Original Citation:
Clinical syndromes associated with Coenzyme Q10 deficiency.
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10.1042/EBC20170107
Università degli Studi di Padova
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1
Clinical syndromes associated with Coenzyme Q10 deficiency 1
MaríaAlcázar-Fabra1,EvaTrevisson2,GloriaBrea-Calvo12
1CentroAndaluzdeBiologíadelDesarrolloandCIBERER,InstitutodeSaludCarlosIII,3
UniversidadPablodeOlavide-CSIC-JA,Sevilla41013,Spain;2ClinicalGeneticsUnit,4
DepartmentofWomen’sandChildren’sHealth,UniversityofPadova,Padova35128,Italy5
6
Addresscorrespondenceto:7
Dr.GloriaBrea-Calvo8
CentroAndaluzdeBiologíadelDesarrollo9
UniversidadPablodeOlavide10
CarreteradeUtrerakm111
41013Sevilla,12
Spain13
Email:[email protected]
Tel.+3495497763715
Abstract 16
PrimaryCoenzymeQdeficienciesrepresentagroupofrareconditionscausedbymutationsin17
oneofthegenesrequiredinitsbiosyntheticpathwayattheenzymaticorregulatorylevel.The18
associated clinical manifestations are highly heterogeneous and mainly affect central and19
peripheral nervous system, kidney, skeletal muscle and heart. Genotype-phenotype20
correlationsaredifficult toestablish,mainlybecauseof thereducednumberofpatientsand21
2
the large variety of symptoms. In addition, mutations in the same COQ gene can cause22
different clinical pictures. Here we present an updated and comprehensive review of the23
clinical manifestations associated to each of the pathogenic variants causing primary CoQ24
deficiencies.25
Abbreviation l ist 26
2,4-dHB, 2,4-dihydroxybenzoic acid; 3,4-dHB, 3,4-dihydroxybenzoate; 4-HB, 4-27
hydrozybenzoate; CNS, central nervous system; CoQ, Coenzyme Q; EEG,28
electroencephalography; ESRD, end-stage renal disease; ETFDH, electron transport29
flavoproteindehydrogenase;HHB,hexaprenyl-hydroxybenzoate;ID,intellectualdisability;LDL,30
low density lipoproteins; mETC, mitochondrial electron transport chain; MRI, magnetic31
resonance imaging;OXPHOS,oxidativephosphorylation;pABA,para-aminobenzoicacid;PNS,32
peripheral nervous system; ROS, reactive oxygen species; SNHL, sensorineural hearing loss;33
SRNS,steroid-resistantnephroticsyndrome;VA,vanillicacid.34
Please,refertotable3forsymptomsabbreviations.35
Coenzyme Q structure and function 36
CoenzymeQ(CoQ)orubiquinoneistheonlyendogenouslysynthetizedredox-activelipidthat37
is found in virtually all endomembranes, plasma membrane and serum lipoproteins, being38
especiallyabundantinmitochondria.It iscomposedofabenzoquinoneringasaheadgroup,39
andapolyisoprenoidchain,whichinsertsthemoleculeintothephospholipidbilayerandvaries40
inlengthdependingonthespecies(figure1A).Inhumans,ithas10isopreneunits(CoQ10),6in41
Saccharomycescerevisiae(CoQ6)andthemainformfoundinmicehas9units(CoQ9),although42
lowamountsofCoQ10canbealsodetectedintheirmembranes.43
SoonafterthefirstdescriptionbyCainandMortonin1955(1),themainfunctionofCoQinthe44
mitochondrial electron transport chain (mETC) was proposed by Crane and cols., who also45
demonstrated its redox proprieties (2). In the mETC CoQ is an essential mobile electron46
3
transportcomponent, shuttlingelectrons fromcomplex I (NADH-ubiquinoneoxidoreductase)47
or complex II (succinate-ubiquinone oxidoreductase) to complex III (succinate-cytochrome c48
oxidoreductase).49
CoQispermanentlygoingthroughoxidation-reductioncycles.Itcanbefoundinacompletely50
reducedform(CoQH2orubiquinol),afterreceivingtwoelectrons,orinacompletelyoxidized51
form (CoQ or ubiquinone). When, as in the mETC, this redox cycle occurs by a two-step52
transfer of one electron each, a semiquinone (or semi-ubiquinone, CoQ•-) intermediate is53
produced(figure1B).54
Computationalpredictionmodelshaverecentlyconfirmedstudiesdescribinghow,intheinner55
mitochondrial membrane, CoQ is mainly located either close to the membrane-water56
interface,with its relatively small head group being shadowed by the bigger polar heads of57
phospholipids, or stabilized in the middle of the bilayer. During the process of electron58
transfer,CoQrapidlytranslocatesfromonesidetotheotheroftheinnermembranebilayer,59
witharatethatvariesdependingontheredoxstateofthemolecule.Thisprocessenablesthe60
interaction with the reducing and oxidizing sites in the proteins of the mETC complexes,61
locatedclosetothemembranesurfaces(3).62
After thediscoveryof its role in themETC,new functionshaveemerged forCoQ,being the63
electronacceptor fordifferentdehydrogenases.Amongothers, inmitochondriaCoQaccepts64
electronsfrom:65
(i) dihydroorotatedehydrogenase,akeyenzymeforpyrimidinebiosynthesis(4),66
(ii) mitochondrial glycerol-3-phosphate dehydrogenase (5), a tissue-specific67
componentofmitochondriaconnectingglycolysis,oxidativephosphorylationand68
fattyacidmetabolism(6),69
(iii) electrontransportflavoproteindehydrogenase(ETFDH),akeyenzymeinvolvedin70
thefattyacidβ-oxidationandbranched-chainaminoacidoxidationpathways(7),71
4
(iv) prolinedehydrogenase1,anenzymerequiredforprolineandargininemetabolism72
(8),73
(v) probably, from hydroxyproline dehydrogenase (or proline dehydrogenase 2),74
involvedintheglyoxylatemetabolism(9)75
(vi) sulphide-quinone oxidoreductase (10) during sulphide detoxification, a gas76
modulatorofrelevantcellularprocessesbuttoxicwheninexcess(11).77
ReducedCoQ(CoQH2)generatedbyalltheseprocessesisefficientlyreoxidisedbycomplexIII78
inthemETC(figure1C).79
The ability to sustain continuous oxidation/reduction cycles makes CoQ not only a great80
electron carrier for different cellular processes, but also a potent membrane antioxidant,81
which protects lipids, proteins and nucleic acids fromharmful oxidative damage (12,13). In82
membranes, CoQH2 has been shown to prevent both initiation and propagation of lipid83
peroxidation (14,15) and, indirectly, to regenerate other antioxidants, such as α-tocopherol84
andascorbate (16). ThehighefficiencyofCoQagainstoxidativestressmayberelatedto its85
ubiquitousdistribution,itslocalizationinthecoreofmembranesandtheavailabilityofdiverse86
dehydrogenases,abletoefficientlyregeneratethemolecule.87
CoQ biosynthesis and regulation in eukaryotes/human 88
LevelsofCoQarequitestableincellsbutitsconcentrationvariesamongdifferenttissuesand89
organs, depending on dietary conditions and age (17–20). Although CoQ is mainly90
endogenouslysynthetizedinmitochondriaandthendistributedtoothercellmembranes(21),91
cells can incorporate a certain amount fromdietary sources. CoQ is synthesized by a set of92
nuclear-encodedCOQproteins,throughapathwaythatisnotcompletelyunderstood.Mostof93
the work on CoQ biosynthesis has been done in Saccharomyces cerevisiae, and at least 1394
yeast genes (coq1 – coq11, Yah1, Arh1) have been identified as players of this process.95
5
Informationabout thehumanpathway isvery scarce,butorthologuesofalmostallof these96
geneshavebeenalreadyidentified(seeDr.Clarkreviewinthissamenumber).97
4-Hydrozybenzoate (4-HB),precursorof thebenzoquinonering, is synthesized fromtyrosine,98
phenylalanine,oralsopara-aminobenzoicacid(pABA)inyeast,throughapoorlycharacterized99
set of reactions (22–24). The isoprenoid tail comes from themevalonate pathway,which is100
shared with cholesterol, among other molecules, and takes place in extra-mitochondrial101
membranes. This side chain is assembled by Coq1p (PDSS1 and PDSS2, acting as a102
heterotetramer,arethehumanorthologues),whichalsodeterminesitslength.Coq2p(human103
orthologue COQ2) condensates head and tail and the resulting molecule undergoes104
subsequentmodifications of the ringmoiety: C5-hydroxylation (yeast Coq6p, human COQ6)105
(25), O-methylations (yeast Coq3p, human COQ3) (26,27), C1-hydroxylation and C1-106
decarboxylation (unidentified), C2-methylation (yeast Coq5p, humanCOQ5) (28,29), andC6-107
hydroxylation(yeastCoq7p,humanCOQ7)(30),butalsoC4-deamination(Coq6p),inthecase108
ofyeastusingpABAasprecursor (24).Yah1andArh1 (humanorthologues,FDXRandFDX2),109
mitochondrialferredoxinandferredoxinreductase,havebeenshowntotransferelectronsto110
Coq6p (31). Mammalian pathway is still incompletely defined and significant efforts are111
requiredinordertodeterminewhetheritcoincideswiththeyeastone(figure2).112
OtherCoqproteinsarethoughttohaveregulatoryfunctions.Coq8p(twohumanorthologues:113
COQ8A(orADCK3/CABC1)andCOQ8B(orADCK4)),displaysfeaturesofanatypicalkinasethat114
possiblyphosphorylatesCoq3p,Coq5pandCoq7p inyeast (32–34).However,COQ8A/ADCK3115
has recently been shown to have a more clear ATPase activity (35) whose role in CoQ116
biosynthesis stillneeds tobe further studied.Coq4p (humanorthologueCOQ4) functionhas117
notbeenelucidatedyet,butitseemstoberequiredfortheformationandmaintenanceofthe118
CoQ biosynthetic complex (36). Coq9p (human orthologue COQ9) is a lipid-binding protein119
stabilizing Coq7p (37,38). Coq10p (human orthologues COQ10A and COQ10B) probably120
6
controlsCoQcorrectlocalizationwithinthemitochondrialmembranes(39).Coq11pisthought121
to be essential for CoQ synthesis in yeast, but lacks a clear human orthologue (40).122
Additionally, threeothergenesof theADCK family (humanADCK1,ADCK2 andADCK5)have123
been proposed to participate in the biosynthetic process, but there is no experimental124
evidenceforthis(34,41).125
ItiswidelyacceptedthatyeastCoq3p-Coq9pproteinsareorganizedinamultiproteincomplex,126
possibly containing some intermediates of the biosynthesis and CoQ itself (40,42,43). The127
complex would probably optimize the orientation of the substrates and active sites of the128
enzymesaswellastheirfunctionalcoordination(36,44–47)(figure2).Evidencesupportingthe129
existence of a conserved complex also inmammals has been recently reported by different130
groupsthroughdiverseapproaches(23,29,35,38,48–52).However,functionalorganizationand131
regulationofmammalianbiosyntheticcomplexisstillelusiveandcouldbedifferentfromthe132
yeastone.133
Little is known about CoQ biosynthesis regulation, which may occur at the transcriptional,134
post-transcriptionalandpost-translational level,orevenduring theassemblyof theputative135
multisubunitcomplex.Transcriptionally, several factorshaveemergedaspossiblecandidates136
(53–55).However,adeepstudyofpromotersandregulationsequencesof theCOQgenes is137
lackingcurrently.Atthepost-transcriptionallevel,severalRNAbindingproteinsthatmodulate138
the stability of COQ transcripts have also been identified (56,57). At the post-translational139
level,processingbyproteases,phosphorylationanddephosphorylationhavebeensuggested140
to have a role in the regulationof someCOQproteins’ activity, but only a very fragmented141
pieceofinformationiscurrentlyavailable(33,34,58,59).142
Clinical manifestations of CoQ deficiencies. 143
CoQdeficiencieshavebeenassociatedwithawide rangeof clinicalmanifestations. Patients144
with CoQ deficiency have reduced levels of CoQ in tissues, which can be caused either by145
7
mutations in the genes participating in CoQ biosynthesis, the so-called primary CoQ146
deficiencies, or by defects not directly linked CoQ biosynthesis, the secondary CoQ147
deficiencies.148
Primary deficiencies. 149
Primary CoQ deficiencies are very rare conditions, usually associated with highly variable150
multisystemic manifestations (figure 3), and genetically caused by autosomal recessive151
mutations.Approximately200patientsfrom130familieshavebeendescribedintheliterature152
sofar(SupplementaryTable1).153
It has been estimated a worldwide total of 123,789 individuals (1 in 50,000) affected by154
primaryCoQdeficiencies,beingonly1,665(lessthan1in3,000,000)duetoknownpathogenic155
variants, taking into account the frequency of the different known or predicted pathogenic156
variantsingivenpopulations(60).157
Todate,tengenesencodingCoQbiosyntheticproteinshavebeenshowntohavepathogenic158
variants causing human CoQ deficiency: PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6, COQ7,159
COQ8A, COQ8B and COQ9 (Table 1, supplementary table 1). They affect multiple organ160
systems in a highly variable way, including central nervous system (CNS) (encephalopathy,161
seizures, cerebellar ataxia, epilepsy or intellectual disability (ID)), peripheral nervous system162
(PNS),kidney(steroid-resistantnephroticsyndrome(SRNS)),skeletalmuscle(myopathy),heart163
(hypertrophic cardiomyopathy) and sensory system (sensorineural hearing loss (SNHL),164
retinopathy or optic atrophy) (Table 2). While mutations in some COQ genes can affect165
different organs (e.g. COQ2, COQ4), pathogenic variants of other COQ genes show a more166
specific phenotype (e.g.COQ8A,COQ8B). Evenmore,mutations in the sameCOQ gene can167
cause very variable clinical phenotypes with different age of onset. The age of onset may168
generally range from birth to early childhood (PDSS1, PDSS2, COQ2, COQ4, COQ5, COQ6,169
8
COQ7,COQ9), or from childhood to adolescence (COQ8A,COQ8B), but there are also some170
adult-onsetcases(COQ2(61);COQ8A(62,63);COQ8B(64)).171
CNS manifestations: 172
Central nervous system is often affected in these patients, showing awide range of clinical173
manifestations, including encephalopathy, hypotonia, seizures, dystonia, cerebellar ataxia,174
epilepsy, stroke-like episodes, spasticity or ID. These symptomsmay be present in patients175
withmutationsinoneofthereportedCOQgenes,buttheyarelessprominentinpatientswith176
pathogenic variants of COQ6 and COQ8B, in whom the more frequent phenotype is renal177
involvement. COQ2 patients manifested early-onset nephrotic syndrome (17/22) which in178
some cases may be accompanied by encephalopathy and seizures (7/22) (65–76). COQ4179
patientsgenerallyshowasevereCNS involvement,withencephalopathyandseizures(9/14),180
hypotonia (10/14)andcerebellarhypoplasia (6/14);andoftena fataloutcomewithdeath in181
the first days (6/14) or months (5/14) of life (77–81). The hallmark phenotype in COQ8A182
patientsisslowprogressivecerebellaratrophyandataxia(43/45),associatedwithID(19/45),183
epileptic seizures (18/45), tremor (18/45), dysarthria (16/45), saccadic eye movements184
(10/45), dystonia (9/45) or spasticity (8/45), among others (62,63,82–93). The only COQ5185
family described shows a phenotype similar to COQ8A patients (94). Some COQ8A patients186
(6/45) (62,84,85,87)andoneCOQ2patient (1/19) (66) sufferedonestroke-likeepisode, that187
contributed significantly to deterioration of the neurological status and may explain the188
heterogeneity of the functional outcome among affected siblings (84). SomeCOQ2 variants189
havealsobeenpredictedtoincreasesusceptibilitytoadult-onsetmultisystematrophy(MSA),190
butthisissueisstillunderdebate(61,95).191
Very few patients with mutations in PDSS1 (70,96), PDSS2 (71,97–100), COQ5 (94), COQ7192
(101,102)andCOQ9(103–106)havebeen identifiedtodefineaspecificphenotype,butthey193
presentedencephalopathy(PDSS1,COQ9),Leigh-likesyndrome(PDSS2,COQ9),ataxia(PDSS2,194
9
COQ5), ID (PDSS1,PDSS2,COQ5,COQ7), seizures (PDSS2,COQ5,COQ9) or spasticity (PDSS2,195
COQ5,COQ7).196
Peripheral nervous system and sensory organs manifestations: 197
Peripheralneuropathyhasbeendescribedin2siblingswithPDSS1mutations,associatedwith198
optic atrophy and early-onset SNHL (70). Also, the 2 COQ7 patients described showed199
peripheral polyneuropathy, again with SNHL and one of them with visual dysfunction200
(101,102). SNHL is very frequent, especially in COQ6 patients (16/26) (69,71,107–109),201
associated with SRNS in all cases, andwith optic atrophy (1/18) (109). One COQ8A patient202
(1/45) also showed early-onset bilateral SNHL (82–84), as well as patients with PDSS2203
mutations (4/7), who manifested retinitis pigmentosa (2/7) and optic atrophy (1/7), too204
(98,100). One patient withCOQ4 mutations (1/14)manifested bilateral hearing loss as well205
(77).Visualimpairmentwasalsoasymptominsomepatientswithopticatrophy(PDSS1(70),206
PDSS2(98,100),COQ2(66),COQ6(109)),retinopathy(COQ2)(74),retinitispigmentosa(PDSS2207
(100),COQ2(61),COQ8B(110))andcataracts(PDSS2(98),COQ8A(62)).208
Renal manifestations: 209
SRNS is frequent in primaryCoQdeficiency patients, specifically in patientswith pathogenic210
variantsofCOQ2,COQ6andCOQ8B.Itgenerallystartsasproteinuriaandifuntreatedevolves211
toend-stagerenaldisease(ESRD)withinchildhood(71).212
COQ2patientsdisplayedearly-onsetnephroticsyndrome(15/22)(65–68,70,71,73,76),isolated213
(9/22)orwithencephalopathyandseizures(6/22),buttherewasalsoonefamilywithonsetin214
adolescence,slowprogressionoftherenaldiseaseandmildneurologicalsymptoms(69).The215
hallmarkofCOQ6pathogenicvariants ischildhood-onsetSNRS (23/26)associatedwithSNHL216
(16/26) (69,71,107–109,111). COQ8B patients mainly presented with an adolescence-onset217
SRNS due to focal segmental glomerulosclerosis, associated with edema (15/74) and218
10
hypertension(10/74),whichgenerallyprogressedtoESRD(50,64,110,112–116).OnsetofSRNS219
maybebefore10yearsofage(29/74).220
PatientswithPDSS1(1/3)(96)andPDSS2(7/7)(71,97–100)mutationsalsoshowedSRNS.One221
COQ9(1/6)(104)andoneCOQ2(1/22)(75)patientdisplayedatubulopathy.222
Muscle manifestations: 223
IsolatedmyopathyhasnotbeenfoundinindividualswithmolecularlyconfirmedprimaryCoQ224
deficiency.Themajorityofthepatientswithapredominantlymuscularphenotypehavebeen225
associated with secondary CoQ deficiency. Myopathy has been described in some patients226
with a multisystemic phenotype (COQ4 (1/14) (81), COQ8A (1/45) (91)). Other muscular227
manifestations include exercise intolerance (COQ8A (8/45) (82,84–86)), muscle weakness228
(COQ2 (1/22) (66), COQ6 (2/26) (109), COQ7 (2/2) (101,102), COQ8A (7/45) (62,85,87,92),229
COQ8B(1/74)(113))andmusclefatigue(COQ8A(2/45)(62,90)andCOQ8B(1/74)(110)).Some230
muscle biopsies have shown lipid accumulation inmuscle (COQ4 (1/14) (81),COQ8A (3/45)231
(62,85),COQ2(1/22)(72)).232
Cardiac manifestations: 233
Themostfrequentheartmanifestationishypertrophiccardiomyopathy,oftenpresentinCOQ4234
patientswithaprenatalonset(7/14)(77–79),whereasCOQ2(3/22)(65,72,75),COQ8B(2/74)235
(64,112,113),COQ7 (1/2) (101)andCOQ9patients (1/6) (104) showaneonatalonset.Other236
less frequently reported cardiac manifestations are valvulopathies (PDSS1 (2/3) (70)), heart237
hypoplasia (COQ4 (1/14) (78)), septal defects (COQ4 (1/14) (81), COQ8B (2/74) (110,116)),238
heartfailure(COQ4(2/14)(78,79)andCOQ8B(1/74)(110)),bradycardia(COQ4(4/14)(77–79),239
COQ9 (2/6) (105,106), or pericardial effusion (COQ8B (1/74) (64,112)). However, it is240
questionable whether somemanifestations such as heart failure, bradycardia or pericardial241
effusion are primary events or are secondary manifestations of some other general242
11
phenomena.243
244
Other manifestations: 245
Less frequent clinical findings include dysmorphic features (81,107), metabolic pathologies246
(diabetesmellitus(70,75),obesity(70)andhypercholesterolemia(69,113)-althoughthelatest247
is often observed during SRNS, independently of its aetiology-), thyroid disease (goiter248
(50,112),hypothyroidism(64)), lunginvolvement(respiratorydistress-veryfrequentinCOQ4249
patients (9/14) (75,78,79,101,105)-, apnea (74,77–79,105) or respiratory failure250
(66,74,75,77,78)), circulatory problems (cyanosis (78,105), hypertension, livedo reticularis251
(70)),liverabnormalities(hepaticinsufficiency(70,72),cholestaticliver(75)),amongothers.252
Biochemical findings: 253
PrimaryCoQdeficiencypatients,particularlythosewithneonatalonset,canshowhigherlevels254
of lactate in plasma or serum. CoQ levels in skeletalmuscle biopsies or fibroblastsmay be255
reduced(117),aswellastheenzymaticactivitiesofcomplexI+IIIand/orII+III(118).256
Pathogenesis 257
The pathogenesis of CoQ deficiency is complex and not completely understood. The258
bioenergeticdefect and the increased reactiveoxygen species (ROS)productionmayhavea259
crucialrole.HoweverthewidespectrumofCoQfunctions,theunclearrolesofsomeCOQgene260
products and the considerable phenotypic variability, suggest that other mechanisms261
contribute to thepathogenesisof thedisease. Inculturedcells ithasbeen foundthat,while262
severeCoQdeficiencies leadtogreatdefects inenergyproductionwithnomajor increase in263
oxidative stress, mild CoQ defects cause a significant increase in ROS production without264
affecting ATP production, but yielding increased cell death levels (119). In addition, as265
expected,CoQdeficiencyimpairsdenovopyrimidinesynthesis,furthercontributingtodisease266
pathogenesis(120).CoQdeficiencycellsalsoshowincreasedmitophagy,beingproposedasa267
12
protective mechanism in disease pathogenesis (121), although other authors defined it as268
detrimental (122).Recently, sulfideoxidationpathway impairmenthasbeenproposedas an269
additionalpathomechanisminprimaryCoQdeficiency,asdifferentinvivoandinvitromodels270
of the disease show a tissue-specific defect in the metabolism of H2S, leading to the271
accumulationofthismolecule,thatmayalterproteinS-sulfhydrilation,inducingchangessuch272
as vasorelaxation, inflammation and ROS production (123). Finally, CoQdeficiency has been273
linked to development of insulin resistance in human andmouse adipocytes, as a result of274
increasedROSproductionviacomplexII(124).275
Genotype-phenotype correlation 276
DuetothesmallnumberofpatientsharbouringmutationsinCOQgenesandthewiderangeof277
clinicalmanifestations,itisarduoustodefinegenotype-phenotypecorrelations.Infact,onlya278
fewfamilieswithpathogenicvariantsofPDSS1,PDSS2,COQ5orCOQ9havebeenpublished,279
being unachievable to establish any correlation. In the case ofCOQ9, studies in twomouse280
models suggest that a key factor appears to be the different degree of impairment of281
formationof theCoQcomplex (49).Even thoughonly2patientswithCOQ7mutationshave282
beendescribed,thereseemstobeacorrelationbetweentheresiduallevelsofCoQ(andlevels283
ofCOQ7protein)andtheseverityofthedisease:fibroblastsfrompatientwiththemostsevere284
phenotypeshowadrasticCoQdeficiency(101),whilethepatientwiththemilderphenotype285
hasa30%decreaseinCoQlevelsinskinfibroblasts(102).Interestingly,onlyfibroblastswitha286
severe deficiency benefit from 2,4-dihydroxybenzoic acid (2,4-dHB) supplementation, while287
CoQbiosynthesiswasinhibitedinthosewiththemilderdefecttreatedwith2,4-dHB.288
COQ8AandCOQ8Bhavethehighestnumberoffamilieswithpathogenicvariantsreported(29289
and38), and inneither case there is any correlationbetween themutationsand theclinical290
phenotype(84,112).InthecaseofCOQ2patients(18familiesdescribed),whoshowthewidest291
clinical spectrum, it has been proposed that the severity of the disease correlates with the292
13
enzymaticresidualactivityandhenceCoQ levels,asshownbyexpressingmutantproteins in293
yeast (125). It is worth tomention thatmost of theCOQ6 patients were diagnosed during294
screeningforSNRS,sotheremaybeareferencebiasinthesecases(71,107,109).Todate,no295
otherclearcorrelationshavebeenobservedforCOQ4patients.296
Diagnosis 297
The diagnosis of primary CoQ deficiency is established with the identification of biallelic298
pathogenicvariantsinanyofthegenescodingforoneoftheproteinsdirectlyinvolvedinCoQ299
biosynthesis.GenomeorspecificgenesequencingisperformedwhendecreasedlevelsofCoQ300
or reduced combined activities of complex I+III and II+III inmitochondria of skeletalmuscle301
biopsiesaredetectedinpatients(126,127).Itisimportanttonotethatbiochemicalanalysisis302
not able to distinguish between primary and secondary CoQ deficiencies (127). Genetic303
identificationofnewpathogenicvariantsisusuallyfollowedbyfunctionalvalidation.304
CoQ levels can also be measured on plasma samples, white blood cells or skin fibroblasts305
obtainedafterskinbiopsyfrompatients(128).However,thereareconcernsaboutCoQplasma306
measurements for diagnosis, since it seems to be influenced by the amount of plasma307
lipoproteins (carriers of CoQ in circulation) and the dietary intake. Muscle or fibroblasts308
represent the preferred diagnosis tissues, although sometimes fibroblasts do not show309
reductionwhilemuscledoes(129).IthasbeenshownthatwhitebloodcellsCoQlevelsalone310
arenotreliabletodiagnoseprimaryCoQdeficiencyinthesettingofnephroticsyndrome(76).311
Denovosynthesiscanalsobemeasuredbyradioactiveprecursor incorporationinfibroblasts312
(130)which isespeciallyuseful todiscriminatebetweenprimaryand secondarydeficiencies.313
Recently,urineCoQmeasurementasnon-invasiveapproachhasbeenproposed(131).314
Management 315
Considering the wide clinical spectrum of this condition, any individual with a diagnosis of316
primaryCoQdeficiencyshouldbeassessed, inorder toestablish theseverityof thedisease.317
14
Importantly, a genetic consultation is recommended for other family members and for318
recurrence riskofpatient’sparents. Basedon thegeneticdefect identified in thepatient,a319
specificfollow-upshouldbeprogrammed.320
Being CNS manifestations very frequent, every patient with a diagnosis of CoQ deficiency321
shouldundergoperiodicalneurologicalexaminations,evenifnormalatdiagnosis. Infact,the322
ageofonsetofthesesymptomsishighlyvariable,rangingfromthefirsthoursordaysof life323
(as inpatientswithCOQ4mutations), up to the seventhdecadeof life (as inCOQ2 patients324
with theadult-onsetmultisystematrophy-likephenotype). Evaluation should includeanEEG325
analysis and a brainMRI. In addition, peripheral nervous system shouldbe assessed for the326
possiblepresenceofperipheralneuropathyinpatientswithPDSS1andCOQ7mutations.327
Patientswithmutations inPDSS1,PDSS2,COQ2,COQ6,COQ7,COQ8AandCOQ8Bmayhave328
eye involvement due to optic atrophy, retinopathy, retinitis pigmentosa and even cataracts329
and should therefore be screened at diagnosis and during the follow-up. Audiometry is330
necessary inCOQ6 patientswho almost invariablymanifest SRNS, but should be performed331
alsoinpatientswithmutationsinPDSS1,COQ8AandCOQ4whomaysometimesmanifestthis332
phenotype.333
Individuals harbouring mutations in COQ2, PDSS1, PDSS2, COQ6, and COQ8Bmay manifest334
renal involvement with SRNS, whose onset may vary from early childhood to adolescence.335
Tubulopathyhasbeen reported rarely.Thesepatients thusneed toundergoperiodical renal336
functiontestswithurineanalysisforproteinuriaandnephrologicalevaluationsfortheriskof337
evolvingtoESRD.338
Acardiologistexaminationwithechocardiogramshouldbeperformed inpatientswithCOQ4339
mutations(whomaypresentwithasevereprenatal-onsetcardiomyopathy)andshouldalsobe340
considered in individualswithmutations inPDSS1 andCOQ8B to exclude the presence of a341
valvulopathyorseptaldefects.342
15
343
Treatment 344
Barriers for tissuesCoQdeliveryhavebeenfounddueto itshighmolecularweightandpoor345
aqueous solubility, but at high doses, dietary supplementation increases CoQ levels in all346
tissues, including heart and brain, especially with certain formulations (132,133). It also347
increases in circulating low density lipoproteins (LDL), where it functions as an efficient348
antioxidant together with α-tocopherol (134,135). CoQ supplementation at high doses has349
been demonstrated to be effective for treatment of both primary and secondary CoQ350
deficiencies(136).Itiscrucialtostartthesupplementationassoonaspossibletogetfavorable351
outcomes and to limit irreversible damage in critical tissues such as the kidney or the CNS352
(126). Different doses of CoQ have been employed for the treatment of primary CoQ353
deficiencies,rangingfrom5mg/kg/day(98)to30-50mg/kg/dayforbothadultsandchildren354
(137) but inmousemodels of this condition evenhigher doses (up to 200mg/kg/day) have355
beenused(138).ExceptforCOQ8Apatients,mostindividualswithprimaryformsshowagood356
response to CoQ treatment, which is usually evident after 10-20 days (137). Different357
formulationsofCoQarenowavailable,bothintheoxidizedandthereducedforms,although358
mostofthedataavailablehavebeenobtainedinpatientstreatedwithubiquinone.359
Alternatively to CoQ10 supplementation, some 4-HB analogues have been proposed as360
potential bypass molecules with higher bioavailability than CoQ. These water-soluble CoQ361
headprecursorswouldbypassenzymaticstepsdisruptedbymutationsinCOQgenes,buttheir362
efficacy may differ depending on the stability of the CoQ biosynthetic complex. Some363
examples are vanillic acid (VA) and 3,4-dihydroxybenzoate (3,4-dHB), able to bypass COQ6364
mutations,or2,4-dHBforCOQ7defects(figure2Cand2D).TheeffectivityofVAand3,4-dHB365
inrestoringCoQbiosynthesishasbeendemonstratedincoq6yeastmutantstrainsexpressing366
pathogenic versions of human COQ6 (111). Notably, VA also stimulates CoQ synthesis and367
16
improves cell viability in COQ9 patient fibroblasts (139). 2,4-dHB was able to increase CoQ368
levels and lifespan in Coq7 (140) and Coq9 defective mice (49), as well as to bypass the369
reaction in human fibroblasts with COQ7 (101,102,139) and COQ9 mutations (139).370
Remarkably,theeffectivityof2,4-dHBdependsonthenatureoftheCOQ7mutationandthe371
residualactivityoftheprotein(102).Ithasalsobeenreportedthattreatmentwithhighdoses372
of4-HB,thusincreasingCOQ2substrateavailability,restoresCoQsynthesisinCOQ2deficient373
celllines,whichalsosuggeststhattheseenzymevariantsretainsomeresidualactivity(141).374
EarlyonsetCoQdeficienciescancausemortality in fewdays.Wehaveobserved thatCoQ is375
efficientlyincorporatedindifferenttissuesbybreastfeedingandplacentainmice(unpublished376
data).Weproposetreatmentofpregnantmothersofhigh-risknewborns(highprobabilityof377
CoQdeficiencyaftergeneticscreeningorduetofamilyhistory)withCoQsupplementation,in378
order to reduce tissue damage during embryonic/fetal development and to increase the379
survivalofnewbornsuntiltheycanbefedwithsupplements.380
Secondary deficiencies 381
CoQlevelscanalsobereducedsecondarytoconditionsnotdirectlylinkedtoCoQbiosynthesis,382
but related to oxidative phosphorylation (OXPHOS), other non-OXPHOS mitochondrial383
processes, or even to non-mitochondrial functions (142). Remarkably, secondary CoQ384
deficiencies are proved to be more common than primary deficiencies (142,143), probably385
because of the diversity of biological functions and metabolic pathways in which CoQ is386
involved in mitochondrial and non-mitochondrial membranes, highlining the importance of387
CoQhomeostasis inhumanhealth.However,there isa lackofconsistencyofCoQdeficiency388
presence among different patients, which could suggest different susceptibility to the389
developmentofsecondarydeficienciesamongdifferentindividuals.Currently,thereisnotany390
general explanation for this, although genetic factors, such as certain polymorphisms, have391
been proposed to be involved (112,142–144). A comprehensive analysis of muscle and392
17
fibroblastssamplesfrompatientsaffectedbyawiderangeofmitochondrialdiseases,showed393
that secondary deficiencies were more frequent in depletion syndromes than in any other394
mitochondrialdisease(142),supportingpreviousobservations(145).Thesamestudyanalysed395
CoQlevels insamplesofpatientsaffectedbydifferentOXPHOSdiseases,butwereunableto396
find anydifferencebetween them. Further studiesonwider cohorts areneeded inorder to397
understandwhethercertaindiseasesaremorepronetodevelopsecondarydeficienciesthan398
others, as well as the underlying molecular mechanism. Nonetheless, it is clear that399
mitochondrial myopathies are frequently associated with CoQ secondary deficiencies (144).400
Besides its reduction in manymitochondrial OXPHOS disorders, other diseases may display401
secondaryCoQdeficiency,includingataxiaandoculomotorapraxiasyndrome(MIM#208920),402
multipleacyl-CoAdehydrogenasedeficiency (MIM#231680),cardiofaciocutaneoussyndrome403
(MIM #115150), methylmalonic aciduria (# 251000), GLUT-1 deficiency syndrome (MIM404
#606777), mucopolysaccharidosys type III (MIM #605270) or multisystem atrophy405
(142,143,146). Themechanisms underlying CoQ secondary defects remain largely unknown,406
butseveralexplanationshavebeenproposedthatarerelatedto:(i)anincreasedrateofCoQ407
degradation due to oxidative damage caused by a non-functional respiratory chain; (ii) a408
decreaseinCoQthroughtheinterferencewiththesignallingpathwaysinvolvedintheprocess409
of biosynthesis; (iii) the reduction of the stability of the CoQ biosynthetic complex or (vi) a410
generaldeteriorationofmitochondrialfunction(142,143).411
Inaddition,CoQseemstobereducedintheprocessofaging(147)andasecondarydeficiency412
of CoQ may be a side effect of hypercholesterolemia treatment with statins, since both413
cholesterolandCoQsharepartoftheirbiosyntheticpathways(148,149).414
Of course, particular symptoms of secondary CoQ deficiencies are highly dependent on the415
original pathology. Myopathies presented as muscular weakness, hypotonia, exercise416
intoleranceormyoglobinuriaarecommonly reportedasmuscularmanifestations indiseases417
18
associated to secondary CoQ deficiencies. Neurological decline and ataxia are also often418
reported (143,150). It is possible that theprimarydisease symptomsarepotentiatedby the419
lack of CoQ (143). In fact, many of these patients partially improve their condition by CoQ420
supplementation, which supports the importance of an early diagnosis also in these cases421
(150).Fromthepointofviewofthemoleculardiagnosis, it isnecessarytoperformagenetic422
analysistodistinguishbetweenprimaryandsecondarydeficiencies(126).423
Concluding remarks 424
The deficiency in CoQ is a genetically and clinically heterogeneous syndrome. Primary425
deficiency diagnosis is a great challenge due to the number of genes involved, the poor426
knowledge of CoQ biosynthesis pathway and its regulation in humans, the small number of427
patients described and the great variety of associated symptoms. Moreover, secondary428
deficienciescanbeconsequencesofmanyothermitochondrialdysfunctionsaddingalayerof429
complexitytothediagnosis.Observationoftheclinicalmanifestationsheredescribedand/or430
the molecular identification of potentially pathological variants of COQ genes should be431
complementedbythebiochemicaldeterminationofCoQ levels,biosynthesis rate ifpossible,432
andthecombinedenzymaticactivitiesofcomplexes I+IIIand I+II inmuscleorfibroblast. It is433
important to identify potential cases as early as possible because high-dose CoQ oral434
supplementation isaveryeffective treatment inmostcases,blocking theprogressionof the435
disease.436
Acknowledgements 437
Authors wish to thank the patients and their families for facilitating the research here438
reviewed.WethankProf.PlácidoNavasforthecriticalrevisionofthemanuscript.439
Declaration of interest 440
Theauthorsreportnoconflictsofinterest.441
19
Funding information 442
MA-F is a predoctoral research fellow from the SpanishMinistry of Education, Culture and443
Sports (FPU14/04873). ET is supportedbyGrantnumberCPDA140508/14 fromUniversityof444
Padova.445
Author contribution statement 446
MA-Fexhaustivelycompiledthemutationsandsymptomsdatafromliteratureandelaborated447
thetables.MA-FandGB-Cmadethefigures.MA-F,ETandGB-Cwroteandeditedthetextand448
GB-Ccoordinatedthework.449
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879
880
881
Summary 882
• CoQisanendogenouslysynthesizedlipidthatisessentialfortheelectrontransportin883
themitochondrialrespiratorychain.884
• PrimaryCoQdeficienciesare rarediseasescausedbymutations ingenesof theCoQ885
biosynthesispathway.886
• CoQ deficiencies are characterized by reduced levels of CoQ affecting energy887
production.888
• PrimaryCoQdeficiencies showhighlyheterogeneousmanifestationsmainlyaffecting889
CNS,PNS,sensoryorgans,kidney,skeletalmuscleandheart.890
• Currently, it is hard to establish any genotype-phenotype correlations for these891
diseases,partiallyduetothelowamountofstudiedpatients.892
• It is essential tobiochemically determineCoQdeficiency since supplementationhas893
positivetherapeuticeffects.894
30
895
Figure legends 896
Figure1.(A)ChemicalstructureofCoenzymeQ(CoQ)and(B)redoxcycleofitsheadgroup.(C)897
Integration of CoQ reduction by different dehydrogenases in the mETC. DHODH:898
Dihidroorotate dehydrogenase; G3PDH: Glycerol 3 phosphate dehydrogenase; ETF-FAD:899
Electron Transfer Flavoprotein; ETF-Qase: Electron Transfer Flavoprotein cCenzyme Q900
reductase; Cyt c: cytochrome c; SQR: sulphide-quinone oxidoreductase; PROD: proline901
dehydrogenase.902
Figure 2. (A) Schematic model of human CoQ biosynthesis pathway. Blue arrows represent903
enzymaticreactionsandcirclednumbersrepresentthedifferentCOQproteinsthatparticipate904
in each step. Brown arrows indicate regulatory mechanisms. Circled question mark shows905
currentlyunidentifiedenzymes.(B)ModelofhumanCoQbiosyntheticcomplex,containingat906
least COQ3-COQ9 and lipids, such as CoQ itself. (C) and (D) green boxes contain 4-HB907
analogues, defined as unnatural CoQprecursors,which are able to lead to CoQproduction,908
bypassingdefectiveCOQenzymessuchasCOQ6(3,4-dihydroxybenzoate(3,4-dHB)orvanillic909
acid (VA)) or COQ7 (2,4-dihydroxybenzoate (2,4-dHB). COQ9 patient fibroblasts can also910
benefit from2,4-dHBandVA.DDMQ:demethoxy-demethyl-CoenzymeQ;DMQ:demethoxy-911
CoenzymeQ;DMeQ:demethyl-CoenzymeQ912
Figure3.Organsandsystemsaffectedin individualswithprimaryCoQdeficiency,associating913
specific clinicalmanifestationswith the genes involved in each one. For abbreviations go to914
Table3.ForfrequencyofeachsymptomlinkedtoaspecificgenegotoTable2.915
916
917
918
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