin membrane plasma the the the # 211530 - coeliac coeliac Van Laeresyndrome – cancer chemotherapy agent Vialetto it ecp we te di the when except diet, ) -
- medications, antipsychotic derived is CoA dehydrogenase deficiency dehydrogenase CoA iolvn eiiny who deficiency, riboflavin )
asd y uain in mutations by caused (O’Callaghan al2019) et
disease
are associated with genetic neuronopathies genetic with associated are (Ho et al 2011 al et (Ho can – Van Laere syndrome Laere Van
however ( MM # OMIM , alcoholism, malignancies alcoholism, ,
1 deficiency
but
without sensorineural deafness sensorineural without
occur during lactation, phototherapy in infants, in phototherapylactation, during occur , Mosegaard et al 2017 al et Mosegaard , 61 5026
t s ey iie or limited very is et (
OMIM # 616839 caused by mutations in the the in mutations by caused a driamycin ) - .
1 (BVVLS1) 1 eeoe taset eee symptoms severe transient developed SLC52A2 a be rpre in reported been has (MADD) SLC52A2 the (Buehler 2011).(Buehler in this issue of the the of issue this in ,
antimalarial drug quinacrine, drug antimalarial . Haploinsufficiency of the the of Haploinsufficiency . or ) ,
,
use of prescription drugs prescription of use ) which a progressive neurologic progressive a .
te hat ise are issues health other D ( – OMIM #614707 OMIM isorders isorders Vialetto .
These include These (Bosch et al 2011) al et (Bosch
resolved with oral with resolved SLC52A3
two neonates, neonates, two Fazio – of riboflavin of Van Laere Laere Van Journal of Journal - Londe gene, )
t ype and or .
This articleisprotected bycopyright.Allrightsreserved. enzyme chain respiratory abnormalities metabolic and myopathy causing years few last Accepted the In 4.3.1 4.3 membrane riboflavin transporters from distinct quite MADD a have patients these that interesting is It endurance o following had patients Both p first fromthe fibroblasts skin cultured and Articlepatients both II) complex for staining 2017). al symptoms subsequently reporting, of features year transporter in mutations biallelic with patients Two
Primary defect ofriboflavinPrimary coenzymemetabolism - l gr wt riboflavin with girl old FAD synthase deficiency FAD synthase
ptnily raal neuromuscular treatable potentially a Muscle biopsy Muscle
presented at 3 years with years 3 at presented ( including including have been reported (Schiff et al 2016, Hellebrekers et al 2017). The first was first 2017). The al et 2016, Hellebrekers al et (Schiffbeen reported have Schiff etal
MADD succinate dehydrogenase ( dehydrogenase succinate and cytochrome and ral ral . had Deficiency of complex II was demonstrated in muscle from the second patient second the from muscle in demonstrated was II complex of Deficiency riboflavin progressive
rmtc mrvmns n h ciia and clinical the in improvements dramatic h nuoahc rsnain f ains ih uain i te plasma the in mutations with patients of presentation neuropathic the early (Schiff et al al et (Schiff
biallelic 2016, Hellebrekers al2016, Hellebrekers et 2017). revealed - deficiencies onset ataxia, myoclonataxia, onset supplementation, c
- oxidase (COX, mitochondrial respiratory chain complex IV) complex chain mitochondrial respiratory (COX,oxidase ( exercise epnie recurrent responsive OMIM variants RFVT2 and RFVT3.
ragged 2016 muscle weakness muscle
( SDH, # Taylor et al 2014, al et Taylor ). intolerance
in ugsie of suggestive 255100 - The red red FLAD1 atient FAD
SLC25A32 fibres nldn ipoe exercise improved including eod ain, 1 er od t h tm of time the at old years 51 patient, second us, dysarthria and dysphagia and dysarthria us, ) -
like predominantly myopathic presentation, myopathic predominantly like - ( dependent mitochondrial respiratory chain respiratory mitochondrial dependent Hellebrekers et al 2017, Schiff et al 2016). al et Schiff2017, al et Hellebrekers
disease noig FAD encoding n childhood in ,
lipid storage and storage lipid
xrie noeac and intolerance exercise
following an episode of influenza, and influenza, of episode an following
MADD
noig h mtcodil FAD mitochondrial the encoding Olsen et al 2016). al et Olsen
manifesting with lipid storage storage lipid with manifesting , n association in , biochemical oehr with together S
ae been have fibres with decreased with fibres
Thirteen
( Hellebrekers et Hellebrekers
tolerance and and tolerance with multiple multiple with
abnormalities abnormalities dniid as identified neurological biochemical patients
a 14 a in -
This articleisprotected bycopyright.Allrightsreserved. reported been all have C18:2 and C18:1 E 2). (Table tested cases all in acids organic urinary and acylcarnitines increased with MADD, deficiency FADS in biochemistry urine Accepted and Blood alAuranen et 2017) difficulties gait with weakness, muscle progressive and intolerance exercise with presented cases onset respectively years 56 and 44 at alive were all T years 16 at eighth the and life of 2016). failure multiorgan of died arrest cardiac sudden of episodes recurrent Article yea 22 at alive placement. defibrillator cardioverter implantable necessitating tachycardias supraventricular recurrent days 3 at died of hours 32 at collapse cardiorespiratory with presented patient One insufficiency. respiratory and feeding) tube necessitating frequently swallow, and suck (poor difficulties infants these of all in infancy in was Onset 2018). al et Yildiz 2017, al et Auranen 2016, al et Olsen 2014, al et (Taylor 1 Table in summarised are features exome whole by identified date to literature the in reported been have levations of levations hree treated with riboflavin with treated
children who presented in infancy were alive were infancy in presented who children Eight of the the of Eight ,
This infant had infant This iaea fo do ad ar and drop foot bilateral C4
(Olsen et al 2016) al et (Olsen rs -
C14 even chain acylcarnitines, C5 and C5 and C5 acylcarnitines, chain even C14 Osn t l 2016) al et (Olsen . eleven
included . Two individuals presented in adul in presented individuals Two .
cases with cases
a s equencing
dramatic response to riboflavin supplementation and was still still was and supplementation riboflavin to response dramatic yooi ad sever and hypotonia .
Tyo e a 04 le ta 21,Yli ta 2018) al et Yildiz 2016, al et Olsen 2014, al et (Taylor Another had cardiomyopathy in the first year of life and and life of year first the in cardiomyopathy had Another
. an nte ifn wo edd a needed who infant Another wans i te le patient older the in weakness m
or
infantile on infantile (Olsen et al 2016, Yildiz et al 2018). al et Yildiz 2016, al et (Olsen
(Olsen et al 2016, Auranen et al 2017) al et Auranen 2016, al et (Olsen through eleven all , cases u oe ain ( patient one but , two , candidate gene panels, gene candidate msl wans laig o feeding to leading weakness muscle e set died, seven within the first 9 first the within seven died, set are
(85%)
at 8 at yia o rbfai dfcec or deficiency riboflavin of typical - years years DC and C10:1, C14:1, C16:1, C14:1, C10:1, and DC t life, at 20 and 44 years, and years, 44 and 20 at life, t . Presenting features in almost almost in features Presenting . and ye e a 2018 al et Ryder
at 7 months (Olsen et al al et (Olsen months 7 at aeae bcue of because pacemaker the third at at third the
Osn t l 2016, al et (Olsen
and their clinical their and In one infant one In . The adult The . 22 years 22 age and age months months were ) - . ,
This articleisprotected bycopyright.Allrightsreserved. 1). (Table infancy in diagnosed all almost died, domain MPTb the in mutations life. of days 3 only at died fourth the Accepted affectingsingle a mutation amino had acid suggested been age. of months 8 and 4 between died five in ( terminationpremature and frameshift in a resulting a is deletion This effect. founder possible a suggesting prevalent, particularly be to appears homozygous the of Nine 2016 Article activity 2016). al et (Olsen activities enzyme chain respiratory muscle normal have and III tested cases 8 of 7 in biopsies muscle skeletal in observed reported been not have fibres of decrease global storage lipid pronounced with deficiency, FADS in pathology muscle characteristic 2018 al et Yildiz 2016, al et (Olsen observed ethylmalonic, been has tiglylglycine and hexanoylglycine acids,methylsuccinic glutaricand suberic, adipic, of excretion urinary Increased 2016). al et (Olsen others on abnormal and elevated was C4 only
five infants from four families four from infants five , Ryder et al2018 , Ryderet /or was ( c.401_404delTTCT, initially reported as reported initially c.401_404delTTCT,
IV with demonstrated in cultured skin fibroblasts fromfibroblasts skin cultured demonstratedin 13 FLAD1 ( Taylor Taylor
(Olsen et al 2016). Three of four individuals with at least one FADS domain FADS one least at with individuals four of Three 2016). al et (Olsen AD n ebr screening newborn on MADD ains eotd ih AS eiiny ee uks, n tre different three and Turkish, were deficiency FADS with reported patients COX ,
et al et uain wr osre i ti pplto (al 1). (Table population this in observed were mutations ). and in another the acylcarnitine profile was normal on so on normal was profile acylcarnitine the another in and
and/or
2014; Olsen 2014;
o far so SDH ( Taylor et al 2014 al et Taylor
. histochemical staining histochemical
Multiple
et al et ovrey al 8 all Conversely, pro psil g possible A
2016; Yildiz Yildiz 2016; long
Rdr t l 2 al et Ryder , resp was ed c.397_400delTTCT) , Olsen et al 2016, Yildiz et al 2018 al et Yildiz 2016, al et Olsen , p.(
iratory chain chain iratory
survival 22 (aliveat rae wt rbfai fr h frt 29 first the for riboflavin with treated Phe134CysfsTer8) , variably affecting complexes I, II, I, complexes affecting variably , enotype all all et al et patients
(Taylor et al 2014). al et (Taylor four
018 2018 - enzyme hntp correlation phenotype patients tested patients tested ). ih ilei fr biallelic with ). There appears to be a a be to appears There
One case was said to said was case One in the MPTb domain domain MPTb the in - ) 56 years), although56 years), , and was observed observed was and , eiinis were deficiencies Decreased FADS FADS Decreased One individual individual One
One mutation mutation One me occasions occasions me
Ragged (Olsen et al et (Olsen ameshift ameshift
and a a and )
. -
4 has has red red All bp bp This articleisprotected bycopyright.Allrightsreserved. test newborn screening mutation in phenotype severe otherwise an attenuated Accepted (Olsen proteins, mutated the of folding /or and stability coli Escherichia long 2016), al et (Olsen supplementation riboflavin to in mutations frameshift biallelic that proposed progression alertness and vomiting tone, muscle activity, spontaneous in mutation c.401_404delTTCT 2017) fat and low (maxwhich fat/day), symptomswas reported her 20g toameliorate Articlereport the and symptoms muscle of amelioration treated in improvements clinical in resulted supplementation Riboflavin identified so difficult far, andsoitis to make genotype firm 2018). al et (Ryder 201 have ahomozygous nonsensemutation MPTb inthe domain of months 8 bi - ). em survival term ochemical abnormalities in one adult patient adult one in abnormalities ochemical . .
This individual
Treatment with riboflavin riboflavin with Treatment et al et The nonsense mutation led to a truncated protein with some residual FADS activity activity FADS residual some with protein truncated a to led mutation nonsense The of life, but life, of Osn t l 06 Yildiz 2016, al et (Olsen
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ntal peetd with presented initially , riboflavin treatment riboflavin a small number of patients with patients of number small t g tre months three age at FLAD1
A supplementation FAD t l 2018 al et 8 an ). tde o te vrxrse mu overexpressed the of Studies increase in muscle strength, and strength, muscle in increase
h emd to seemed an erapy with high moderatecarbohydrate, with protein erapy
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8 Rdr t l 2018 al et Ryder , - supporting a chaperone a supporting
year initiated in the newborn period newborn the in initiated who was further described further was who but the doses used so far have not led to led not have far so used doses the but MADD - from 3 years of age of years 3 from old boy old in
FLAD1 eut n id mrvmns in improvements mild in result
two - iceia abnormalities biochemical phenotype predictionsphenotype
, Yildiz infcnl ipoe protein improved significantly but
FLAD1 with a with ains homozygous patients FLAD1 may be partially responsive partially be may
failed to prevent disease disease prevent to failed
t l 201 al et seven ) homozygous
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mutations have been have mutations - nldn dramatic including like action of FAD FAD of action like
and w and of improvements of improvements tant proteins in in proteins tant in a in 8 ( eight ) Auranen et al Auranen et .
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subsequent at present may have may nonsense nonsense
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This articleisprotected bycopyright.Allrightsreserved. 3) Table see (also above indicated as roles diverse The 4.4 and MADD of sequencing genome whole and exome a in result ( e was deficiency reactions. cellular many for cofactor essential an FAD, of discussedabove, as since, life incompatiblewith RFK 4.3.2 riboflavin 2018) al et e include strategies therapeutic the h with treatment postnatal presymptomatic siblings untreated and treated treatment and diagnosis early of benefits The analysis mutational awaiting be should supplementation riboflavin suspected is diagnosis the if and In
Accepted 2009) al et Yazdanpanah Article summary
Disorders thehuman of flavoproteome
ies symptoms disease human flavoproteome has been reported to comprise at least 90 distinct proteins distinct 90 least at comprise to reported been has flavoproteome human
Riboflavin kinaseRiboflavin deficiency deficiency
(Yildiz et al 2018) clinical presentation clinical - or , like clinicallike presentations may identify all patients with FADS deficiency should receive high receive should deficiency FADS with patients all the the
mbryonic a nvr en eotd n humans. in reported been never has mitochond ha . s lethal H
. ,
rial FAD transporter in those in transporter FAD rial
been owever, with nhancing the activity of the truncated FADS isoform FADS truncated the of activity the nhancing
similar to similar (Olsen et al 2016). The potential potential The 2016). al et (Olsen
eoe a 75 f etto in gestation of 7.5 day before
subsequent raised
t s possible is it that seen in seen that undiagnosed
igh dose riboflavin dose igh
but are
withdrawal
eurs ute exploration further requires RFK exemplified by exemplified affected
that Lehr e a 2013) al et (Lienhart
patients with patients is the rate the is patients with lipid storage myopathies storage lipid with patients
hypomorphic It is possible that this might be be might this that possible is It In support of this hypothesis this of support In
if the diagnosis is not confirmed not is diagnosis the if patients who do not benefit from from benefit not do who patients
case that that - s discordant outcome between outcome discordant limiting step in the synthesis the in limiting step
in the fullness oftime.in fullness the may prevent or ameliorate or prevent may a FLAD1
- knockout dose vne of avenue RFK implemented
riboflavin therapy riboflavin
. mutations Human diseases diseases Human
. mutations may may mutations os model mouse te future Other rntl or prenatal
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This articleisprotected bycopyright.Allrightsreserved. of whom metabolic 2007 2014) Grünert or insufficiency presentation, clinical frequent onset with associated c ( by (encoded dehydrogenase MADD brieflydiscussed below. mitochondrial the of some but disorders treatments. all of description potential as explored been have riboflavin of doses pharmacological disorders synthesis variegata epilepsy, responsive mit disorders, including heterogeneous, with associated been have
Accepted by encoded Article oenzyme ) . utytmc om n a and form multsystemic
R
, and for several several for and , , ( (93%) (93%) iboflavin iboflavin OMIM OMIM (Table abnormalities Q hoi gauoaos disease granulomatous chronic 10 ETFA ochondrial and peroxisomal fatt peroxisomal and ochondrial
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te ae a aeascnaycezm Q coenzyme secondary a have may cases Other have MADD rhabdomyolysis the 3 # ). Riboflavin responsiveness has not been reported for many of these these of many for reported been not has responsiveness Riboflavin ).
supplementation 231680 and mitochondrial ETFDH trimethylaminuri
in
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over 95% of 95% over approximately ) eg snrm ad te mtcodil eprtr chain respiratory mitochondrial other and syndrome Leigh of the human flavoproteome human the of
eeoeeu and heterogeneous ETFDH mutations s asd by caused is conditions ) manifest
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, hzmlc chondrodyspla rhizomelic a,
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ing
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successfully half of these proteins and are and proteins these of half t s o cer hte teaetc ras of trials therapeutic whether clear not is it
, as
n dfcs of defects and y acid oxidation disorders, disorders, oxidation acid y n o te w electron two the of one eiiny of deficiency xrie intolerance exercise have myopathic
(Olsen et al 2003) al et (Olsen en lsiid into classified been
ameliorate
- is beyond the scope of this review, review, this of scope the beyond is onset MADD onset steroidogenesis electron form 10 clini d
, deficiency -
. o dhdoeae to dehydrogenases CoA sia punctata, punctata, sia occasionally
h latter The - - rnfr flavoproteins transfer rnfr flavoprotein transfer . patients pyridoxal phosphate phosphate pyridoxal clin C cal cal ( le e a 2007; al et Olsen linical p linical a ically severe
symptoms and and symptoms
n bl acid bile and ( , Gempel et al et Gempel
the is the most most the is respiratory henotype extremely porphyria porphyria majority neonatal
full A s This articleisprotected bycopyright.Allrightsreserved. encephalopathy hypotonia progressive with deficien encephalopathy DLD of spectrum phenotypic branched Accepted and ketoglutaric, branched alanine, plasma elevated reflect branched α (PDHc), complex dehydrogenase by shared D 1997) has responsiveness onelarge in patients Article2014) al improving by chaperone chemical levels protein ACAD9 increase with 2016) al et abnormalities cardiomyopathy, combined or dilated hypertrophic, severe to hypertrophy electrical isolated from ranging presentations clinical major additional ACAD9 ihydrolipoamide
isolated complex I deficiency I complex isolated . It . It
PDHC and TCA cycle cycle TCA and PDHC
. - is possible is possible that is Therapeutic response to r to response Therapeutic chain α chain
he mitochondrial three onihig function moonlighting .
bifunctional a ACAD9
including stroke including ,
Leigh - keto acid keto xrie noeac ad ypty lci aioi ad neurological and acidosis lactic myopathy, and intolerance exercise dehydro also multinational cohort of ACAD9 deficiency (Repp et al 201 al et (Repp deficiencyACAD9of multinationalcohort mutations are the most frequent cause of cause frequent most the are mutations
syndrome FMN en eotd n othe in reported been - genase enzyme hi 2 chain dehydrogenase complex dehydrogenase - f ACAD9 of may stabilise like episodes, ataxic gait, brad gait, ataxic episodes, like
α and defect - ,
eocd dehydrogenase ketoacid -
and the in iboflavin (Collet et al 2016). al et (Collet chain amino acids and increased urinary lactic, pyruvic, 2 pyruvic, lactic, urinary increased and acids amino chain (
-
lo nw a E3, as known also hydroxy rescue complex I complex rescue primarily at ai oxidation acid fatty
- folding of specific ACAD9 mutant proteins (Nouws et et (Nouws proteins mutant ACAD9 specific of folding a s eoltrt dhdoeae ope (GC and (KGDC) complex dehydrogenase ketoglutarate ad include and , recurrent cy
deficiency deficiency , the complex Iholoenzyme.
supplementation was reported in 65% of treated treated of 65% in reported was supplementation - failure to thrive, to failure
n 2 and r forms of complex I deficiency (Ogle et al al et (Ogle deficiency I complex of forms r novd in involved s variable is Reye
- (BCKDC) eocd ( ketoacid
Riboflavin r early are assembly and assembly nrae bod att ad pyruvate, and lactate blood increased - like like noe by encoded
(FAO) multi ,
ope I complex presentation with presentation ykinesia
n encompasses and hypoglycemia, ketoacidosis and ketoacidosis hypoglycemia, hypertroph .
e erer t l 2016 al et Meirleir De - -
nye complexes: enzyme onset
The metabolic derangements metabolic The has been shown to shown been has Nus t l 2014). al et (Nouws
may also function as a as function also may and DLD
cardiac involvement involvement cardiac biogenesis
bradylalia bradylalia ic is )
cardiomyopathy
8 normal intellect intellect normal ) flavoprotein a
. Riboflavin al onset early ,
( with
directly Dewulf pyruvate
). The
an The The -
This articleisprotected bycopyright.Allrightsreserved. transporter FADmitochondrial the and transporters riboflavin membrane recent of T Conclusions cerebellar ataxia partially responsive toriboflavin (Heimer 2018). etal OMIM neuropathy, sensorimotor axonal ( oxidative combined with encephalomyopathy phenotypes clinical of spectrum wide to exposure mediat phosphorylation oxidative role dual a with flavoprotein X The riboflavin protein restoration partial abnormalities, metabolic of improvement weakness, muscle described been ketoacidosislactate, blood riboflavin no and
Accepted 2010) al et Ghezzi Article h e aiu piay r eodr defects secondary or primary various re re is years,
ing a supporting fibroblasts, in production ROS reduced and , residual neurologic residual - #
linked increasing evidence increasing 310490 -
promoting DLD responsive responsive programmed cell death when translocating from mitochondria to the nucleus nucleus the to mitochondria from translocating when death cell programmed
apoptotic stimuli (Joza et al 2009). 2009). al et (Joza stimuli apoptotic
def
(Carrozzo et al 2014) al et (Carrozzo ects AIFM1 )
( Rinaldi e Rinaldi ,
of to ypti peoye with phenotype myopathic
FAD synthase in the inthe FAD synthase
Cowchock ee noe apoptosis encodes gene
,
and protein stability andfoldingprotein deficits between acute metabolic episodes metabolic acute between deficits elevation ofelevation t
for a for al 2012) al
redox control and control redox
s a as
sensorineural potential potential
syndrome, an X an syndrome, .
. Riboflavin supplementation led to led supplementation Riboflavin
n R
creatine kinase kinase creatine ecently FAD agn from ranging of role flavocoenzyme
aneac o te cellular the of maintenance - eedn ND oxidoreductase NADH dependent
hshrlto deficiency phosphorylation efes n cgiie impairment cognitive and deafness of AIFM1 AIFM1 also also xrinl fatigue exertional - riboflavin riboflavin nuig atr AF, mitochondrial a (AIF), factor inducing - linked Charcot linked
as a caspase a as (Carrozzo al et 2014) and mitochondrial proliferation mitochondrial and
mutations have been reported to cause cause to reported been have mutations mutatio svr, early severe, a
biosynthetic pathway biosynthetic in the prevention and treatment treatment and prevention the in ns have been associated with associated been have ns - - independent death effector death independent ,
Marie
(Quinonez et el 2014) el et (Quinonez chaperone of elevation intermittent
complete resolution of resolution complete have all been linkedbeen all have - ne mitochondrial onset - flavoproteome.
ot dsae with disease Tooth . (
OMIM
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the f h DLD the of involved
(CMTX4, # plasma 300816 has
In In also . A .
on in a )
This articleisprotected bycopyright.Allrightsreserved. Ethics Biomedical Centre andthe Research Li Hospital Street Ormond Great NIHR the Charity, Children's Hospital Street Ormond Accepted Great Program Support Infrastructure Operational The andAcknowledgements funding Reports. and JIMD Disease. Metabolic Inherited no has she declares SB ofinterestConflict Compliance with ethic Article deficiency. secondary flavocoenzyme ribo of doses pharmacological flavocoenzyme enigma. Fu phenotypes. myopathic with associated are synthesis FAD and transport FAD mitochondrial of defects whereas (BVVL) neuronopathy a the why known disease human to udc C Murdoch
approval Because of the p the of Because deficiency, plasma membrane plasma eiinis ery eonto o tee dis these of recognition early deficiencies,
ide’ Rsac Isiue is Institute Research hildren’s Human .
s guidelines conflict of interest. JC is a communicating editor of the Journal of Journal the of editor communicating a is JC interest. of conflict otential
and iolvn iae deficiency kinase riboflavin
SR is an editor of the of editor an is SR lvn r rqie fr non ros associ errors inborn for required are flavin r
esponse to treatment to esponse beneficial effect ofbeneficial effect
riboflavin transport riboflavin
ly Foundation. .
SR is supported by research grant funding from from funding grant research by supported is SR te rsac wl b nee t urvl this unravel to needed be will research rther
upre b te itra Government's Victorian the by supported riboflavin
Disease Metabolic Inherited of Journal
er may be may
disorders disorders remains to be described. described. be to remains
more variable in patients in variable more in both in orders manifest predominantly as as predominantly manifest
primary and secondary primarysecondary and is imperative td with ated . t s not is It primary Supra
with with -
This articleisprotected bycopyright.Allrightsreserved. effect ofvitaminlike B2. mitochondrial responsive Riboflavin phe new a is myopathy (2014) al et G Fiermonte A, Torraco R, Carrozzo Accepted Alternative Medicine Riboflavin B2: Vitamin (2011) BA Buehler Res Commun of characterization C Brizio errorofmetabolisminborn withpotential treatment. new a MADD: mild mimicking defect transporter riboflavin a with associated is syndrome I NG, Abeling AM, Bosch Article metabolism Metab Inherit in humans. Dis J M Barile acyl multiple with Patient Disorders27:581 Neuromuscular (2017) al et P and disease deficiency dehydrogenation Piirilä A, Paetau MA, Auranen References approvalEthics wasnotrequiredfor publication of this ,
, Giancaspero TA Giancaspero
alci M Galluccio :
344(3):1008
two
16(2): 88 notype of dihydrolipoamide dehydrogenase deficiency. The chaperon The deficiency. dehydrogenase dihydrolipoamide of notype
recombinant ,
Mitochondrion at R Wait - ,
1016 Leone P Leone j s L lst - 90. .
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mutations benefits benefits mutations , ua FAD human
Indiveri C Indiveri
J Inherit Dis Metab - 57. - Vialetto review - xrsin in expression
(2016) Riboflavin transport and and transport Riboflavin (2016) .
yteae Bohm Biophy Biochem synthetase. -
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This articleisprotected bycopyright.Allrightsreserved. Genet X Severe apoptosis (2010) in mutation al a with et associated encephalomyopathy F Invernizzi I, Sevrioukova D, Ghezzi AcceptedPubMed Central PMCID:PMC4345103. gene. Brain. 2007 Aug;130 mutationsby inthe electron Lochmüllermyopathic form H,Horvath R.The ofcoenzymeQ10 caused deficiencyis C,Hirano Kale G,TokatliA,Quinzii M,Naini A, DiMauroS,Prokisch H, H,GempelTopaloglu K, TalimP, BG, B,Schneiderat Schoser HansVH,PálmafyB, Metabolism patients. nine on Report mutations: ACAD9 to due involvement Barrea JP, Dewulf Article Diseases DiagnosisMetabolic andTreatment. J Walter MR, Baumgartner JM, Saudubray In Cycle. Acid Tricarboxylic the LJ, Meirleir De Genetics childhood. in mutations ACAD9 to due hypertrophy cardiac of outcome clinical variable and incidence High (2016) al et Bonnet Z, Assouline M, Collet human Am urine. Nutr46:830 JClin and identification catabolites: Flavin (1987) DB JL,McCormick Chastain
86: 639
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– C, Vincent MF (2016) Evidence of a wide spectrum of cardiac cardiac of spectrum wide a of Evidence (2016) MF Vincent C, 189. - Cazorla A, Brivet M (2016) M Brivet A, Cazorla
(Pt 8):2037 - transferring – 834 - 44. Epub 2007 Apr 5. PubMed PMID: 17412732; 44. Epub2007Apr PMID:17412732; 5.PubMed -
flavoprotein dehydrogenase (ETFDH) .
Heidelberg: Disorders of Pyruvate Metabolism and and Metabolism Pyruvate of Disorders Springer Berlin - nuig factor inducing European Journal of Human Human of Journal European oeua Gntc and Genetics Molecular - ikd mitochondrial linked
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This articleisprotected bycopyright.Allrightsreserved. Genetics phenotype. neuromuscular severe a with patient a in mutation DMEI Hellebrekers Accepted cerebellar ataxia partially responsive toriboflavin. Eyal G, Heimer dehydrogenase deficiency. late of heterogeneity genetical and Clinical (2014) SC Grünert 489. C20ORF54 in mutations by caused is deafness, with palsy bulbar (2010) al et YJ Crow M, Wiseman P, Green Articlemitochondrial translocator FLX1.Biomed 2014:101286. ResInt. lifespan decreased and homeostasis ROS of Alteration (2014) M Barile M, Caselle E, Boles A, Miccolis E, Dipalo TA, Giancaspero homeostasiscofactor and flavoprotein biogenesis.FrontChem. 22:3:30. Brizio M, Colella TA, Giancaspero createalocalflavinnucleus cofactor Biol pool. J Chem. 288(40):29069 the in degradation and synthesis FAD (2013) al et C Panebianco G, Busco TA, Giancaspero
25: 886
– , h X t l 21) uain i AF1 as a X an cause AIFM1 in Mutations (2018) al et X Zhu E, 888. ,
alvl SCEH Sallevelt
Orphanet JournalofRare Diseases
e a (05 Rmiig hlegs n ellr flavin cellular in challenges Remaining (2015) al et C ,
huisn TEJ Theunissen
in S. cerevisiae elicited by deletion of the the of deletion by elicited cerevisiae S. in Brown Eur JPaediatrNeurol - Vialetto
et al al et -
9:117. Van Laere syndrome, a ponto a syndrome, Laere Van - onset multiple acyl multiple onset European
. (2017) Novel SLC25A32 SLC25A32 Novel (2017)
Am J Hum Genet Hum J Am
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22(1):93 Journal of Human of Journal - ikd childhood linked
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86: 485 86:
- - This articleisprotected bycopyright.Allrightsreserved. Nutrient Efficacy and Dose Mechanisms, Brain: the and Vitamins B (2016) DO Kennedy AcceptedStructure arch site active novel a and fold barrel beta a reveals kinase riboflavin human of structure Grishin F, Mseeh Q, Zhou S, Karthikeyan NY AcadSci apoptosis an just not AIF: (2009) al et E Hangen JA, Pospisilik N, Joza vanJoostenV, WJ(2007)Flavoenzymes. Berkel supplementation.riboflavin ClinChem48:1571 low after and baseline at erythrocytes and plasma human in dinucleotide adenine flavin Article H McNulty MC, McKinley S, Hustad transporter geneGPR172B. 32:E1976 Hum Mutat neonatal transient Yonezawa G, Ho Chemistry Publishing No Focus in Components Nutritional and Food In BJ, Henriques Preedy VR. Preedy s
11: 265 8(2):68
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Rodrigues B Vitamins and Folate: Chemistry, Analysis, Function and Effects and Function Analysis, Chemistry, Folate: and Vitamins B . - -
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onsetmicrodeletion aciduria by type glutaric caused in riboflavin a 2,is the , aua e a (01 Mtra rbfai dfcec, eutn in resulting deficiency, riboflavin Maternal (2011) al et S Masuda A, - ,
11. chapter 37.
JV, Gomes CM (2013) Riboflavin and b and Riboflavin (2013) CM Gomes JV,
t l 20) iolvn fai mnncetd, and mononucleotide, flavin Riboflavin, (2002) al et
NV, Osterman AL, Zhang H (2003) Crystal Crystal (2003) H Zhang AL, Osterman NV, – Curr 1577. - E1984. 4. .
Opin
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Biol - oxidation Flavoenzymes oxidation h Ryl oit of Society Royal The 11:195 - inducing factor. inducing – 202. –
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This articleisprotected bycopyright.Allrightsreserved. 1311 deficiencies. oxidation acid fatty in function moonlighting a with factor LG Nijtmans H, Brinke Te Accepted J, Nouws deficiency. riboflavin transient and skipping exon S Mosegaard Rev pyridoxine. and riboflavin vitamins: B interconnected Two (1989) DB McCormick Parkinson's ET,BohlegaMarashly SA(2017) Article Biophys Lienhart Sci G Levy An Emergency Protein? Humans: in Synthase FAD of Isoform Monofunctional Novel a of Modeling Protein and Characterization Production, Bacterial (2018) al e A Barbiroli M, Galluccio P, Leone .
55(3):285 69:1170 – 1319.
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Mol GenetMetab Mol
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and – Molecules 162. 16) Factors (1966)
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23: 23: This articleisprotected bycopyright.Allrightsreserved. Riboflavin (vitaminPowers HJ(2003) B AcceptedPinto combined respiratory responsive Riboflavin (2016) al et TA Giancaspero E, Konarikova RKJ, Olsen Aug;130(Pt 8):2045 riboflavin N,Gregersen DM, as Turnbull AA.mutations Morris ETFDH amajor of cause Frerman MW, Beresford FE, DeanJC,Cornelius N,Andersen O,OldforsA,Holme E, Olsen RK,Olpin SE,Andresen BS,Mi Article deficiency.CoA dehydrogenation acyl multiple with patients in phenotype and Clear genotype (2003) ETF/ETFDH between N relationship Gregersen F, Skovby P, Bross E, Christensen BS, Andresen RK, Olsen andmutation complex Ideficiency responsive to riboflavin (1997) al et E Fagan J, Christodoulou RF, Ogle Dis[inMetab press] Pathomechanisms (2019) and Presentation H Houlden A, Bosch B, O’Callaghan
JT ,
Zempleni - multipleresponsive acyl uain i FD ytae as mlil acyl multiple cause synthase FAD in mutations
J -
54. Epub 2007Jun20.PubMedPMID: 17584774. - ( chain deficiency. 2016) Riboflavin. Hum Mutat - CoA defic dehydrogenation
f ua Rbfai Tasotr Deficiency Transporter Riboflavin Human of edzybrodzka ZH,Pourfarzam B, M,Merinero
Am Genet JHum Adv Nutr - 2) and 2) and health.
22: 12
Mitochondrial myopathy with tRNA with myopathy Mitochondrial
7(5):973 An Update on the Genetics, Clinical Clinical Genetics, the on Update An – 23. Am Nutr JClin
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This articleisprotected bycopyright.Allrightsreserved. acyl multiple in role potential its and transporter FAD mitochondrial human the of Identification AcceptedSpaan ErrorsBiomarkers Metabolism in Inborn of Smith 47:357Eur JNutr defects. heart congenital with offspring having of risk the and nicotinamide and riboflavin Verkleij M, Rakhshandehroo HP, Smedts riboflavin Veauville M, Schiff Article 2018 Oct12.doi: Acyl Multiple Z, Nochi M, Tolomeo B, Ryder a mutation in apoptosis Sevrioukova C, Grunseich C, Rinaldi Rare Dis effective? supplementation riboflavin is deficiency: ACAD9 with patients 70 of Repp BM - CoA
AN LD, Garg U (2017) U Garg LD,
13(1):120. , - , dehydrogenase deficiency.
responsive exerciseresponsive intolerance.
Mastantuono E js L Ijlst - CoA Dehydrogenase CoA 10.1007/8904_2018_139. PubMed ofprint] [Epubahead PMID:30311138. - , 3
van
65. - eli A Acquaviva A, Merllie
- inducing factor. inducing orud CW Roermund ,
Alston CL Alston Disorders of vitamins and cofactors. and vitamins of Disorders et al (2018) al et Deficiency ( Deficiency
Mol GenetMetab Mol
IF al(2018) Clinical,et biochemical andgeneticspectrum Am JHum Genet ,
et al (2012) Cowchock syndrome is associated with associated is syndrome Cowchock (2012) al et ibr FA Wijburg - New E aor A e al et AC Hagoort , first , first ed -
oran (2016) C Bourdain A Novel Truncating FLAD1 Variant, Causing Causing Variant, FLAD1 Truncating Novel A MADD) in an 8 an in MADD) ng JMed . Elsevier. ,
86(4):441 adr RJ Wanders
91(6):1095
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, 361 (2008) (2008) - - In Garg U, Smith LD Smith U, Garg In 44 - Year SLC25A32 397. - 7 , 797. –
aehm HR Waterham Maternal intake of fat, fat, of intake Maternal 1102. -
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This articleisprotected bycopyright.Allrightsreserved. Med RFVT/SLC52functionalofcharacterizationandgeneticdiseases nomenclature, Yonezawa Accepted Infancy. Early in Disorders Neuromuscular Hypotonia with Siblings Turkish 2 in Mutations FLAD1 of Detection Tokatli HH, Nygaard Z, Akcoren HS, Sivri RKJ, Olsen Y, Yildiz TNF couples kinase 1toreceptor NADPH oxidase Riboflavin (2009) al et V Tchikov K, Wiegmann B, Yazdanpanah isoformsynthetase 1.Mitochondrion 10(3):2 FAD human of localization Mitochondrial (2010) al et M Colella C, Brizio EM, Torchetti Article4449 apo to FAD delivers that machinery the of component EM Torchetti Chem mitochondria. into folates of entry for carrier the encoding gene human a of cloning phenotype: glyB the of complementation mediated Retrovirally (2000) RG Moran SA, Titus 68 deficiencies complex chain respiratory mitochondrial multiple of basis genetic (20 al et H Griffin A, Pyle RW, Taylor - 77.
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Available 31Mayonline 2018.DOI: alci M Galluccio No .
Nature vel riboflavin transporter family RFVT/SLC52: identification, familyRFVT/SLC52: transporter riboflavin vel
460: 1159 1
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Use of whole of Use 63 - 273. - 1163.
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- - flavoproteins. exome sequencing to determine the the determine to sequencing exome 10.1016/j.nmd.2018.05.009
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This articleisprotected bycopyright.Allrightsreserved. Accepted Article and orally of Pharmacokinetics (1996) DB intrav McCormick JR, Galloway J, Zempleni enously administered riboflavin inhealthy humans. Am JClinNutr
63:54 – 66.
This articleisprotected bycopyright.Allrightsreserved. Accepted8 (S5) 7 (S4b) 6 (S4a) 5 (S3) 4 (S2) Article3 (S1b) 2 (S1a) 1 Patient* caseswithdeficiencyTable 1:Reported synthase FAD
(30)
M F F F F M F M Sex
Italian Finnish Turkish Turkish Turkish Ethnicity Turkish Turkish Turkish
life months of First 8m 4m 44y 20y 3m 32hr 4m onset Age at
7 16y 8y Alive 56y Alive 44y Alive 22y Alive 3d 8m death Age at m
Phenotype (pacemaker), diedof sudden cardiac arrest months, recurrent episodes of respiratory 6 infection at fewfirst Poor sucking andhypotoniain ofpneumoniadied scoliosis,weakness, tube fed, muscleSevere hypotonia and from infancy Increasing ofbotharmsdrop, weakness difficulties, foot bilateral intolerance,Exercise gait progressive muscle weakness intolerance,Exercise responsive riboflavin of life, Cardiomyopathy infirst year collapseCardiorespiratory myopathylipid Respiratory insufficiency,
recurrent SVTrecurrent (ICD),
months life, of muscle
hypotonia
Mutations c.401_404delTTCT; Homozygous frameshiftdeletion c.526_537delinsCA;p. Homozygous frameshiftindel c.526_537delinsCA;p. Homozygous frameshiftindel c.1588C>T;p. c.836delT;p. Compoundheterozygous and c.1588C>T;p. c.568_569dupGC;p. Compoundheterozygous c.1484_1486delCCT;p. Homozygous in c.1484_1486delCCT;p. Homozygous in c.397_400delTTCT) reported (originally as c.401_404delTTCT; Homozygous frameshiftdeletion
( Phe279Serfs*45 ( Arg530Cys - - frame deletion frame deletion ( Arg530Cys ( p. p.
Val191Glnfs*10 ( ( ( ( Phe134C Phe134C Ala176Glnfs*8 Ala176Glnfs*8 ( ( Ser495del Ser495del
)
) )
and
ysfs ysfs ) )
∗ ∗ 8 8 )
) ) ) )
MPTb MPTb MPTb FADS MPTb, FADS MPTb, FADS FADS MPTb affected domain Enzyme
2016 Olsen 2016 Olsen 2016 Olsen 2016 Olsen al Auranen 2016 Olsen 2016 Olsen 2016 Olsen 2014 Taylor Reference
2017 ; et alet alet alet alet alet alet alet et al
et et
This articleisprotected bycopyright.Allrightsreserved. Accepted13 12 11 Article10 (S7) 9 (S6)
(P2) (P1)
M F M F F
Turkish Turkish Italian Pa Turkish lestinian
of diagnosis NBS 2m 2m 2m birth
8y Alive 5m 6m 4m 9m
respiratory insufficiency frequent vomiting, Hypotonia, poorsuck, failuremultiorgan after cessationafter oforal first speech noted Myopathic facies movements. vomiting, decreased difficulties, swallowing poor suck, distinctcontrol, hoarse cry, Weak, floppy,nohead of aspiration pneumonia treatment 5m (extubated ventilationinvasive insufficiency requiring vomiting, respiratory feeding,suck, tube persistent movements,decreased poor Progressive andweakness leading to death ventilationinvasive and months, requiringnon respiratory deteriorationat4 feeding,nasogastric sudden swallowing difficulties, and muscle weakness, neonatalhypotoniaSevere pneumonia shockof following septic
commenced)
tube feeding,
after riboflavinafter
and nasal
at severe severe
from 2.5 3 - years, , died , died
died died - c.498delC+c.508T>C; c.324delG;p. Compoundheterozygous c.745C>T H c.401_404delTTCT; Homozygous frameshiftdeletion c.401_404delTTCT; Homozygous frameshiftdeletion c.401_404delTTCT; Homozygous frameshiftdeletion Ser167Profs*20+p.Phe170Leu omozygo ; p. us nonsense variant nonsense us ( ( Arg249*) Arg109Alafs*3 p. p. p. ( ( ( ( Phe134C Phe134C Phe134C
p.
)
and )
ysfs ysfs ysfs ∗ ∗ ∗ 8 8 8 ) ) )
MPTb MPTb MPTb MPTb MPTb
2018 Ryder 2018 Yildiz 2018 Yildiz 2016 Olsen 2016 Olsen
et alet alet et al et et al et al
This articleisprotected bycopyright.Allrightsreserved. Accepted domain;molybdopterin binding Article cardioverter implantable to refers brackets in number * Key: - defibrillator; screening. newborn through up picked MADD, NBS newbornscreening; dniiain number identification ne insertion/deletion; indel
years. E years. with speech at difficulty 6 velopharyngeal riboflavin. intolerance exerciseworsening with SVT
fatigue on
volving myopathy n rgnl publication; original in supraventricular tachycardia S
at evere evere
months; m 8 years.
chewing and chewing and i nsufficiency
MADD
days; d utpe clo dhdoeae deficiency dehydrogenase acylCoA multiple ; y years AS A snhs domain; synthase FAD FADS
hr hours; hours; hr ;
MPTb ICD This articleisprotected bycopyright.Allrightsreserved. Accepted Article fibroblasts activity in FADSDecreased Normal RCEs deficiencies RCEMultiple activities: RCEMuscle organic acids urinary Increased acylcarnitines plasmaIncreased Abnormality Table 2
Biochemical abnormalities in reported FADS deficiency
4 1/8 7/8 9 10 Number / / 4 9 / 10
100% 12.5% 87.5% 100% 100% % tested ofthose
Ryder Olsen Olsen Yildiz Olsen Taylor Ryder Yildiz Olsen Ryder Yildiz Olsen Reference(s) et al et al et al et alet alet alet alet alet et al et al et al et al et
2018 2018 2018
2014; 2014; 2016 2016 2016; 2016; 2016; 2018 2018 2018
; ;
;
This articleisprotected bycopyright.Allrightsreserved. D2HGDH CYBB CYB5R3 AcceptedCOQ6 AIFM1 AGPS ACOX2 ACOX1 ArticleACADVL ACADS ACADM ACAD9 symbol Gene Table 3
: Disorders of of the: Disorders humanflavoproteome
monooxygenase 6 Q Coenzyme factor Apoptosis synthase acetonephosphate Alkyldihydroxy peroxisomal branched Acyl peroxisomal palmitoyl, Acyl long dehydrogenase, Acyl short dehydrogenase, Acyl medium dehydrogenase, Acyl 9 member family, dehydrogenase Acyl Protein Hydroxyglutarate Hydroxyglutarate D 245), b( Cytochrome reductase 3 b5 Cytochrome - 2 ------chain CoA CoA oxidase,CoA oxidase,CoA CoA CoA CoA
beta subunit chain
-
chain - chain, chain, -
inducing inducing
10
-
- very very
1.3.8.8 (BRENDA) E 1.1.99.39 N/A 1.6.2.2 N/A N/A 2.5.1.26 N/A 1.3.3.6 1.3.8.9 1.3.8.1 1.3.8.7 . C .
number
FAD FAD FAD FAD Cofactor FAD FAD FAD FAD? FAD FAD FAD FAD
201475 201470 201450 611126 OMIM 600721 306400 250800 614650 300614 310490 300816 600121 617308 264470
#
myopathy adult hypoglycaemia, hypoketotic infantile/ cardiomyopathy, Neonatal asymptomatic NBS by cases identified many Variable features, fasting prolonged with encephalopathy hypoglycaemic Hypoketotic onset muscle intolerance later exercise acidosis, lactic with cardiomyopathy hypertrophic onset Infantile Phenotype aciduria aciduria D disease, X granulomatous Chronic Methaemoglobinaemia deafness sensorineural and (FSGS) syndrome nephrotic severe progressive deficiency Q coenzyme Primary deafness syndrome, X Cowchock deficiency, OXPHOS Combined 3 type punctata chondrodysplasia Rhizomelic 6 type defect synthesis Bile acid adrenoleukodystrophy neonatal syndrome or Zellweger resembling disorder oxidation Peroxisomal - 2 - hydroxyglutaric hydroxyglutaric
weakness
- early childhood childhood early
developmental developmental - – linked
- infantile onset infantile onset fatty acid fatty linked linked
10 - onset
and and
This articleisprotected bycopyright.Allrightsreserved. KDM1A IYD IVD AcceptedGFER GCDH FOXRED1 FMO3 FLAD1 FDXR ArticleETFDH ETFB ETFA DUOX2 DLD DHODH DHCR
dehydrogenase Glutaryl 1 protein domain oxidoreductase FAD monooxygenase 3 Flavin FAD synth reductase Ferredoxin dehydrogenase flavoprotein transfer Electron subunit beta flavoprotein transfer Electron subunit alpha flavoprotein transfer Electron 2 Dual oxidase dehydrogenase Dihydrolipoyl dehydrogenase Dihydroorotate reductase Dehydrocholesterol 24 dehydrogenase demethylase 1A demethylase Lysine deiodinase Iodotyrosine dehydrogenase Isovaleryl like erv1 factor, Growth -
- dependent dependent - - containing containing
- specific containing containing -
CoA
-
CoA ase
- 1.3.1.72 1.14.11.B1 N/A 1.3.8.4 1.8.3.2 1.3.8.6 N/A 1.14.13.8 2.7.7.2 1.18.1.2 1.5.5.1 N/A N/A 1.6.3.1 1.8.1.4 1.3.5.2
FAD FAD FAD FAD FAD FMN FAD FAD FMN FAD FAD FAD FAD FAD FMN FAD
231680 231680 231680 607200 246900 263750 602398 616728 274800 243500 613076 231670 252010 256000 602079 255100 617717
MADD MADD MADD 6 dyshormonogenesis Thyroid KGDHC and PDHC BCKDHC, of deficiency Combined dysostosis acrofacial syndrome Miller anomalies congenital Desmosterolosis features dysmorphic and hypotonia, epilepsy, delay, retardation, and distinctive distinctive and retardation, psychomotor Cleft palate, 4 dyshormonogenesis Thyroid ketoacidosis of episodes recurrent acidemia Isovaleric delay developmental and loss congenital myopathy, Mitochondrial disorder movem progressive lesionsand ganglia basal macrocephaly, I type aciduria Glutaric deficiency mitochondrial syndrome, Leigh Trimethylaminuria storage myopathy Lipid atrophy optic Auditory
neuropathy and neuropathy
cataract, hearing cataract, hearing
complex I
- -
multiple postaxial postaxial
ent -
–
This articleisprotected bycopyright.Allrightsreserved. SUGCT SLC52A3 AcceptedSLC52A2 SLC52A1 SLC25A32 SDHA PRODH PPOX POR ArticlePNPO NDUFV2 NDUFV1 MTRR MTHFR L2HGDH
transporter nucleotide flavin Mitochondrial A subunit flavoprotein dehydrogenase Succinate 1 dehydrogenase Proline oxidase Protoporphyrinogen oxidoreductase P450 Cytochrome oxidase phosphate 5' Pyridoxal 2 flavoprotein oxi NADH 1 flavoprotein oxidoreductase NADH reductase synthase Methionine reductase tetrahydrofolate 5,10 dehydrogenase Hydroxyglutarate L glutarate Succinyl (RFVT3) 3 transporter Riboflavin (RFVT2) 2 transporter Riboflavin (RFVT1) transporter Riboflavin -
2 doreductase - - Methylene - -
ubiquinone ubiquinone ubiquinone - -
CoA CoA:
1 -
-
1.1.99.2 N/A N/A N/A N/A N/A N/A 1.5.99.8 1.3.3.4 1.6.2.4 1.4.3.5 1.6.5.3 1.6.5.3 1.16.1.8 1.5.1.20
FMN FMN FMN FMN FAD FAD FAD FAD FAD FAD FAD FAD FAD FAD FMN
610090 252010 252010 236270 236250 236792 231690 211530 615026 616839 614165 252011 256000 239500 176200 201750
614707
Pyridoxal phosphate phosphate Pyridoxal deficiency complex I Mitochondrial deficiency complex I Mitochondrial anaemia) megaloblastic and (homocystinuria deficiency Cobalamin E deficiency MTHFR to due Homocystinuria MRI nucleion dentate and putamina in changes signal and atrophy, cerebellar leukoencephalopathy, subcortical aciduria L facial features Glutaric aciduria type III type aciduria Glutaric BVVL BVVL deficiency Riboflavin exercise intolerance responsive Riboflavin paragangliomas deficiency, mitochondrial syndrome, Leigh I Hyperprolinaemia type variegata Porphyria steroidogenesis disordered anomalies and genital with Antley epilepsy responsive - 2 - hydroxyglutaric hydroxyglutaric
- syndrome syndrome Bixler syndrome –
PMR with with PMR
complex II
This articleisprotected bycopyright.Allrightsreserved. Accepted PMR Article ( Man in Inheritance Mendelian deficiency dehydrogenase glomerulosclerosis; mononucleotide; flavin FMN dinucleotide; adenine FAD flavin system (http://www.brenda enzyme information Key: Lienhartin etal 1 fromselected Table flavoproteins List of XDH TXNRD2
BCKDHC branched BCKDHC psychomotor retardation
dehydrogenase Xanthine 2 reductase disulphide Thioredoxin transferase
KGDHC alpha KGDHC -
(see main text for clinical details) clinical (see for main text chain alpha chain
https://www.omim.org
- ketoglutarate dehydrogenase comp dehydrogenase ketoglutarate - 1.8.1.9 1.17.1.4 keto acid dehydrogenase complex; dehydrogenase acid keto
- enzymes.org); enzymes.org); ) ; FAD FAD PDHC pyruvate dehydrogenase complex; complex; dehydrogenase PDHC pyruvate
2013 ;
NBS newborn screening; screening; NBS newborn BVVL Brown FSGS
278300 617825
focal segmental segmental focal lex; BRENDA Comprehensive Comprehensive BRENDA MADD
- Vialetto multiple acylCoA multiple acylCoA xanthine stones xanthine typeI, Xanthinuria deficiency Familial glucocorticoid - OMIM OMIM Online Van Laere; Van
This articleisprotected bycopyright.Allrightsreserved. Accepted 545 39; Dis (2016): Metab Inher remain cytosol matrix the mitochondrial to the FAD from Articleinto from cytosol the FAD mitochondrial step. depicted Wehave date. to established brain. RFVT2 immunoglobulins. or albumin either to bound blood in istransported plasma riboflavin Circulating as hRFT3). known (also RFVT2 and expres by basolaterally blood portal releasedinto and as hRFT2) known (also RFVT3 expressed apically via the intestine into is absorbed then Riboflavin enterocytes. borderileal of brush atthe riboflavin by hydrolases to areconverted FMN FADand Dietary 1a Figure legend Figure
Subsequent conversion into flavocoenzymes occurs in tissue cells, as shown in figure1 in cells,asshown tissue in flavocoenzymesinto occurs conversion Subsequent
The The
precise s
mechanism of im mechanism of - transporter (FADT) (FADT) transporter
the mitochondria -
557. port of r of port
RFVT? RFVT? .
The question mark indicates that that mark indicates question The is an inner mitochondrial membrane carrier that imports FAD imports that carrier membrane mitochondrial inner is an iboflavin into the mitochondrial matrix mitochondrial the iboflavin into - mediated transport allows riboflavin uptake into the uptake allows riboflavin mediatedtransport as a putative riboflavin transporter riboflavin a putative s to be established be s to sed RFVT1 (also known as hRFT1) ashRFT1) known (also RFVT1 sed FADT .
See also Barile et al,J See alsoBarile - mediated efflux of of mediated efflux
responsible for this this for responsible has not been has not b.
The The This articleisprotected bycopyright.Allrightsreserved. Accepted Article FAD synthase. by catalysed adenylation γ the facilitates Zn ATP. stepsrequire Both synthase. kinase FAD and riboflavin involving apathway sequential formed by are flavocoenzymes riboflavin, of uptake After cellular 1b Figure
- phosphate exchange catalysed by riboflavin kinase, whilst Mg kinase, whilst riboflavin by catalysed exchange phosphate
2+
is the preferred metal ion which which metal ion is preferred the 2+
is used in the in is used
This articleisprotected bycopyright.Allrightsreserved. Accepted Article