Introduction

Coenzyme Q10 (CoQ10) is the predominant human form of endogenous ubiquinone. Synthesized in the mitochondrial inner membrane, CoQ10 is comprised of a ubiquinone head group attached to a tail of 10 five-carbon isoprenoid units, that anchors the molecule to the membranes [1]. In additions to its central role in the mitochondrial respiratory chain as electrons carrier from complex I and II to complex III [2], CoQ10 is now thought to be involved in a number of cellular functions (Table 1) [1]. Intracellular synthesis is the major source of CoQ10, although a small proportion is acquired through diet. The complexity of the biosynthesis (Fig. 1) suggests that defects in different biosynthetic enzymes or regulatory proteins may cause different clinical syndromes.

Table 1 Functions of coenzyme Q (modified from [1])
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Fig. 1
figure 1

CoQ10 biosynthetic pathway with eight known biosynthetic enzymes denoted as COQ1-8. CoQ10 is composed of a benzoquinone and a decaprenyl side chain. While the quinone ring is derived from amino acids tyrosine or phenylalanine, the isoprenoid side chain is produced by addition of isopentenyl pyrophosphate molecules to geranylgeranyl pyrophosphate (derived from mevalonate pathway) by decaprenyl diphosphate synthase. After para-hydroxybenzoate and decaprenyl pyrophosphate are produced, at least seven enzymes (encoded by COQ2-8) catalyze condensation, methylation, decarboxylation, and hydroxylation reactions to synthesize CoQ10

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Primary CoQ10 deficiency is an autosomal recessive condition with a clinical spectrum that encompasses at least five major phenotypes: (1) encephalomyopathy characterized by the triad of recurrent myoglobinuria, brain involvement and ragged red fibers; (2) severe infantile multisystemic disease; (3) cerebellar ataxia; (4) Leigh syndrome with growth retardation, ataxia and deafness; and (5) isolated myopathy [12–26].

Generalized weakness, exercise intolerance, and recurrent myoglobinuria are the distinctive features in the first four patients reported with the encephalomyopathic form, [12–15]; however, myoglobinuria was absent in another patient [16]. All the patients described so far have proximal muscle weakness [12–16] The brain involvement is variable; seizures are a common finding [12, 13], in association with cognitive impairment [12] and cerebellar symptoms [12, 15, 16].

The second variant, described in three families, manifests as an infantile encephalopathy with renal involvement. Rötig and colleagues initially described two siblings with defects of multiple quinone-dependent enzymes ascribed to a deficiency of CoQ10 in various tissues [17]. The patients presented with retinitis pigmentosa, optic nerve atrophy, bilateral sensorineuronal deafness, nephrotic syndrome, progressive ataxia, and cardiomyopathy. In Rahman’s patient, hypothermia, lactic acidosis, cerebral and cerebellar atrophy, and developmental delay were associated with renal tubulopathy and ventricular hypertrophy [18]. Last year, we described two siblings who presented with nephrotic syndrome due to glomerulosclerosis, and the older sibling developed hypotonia, psychomotor delay, seizures, stroke-like episodes, and cerebellar and cerebral atrophy [19]. Interestingly, in these infantile-onset patients, deficiency of CoQ10 is present not only in skeletal muscle, but also in other tissues and cells including skin fibroblasts. In addition, two adult sisters with encephalopathy, growth retardation, infantilism, ataxia, deafness and lactic acidosis have been described by Van Maldergam [23].

Cerebellar ataxia is the most common phenotype associated with CoQ10 deficiency with 21 reported patients [20–22, 26]. Cerebellar ataxia and cerebellar atrophy are present in all the patients. Epilepsy is the most common associated feature, but pyramidal signs, mental retardation, myopathic weakness, and delayed motor milestones are other variably associated symptoms and signs. Except for two adult brothers with cerebellar ataxia and hypogonadism [22], the condition begins in childhood or adolescence. Muscle morphology does not show ragged-red fibers and lipid storage myopathy and CoQ10 is moderately reduced in skin fibroblasts.

The clinical presentation of the variant isolated myopathy, recently described in four patients, is subacute onset of exercise intolerance and proximal limb weakness at variable ages. All patients have lipid storage and ragged-red fibers in muscle, as well as increased serum lactate and creatine kinase (CK) [24, 25]. In all the patients with different phenotypes, respiratory chain enzymes analyses show reduced activities of complex I + III and II + III with normal activities of isolated complex I and III.

In most of the reported patients, the exact site and nature of the defects in the biosynthesis of CoQ10 have not yet been identified. Because ubiquinone biosynthesis is complex and not fully defined (Fig. 1), identification of the molecular genetic defect is not straightforward.

Undetectable CoQ10 and low levels of decaprenylpyrophosphate, an intermediate compound in the synthesis of the lateral chain of CoQ10 were found in the fibroblasts of the patient reported by Rötig and colleagues suggesting a defect in the synthesis of the decaprenyl side-chain, but they did not find any mutation in the cDNA of COQ1, the gene encoding transprenyltransferase, the enzyme that synthesizes decaprenylpyrophosphate [17].

This year, in two siblings with the infantile form of CoQ10 deficiency, we reported a homozygous missense mutation (Y297C) in the COQ2 gene, which encodes para-hydroxybenzoate (PHB) polyprenyl transferase. PHB-polyprenyl transferase mediates the conjugation of the benzoquinone ring with the decaprenyl side chain. Biochemical assays measuring incorporation of radiolabeled PHB or decaprenyl-PP into CoQ10 in skin fibroblasts from the proband showed 23–25% of control fibroblasts activity [27] confirming the defect of CoQ10 biosynthesis.

The finding of a homozygous stop codon mutation in the APTX gene which is known to cause ataxia-oculomotor-aprataxia 1 (AOA1), in three siblings with cerebellar ataxia and CoQ10 deficiency, supports the hypothesis that the ataxic form is a genetically heterogeneous disease in which CoQ10 deficiency can be secondary [28]. Aprataxin is a member of the histidine triad superfamily and may be involved in nuclear DNA single strand break repair [29–31]. Despite the lack of an obvious link between aprataxin and regulation of CoQ10 synthesis or catabolism, our findings, coupled with the clinical improvement of patients after CoQ10 supplementation, suggest that CoQ10 deficiency plays a pathogenic role in AOA1. Intriguingly, both CoQ10 and cholesterol share a common biosynthetic pathway, therefore, in AOA1, altered levels of these molecules could be due to aberrant biosynthesis.

Patients with all forms of CoQ10 deficiency have shown clinical improvement with oral CoQ10 supplementation. The beneficial effects of exogenous CoQ10 require high doses and long-term administration [32, 33]; its oral bioavailability is poor due to its extreme hydrophobicity; therefore, only a small fraction of orally administered CoQ10 reaches the circulatory system, and augmentation of mitochondrial CoQ10 content is even less effective. Beneficial effects of CoQ10 supplementation are supported by in vitro correction of biochemical and histological abnormalities [12–14, 17]. However, while muscle abnormalities improve clinically and biochemically, in general, cerebral symptoms are only partially ameliorated [16]. This difference could be explained by the presence of irreversible structural brain damage before treatment or the poor penetration of CoQ10 across the blood-brain barrier. Increases in plasma concentrations of CoQ10 after oral supplementation in both humans and animals has been well-documented, but early work questioned whether CoQ10 accumulates in tissues [34] and studies of 45-day-old rodents showed little or no change in rodent brain CoQ10 concentrations after oral administration perhaps because levels of CoQ10 are tightly regulated in young animals or may be saturated in membranes [34, 35]. In contrast, administration of very high doses of CoQ10 (200 mg/kg daily) to 12–24 month-old rats produced significant increases in brain CoQ10 levels [36], but a more recent study of the regional distribution of CoQ in 16 week-old rat brain before and after 4 weeks of moderately high exogenous dietary CoQ10 (20 mg/kg daily) supplementation showed that the concentration of CoQ was essentially unchanged in the cortex and in the striatum [37]. That study also demonstrated that the cerebellum, of the 7 brain regions dissected, contains the lowest levels of CoQ. If human brain has the same regional distribution of CoQ10 as rat brain, the cerebellum may have the narrowest safety margin and therefore would be the first tissue to suffer from a pathological shortage of CoQ10. Moreover, to function as an antioxidant, CoQ10 must be in the reduced form but normally only 20% of the lipid is reduced in the brain. The high proportion of oxidized CoQ10 in the brain could be a reflection of the high oxygen consumption in this tissue, causing an increased demand of anti-oxidants [38]. Therefore, CoQ10 deficiency could be another form of inherited ataxia due to oxidative damage, as vitamin E deficiency.

Oxidative damage and mitochondrial dysfunction have also been implicated in neurodegenerative diseases such Parkinson disease (PD), Alzheimer disease (AD), and Friedreich’s ataxia (FRDA) [39–41]. Preclinical studies have indicated that CoQ10 can protect the nigrostriatal dopaminergic system and high doses (1200 mg daily) of CoQ10 for 16 months appeared to slow progression PD [40, 42]. In 10 FRDA patients treated for 47 months high doses of CoQ10 (400 mg daily) with vitamin E (2100 IU daily), improved bioenergetics in heart and skeletal muscle, improved cardiac function by echocardiography, and, possibly less clinical decline compared to historical controls [43]. Larger studies are necessary to better define the short- and long-term effects of CoQ10 as primary or adjunctive therapy in neurodegenerative diseases.

Deficiency of CoQ10 has been associated with a variety of neurological disorders that respond to oral supplementation. We have demonstrated that CoQ10 deficiency can be primary due to a defect of biosynthesis or secondary as in patients with APTX mutations. The response of both groups of patients to oral supplementation suggests that exogenous CoQ10 is taken up by affected tissues and can correct biochemical derangements. Further studies to define CoQ10 deficiency syndrome will reveal new causes, enhance our understanding of its pathogenesis, and may provide novel insights that may be relevant to other neurodegenerative diseases.