Original Citation:

Clinical syndromes associated with Coenzyme Q10 deficiency.

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10.1042/EBC20170107

Università degli Studi di Padova

Padua Research Archive - Institutional Repository

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:gbrecal@upo.es14

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