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Essays in Biochemistry (2018) 62 377–398
https://doi.org/10.1042/EBC20170107
Received: 02 March 2018
Revised: 02 May 2018
Accepted: 15 May 2018
Version of Record published:
20 July 2018
Review Article
Clinical syndromes associated with Coenzyme Q10
deficiency
Mar´ıa Alc ´
azar-Fabra1, Eva Trevisson2and Gloria Brea-Calvo1
1Centro Andaluz de Biolog´
ıa del Desarrollo and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla 41013, Spain; 2Clinical Genetics Unit,
Department of Women’s and Children’s Health, University of Padova, Padova 35128, Italy
Correspondence: Gloria Brea-Calvo (gbrecal@upo.es)
Primary Coenzyme Q deciencies represent a group of rare conditions caused by mutations
in one of the genes required in its biosynthetic pathway at the enzymatic or regulatory level.
The associated clinical manifestations are highly heterogeneous and mainly affect central
and peripheral nervous system, kidney, skeletal muscle and heart. Genotype–phenotype
correlations are difcult to establish, mainly because of the reduced number of patients and
the large variety of symptoms. In addition, mutations in the same COQ gene can cause
different clinical pictures. Here, we present an updated and comprehensive review of the
clinical manifestations associated with each of the pathogenic variants causing primary CoQ
deciencies.
Coenzyme Q structure and function
Coenzyme Q (CoQ) or ubiquinone is the only endogenously synthetized redox-active lipid that is found
in virtually all endomembranes, plasma membrane and serum lipoproteins, being especially abundant in
mitochondria. It is composed of a benzoquinone ring as a head group, and a polyisoprenoid chain, which
inserts the molecule into the phospholipid bilayer and varies in length depending on the species (Figure
1A). In humans, it has 10 isoprene units (CoQ10), 6 in Saccharomyces cerevisiae (CoQ6)andthemain
form found in mice has 9 units (CoQ9), although low amounts of CoQ10 canbealsodetectedintheir
membranes.
Soon after the first description by Cain and Morton in 1955 [1], the main function of CoQ in the mi-
tochondrial electron transport chain (mETC) was proposed by Crane et al. [2], who also demonstrated
its redox proprieties. In the mETC, CoQ is an essential mobile electron transport component, shuttling
electrons from complex I (NADH-ubiquinone oxidoreductase) or complex II (succinate-ubiquinone ox-
idoreductase) to complex III (succinate-cytochrome c oxidoreductase).
CoQ is permanently going through oxidation-reduction cycles. It can be found in a completely reduced
form (CoQH2or ubiquinol), after receiving two electrons, or in a completely oxidized form (CoQ or
ubiquinone). When, as in the mETC, this redox cycle occurs by a two-step transfer of one electron each,
a semiquinone (or semi-ubiquinone, CoQH•) intermediate is produced (Figure 1B).
Computational prediction models have recently confirmed studies describing how, in the inner mi-
tochondrial membrane, CoQ is mainly either located close to the membrane–water interface, with its
relatively small head group being shadowed by the bigger polar heads of phospholipids or stabilized in
the middle of the bilayer. During the process of electron transfer, CoQ rapidly translocates from one side
to the other of the inner membrane bilayer, with a rate that varies depending on the redox state of the
molecule. This process enables the interaction with the reducing and oxidizing sites in the proteins of the
mETC complexes, located close to the membrane surfaces [3].
After the discovery of its role in the mETC, new functions have emerged for CoQ, being the electron
acceptor for different dehydrogenases. Among others, in mitochondria CoQ accepts electrons from:
(i) dihydroorotate dehydrogenase, a key enzyme for pyrimidine biosynthesis [4],
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2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society 377
Essays in Biochemistry (2018) 62 377–398
https://doi.org/10.1042/EBC20170107
Figure 1. CoQ structure and functional integration in the mitochondrial inner membrane
(A) Chemical structure of Coenzyme Q (CoQ) and (B) redox cycle of its head group. (C) Integration of CoQ reduction by different de-
hydrogenases in the mETC; Cyt c, cytochrome c; DHODH, dihidroorotate dehydrogenase; ETF-FAD, electron transfer avoprotein;
ETF-Qase, electron transfer avoprotein cCenzyme Q reductase; G3PDH, glycerol-3-phosphate dehydrogenase; PROD, proline
dehydrogenase; SQR, sulphide-quinone oxidoreductase.
(ii) mitochondrial glycerol-3-phosphate dehydrogenase [5], a tissue-specific component of mitochon-
dria connecting glycolysis, oxidative phosphorylation and fatty acid metabolism [6],
(iii) electron transport flavoprotein dehydrogenase (ETFDH), a key enzyme involved in the fatty acid
β-oxidation and branched-chain amino acid oxidation pathways [7],
(iv) proline dehydrogenase 1, an enzyme required for proline and arginine metabolism [8],
(v) probably, from hydroxyproline dehydrogenase (or proline dehydrogenase 2), involved in the glyoxy-
late metabolism [9]
(vi) sulphide-quinone oxidoreductase [10] during sulphide detoxification, a gas modulator of relevant
cellular processes but toxic when in excess [11].
Reduced CoQ (CoQH2) generated by all these processes is efficiently reoxidized by complex III in the mETC
(Figure 1C).The ability to sustain continuous oxidation/reduction cycles makes CoQ not only a great electron carrier
for different cellular processes, but also a potent membrane antioxidant, which protects lipids, proteins and nucleic
acids from harmful oxidative damage [12,13]. In membranes, CoQH2has been shown to prevent both initiation and
propagation of lipid peroxidation [14,15] and, indirectly, to regenerate other antioxidants, such as α-tocopherol and
ascorbate [16]. The high efficiency of CoQ against oxidative stress may be related to its ubiquitous distribution, its
localization in the core of membranes and the availability of diverse dehydrogenases, able to efficiently regenerate the
molecule.
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2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
Essays in Biochemistry (2018) 62 377–398
https://doi.org/10.1042/EBC20170107
Figure 2. CoQ biosynthesis pathway
(A) Schematic model of human CoQ biosynthesis pathway. Blue arrows represent enzymatic reactions and circled numbers rep-
resent the different COQ proteins that participate in each step. Brown arrows indicate regulatory mechanisms. Circled question
mark shows currently unidentied enzymes. (B) Model of human CoQ biosynthetic complex, containing at least COQ3–COQ9
and lipids, such as CoQ itself. (Cand D) Green boxes contain 4-HB analogues, dened as unnatural CoQ precursors, which are
able to lead to CoQ production, bypassing defective COQ enzymes such as COQ6 (3,4-dihydroxybenzoate (3,4-dHB) or vanillic
acid (VA)) or COQ7 (2,4-dihydroxybenzoate (2,4-dHB). COQ9 patient broblasts can also benet from 2,4-dHB and VA; DDMQ,
demethoxy-demethyl-Coenzyme Q; DMQ, demethoxy-Coenzyme Q; DMeQ, demethyl-Coenzyme Q.
CoQ biosynthesis and regulation in eukaryotes/human
Levels of CoQ are quite stable in cells but its concentration varies among different tissues and organs, depending on
dietary conditions and age [17-20]. Although CoQ is mainly endogenously synthetized in mitochondria and then
distributed to other cell membranes [21], cells can incorporate a certain amount from dietary sources. CoQ is syn-
thesized by a set of nuclear-encoded COQ proteins, through a pathway that is not completely understood. Most of
the work on CoQ biosynthesis has been done in Saccharomyces cerevisiae, and at least 13 yeast genes (coq1–coq11,
Yah 1 and Arh1) have been identified as players of this process. Information about the human pathway is very scarce,
but orthologues of almost all of these genes have been already identified [22].
4-Hydrozybenzoate (4-HB), precursor of the benzoquinone ring, is synthesized from tyrosine, phenylalanine or
also para-aminobenzoic acid (pABA) in yeast, through a poorly characterized set of reactions [23-25]. The isoprenoid
tail comes from the mevalonate pathway, which is shared with cholesterol, among other molecules, and takes place
in extra-mitochondrial membranes. This side chain is assembled by Coq1p (PDSS1 and PDSS2, acting as a heterote-
tramer, are the human orthologues), which also determines its length. Coq2p (human orthologue COQ2) condensates
head and tail and the resulting molecule undergoes subsequent modifications of the ring moiety: C5-hydroxylation
c
2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society 379
Essays in Biochemistry (2018) 62 377–398
https://doi.org/10.1042/EBC20170107
Figure 3. Organs and systems involved in CoQ primary deficiencies.
Organs and systems affected in individuals with primary CoQ deciency, associating specic clinical manifestations with the genes
involved in each one. For abbreviations refer to Table 3. For frequency of each symptom linked to a specic gene refer to Table 2.
(yeast Coq6p, human COQ6) [26], O-methylations (yeast Coq3p, human COQ3) [27,28], C1-hydroxylation and
C1-decarboxylation (unidentified), C2-methylation (yeast Coq5p, human COQ5) [29,30] and C6-hydroxylation (east
Coq7p, human COQ7) [31], but also C4-deamination (Coq6p), in the case of yeast using pABA as precursor [25].
Yah1 and Arh1 (human orthologues, FDXR and FDX2), mitochondrial ferredoxin and ferredoxin reductase, have
been shown to transfer electrons to Coq6p [32]. Mammalian pathway is still incompletely defined and significant
efforts are required in order to determine whether it coincides with the yeast one (Figure 2).
Other Coq proteins are thought to have regulatory functions. Coq8p (two human orthologues: COQ8A (or
ADCK3/CABC1) and COQ8B (or ADCK4)) displays features of an atypical kinase that possibly phosphorylates
Coq3p, Coq5p and Coq7p in yeast [33-35]. However, COQ8A/ADCK3 has recently been shown to have a more
clear ATPase activity [36] whose role in CoQ biosynthesis still needs to be further studied. Coq4p (human ortho-
logue COQ4) function has not been elucidated yet, but it seems to be required for the formation and maintenance of
the CoQ biosynthetic complex [37]. Coq9p (human orthologue COQ9) is a lipid-binding protein stabilizing Coq7p
[38,39]. Coq10p (human orthologues COQ10A and COQ10B) probably controls CoQ correct localization within the
mitochondrial membranes [40]. Coq11p is thought to be essential for CoQ synthesis in yeast, but lacks a clear human
orthologue [41]. Additionally, three other genes of the ADCK family (human ADCK1,ADCK2 and ADCK5)have
been proposed to participate in the biosynthetic process, but there is no experimental evidence for this [35,42].
It is widely accepted that yeast Coq3p–Coq9p proteins are organized in a multiprotein complex, possibly con-
taining some intermediates of the biosynthesis and CoQ itself [41,43,44]. The complex would probably optimize the
orientation of the substrates and active sites of the enzymes as well as their functional coordination [37,45-48] (Figure
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2). Evidence supporting the existence of a conserved complex also in mammals has been recently reported by dif-
ferent groups through diverse approaches [24,30,36,39,49-53]. However, functional organization and regulation of
mammalian biosynthetic complex is still elusive and could be different from the yeast one.
Little is known about CoQ biosynthesis regulation, which may occur at the transcriptional, post-transcriptional and
post-translational level, or even during the assembly of the putative multisubunit complex. Transcriptionally, several
factors have emerged as possible candidates [54-56]. However, a deep study of promoters and regulation sequences of
the COQ genes is lacking currently. At the post-transcriptional level, several RNA binding proteins that modulate the
stability of COQ transcripts have also been identified [57,58]. At the post-translational level, processing by proteases,
phosphorylation and dephosphorylation have been suggested to have a role in the regulation of some COQ proteins’
activity, but only a very fragmented piece of information is currently available [34,35,59,60].
Clinical manifestations of CoQ deficiencies
CoQ deficiencies have been associated with a wide range of clinical manifestations. Patients with CoQ deficiency have
reduced levels of CoQ in tissues, which can be caused either by mutations in the genes participating in CoQ biosyn-
thesis, the so-called primary CoQ deficiencies, or by defects not directly linked CoQ biosynthesis, the secondary CoQ
deficiencies.
Primary deficiencies
Primary CoQ deficiencies are very rare conditions, usually associated with highly variable multisystemic manifes-
tations (Figure 3), and genetically caused by autosomal recessive mutations. Approximately 200 patients from 130
families have been described in the literature so far (Supplementary Table S1).
It has been estimated a worldwide total of 123,789 individuals (1 in 50,000) affected by primary CoQ deficiencies,
being only 1,665 (less than 1 in 3,000,000) due to known pathogenic variants, taking into account the frequency of
the different known or predicted pathogenic variants in given populations [118].
To date, ten genes encoding CoQ biosynthetic proteins have been shown to have pathogenic variants causing hu-
man CoQ deficiency: PDSS1,PDSS2,COQ2,COQ4,COQ5,COQ6,COQ7,COQ8A,COQ8B and COQ9 (Table
1 , Supplementary Table S1). They affect multiple organ systems in a highly variable way, including central nervous
system (CNS) (encephalopathy, seizures, cerebellar ataxia, epilepsy or intellectual disability (ID)), peripheral ner-
vous system (PNS), kidney (steroid-resistant nephrotic syndrome (SRNS)), skeletal muscle (myopathy), heart (hy-
pertrophic cardiomyopathy) and sensory system (sensorineural hearing loss (SNHL), retinopathy or optic atrophy)
(Table 2 ). While mutations in some COQ genes can affect different organs (e.g. COQ2 and COQ4), pathogenic
variants of other COQ genes show a more specific phenotype (e.g. COQ8A and COQ8B). Even more, mutations in
the same COQ gene can cause very variable clinical phenotypes with different age of onset. The age of onset may
generally range from birth to early childhood (PDSS1,PDSS2,COQ2,COQ4,COQ5,COQ6,COQ7 andCOQ9),
or from childhood to adolescence (COQ8A andCOQ8B),buttherearealsosomeadult-onsetcases(COQ2 [69];
COQ8A [99,106]; COQ8B [110]).
CNS manifestations
Central nervous system is often affected in these patients, showing a wide range of clinical manifestations, includ-
ing encephalopathy, hypotonia, seizures, dystonia, cerebellar ataxia, epilepsy, stroke-like episodes, spasticity or ID.
These symptoms may be present in patients with mutations in any of the reported COQ genes, but they are less
prominentinpatientswithpathogenicvariantsof COQ6 and COQ8B, in whom the more frequent phenotype is
renal involvement. COQ2 patients manifested early-onset nephrotic syndrome (17/22) which in some cases may
be accompanied by encephalopathy and seizures (7/22) [62, 65, 68, 71-79]. COQ4 patients generally show a severe
CNS involvement, with encephalopathy and seizures (9/14), hypotonia (10/14) and cerebellar hypoplasia (6/14); and
often a fatal outcome with death in the first days (6/14) or months (5/14) of life [80-84]. The hallmark phenotype
in COQ8A patients is slow progressive cerebellar atrophy and ataxia (43/45), associated with ID (19/45), epileptic
seizures (18/45), tremor (18/45), dysarthria (16/45), saccadic eye movements (10/45), dystonia (9/45) or spasticity
(8/45), among others [99,106,96-98, 100-105, 107-109]. The only COQ5 family described shows a phenotype similar
to COQ8A patients [85]. Some COQ8A patients (6/45) [99,97,98,102] and one COQ2 patient (1/19) [72] suffered one
stroke-like episode, which contributed significantly to deterioration of the neurological status and may explain the
heterogeneity of the functional outcome among affected siblings [97]. Some COQ2 variants have also been predicted
to increase susceptibility to adult-onset multisystem atrophy (MSA), but this issue is still under debate [69,119]. Very
few patients with mutations in PDSS1 [62,61], PDSS2 [65,63, 64, 66, 67], COQ5 [85], COQ7 [91,90] and COQ9
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Essays in Biochemistry (2018) 62 377–398
https://doi.org/10.1042/EBC20170107
Tab l e 1 Pathogenic variants of COQ genes found in primary CoQ deficiency patients reported in the literature
Gene
Length
(AA) Exons RefSeq1Pathogenic variants
F (P) cDNA mutation AA modification Exon Ref.
PDSS1 415 12 exons NM 014317.4
NP 055132.2
1 (1) c.661 662insT p.Arg221Leufs* 7 [61]
1 (2) c.924T>G p.Asp308Glu 10 [62]
1 (1) c.1108A>C p.Ser370Arg 12 [61]
PDSS2 399 8 exons NM 020381.3
NP 065114.3
1 (1) c.485A>G p.His162Arg 3 [63]
1 (1) c.964C>T p.Gln322* 6 [64]
1 (1) c.1042 1148-2816 del p.? 8 [63]
2 (2) c.1145C>T p.Ser382Leu 8 [65,64]
1 (1) c.1151C>A p.Ala384Asp 8 [65]
1 (3) NK NK NK [66,67]
COQ2 2421 7 exons NM 015697.7
NP 056512.5
1 (1) c.176dupT p.Ala60Argfs*33 1 [68]
1 (1) c.382A>G p.Met128Val 1 [69,70]
3 (3) c.437G>A4p.Ser146Asn 2 [71,72,73,70]
1 (1) c.518G>A p.Arg173His 2 [65]
1 (1) c.545T>G p.Met182Arg 2 [74]
1 (1) c.590G>A p.Arg197His 3 [72,70]
7 (7) c.683A>G p.Asn228Ser 3 [72,65,75,68,70]
1 (1) c.701delT p.Leu234fs*14 4 [75,70]
1 (1) c.856C>T p.Leu286Phe 5 [65]
1 (1) c.881C>T p.Thr294Ile 5 [68]
2 (3) c.890A>G p.Tyr297Cys 5 [72, 76, 77,65,70]
1 (2) c.905C>T p.Ala302Val 5 [78,70]
1 (1) c.973A>G p.Thr325Ala 6 [68]
2 (2) c.1159C>T4p.Arg387* 7 [73,68,70]
1 (2) c.1169G>C p.Gly390Ala 7 [79]
1 (2) c.1197delT p.Asn401Ilefs*15 7 [62]
COQ4 265 7 exons NM 016035.4
NP 057119.2
1 (1) c.23 33 del TCCTCCGTCGG p.Val8Alafs*19 1 [80]
1 (2) c.155T>C p.Leu52Ser 2 [81]
1 (1) c.190C>T p.Pro64Ser 2 [81]
1 (2) c.197 198 del GCinsAA p.Arg66Gln 2 [82]
2 (3) c.202G>C p.Asp68His 2–3 [82,83]
1 (2) c.245T>A p.Leu82Gln 3 [82]
1 (1) c.311G>T p.Asp111Tyr 4 [80]
1 (1) c.356C>T p.Pro119Leu 4 [80]
1 (1) c.421C>T p.Arg141* 5 [81]
1 (1) c.433C>G p.Arg145Gly 5 [81]
1 (1) c.469C>A p.Gln157Lys 5 [83]
1 (2) c.473G>A p.Arg158Gln 5 [82]
1 (2) c.521 523 delCCA p.Thr174del 5 [81]
3 (3) c.718C>T p.Arg240Cys 7 [81,82]
1 (1) 3.9 Mb deletion of chromosome 9q34.13, including COQ4 gene [84]
COQ5 327 7 exons NM 032314.3
NP 115690.3
1 (3) 9590 pb tandem duplication of the last 4 exons of COQ5 after 1 kb of
3’-UTR (modifies the 3’-UTR) (base pair positions on Chr 12:
120,940,150–120,949,950/hg19)
[85]
COQ6 468 12 exons NM 182476.2
NP 872282.1
6 (6) c.189 191delGAA p.Lys64del 2 [86]
1 (1) c.484C>T3p.Arg162* 5 [87]
1 (1) c.564G>A3p.Trp188* 5 [87]
Continued over
382 c
2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
Essays in Biochemistry (2018) 62 377–398
https://doi.org/10.1042/EBC20170107
Tab l e 1 Pathogenic variants of COQ genes found in primary CoQ deficiency patients reported in the literature
(Continued)
Gene
Length
(AA) Exons RefSeq1Pathogenic variants
F (P) cDNA mutation AA modification Exon Ref.
1 (1) c.686A>C p.Gln229Pro 6 [86]
2 (7) c.763G>A p.Gly255Arg 7 [87,88]
6 (6) c.782C>T p.Pro261Leu 7 [79,86]
4 (6) c.1058C>A p.Ala353Asp 9 [87,88]
1 (1) c.1078C>T p.Arg360Trp 9 [89]
1 (1) c.1154A>C p.Asp385Ala 11 [65]
2 (2) c.1235A>G3p.Tyr412Cys 11 [65,88]
1 (1) c.1341G>A p.Trp447* 11 [87,88]
1 (1) c.1383delG p.Gln461fs*478 12 [87,88]
COQ7 217 6 exons NM 016138.4
NP 057222.2
1 (1) c.332T>C (and c.308C>T) 5p.Leu111Pro (and p.
Thr103Met)
3[90]
1 (1) c.422T>A p.Val141Glu 4 [91,90]
COQ9 318 9 exons NM 020312.3
NP 064708.1
1 (1) c.521+1delG p.Ser127 Arg202del Intron 5 [92]
1 (4) c.521+2T>C p.Ser127 Arg202del Intron 5 [93]
1 (4) c.711+3G>C p.Ala203 Asp237del Intron 7 [93]
1 (1) c.730C>T p.Arg244* 7 [94,95]
COQ8A /
ADCK3
647 15 exons NM 020247.4
NP 064632.2
1 (1) c.500 521 del 22insTTG p.Gln167Leufs*36 3 [96]
1 (2) c.589-3C>G p.Leu197Valfs*20 Intron 3 [97]
1 (2) c.637C>T p.Arg213Trp 4 [97,98]
2 (3) c.811C>T p.Arg271Cys 6 [99,97]
1 (2) c.815G>T p.Gly272Val 6 [97,98]
1 (1) c.815G>A p.Gly272Asp 6 [97,98]
1 (1) c.827A>G p.Lys276Arg 6 [100]
1 (2) c.830T>C p.Leu277Pro 6 [101]
5 (7) c.895C>T p.Arg299Trp 7 [99,97,102]
1 (2) c.910G>A p.Ala304Thr 7 [99]
1 (1) c.911C>T p.Ala304Val 7 [99]
1 (1) c.993C>T6p.Lys314 Gln360del (deletion
of exon 8?)
8 [96, 97, 103]
3 (6) c.1042C>T p.Arg348* 8 [104,105]
1 (1) c.1081-1 1082 dupGTA p. Gln360 Tyr361ins* Intron 8
/Exon
9
[97]
1 (2) c.1136T>A p.Leu379* 9 [104]
1 (2) c.1228C>T p.Arg410* 10 [97]
1 (2) c.1286A>G3p.Tyr429Cys 11 [99]
1 (1) c.1358delT p.Leu453Argfs*24 11 [97]
1 (4) c.1398+2T>C7p.Asp420Trpfs*40
p.Ile467Alafs*22
11–12 [96]
1 (2) c.1506+1G>A p.Val503Metfs*21 Intron
12
[101]
1 (1) c.1511 1512delCT p.Ala504fs* 13 [106]
1 (1) c.1523T>C p.Phe508Ser 13 [97]
1 (1) c.1541A>G p.Tyr514Cys 13 [96]
1 (1) c.1645G>A p.Gly549Ser 14 [96, 97, 103]
1 (1) c.1651G>A p.Glu551Lys 14 [98]
1 (1) c.1702delG p.Glu568Argfs* 15 [100]
1 (2) c.1732T>G p.Phe578Val 15 [102]
2 (3) c.1750 1752 delACC p.Thr584del 15 [96,107]
1 (2) c.1805C>G p.Pro602Arg 15 [107]
1 (1) c.1813dupG p.Glu605Glyfs*125 15 [97,98]
1 (2) c.1844G>A p.Gly615Asp 15 [97]
1 (2) c.1844dupG p.Ser616Leufs*114 15 [108]
Continued over
c
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https://doi.org/10.1042/EBC20170107
Tab l e 1 Pathogenic variants of COQ genes found in primary CoQ deficiency patients reported in the literature
(Continued)
Gene
Length
(AA) Exons RefSeq1Pathogenic variants
F (P) cDNA mutation AA modification Exon Ref.
1 (1) 29 kb partial deletion of the gene including exons 3–15 (base pair
position: 227,150,977-227,195,656, hg19)
[97]
1 (1) 2.9 Mb duplication at chromosome region 1q42.11q42.13 (including
ADCK3)
[109]
COQ8B/
ADCK4
544 15 exons NM 024876.3
NP 079152.3
1 (1) c.101G>A p.Trp34* 2 [51]
4 (8) c.293T>G p.Leu98Arg 5 [110,111]
1 (2) c.449G>A p.Arg150Gln 6 [112]
3 (5) c.532C>T p.Arg178Trp 7 [51,111,113,114]
3 (4) c.645delT p.Phe215Leufs*14 8 [51,111,113]
1 (1) c.649G>A p.Ala217Thr 8 [113]
5 (5) c.737G>A p.Ser246Asn 9 [114,115]
1 (2) c.748G>A p.Asp250Asn 9 [111]
1 (1) c.748G>T p.Asp250Tyr 9 [116]
3 (4) c.748G>C8p.Asp250His 9 [117,114]
2 (3) c.759C>A p.Asn253Lys 9 [112]
1 (3) c.857A>G p.Asp286Gly 10 [51,113]
1 (1) c.929C>T p.Pro310Leu 10 [111]
1 (1) c.954 956 dupGAC p.Thr319dup 11 [51]
1 (2) c.958C>T p.Arg320Trp 11 [51,113]
1 (2) c.1027C>T p.Arg343Trp 11 [51]
5 (13) c.1199dupA p.His400Glnfs*11 13 [51,110,111,113]
7 (20) c.1339dupG p.Glu447Glyfs*10 15 [110,111,113]
1 (2) c.1356 1362 delGGGCCCT p.Gln452Hisfs* 15 [51]
2 (3) c.1430G>A p.Arg477Gln 15 [51,110,113]
1 (3) c.1447G>T p.Glu483* 15 [51,113]
1 (1) c.1468C>T p.Arg490Cys 15 [112]
1 (1) c.1493 1494 CC>AA p.Ala498Glu 15 [111]
1Reference sequences correspond to longest transcript.
2COQ2: Several initiation codons. Nomenclature is given for ATG1, but ATG4 corresponds to first amino acid (371 aa length protein) [70].
3These pathogenic variants were found in simple heterozygosis in at least one patient.
4The patient with these two mutations also carries a novel mutation in MT-ND1 (3754C>A) with 22% of heteroplasmy in peripheral blood, which
may contribute to the disease [73].
5COQ7 c.308C>T polymorphism seems to increase COQ7 protein instability and intensify the effect of the mutation. The patient also has a 1555A>G
mutation in mtDNA, not previously reported, which may contribute to the disease [90].
6Pathogenic variant c.993C>TofCOQ8A shows a conflicting protein change. Based on the sequence, it should be a synonymous change (p.Phe331
=)[96].
7COQ8A c.1398+2T>C6 variant affects a splice donor site, different splice variants are expressed: p.Asp420Trpfs*40 and p.Ile467Alafs*22 [96].
8Two siblings with this variant in homozygosis also had an homozygous mutation in NPHS1 gene (c.1339G>A; p.Glu447Lys) [117].
*stands for premature STOP codon.
Abbreviations: AA, amino acid; F(P): F, number of families with each mutation; P, number of patients with each mutation.
[92-95] have been identified to define a specific phenotype, but they presented encephalopathy (PDSS1 and COQ9),
Leigh-like syndrome (PDSS2 and COQ9), ataxia (PDSS2 and COQ5), ID (PDSS1,PDSS2,COQ5 and COQ7),
seizures (PDSS2,COQ5 and COQ9)orspasticity(PDSS2,COQ5 and COQ7).
Peripheral nervous system and sensory organs manifestations
Peripheral neuropathy has been described in two siblings with PDSS1 mutations, associated with optic atrophy
and early-onset SNHL [62]. Also, the two COQ7 patients described showed peripheral polyneuropathy, again with
SNHL and one of them with visual dysfunction [91,90]. SNHL is very frequent, especially in COQ6 patients (16/26)
[79,65,86, 87, 89], associated with SRNS in all cases, and with optic atrophy (1/18) [86]. One COQ8A patient (1/45)
384 c
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Essays in Biochemistry (2018) 62 377–398
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Tab l e 2 Clinical manifestations in primary CoQ deficiency
Gene F P Age Clinical manifestations LA
CoQ
defi-
ciency CoQ treatment References
Onset
Last examination
(*death) CNS
PNS/sensory
organs Kidney Muscle Heart Other
Treat-
ment Effect
PDSS1 2 3 First years of
life (3)
1.5yo* (1),
14–22yo (2)
- Encephalopathy (2)2
-ID(2)
-DD(1)
- PNSN (2)
-OA(2)
- SNHL (2)
-SRNSand
ESRD (1)
-Vp(2) -LR(2)
-Obesity(2)
-HT(1)
(3) F (2)
WBC
(1)
[62,61]
PDSS2 57 <1yo (6),
2yo (1)
8mo* (2),
8yo* (1),
8–12yo (2),
NK (2)
- ARCA2 (3)
-ID(3)
-Ht(2)
-LS(1)
-Sz(1)
-Sp(1)
- Dystonia (1)
-Ny(1)
- Pyramidal
syndrome (1)
- Cerebral palsy (1)
-DD(1)
- Encephalopathy (1) 2
- SNHL (4)
-RP(2)
-Myopia(2)
-Visual
dysfunction (2)
-OA(1)
- Cataract (1)
-SRNS(7)
-ESRD(2)
- HCM (2) - Oedema (2)
-Neonatal
pneumonia (1)
-HT(1)
(2) M (1)
F(1)
Yes (2) No benefits (2) [65,63, 64, 66,
67]
COQ2 18 22 <2yo (15),
16-18yo (2),
70yo (1),
NK (1)
<2yo* (9),
2–4yo (5),
12yo (1),
23–37yo (2),
71yo (1),
NK (4)
- Encephalopathy (7) 2
-Sz(7)
-Ht(5)
-Ep(4)
-Ny(3)
-My(2)
- Dystonia (2)
- Muscle stiffness (1)
-SLL(1)
-Tr(1)
-DD(1)
-MSA(1)
-CAt (1)
-Rp(2)
-OA(1)
-RP(1)
- SRNS (17)
-ESRD(8)
-Tp(1)
-Only
proteinuria (1)
-LAM(1)
-MW(1)
- HCM (3) - Oedema (7)
-RF(4)
-LF(3)
-DM(3)
- Apnoea (2)
-RD(1)
- Cholestatic liver (1)
-HT(1)
-CLD(1)
- Hypercholestero-
laemia
(1)
(8) M (5)
F(3)
Yes (9) - No benefits (2)
- No deterioration (2)
- Renal function
restored (4)
- Neuromuscular
functions restored (1)
[69,62, 65, 68,
71-79,70]
COQ4 11 14 Birth (13),
10mo (1)
<4do* (6),
1mo–2yo* (5),
3yo (1),
18yo (1),
NK (1)
- Ht (10)
- Encephalopathy (7) 2
-CHyp(6)
-Sz(5)
-Ep(5)
-DD(4)
-ID(2)
-My(1)
-THyp(1)
- CAt (1)
-Sp(1)
-HL(1)
- PNSN (1)
- Delayed visual
maturation (1)
-Myopathy(1) -HCM(7)
- Bradycardia (4)
-HF(2)
- Cardiomegaly (1)
- HHyp (1)
-Septal
defects (1)
-RD(9)
- Apnoea (4)
-RF(2)
- Cyanosis (1)
- Dysmorphic
features (1)
- Recurrent
respirato ry
infections (1)
(9) M (6)
F(3)
Yes (3) - No benefits (1)
-Muscle
improvement (1)
- Lactic acidosis and
cardiac function
improved (1)
[80-84]
COQ5 1 3 Early
childhood (3)
14–22yo (3) - ID (3)
- ARCA2 (3)
- CAt (3)
-Dy(3)
-Ny(3)
-My(2)
-Sz(2),
-DD(2)
-Ep(1)
- SEM (1)
-Tr(1)
-Sp(1)
WBC
(3)
M(1)
Yes (3) - Improvement of
ataxia (3)
[85]
Continued over
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Tab l e 2 Clinical manifestations in primary CoQ deficiency (Continued)
Gene F P Age Clinical manifestations LA
CoQ
defi-
ciency CoQ treatment References
Onset
Last examination
(*death) CNS
PNS/sensory
organs Kidney Muscle Heart Other
Treat-
ment Effect
COQ6119
263
<1.5yo (9),
2–6yo (13),
NK (4)
5–6yo* (2),
17yo* (1),
NK*(2),
0.5–11yo (14),
NK (7)
-Sz(2)
-DD(2)
- ARCA2 (1)
-ID(1)
-Pt(1)
-Exotropia(1)
-Ny(1)
- SNHL (16)
-OA(1)
- SRNS (23)
- ESRD (15)
-Only
proteinuria (1)
- MW (2) - Cardiovascular
abnormality (1)
- Dysmorphic
features (1)
Yes ( 4) - Im pr o ve d
proteinuria (3)
- Improved SNHL (1)
- Improved renal
function (1)
- Improved gro wth
retardatio n (1)
[79,65,86, 87,
89,88]
COQ7 22 <1yo (2) 6–9yo (2) - Ht (2)
-DD(2)
-ID(1)
-Sp(1)
-PNSN(2)
-SNHL(2)
-Visual
dysfunction (1)
-Kidney
dysfunction (1)
- Dysplastic
kidneys (1)
- MW (2) - HCM (1) - HT (1)
-RD(1)
-LHyp(1)
(2) M (1)
F(2)
Yes (2) - No deterioration (2) [91,90]
COQ9 3 6 Birth (6) Birth* (2),
12ho* (1),
3do* (1),
18do* (1),
2yo* (1)
-DD(5)
-Sz(2)
- Encephalopathy (2) 2
-LS(2)
- CAt (1)
- Dystonia (1)
- Opisthotonus (1)
- Muscle stiffness (1)
- Multifocal global ischaemic
events (1)
-Ht(1)
-Tp(1)
-Enlarged
kidneys (1)
- Bradycardia (2)
- Cardiomegaly (1)
- HCM (1)
- Oligohydramnios
(3)
- Apnoea (2)
-RD(1)
- Cyanosis (1)
- Reduced
haematopoiesis in
liver (1)
(4) M (1)
F(3)
Yes (3) - No benefits (2)
- Plasma lactate
reduced (1)
[92-95]
COQ8A 1
/ ADCK3
29 45 1–4yo (24),
5–11yo (13),
14–27yo(8)
22yo*(1),
26yo*(1),
3–7yo (2),
15–50yo (40),
81yo (1)
- CAt (44)
- ARCA2 (43)
- ID (19)
- Tr (18)
- Dy (16)
- My (13)
- Sz (12)
- Ep (11)
- SEM (10)
- Dystonia (9)
-Sp(8)
-Ny(6)
-SLL(6)
- Migraine (5)
-Pt(3)
-Ht(3)
- Depression (3)
-Chorea(2)
-DD(2)
- Pyramidal
syndrome (1)
- Slow ocular
pursuit (1)
- Encephalopathy (1) 2
-Strabismus(1)
-SNHL(2)
-Visual
dysfunction (1)
- Cataracts (1)
- Visual aureas
(1)
- Rod–cone
dysfunction (1)
-EI(8)
-MW(7)
-MF(3)
-LAM(3)
-Myopathy(1)
- Cardiomyopathy (1) - Recurrent
respirato ry
infections (1)
(6) M (11)
F(4)
WBC
(1)
Yes (18) - No benefits (8)
- Slight improvement
of cerebellar signs (2)
- Improvement of
tremor and
myoclonus (2)
- Improvement of
ataxia (4)
- Improvement in
motor abilities (2)
- Improvement in
fatigue
and speech (1)
- Improvement of
cognitive abilities (1)
- Stabilization of the
ataxia (1)
[99,106,96-98,
100-105,
107-109]
Continued over
386 c
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Tab l e 2 Clinical manifestations in primary CoQ deficiency (Continued)
Gene F P Age Clinical manifestations LA
CoQ
defi-
ciency CoQ treatment References
Onset
Last examination
(*death) CNS
PNS/sensory
organs Kidney Muscle Heart Other
Treat-
ment Effect
COQ8B 1
/ ADCK4
38 74 <1yo–
10yo (29),
11yo–
21yo (38),
23–32yo (7)
15yo* (1),
25yo* (1),
29yo* (1),
1–9yo (6),
10–20yo (51),
21–39yo (14)
-Sz(4)
-ID(4)
- Headaches (2)
-Ep(2)
-DD(1)
- Encephalopathy (1) 2
-Autism(1)
-
Hypermetropia
- Astigmatism
(2)
-Visual
dysfunction (1)
-RP(1)
- SRNS (63)
- ESRD (45)
- CKD (17)
- Haematuria
(8)
-Only
proteinuria (8)
- Medullary
nephrocalci-
nosis (6)
-Enlarged
kidneys (1)
-MF(1)
-MW(1)
- HCM (2)
-Septal
defects (2)
-DCM(1)
- Cardiomyopathy (1)
-HF(1)
- Pericardial effusion
(1)
- Oedema (15)
- HT (10)
- Goitre (2)
-Nocturnal
enuresis (2)
- Polyuria (1)
- Polydipsia (1)
- Lupus-like
symptoms (1)
- Hypospadias (1)
- Dyspnoea (1)
- Splenomegaly (1)
- Hepatomegaly (1)
- Hypercholestero-
laemia (1)
- Dysplastic ears (1)
- Recurrent
otitis (1)
- Hypothyroidism (1)
F (5) Yes (28) - No benefits (7)
- Improvement
of proteinuria (17)
- Improvement of
oedema (1)
better physical fitness
and
- Reduced fatigue (1)
- Stabilization of
renal function (1)
-NK(2)
[51,110,111,
112-114, 116,
117]
1COQ6,COQ8B (SRNS) and COQ8A (ARCA2) variants show a very specific phenotype, but the possibility of a broader phenotype cannot be excluded, since many of the known pathogenic
variants were identified in studies that screened cohorts of patients with specific subsets of well-defined symptoms.
2Encephalopathy is defined as a wide spectrum of brain manifestations, often not described in detail.
3There are three COQ6 patients without any information.
Numbers between brackets indicate the number of patients with the specific manifestation.
*These patients died at the indicated age.
Abbreviations: CoQ deficiency (WBC, white blood cell, F, fibroblasts; M, muscle); do, days old; F, number of families; ho, hours old; LA, lactic acidosis;mo,monthsold;NK,notknown;P,
number of patients; wo, weeks old; yo, years old.
For clinical manifestations abbreviations, please refer to Table 3 and main text.
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Tab l e 3 Clinical manifestations in primary CoQ deficiency
CNS PNS/sensory organs Renal Muscle Heart Other
- Autism,
- Autosomal recessive,
cerebellar ataxia 2 (ARCA2)
- Cerebellar atrophy (CAt)
- Cerebellar hypoplasia
(CHyp)
- Cerebral palsy
-Chorea
- Depression
- Developmental delay (DD)
- Dysarthria (Dy)
- Dystonia
- Encephalopathy
- Epilepsy (Ep)
- Exotropia
- Headaches
- Hypotonia (Ht)
- Intellectual deficiency (ID)
- Leigh-like syndrome (LS)
- Migraine
- Multifocal global
ischaemic events
- Muscle stiffness
- Myoclonus (My)
- Mystagmus (Ny)
- Opisthotonus
-Ptosis(Pt)
- Pyramidal syndrome
- Saccadic eye
movements (SEM)
- Seizures (Sz)
- Slow ocular pursuit
- Spasticity (Sp)
- Sporadic multisystem
atrophy (MSA),
- Strabismus
- Stroke-like lesions (SLL)
- Thalamic hypoplasia
(THyp)
-Tremor(Tr)
- Astigmatism
- Cataracts
- Delayed visual maturation
- Hearing loss (HL)
- Hypermetropia
- Myopia
- Optic nerve atrophy (OA)
- Peripheral neuropathy
(PNSN)
- Retinitis pigmentosa (RP)
- Retinopathy (Rp)
- Rod–cone dysfunction
- Sensorineural hearing
loss (SNHL)
- Visual aureas
- Visual dysfunction
- Chronic kidney disease
(CKD)
- Dysplastic kidneys
- End-stage renal disease
(ESRD)
- Enlarged kidneys
- Haematuria
- Kidney dysfunction
- Proteinuria
- Steroid resistant
nephrotic syndrome
(SRNS)
- Tubulopathy (Tp)
- Exercise intolerance (EI)
- Lipid accumulation in
muscle (LAM)
- Muscle fatigue (MF)
- Muscle weakness (MW)
- Myopathy
- Bradycardia
- Cardiomegaly
- Cardiomyopathy
- Cardiovascular
abnormality
- Dilated cardiomyopathy
(DCM)
- Heart failure(HF)
- Heart hypoplasia (HHyp)
- Hypertrophic
cardiomyopathy (HCM)
- Pericardial effusion
- Septal defects
- Valvulopathy (Vp)
- Dysmorphic features
- Oedema
- Diabetes mellitus (DM)
- Obesity
- Hypercholesterolaemia
- Goitre
- Hypothyroidism
- Respiratory distress (RD)
- Neonatal pneumonia
- Respiratory failure (RF)
- Apnoea
- Chronic lung disease (CLD)
- Recurrent respiratory
infections
-Lung hypoplasia (LHyp)
- Cyanosis
- Hypertension (HT)
- Livedo reticularis (LR)
- Dyspnoea
- Nocturnal enuresis
- Polyuria
- Polydipsia
- Liver failure (LF)
- Cholestatic liver
- Hepatomegaly
-Reduced haematopoiesis in
liver
- Lupus-like symptoms
- Splenomegaly
- Recurrent otitis
- Hypospadias
- Oligohydramnios
also showed early-onset bilateral SNHL [96, 97, 103], as well as patients with PDSS2 mutations (4/7), who mani-
fested retinitis pigmentosa (2/7) and optic atrophy (1/7), too [66,63]. One patient with COQ4 mutations (1/14) man-
ifested bilateral hearing loss as well [80]. Visual impairment was also a symptom in some patients with optic atrophy
(PDSS1 [62], PDSS2 [66,63], COQ2 [72] and COQ6 [86]), retinopathy (COQ2) [78], retinitis pigmentosa (PDSS2
[63], COQ2 [69] and COQ8B [111]) and cataracts (PDSS2 [66] and COQ8A [99]).
Renal manifestations
SRNS is frequent in primary CoQ deficiency patients, specifically in patients with pathogenic variants of COQ2,
COQ6 and COQ8B. It generally starts as proteinuria and if untreated evolves to end-stage renal disease (ESRD) within
childhood [65]. COQ2 patients displayed early-onset nephrotic syndrome (15/22) [71, 72, 76, 77,62,65,75,68], iso-
lated (9/22) or with encephalopathy and seizures (6/22), but there was also one family with onset in adolescence, slow
progression of the renal disease and mild neurological symptoms [79]. The hallmark of COQ6 pathogenic variants
is childhood-onset SNRS (23/26) associated with SNHL (16/26) [79,65,86, 87, 89,88]. COQ8B patients mainly pre-
sented with an adolescence-onset SRNS due to focal segmental glomerulosclerosis, associated with oedema (15/74)
and hypertension (10/74), which generally progressed to ESRD [51,110,111,112-114, 116, 117]. Onset of SRNS may
be before 10 years of age (29/74). Patients with PDSS1 (1/3) [61] and PDSS2 (7/7) [65,63, 64, 66, 67] mutations also
showed SRNS. One COQ9 (1/6) [95] and one COQ2 (1/22) [73] patient displayed a tubulopathy.
Muscle manifestations
Isolated myopathy has not been found in individuals with molecularly confirmed primary CoQ deficienc y. The major-
ity of the patients with a predominantly muscular phenotype have been associated with secondary CoQ deficiency.
Myopathy has been described in some patients with a multisystemic phenotype (COQ4 (1/14) [84] and COQ8A
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(1/45) [100]). Other muscular manifestations include exercise intolerance (COQ8A (8/45) [96,97, 98, 104]), muscle
weakness (COQ2 (1/22) [72], COQ6 (2/26) [86], COQ7 (2/2) [91,90], COQ8A (7/45) [99,98,102,109] and COQ8B
(1/74) [117]) and muscle fatigue (COQ8A (2/45) [99,108] and COQ8B (1/74) [111]). Some muscle biopsies have
shown lipid accumulation in muscle (COQ4 (1/14) [84], COQ8A (3/45) [99,98] and COQ2 (1/22) [74]).
Cardiac manifestations
The most frequent heart manifestation is hypertrophic cardiomyopathy, often present in COQ4 patients with a pre-
natal onset (7/14) [80-82], whereas COQ2 (3/22) [71,74,73], COQ8B (2/74) [110,113,117], COQ7 (1/2) (101) and
COQ9 patients (1/6) [95] show a neonatal onset. Other less frequently reported cardiac manifestations are valvu-
lopathies (PDSS1 (2/3) [62]), heart hypoplasia (COQ4 (1/14) [81]), septal defects (COQ4 (1/14) [84] and COQ8B
(2/74) [111,112]), heart failure (COQ4 (2/14) [81,82] and COQ8B (1/74) [111]), bradycardia (COQ4 (4/14) [80-82],
COQ9 (2/6) [92,93] or pericardial effusion (COQ8B (1/74) [110,113]). However, it is questionable whether some
manifestations such as heart failure, bradycardia or pericardial effusion are primary events or are secondary mani-
festations of some other general phenomena.
Other manifestations
Less frequent clinical findings include dysmorphic features [84,87], metabolic pathologies (diabetes mellitus [62,73],
obesity [62] and hypercholesterolaemia [79,117], although the latest is often observed during SRNS, independently
of its aetiology), thyroid disease (goitre [51,113], hypothyroidism [110]), lung involvement (respiratory distress, very
frequent in COQ4 patients (9/14) [73,81,82,91,92], apnoea [78,80-82,92] or respiratory failure [72,78,73,80,81]), cir-
culatory problems (cyanosis [81,92], hypertension, livedo reticularis [62]), liver abnormalities (hepatic insufficiency
[62,74], cholestatic liver [73]), among others.
Biochemical findings
Primary CoQ deficiency patients, particularly those with neonatal onset, can show higher levels of lactate in plasma
or serum. CoQ levels in skeletal muscle biopsies or fibroblasts may be reduced [120], as well as the enzymatic activities
of complex I+III and/or II+III [121].
Pathogenesis
The pathogenesis of CoQ deficiency is complex and not completely understood. The bioenergetic defect and the
increased reactive oxygen species (ROS) production may have a crucial role. However the wide spectrum of CoQ
functions, the unclear roles of some COQ gene products and the considerable phenotypic variability, suggests that
other mechanisms contribute to the pathogenesis of the disease. In cultured cells it has been found that, while severe
CoQ deficiencies lead to great defects in energy production with no major increase in oxidative stress, mild CoQ
defects cause a significant increase in ROS production without affecting ATP production, but yielding increased cell
death levels [115]. In addition, as expected, CoQ deficiency impairs de novo pyrimidine synthesis, further contribut-
ing to disease pathogenesis [122]. CoQ deficiency cells also show increased mitophagy, being proposed as a protective
mechanism in disease pathogenesis [123], although other authors defined it as detrimental [124]. Recently, sulphide
oxidation pathway impairment has been proposed as an additional pathomechanism in primary CoQ deficiency, as
different in vivo and in vitro models of the disease show a tissue-specific defect in the metabolism of H2S, leading
to the accumulation of this molecule, which may alter protein S-sulfhydrilation, inducing changes such as vasore-
laxation, inflammation and ROS production [125]. Finally, CoQ deficiency has also been linked to development of
insulin resistance in human and mouse adipocytes, as a result of increased ROS production via complex II [126].
Genotype–phenotype correlation
Due to the small number of patients harbouring mutations in COQ genes and the wide range of clinical manifesta-
tions, it is arduous to define genotype–phenotype correlations. In fact, only a few families with pathogenic variants
of PDSS1,PDSS2,COQ5 or COQ9 have been published, being unachievable to establish any correlation. In the case
of COQ9, studies in two mouse models suggest that a key factor appears to be the different degree of impairment
of formation of the CoQ complex [50]. Even though only two patients with COQ7 mutations have been described,
there seems to be a correlation between the residual levels of CoQ (and levels of COQ7 protein) and the severity of
the disease: fibroblasts from the patient with the most severe phenotype show a drastic CoQ deficiency [91], while
the patient with the milder phenotype has a 30% decrease in CoQ levels in skin fibroblasts [90]. Interestingly, only
fibroblasts with a severe deficiency benefit from 2,4-dihydroxybenzoic acid (2,4-dHB) supplementation, while CoQ
biosynthesis was inhibited in those with the milder defect treated with 2,4-dHB.
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COQ8A and COQ8B have the highest number of families with pathogenic variants reported (29 and 38), and in
neither case there is any correlation between the mutations and the clinical phenotype [97,113]. In the case of COQ2
patients (18 families described), who show the widest clinical spectrum, it has been proposed that the severity of the
disease correlates with the enzymatic residual activity and hence CoQ levels, as shown by expressing mutant proteins
inyeast[70].ItisworthtomentionthatmostoftheCOQ6 patients were diagnosed during screening for SNRS, so
there may be a reference bias in these cases [65,87,86]. To date, no other clear correlations have been observed for
COQ4 patients.
Diagnosis
ThediagnosisofprimaryCoQdeficiencyisestablishedwiththeidentificationofbiallelicpathogenicvariantsinanyof
the genes coding for one of the proteins directly involved in CoQ biosynthesis. Genome or specific gene sequencing is
performed when decreased levels of CoQ or reduced combined activities of complex I+III and II+III in mitochondria
of skeletal muscle biopsies are detected in patients [127,128]. It is important to note that biochemical analysis is not
able to distinguish between primary and secondary CoQ deficiencies [128]. Genetic identification of new pathogenic
variants is usually followed by functional validation.
CoQ levels can also be measured on plasma samples, white blood cells or skin fibroblasts obtained after skin biopsy
from patients [129]. However, there are concerns about CoQ plasma measurements for diagnosis, since it seems to
be influenced by the amount of plasma lipoproteins (carriers of CoQ in circulation) and the dietary intake. Muscle
or fibroblasts represent the preferred diagnosis tissues, although sometimes fibroblasts do not show reduction while
muscle does [130]. It has been shown that white blood cells CoQ levels alone are not reliable to diagnose primary
CoQ deficiency in the setting of nephrotic syndrome [68]. De novo synthesis can also be measured by radioactive
precursor incorporation in fibroblasts [131] which is especially useful to discriminate between primary and secondary
deficiencies. Recently, urine CoQ measurement as non-invasive approach has been proposed [132].
Management
Considering the wide clinical spectrum of this condition, any individual with a diagnosis of primary CoQ deficiency
should be assessed, in order to establish the severity of the disease. Importantly, a genetic consultation is recom-
mended for other family members and for recurrence risk of patient’s parents. Based on the genetic defect identified
in the patient, a specific follow-up should be programmed.
Being CNS manifestations very frequent, every patient with a diagnosis of CoQ deficiency should undergo peri-
odical neurological examinations, even if normal at diagnosis. In fact, the age of onset of these symptoms is highly
variable, ranging from the first hours or days of life (as in patients with COQ4 mutations),uptotheseventhdecade
of life (as in COQ2 patients with the adult-onset multisystem atrophy-like phenotype). Evaluation should include an
EEG analysis and a brain MRI. In addition, peripheral nervous system should be assessed for the possible presence
of peripheral neuropathy in patients with PDSS1 and COQ7 mutations.
Patients with mutations in PDSS1,PDSS2,COQ2,COQ6,COQ7,COQ8A and COQ8B may have eye involve-
ment due to optic atrophy, retinopathy, retinitis pigmentosa and even cataracts and should therefore be screened
at diagnosis and during the follow-up. Audiometry is necessary in COQ6 patients who almost invariably manifest
SRNS, but should be performed also in patients with mutations in PDSS1,COQ8A and COQ4 who may sometimes
manifest this phenotype.
Individuals harbouring mutations in COQ2,PDSS1,PDSS2,COQ6 and COQ8B may manifest renal involvement
with SRNS, whose onset may vary from early childhood to adolescence. Tubulopathy has been reported rarely. These
patients thus need to undergo periodical renal function tests with urine analysis for proteinuria and nephrological
evaluations for the risk of evolving to ESRD.
A cardiologist examination with echocardiogram should be performed in patients with COQ4 mutations (who may
present with a severe prenatal-onset cardiomyopathy) and should also be considered in individuals with mutations
in PDSS1 and COQ8B to exclude the presence of a valvulopathy or septal defects.
Treatment
Barriers for tissues CoQ delivery have been found due to its high molecular weight and poor aqueous solubility, but
at high doses, dietary supplementation increases CoQ levels in all tissues, including heart and brain, especially with
certain formulations [133,134]. It also increases in circulating low-density lipoproteins (LDL), where it functions as
an efficient antioxidant together with α-tocopherol [135,136]. CoQ supplementation at high doses has been demon-
strated to be effective for treatment of both primary and secondary CoQ deficiencies [137]. It is crucial to start the
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supplementation as soon as possible to get favourable outcomes and to limit irreversible damage in critical tissues
such as the kidney or the CNS [127]. Different doses of CoQ have been employed for the treatment of primary CoQ
deficiencies, ranging from 5 mg/kg/day [66] to 30–50 mg/kg/day for both adults and children [138] but, in mouse
models of this condition, even higher doses (up to 200 mg/kg/day) have been used [139]. Except for COQ8A patients,
most individuals with primary forms show a good response to CoQ treatment, which is usually evident after 10–20
days [138]. Different formulations of CoQ are now available, both in the oxidized and the reduced forms, although
most of the data available have been obtained in patients treated with ubiquinone.
Alternatively to CoQ10 supplementation, some 4-HB analogues have been proposed as potential bypass molecules
with higher bioavailability than CoQ. These water-soluble CoQ head precursors would bypass enzymatic steps dis-
rupted by mutations in COQ genes, but their efficacy may differ depending on the stability of the CoQ biosynthetic
complex. Some examples are vanillic acid (VA) and 3,4-dihydroxybenzoate (3,4-dHB), able to bypass COQ6 muta-
tions, or 2,4-dHB for COQ7 defects (Figure 2C,D). The effectivity of VA and 3,4-dHB in restoring CoQ biosynthesis
has been demonstrated in coq6 yeast mutant strains expressing pathogenic versions of human COQ6 [88]. Notably,
VA also stimulates CoQ synthesis and improves cell viability in COQ9 patient fibroblasts [140]. 2,4-dHB was able to
increase CoQ levels and lifespan in Coq7 [141] and Coq9 defective mice [50], as well as to bypass the reaction in hu-
man fibroblasts with COQ7 [91,90,140] and COQ9 mutations [140]. Remarkably, the effectivity of 2,4-dHB depends
onthenatureoftheCOQ7 mutation and the residual activity of the protein [90]. It has also been reported that treat-
ment with high doses of 4-HB, thus increasing COQ2 substrate availability, restores CoQ synthesis in COQ2-deficient
cell lines, which also suggests that these enzyme variants retain some residual activity [142].
Early onset CoQ deficiencies can cause mortality in few days. We have observed that CoQ is efficiently incorporated
in different tissues by breastfeeding and placenta in mice (unpublished data). We propose treatment of pregnant
mothers of high-risk newborns (high probability of CoQ deficiency after genetic screening or due to family history)
with CoQ supplementation, in order to reduce tissue damage during embryonic/foetal development and to increase
the survival of newborns until they can be fed with supplements.
Secondary deficiencies
CoQ levels can also be reduced secondary to conditions not directly linked to CoQ biosynthesis, but related to ox-
idative phosphorylation (OXPHOS), other non-OXPHOS mitochondrial processes, or even to non-mitochondrial
functions [143]. Remarkably, secondary CoQ deficiencies are proved to be more common than primary deficiencies
[143,144], probably because of the diversity of biological functions and metabolic pathways in which CoQ is involved
in mitochondrial and non-mitochondrial membranes, highlighting the importance of CoQ homoeostasis in human
health. However, there is a lack of consistency of CoQ deficiency presence among different patients, which could sug-
gest different susceptibility to the development of secondary deficiencies among different individuals. Currently, there
is not any general explanation for this, although genetic factors, such as certain polymorphisms, have been proposed
to be involved [113,143-145]. A comprehensive analysis of muscle and fibroblasts samples from patients affected by a
wide range of mitochondrial diseases showed that secondary deficiencies were more frequent in depletion syndromes
than in any other mitochondrial disease [143], supporting previous observations [146]. The same study analysed CoQ
levels in samples of patients affected by different OXPHOS diseases, but were unable to find any difference between
them. Further studies on wider cohorts are needed in order to understand whether certain diseases are more prone to
develop secondary deficiencies than others, as well as the underlying molecular mechanism. Nonetheless, it is clear
that mitochondrial myopathies are frequently associated with CoQ secondary deficiencies [145]. Besides its reduction
in many mitochondrial OXPHOS disorders, other diseases may display secondary CoQ deficiency, including ataxia
and oculomotor apraxia syndrome (MIM #208920), multiple acyl-CoA dehydrogenase deficiency (MIM #231680),
cardiofaciocutaneous syndrome (MIM #115150), methylmalonic aciduria (# 251000), GLUT-1 deficiency syndrome
(MIM #606777), mucopolysaccharidosys type III (MIM #605270) or multisystem atrophy [143,144,147]. The mecha-
nisms underlying CoQ secondary defects remain largely unknown, but several explanations have been proposed that
are related to: (i) an increased rate of CoQ degradation due to oxidative damage caused by a non-functional respi-
ratory chain; (ii) a decrease in CoQ through the interference with the signalling pathways involved in the process of
biosynthesis; (iii) the reduction in the stability of the CoQ biosynthetic complex or (vi) a general deterioration of mi-
tochondrial function [143,144]. In addition, CoQ seems to be reduced in the process of ageing [148] and a secondary
deficiency of CoQ may be a side effect of hypercholesterolaemia treatment with statins, since both cholesterol and
CoQ share part of their biosynthetic pathways [149,150].
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Of course, particular symptoms of secondary CoQ deficiencies are highly dependent on the original pathology.
Myopathies presented as muscular weakness, hypotonia, exercise intolerance or myoglobinuria are commonly re-
ported as muscular manifestations in diseases associated with secondary CoQ deficiencies. Neurological decline and
ataxia are also often reported [144,151]. It is possible that the primary disease symptoms are potentiated by the lack of
CoQ [144]. In fact, many of these patients partially improve their condition by CoQ supplementation, which supports
the importance of an early diagnosis also in these cases [151]. From the point of view of the molecular diagnosis, it is
necessary to perform a genetic analysis to distinguish between primary and secondary deficiencies [127].
Concluding remarks
The deficiency in CoQ is a genetically and clinically heterogeneous syndrome. Primary deficiency diagnosis is a great
challenge due to the number of genes involved, the poor knowledge of CoQ biosynthesis pathway and its regula-
tioninhumans,thesmallnumberofpatientsdescribedandthegreatvarietyofassociatedsymptoms.Moreover,
secondary deficiencies can be consequences of many other mitochondrial dysfunctions adding a layer of complex-
ity to the diagnosis. Observation of the clinical manifestations here described and/or the molecular identification of
potentially pathological variants of COQ genes should be complemented by the biochemical determination of CoQ
levels, biosynthesis rate if possible, and the combined enzymatic activities of complexes I+III and II+III in muscle or
fibroblast. It is important to identify potential cases as early as possible because high-dose CoQ oral supplementation
is a very effective treatment in most cases, blocking the progression of the disease.
Summary
•CoQ is an endogenously synthesized lipid that is essential for the electron transport in the mito-
chondrial respiratory chain.
•Primary CoQ deciencies are rare diseases caused by mutations in genes of the CoQ biosynthesis
pathway.
•CoQ deciencies are characterized by reduced levels of CoQ affecting energy production and
other processes.
•Primary CoQ deciencies show highly heterogeneous manifestations mainly affecting CNS, PNS,
sensory organs, kidney, skeletal muscle and heart.
•Currently, it is hard to establish any genotype–phenotype correlations for these diseases, partially
due to the low amount of studied patients.
•It is essential to biochemically determine CoQ deciency since supplementation has positive ther-
apeutic effects.
Acknowledgements
Authors wish to thank the patients and their families for facilitating the research here reviewed. We thank Prof. Pl´
acido Navas for
the critical revision of the manuscript.
Competing Interests
The authors declare that there are no competing interests associated with the manuscript.
Funding
This work has been partially funded by the Spanish Ministry of Health, Instituto de Salud Carlos III (ISCIII), FIS PI14-01962 and FIS
PI17-01286. M.A.-F. is a predoctoral research fellow from the Spanish Ministry of Education, Culture and Sports [FPU14/04873].
E.T. is supported by grant number [CPDA140508/14] from University of Padova.
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Essays in Biochemistry (2018) 62 377–398
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Author Contribution
M.A.-F. exhaustively compiled the mutations and symptoms data from literature and elaborated the tables. M.A.-F. and G.B.-C.
made the gures. M.A.-F., E.T. and G.B.-C. wrote and edited the text and G.B.-C. coordinated the work.
Abbreviations
2,4-dHB, 2,4-dihydroxybenzoic acid; 3,4-dHB, 3,4-dihydroxybenzoate; 4-HB, 4-hydrozybenzoate; CNS, central nervous sys-
tem; CoQ, coenzyme Q; EEG, electroencephalography; ESRD, end-stage renal disease; ETFDH, electron transport avo-
protein dehydrogenase; HHB, hexaprenyl-hydroxybenzoate; ID, intellectual disability; LDL, low-density lipoprotein; mETC,
mitochondrial electron transport chain; MRI, magnetic resonance imaging; OXPHOS, oxidative phosphorylation; pABA,
para-aminobenzoic acid; PNS, peripheral nervous system; ROS, reactive oxygen species; SNHL, sensorineural hearing loss;
SRNS, steroid-resistant nephrotic syndrome; VA, vanillic acid.
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