Article

Primary coenzyme Q10 deficiency and the brain

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Abstract

Our findings in 19 new patients with cerebellar ataxia establish the existence of an ataxic syndrome due to primary CoQ10 deficiency and responsive to CoQ10 therapy. As all patients presented cerebellar ataxia and cerebellar atrophy, this suggests a selective vulnerability of the cerebellum to CoQ10 deficiency. We investigated the regional distribution of coenzyme Q10 in the brain of adult rats and in the brain of one human subject. We also evaluated the levels of coenzyme Q9 (CoQ9) and CoQ10 in different brain regions and in visceral tissues of rats before and after oral administration of CoQ10. Our results show that in rats, amongst the seven brain regions studied, cerebellum contains the lowest level of CoQ. However, the relative proportion of CoQ10 was the same (about 30% of total CoQ) in all regions studied. The level of CoQ10 is much higher in brain than in blood or visceral tissue, such as liver, heart, or kidney. Daily oral administration of CoQ10 led to substantial increases of CoQ10 concentrations only in blood and liver. Of the four regions of one human brain studied, cerebellum again had the lowest CoQ10y concentration.

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... CoQ 10 deficiency has been observed in patients with Parkinsons disease, Huntington,s disease, tuberous sclerosis, motor neuron disease, and cerebellar ataxia, CoQ 10 supplementation may be useful in these conditions [4] [5] [6] [7]. CoQ 10 deficiency has also been observed in patients receiving statins , which is known to cause myopathy and rhabdomyolysis [8] [9] [10]. ...
... Naini and coworkers in 19 new patients with cerebellar ataxia established the existence of an ataxic syndrome due to primary CoQ 10 deficiency and responsive to CoQ 10 treatment [6]. Since all patients presented with cerebellar ataxia and cerebellar atrophy, this poses the possibility of a selective vulnerability of the cerebellam to CoQ 10 deficiency. ...
... CoQ 10 and the level of CoQ 10 was much higher in brain than in blood or visceral tissue, such as heart,liver or kidney indicating that it has vital role in brain function and degeneration [6]. However, there is lack of evidence, to demonstrate the cerebrospinal fluid levels of CoQ 10 in normal subjects, compared to neurological degenerative diseases. ...
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There is significant interest in coenzyme Q10(CoQ10) as a potential treatment for neurodegenerative diseases and in its promise as a neuroprotectant. Experimental studies indicate that CoQ10 can protect against brain disorders by in- hibiting neuronal damage. There is a need to demonstrate CSF levels of CoQ10 in humans. Subjects and Methods: After clearance from the hospital ethical committee, all of the subjects presenting with a suspicion of neurological diseases were asked to give written informed consent for lumber puncture for testing of CSF. CoQ10 con- centration in CSF was examined by HPLC with electrochemical detection system at the Division of Molecular Neuroge- netics, College of Physicians and Surgeons, New York,USA. Clinical and laboratory data were obtained from all of the patients (n=38) to confirm clinical diagnosis. CAT scan of the head was done in all of the patients presenting with seizures and stroke. All CSF specimens were examined for cells, sugar and proteins and those suspected of being contaminated with blood were excluded from study. Results: The age varied between 17 to 60 years and the number of males (n=16) were less than females (n=21). Patients were suffering from epileptic seizures (n=19), tuberculous meningitis (n=5) and stroke (n=4). The rest of the 9 patients presented with headache of non-neurological condition with or without fever. The CSF concentration of CoQ10 was sig- nificantly lower among these subjects; mean ± SD ( 0.59 ± 0.12 ng/ml), which appears to represent the normal level of CoQ10 in healthy subjects. The concentration of CoQ10 in CSF tended to be higher among patients with TBM ( 1.27 ± 0.60 ng/ml), seizures ( 1.26 ± 0.34 ng/ml) and stroke ( 0.83 ± 0.20 ng/ml) compared to subjects without neurological problem. These findings indicate that there is greater release of CoQ10 or increased synthesis in the tissues possibly to fight against oxidative stress caused by brain disorders. Conclusions: This study shows that the level of CoQ10 in the csf is substantially lower than that in serum by three orders of magnitude and tends to be elevated under pathological conditions associated with brain injury. Further studies in a larger number of subjects are necessary to confirm our findings.
... Beyindeki CoQ 10 seviyesi kan, karaciğer, kalp ve böbrek dokularındaki CoQ 10 seviyelerinden daha yüksektir ve tüm beyin bölgelerinde CoQ 10 'un göreceli oranı aynıdır (38). Çalışmamızda CoQ 10 takviyesi beyin MDA seviyesini önemli düzeyde etkilememiştir. ...
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... Cell pellets were stored at −20°C until CoQ10 level was quantified using a modified form of a previously established high performance liquid chromotography (HPLC) method. 11,12 For mitochondrial fractions, Mitosciences Mitochondria Isolation Kit for Cultured Cells (MS852) was used to separate the mitochondrial portion of the cells before following the same HPLC protocol to quantify the CoQ10 levels. Immunoblotting was used to validate separation of mitochondria. ...
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... CoQ10 deficiency has been observed in patients with Parkinsons disease, Huntington,s disease, tuberous sclerosis, motor neuron disease, and cerebellar ataxia, CoQ10 supplementation may be useful in these conditions [53][54][55][56]. Low levels of CoQ10 have been described also in myocardial biopsies from patients with various cardiovascular diseases [57,58]. ...
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Coenzyme Q(10) (CoQ(10) ) is a key component of the mitochondrial respiratory chain and, therefore, is essential for the bioenergetics of oxidative phosphorylation. It is also endowed with antioxidant properties, and recent studies pointed out its capability of affecting the expression of different genes. In this review, we analyze the data on the mechanisms by which CoQ(10) interacts with skin aging processes. The effect of CoQ(10) in preserving mitochondrial function cooperates in maintaining a proper energy level, which serves to prevent the aging skin from switching to anaerobic energy production mechanisms. Furthermore, the antioxidant capacity of CoQ(10) contributes to a positive effect against UV-mediated oxidative stress. Some of these effects have been assessed also in vivo, by the sensitive technique of ultraweak photoemission. Finally, CoQ(10) has been shown to influence, through a gene induction mechanism, the synthesis of some key proteins of the skin and to decrease the expression of some metalloproteinase such as collagenase. These mechanisms may also contribute to preserve collagen content of the skin.
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For a number of years, coenzyme Q10 (CoQ10) was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical use of CoQ10. Also at the inner mitochondrial membrane level, CoQ10 is recognized as an obligatory co-factor for the function of uncoupling proteins and a modulator of the mitochondrial transition pore. Furthermore, recent data indicate that CoQ10 affects expression of genes involved in human cell signalling, metabolism, and transport and some of the effects of CoQ10 supplementation may be due to this property. CoQ10 deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also statin treatment. Many neurodegenerative disorders, diabetes, cancer and muscular and cardiovascular diseases have been associated with low CoQ10 levels, as well as different ataxias and encephalomyopathies. CoQ10 treatment does not cause serious adverse effects in humans and new formulations have been developed that increase CoQ10 absorption and tissue distribution. Oral CoQ10 is a frequent antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
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Objective: Evidence of oxidative stress was reported in individuals with Down syndrome. There is a growing interest in the contribution of the immune system in Down syndrome. The aim of this study is to evaluate the coenzyme Q10 and selected pro-inflammatory markers such as interleukin 6 and tumor necrosis factor α in children with Down syndrome. Methods: Eighty-six children (5–8 years of age) were enrolled in this case-control study from two public institutions. At the time of sampling, the patients and controls suffered from no acute or chronic illnesses and received no therapies or supplements. The levels of interleukin 6, tumor necrosis factor α, coenzyme Q10, fasting blood glucose, and intelligence quotient were measured. Results: Forty-three young Down syndrome children and forty-three controls were included over a period of eight months (January–August 2014). Compared with the control group, the Down syndrome patients showed significant increase in interleukin 6 and tumor necrosis factor α (p = 0.002), while coenzyme Q10 was significantly decreased (p = 0.002). Also, body mass index and fasting blood glucose were significantly increased in patients. There was a significantly positive correlation between coenzyme Q10 and intelligence quotient levels, as well as between interleukin 6 and tumor necrosis factor α. Conclusion: Interleukin 6 and tumor necrosis factor α levels in young children with Down syndrome may be used as biomarkers reflecting the neurodegenerative process in them. Coenzyme Q10 might have a role as a good supplement in young children with Down syndrome to ameliorate the neurological symptoms.
Chapter
Human coenzyme Q (CoQ10) or ubiquinone is mainly known for its bioenergetic role as a proton and electron carrier in the inner mitochondrial membrane and is also an endogenous lipophilic antioxidant, ubiquitous in biological membranes. It is also present in plasma lipoproteins, where it plays a well-recognized antioxidant role. More recently coenzyme Q10 was also shown to affect gene expression by modulating the intracellular redox status. Its involvement in many cellular and extracellular functions suggests that its use as a food supplement could be beneficial in conditions associated with increased oxidative stress underlying different pathological conditions. In reproductive biology, CoQ10 has been shown to play a role in fertility of both males and females.
Article
Objective: Evidence of oxidative stress was reported in individuals with Down syndrome. There is a growing interest in the contribution of the immune system in Down syndrome. The aim of this study is to evaluate the coenzyme Q10 (CoQ10) and selected pro-inflammatory markers such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) in children with Down syndrome. Methods: Eighty-six children (5-8 years of age) were enrolled in this case-control study from two public institutions. At the time of sampling, the patients and controls suffered from no acute or chronic illnesses and received no therapies or supplements. The levels of IL-6, TNFα, CoQ10, fasting blood glucose, and intelligence quotient were measured. Results: Forty-three young Down syndrome children and forty-three controls were included over a period of eight months (January-August 2014). Compared with the control group, the Down syndrome patients showed significant increase in IL-6 and TNFα (p=0.002), while CoQ10 was significantly decreased (p=0.002). Also, body mass index and fasting blood glucose were significantly increased in patients. There was a significantly positive correlation between CoQ10 and intelligence quotient levels, as well as between Il-6 and TNFα. Conclusion: IL-6 and TNFα levels in young children with Down syndrome may be used as biomarkers reflecting the neurodegenerative process in them. Coenzyme Q10 might have a role as a good supplement in young children with Down syndrome to ameliorate the neurological symptoms.
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The knowledge about the genetic spectrum underlying paediatric mitochondrial diseases is rapidly growing. As a consequence, the range of neuroimaging findings associated with mitochondrial diseases became extremely broad. This has important implications for radiologists and clinicians involved in the care of these patients. Here, we provide a condensed overview of brain magnetic resonance imaging (MRI) findings in children with genetically confirmed mitochondrial diseases. The neuroimaging spectrum ranges from classical Leigh syndrome with symmetrical lesions in basal ganglia and/or brain stem to structural abnormalities including cerebellar hypoplasia and corpus callosum dysgenesis. We highlight that, although some imaging patterns can be suggestive of a genetically defined mitochondrial syndrome, brain MRI-based candidate gene prioritization is only successful in a subset of patients.
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The COQ2 gene encodes an essential enzyme for biogenesis, coenzyme Q10 (CoQ10). Recessive mutations in this gene have recently been identified in families with multiple system atrophy (MSA). Moreover, specific heterozygous variants in the COQ2 gene have also been reported to confer susceptibility to sporadic MSA in Japanese cohorts. These findings have suggested the potential usefulness of CoQ10 as a blood-based biomarker for diagnosing MSA. This study measured serum levels of CoQ10 in 18 patients with MSA, 20 patients with Parkinson’s disease and 18 control participants. Although differences in total CoQ10 (i.e., total levels of serum CoQ10 and its reduced form) among the three groups were not significant, total CoQ10 level corrected by serum cholesterol was significantly lower in the MSA group than in the Control group. Our findings suggest that serum CoQ10 can be used as a biomarker in the diagnosis of MSA and to provide supportive evidence for the hypothesis that decreased levels of CoQ10 in brain tissue lead to an increased risk of MSA.
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Background Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States. Results We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient. Conclusions The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA. Electronic supplementary material The online version of this article (doi:10.1186/1750-1326-9-44) contains supplementary material, which is available to authorized users.
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Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of alpha-synuclein protein in the cytoplasm of oligodendrocytes, the myelin-producing support cells of the central nervous system (CNS). The brain is the most lipid-rich organ in the body and disordered metabolism of various lipid constituents is increasingly recognized as an important factor in the pathogenesis of several neurodegenerative diseases. alpha-Synuclein is a 17 kDa protein with a close association to lipid membranes and biosynthetic processes in the CNS, yet its precise function is a matter of speculation, particularly in oligodendrocytes. alpha-Synuclein aggregation in neurons is a well-characterized feature of Parkinson's disease and dementia with Lewy bodies. Epidemiological evidence and in vitro studies of alpha-synuclein molecular dynamics suggest that disordered lipid homeostasis may play a role in the pathogenesis of alpha-synuclein aggregation. However, MSA is distinct from other alpha-synucleinopathies in a number of respects, not least the disparate cellular focus of alpha-synuclein pathology. The recent identification of causal mutations and polymorphisms in COQ2, a gene encoding a biosynthetic enzyme for the production of the lipid-soluble electron carrier coenzyme Q10 (ubiquinone), puts membrane transporters as central to MSA pathogenesis, although how such transporters are involved in the early myelin degeneration observed in MSA remains unclear. The purpose of this review is to bring together available evidence to explore the potential role of membrane transporters and lipid dyshomeostasis in the pathogenesis of alpha-synuclein aggregation in MSA. We hypothesize that dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes underlies the unique neuropathology of MSA.
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Structural changes and abnormal function of mitochondria have been documented in Down's syndrome (DS) cells, patients, and animal models. DS cells in culture exhibit a wide array of functional mitochondrial abnormalities including reduced mitochondrial membrane potential, reduced ATP production, and decreased oxido-reductase activity. New research has also brought to central stage the prominent role of oxidative stress in this condition. This review focuses on recent advances in the field with a particular emphasis on novel translational approaches involving the utilization of coenzyme Q(10) (CoQ(10) ) to treat a variety of clinical phenotypes associated with DS that are linked to increased oxidative stress and energy deficits. CoQ(10) has already provided promising results in several different conditions associated with altered energy metabolism and oxidative stress in the CNS. Two studies conducted in Ancona investigated the effect of CoQ(10) treatment on DNA damage in DS patients. Although the effect of CoQ(10) was evidenced only at single cell level, the treatment affected the distribution of cells according to their content in oxidized bases. In fact, it produced a strong negative correlation linking cellular CoQ(10) content and the amount of oxidized purines. Results suggest that the effect of CoQ(10) treatment in DS not only reflects antioxidant efficacy, but likely modulates DNA repair mechanisms.
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Coenzyme Q₁₀ (Co Q₁₀) or ubiquinone was known for its key role in mitochondrial bioenergetics as electron and proton carrier; later studies demonstrated its presence in other cellular membranes and in blood plasma, and extensively investigated its antioxidant role. These two functions constitute the basis for supporting the clinical indication of Co Q₁₀. Furthermore, recent data indicate that Co Q₁₀ affects expression of genes involved in human cell signalling, metabolism and transport and some of the effects of Co Q₁₀ supplementation may be due to this property. Co Q₁₀ deficiencies are due to autosomal recessive mutations, mitochondrial diseases, ageing-related oxidative stress and carcinogenesis processes, and also a secondary effect of statin treatment. Many neurodegenerative disorders, diabetes, cancer, fibromyalgia, muscular and cardiovascular diseases have been associated with low Co Q₁₀ levels. Co Q₁₀ treatment does not cause serious adverse effects in humans and new formulations have been developed that increase Co Q₁₀ absorption and tissue distribution. Oral Co Q₁₀ treatment is a frequent mitochondrial energizer and antioxidant strategy in many diseases that may provide a significant symptomatic benefit.
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Co-Q10 is a lipid-soluble benzoquinone that is an important factor in free radical scavenging, mitochondrial membrane stability and ATP synthesis. Dietary Co-Q10 is a powerful antioxidant that has been useful in lessening the damage associated with ischemia-reperfusion injuries and aiding in the recovery of myocardial function after myocardial infarction. However, the role of dietary Co-Q10 in oxidative damage and repair is not well understood. Previous LC-EC methods have used packed carbon bed electrodes with high overpotentials that were sufficient to oxidize and reduce several biological compounds, thereby decreasing the selectivity that can be achieved with EC detection. Thin-layer cell dual electrode detection enables monitoring of reduced and oxidized forms of Co-Q10 simultaneously and selectively. The oxidation (+0.45 V vs. Ag/AgCl) and reduction (−0.4 V vs. Ag/AgCl) electrode potentials were optimized to oxidize and reduce the electroactive quinone moiety. The reduced form of Co-Q10 was prepared from the commercially available oxidized form using a Jones reductor. Confirmation of its formation was determined using the current ratios of the peak and half wave potentials from previously generated hydrodynamic voltammograms, using the oxidized form with electrodes in a series configuration. This analytical system was successfully applied to determine basal concentrations of oxidized (510 nM) and reduced (500 nM) Co-Q10 in human plasma. Peak identity of oxidized and reduced Co-Q10 was confirmed by two orthogonal methods: by the current ratios at +0.45 V and +0.25 V and −0.4 V and −0.2 V (vs. Ag/AgCl) as well as by retention time. Detection limits were determined to be 5 nM, with a linear range of three orders of magnitude.
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Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1-40 μM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 μM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 μM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 μM mevalonate or 10 μM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 μM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine.
Article
Ubiquinone (UQ), also known as coenzyme Q (CoQ), is a redox-active lipid present in all cellular membranes where it functions in a variety of cellular processes. The best known functions of UQ are to act as a mobile electron carrier in the mitochondrial respiratory chain and to serve as a lipid soluble antioxidant in cellular membranes. All eukaryotic cells synthesize their own UQ. Most of the current knowledge on the UQ biosynthetic pathway was obtained by studying Escherichia coli and Saccharomyces cerevisiae UQ-deficient mutants. The orthologues of all the genes known from yeast studies to be involved in UQ biosynthesis have subsequently been found in higher organisms. Animal mutants with different genetic defects in UQ biosynthesis display very different phenotypes, despite the fact that in all these mutants the same biosynthetic pathway is affected. This review summarizes the present knowledge of the eukaryotic biosynthesis of UQ, with focus on the biosynthetic genes identified in animals, including Caenorhabditis elegans, rodents, and humans. Moreover, we review the phenotypes of mutants in these genes and discuss the functional consequences of UQ deficiency in general.
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Purpose: To collate evidence on nutrient deficiencies caused by drugs. Design: Search of Medline and other databases, and published literature. Materials and methods: Medline, Scirus and Google Scholar databases, journal articles and books. Results: There is evidence that many drugs, medicinal or recreational, produce deficiencies in vitamins, minerals, fatty acids and/or amino acids. Some drugs cause multiple deficiencies. They may reduce conversion of vitamins to their active forms, or inhibit the production of important metabolites. By killing beneficial bacteria in the gut, they may cause vitamin deficiency. They may reduce absorption, or cause excretion of nutrients. Conclusions: Many drugs have been identified, which appear to cause deficiencies in essential nutrients and their metabolites. Nutrients could be prescribed with drugs, to limit the damage done, provided that this does not undermine the action of the drugs. Further research is needed to confirm the results of those studies that have been carried out, and to find out about nutrient depletion from new drugs.
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Background: Several cardiovascular, neurological and other diseases are associated with coenzyme Q10(CoQ) deficiency. The objective is to evaluate possible benefits of ubiquinone supplementation in cardiovascular diseases and degenerative diseases of the brain. Methods: An internet search in PubMed, Vitasearch, In Circulation. Net, till 2008, discussions with colleagues, own experiences. Results: Ubiquinone (Coenzyme Q10) deficiency has been observed in several cardiovascular and neurological diseases. CoQ10 has strong influence on lipid metabolism, oxidation of blood lipids, vascular inflammation and on the cell mem-branes of cardiac and arterial cells and neurons. These pathogenetic mechanisms seem to be important in patients with neurological and cardiac disease as well as in brain-heart connection. Its supplementation has several beneficial effects in-cluding the stabilisation of atherosclerotic plaque and decreasing the size of myoacardial infarction and the protection of neurons. Antioxidant properties of CoQ10 are responsible for the prevention of many drug side effects. Several studies have suggested the beneficial effect of CoQ10 in neuro-cardiovascular diseases, that will require further confirmation. Adverse effects such as nausea and vomiting may be reduced by using highly bio-available brands, that reduce the oral dosage of COQ. Conclusions: CoQ10 is still in the investigational stages and the list of possible indications related to brain and heart dis-eases and their linkage, appears to be quite extensive. There is still the need for a number of large, double blind multicen-ter, randomized, controlled clinical trials, in order to confirm the possible beneficial effects of CoQ10 supplementation in different neurocardiological conditions.
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For a number of years, coenzyme Q (CoQ10 in humans), was known for its key role in mitochondrial bioenergetics; later studies demonstrated its presence in other subcellular fractions and in plasma, and also extensively investigated its antioxidant role. This chapter discusses the relationship between the acknowledged bioenergetic role of CoQ10 and some clinical effects. The antioxidant properties of CoQ10 are then analyzed especially for their consequences on protection of circulating human low-density lipoproteins and prevention of atherogenesis. The relationship between CoQ10 and statins is also discussed in the light of possible involvement of CoQ10 deficiency in the issue of statin side effects. New aspects of the antioxidant involvement of coenzyme Q are also discussed together with their relevance in cardiovascular disease. Data are reported on the efficacy of CoQ10 in ameliorating endothelial dysfunction in patients affected by ischemic heart disease. Many of the effects of CoQ10, which were classically ascribed to its bioenergetic properties, are now considered as the result of its biochemical interaction with nitric oxide (NO), NO synthase and reactive oxygen species capable of inactivating NO. Clinical studies are reported highlighting the effect of CoQ10 on extracellular SOD, which is deeply involved in endothelial dysfunction. Previous studies have shown decreased levels of CoQ10 in the seminal plasma and sperm cells of infertile men with different kinds of asthenospermia. Research has been extended to supplementation with CoQ10 of infertile men affected by idiopathic asthenozoospermia. CoQ10 levels increased significantly in seminal plasma and sperm cells after 6 months of treatment with concomitant improvement of sperm cell motility.
Article
Primary coenzyme Q10 (CoQ10; MIM# 607426) deficiencies are an emerging group of inherited mitochondrial disorders with heterogonous clinical phenotypes. Over a dozen genes are involved in the biosynthesis of CoQ10, and mutations in several of these are associated with human disease. However, mutations in COQ5 (MIM# 616359), catalyzing the only C-methylation in the CoQ10 synthetic pathway, have not been implicated in human disease. Here, we report three female siblings of Iraqi-Jewish descent, who had varying degrees of cerebellar ataxia, encephalopathy, generalized tonic-clonic seizures and cognitive disability. Whole exome and subsequent whole genome sequencing identified biallelic duplications in the COQ5 gene, leading to reduced levels of CoQ10 in peripheral white blood cells of all affected individuals and reduced CoQ10 levels in the only muscle tissue available from one affected proband. CoQ10 supplementation led to clinical improvement and increased the concentrations of CoQ10 in blood. This is the first report of primary CoQ10 deficiency caused by loss of function of COQ5, with delineation of the clinical, laboratory, histological and molecular features, and insights regarding targeted treatment with CoQ10 supplementation. This article is protected by copyright. All rights reserved
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Data from the Italian Ministry of Health show that approximately 300-500 per 100.000 Italians are admitted to hospital each year for either TBI or subarachnoid haemorrhage with an annual mortality of 20 per 100.000; 90% of these TBI are of medium severity. Traumatic brain injury-induced hypopituitarism in adults are more common than previously thought. The paucity of clinical reports relating to adolescents with past-TBI induced hypothalamic-pituitary-dysfunction suggests that this phenomenon might be less common that that observed in adults. In the last 25 years, in our Unit a pituitary dysfunction was established during childhood and adolescence in 3 patients (one patient had a precocious puberty, one patient had a gonadal dysfunction and one patient had a partial growth hormone deficiency). In all patients the TBI was severe (unpublished data, 2008). The physiopathological basis of hypopituitarism is lacking. Nevertheless, necrotic, hypoxic, ischemic and shearing lesions are at the hypothalamus and/or the pituitary are likely important factors. The subjects at highest risk appear to be those who have suffered a moderate or severe trauma. Clinical signs of anterior hypopituitarism are often subtle and may be masked by sequalae of TBI. Therefore, post-traumatic anterior pituitary dysfunction may remain undiagnosed and, possibly, aggravate symptoms of brain injury. Moreover it may, if undiagnosed, lead to potentially fatal endocrine crisis. Therefore, adolescents with moderate-severe traumatic brain injury should be screened for such endocrine deficiencies so that replacement therapy can be initiated to optimized the rehabilitation and outcome.
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Rates of mitochondrial superoxide anion radical (O·̄2) generation are known to be inversely correlated with the maximum life span potential of different mammalian species. The objective of this study was to understand the possible mechanism(s) underlying such variations in the rate of O·̄2 generation. The hypothesis that the relative amounts of the ubiquinones or coenzyme Q (CoQ) homologues, CoQ9 and CoQ10, are related with the rate of O·̄2 generation was tested. A comparison of nine different mammalian species, namely mouse, rat, guinea pig, rabbit, pig, goat, sheep, cow, and horse, which vary from 3.5 to 46 years in their maximum longevity, indicated that the rate of O·̄2 generation in cardiac submitochondrial particles (SMPs) was directly related to the relative amount of CoQ9 and inversely related to the amount of CoQ10, extractable from their cardiac mitochondria. To directly test the relationship between CoQ homologues and the rate of O·̄2 generation, rat heart SMPs, naturally containing mainly CoQ9 and cow heart SMPs, with high natural CoQ10 content, were chosen for depletion/reconstitution experiments. Repeated extractions of rat heart SMPs with pentane exponentially depleted both CoQ homologues while the corresponding rates of O·̄2 generation and oxygen consumption were lowered linearly. Reconstitution of both rat and cow heart SMPs with different amounts of CoQ9 or CoQ10 caused an initial increase in the rates of O·̄2 generation, followed by a plateau at high concentrations. Within the physiological range of CoQ concentrations, there were no differences in the rates of O·̄2generation between SMPs reconstituted with CoQ9 or CoQ10. Only at concentrations that were considerably higher than the physiological level, the SMPs reconstituted with CoQ9 exhibited higher rates of O·̄2 generation than those obtained with CoQ10. These in vitrofindings do not support the hypothesis that differences in the distribution of CoQ homologues are responsible for the variations in the rates of mitochondrial O·̄2 generation in different mammalian species.
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Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.
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Uncoupling proteins (UCPs) are thought to be intricately controlled uncouplers that are responsible for the futile dissipation of mitochondrial chemiosmotic gradients, producing heat rather than ATP. They occur in many animal and plant cells and form a subfamily of the mitochondrial carrier family. Physiological uncoupling of oxidative phosphorylation must be strongly regulated to avoid deterioration of the energy supply and cell death, which is caused by toxic uncouplers. However, an H+ transporting uncoupling function is well established only for UCP1 from brown adipose tissue, and the regulation of UCP1 by fatty acids, nucleotides and pH remains controversial. The failure of UCP1 expressed in Escherichia coli inclusion bodies to carry out fatty-acid-dependent H+ transport activity inclusion bodies made us seek a native UCP cofactor. Here we report the identification of coenzyme Q (ubiquinone) as such a cofactor. On addition of CoQ10 to reconstituted UCP1 from inclusion bodies, fatty-acid-dependent H+ transport reached the same rate as with native UCP1. The H+ transport was highly sensitive to purine nucleotides, and activated only by oxidized but not reduced CoQ. H+ transport of native UCP1 correlated with the endogenous CoQ content.
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Based on the discovery of coenzyme Q (CoQ) as an obligatory cofactor for H(+) transport by uncoupling protein 1 (UCP1) [Echtay, K. S., Winkler, E. & Klingenberg, M. (2000) Nature (London) 408, 609-613] we show here that UCP2 and UCP3 are also highly active H(+) transporters and require CoQ and fatty acid for H(+) transport, which is inhibited by low concentrations of nucleotides. CoQ is proposed to facilitate injection of H(+) from fatty acid into UCP. Human UCP2 and 3 expressed in Escherichia coli inclusion bodies are solubilized, and by exchange of sarcosyl against digitonin, nucleotide binding as measured with 2'-O-[5-(dimethylamino)naphthalene-1-sulfonyl]-GTP can be restored. After reconstitution into vesicles, Cl(-) but no H(+) are transported. The addition of CoQ initiates H(+) transport in conjunction with fatty acids. This increase is fully sensitive to nucleotides. The rates are as high as with reconstituted UCP1 from mitochondria. Maximum activity is at a molar ratio of 1:300 of CoQ:phospholipid. In UCP2 as in UCP1, ATP is a stronger inhibitor than ADP, but in UCP3 ADP inhibits more strongly than ATP. Thus UCP2 and UCP3 are regulated differently by nucleotides, in line with their different physiological contexts. These results confirm the regulation of UCP2 and UCP3 by the same factors CoQ, fatty acids, and nucleotides as UCP1. They supersede reports that UCP2 and UCP3 may not be H(+) transporters.
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The authors measured coenzyme Q10 (CoQ10) concentration in muscle biopsies from 135 patients with genetically undefined cerebellar ataxia. Thirteen patients with childhood-onset ataxia and cerebellar atrophy had markedly decreased levels of CoQ10. Associated symptoms included seizures, developmental delay, mental retardation, and pyramidal signs. These findings confirm the existence of an ataxic presentation of CoQ10 deficiency, which may be responsive to CoQ10 supplementation.
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Daily oral or ip administration of coenzyme Q10 to rats for time periods of 2 to 10 weeks leads to its accumulation in liver, concentrating in the soluble fraction of the liver cells. No uptake of coenzyme Q10 can be detected in the heart or kidney. Intraperitoneal administration also results in the accumulation of coenzyme Q10 in the spleen. It is concluded that the normal endogenous levels of quinone in the rat heart and kidney cannot be supplemented over the long term by administration of exogenous quinone.
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Ubiquinones and tocopherols (vitamin E) are intrinsic lipid components which have a stabilizing function in many membranes attributed to their antioxidant activity. The antioxidant effects of tocopherols are due to direct radical scavenging. Although ubiquinones also exert antioxidant properties the specific molecular mechanisms of their antioxidant activity may be due to: (i) direct reaction with lipid radicals or (ii) interaction with chromanoxyl radicals resulting in regeneration of vitamin E. Lipid peroxidation results have now shown that tocopherols are much stronger membrane antioxidants than naturally occurring ubiquinols (ubiquinones). Thus direct radical scavenging effects of ubiquinols (ubiquinones) might be negligible in the presence of comparable or higher concentrations of tocopherols. In support of this our ESR findings show that ubiquinones synergistically enhance enzymic NADH- and NADPH-dependent recycling of tocopherols by electron transport in mitochondria and microsomes. If ubiquinols were direct radical scavengers their consumption would be expected. Further proving our conclusion HPLC measurements demonstrated that ubiquinone-dependent sparing of tocopherols was not accompanied by ubiquinone consumption.
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The electron transport system of muscle mitochondria was examined in a familial syndrome of lactacidemia, mitochondrial myopathy, and encephalopathy. The propositus, a 14-year-old female, and her 12-year-old sister had suffered from progressive muscle weakness, abnormal fatigability, and central nervous system dysfunction since early childhood. In the propositus, the state 3 respiratory rate of muscle mitochondria with NADH-linked substrates and with succinate was markedly reduced. The levels of cytochromes a + a3, b, and c + c1 were normal. The activities of complexes I, II, III, and IV of the electron transport chain were normal or increased. By contrast, the activities of complex I-III and of complex II-III, both of which need coenzyme Q10 (CoQ10), were abnormally low. On direct measurement, the mitochondrial CoQ10 content was 3.7% of the mean value observed in 10 controls. Serum and cultured fibroblasts of the propositus had normal CoQ10 contents. In the younger sister, the respiratory activities and CoQ10 level of muscle mitochondria were similar to those observed in the propositus. The findings establish CoQ10 deficiency as a cause of a familial mitochondrial cytopathy and suggest that the disease results from a tissue-specific defect of CoQ10 biosynthesis.
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The essential role of coenzyme Q in biological energy transduction is well established. Coenzyme Q is a unique carrier for two-electron transfer within the lipid phase of the mitochondrial membrane. The function is essential for proton-based energy coupling. The sites of entry and exit of electrons into the quinone are at specific quinone-binding sites which are constructed to allow only two-electron transfer and thus prevent damaging free radical formation by direct reaction of oxygen with the semiquinone. Failure of proper function with diminished energy supply can be related to insufficient quinone, modification of lipid fluidity, or lipid protein interaction and damage or poisoning in binding sites. Supplementation with coenzyme Q can act by reversal of deficiency or decreased mobility, or by overcoming binding site modification. Coenzyme Q has also been shown to increase antioxidant protection in membranes. New sites for coenzyme Q function in Golgi and plasma membrane show evidence for a role in growth control and secretion-related membrane flow.
Article
Coenzyme Q10 (CoQ10) transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There is one published report of human CoQ10 deficiency describing two sisters with encephalopathy, proximal weakness, myoglobinuria, and lactic acidosis. We report a patient who had delayed motor milestones, proximal weakness, premature exertional fatigue, and episodes of exercise-induced pigmenturia. She also developed partial-complex seizures. Serum creatine kinase was approximately four times the upper limit of normal and venous lactate was mildly elevated. Skeletal muscle biopsy revealed many ragged-red fibers, cytochrome c oxidase-deficient fibers, and excess lipid. In isolated muscle mitochondria, impaired oxygen consumption was corrected by the addition of decylubiquinone. During standardized exercise, ventilatory and circulatory responses were compatible with a defect of oxidation-phosphorylation, which was confirmed by near-infrared spectroscopy analysis. Biochemical analysis of muscle extracts revealed decreased activities of complexes I+II and I+III, while CoQ10 concentration was less than 25% of normal. With a brief course of CoQ10 (150 mg daily), the patient reported subjective improvement. The triad of CNS involvement, recurrent myoglobinuria, and ragged-red fibers should alert clinicians to the possibility of CoQ10 deficiency.
Article
We report severe coenzyme Q10 deficiency of muscle in a 4-year-old boy presenting with progressive muscle weakness, seizures, cerebellar syndrome, and a raised cerebro-spinal fluid lactate concentration. State-3 respiratory rates of muscle mitochondria with glutamate, pyruvate, palmitoylcarnitine, and succinate as respiratory substrates were markedly reduced, whereas ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine were oxidized normally. The activities of complexes I, II, III and IV of the electron transport chain were normal, but the activities of complexes I+III and II+III, both systems requiring coenzyme Q10 as an electron carrier, were dramatically decreased. These results suggested a defect in the mitochondrial coenzyme Q10 content. This was confirmed by the direct assessment of coenzyme Q10 level by high-performance liquid chromatography in patient's muscle homogenate and isolated mitochondria, revealing levels of 16% and 6% of the control values, respectively. We did not find any impairment of the respiratory chain either in a lymphoblastoid cell line or in skin cultured fibroblasts from the patient, suggesting that the coenzyme Q10 depletion was tissue-specific. This is a new case of a muscle deficiency of mitochondrial coenzyme Q in a patient suffering from an encephalomyopathy.
Article
The effect of lifelong oral supplementation with ubiquinone Q10 (10 mg/kg/day) was examined in Sprague-Dawley rats and C57/B17 mice. There were no significant differences in survival or life-span found in either rats or mice. Histopathologic examination of different rat tissues showed no differences between the groups. In Q10 supplemented rats, plasma and liver Q10 levels were 2.6 to 8.4 times higher at all age points than in control rats. Interestingly, in supplemented rats the Q9 levels also were significantly higher (p<0.05) in plasma and liver at ages 18 and 24 months. Neither Q9 nor Q10 levels were affected by supplementation in kidney, heart, or brain tissues. In spite of the significant changes in plasma and liver ubiquinone concentrations, lifelong Q10 supplementation did not prolong or shorten the lifespan of either rats or mice.
Article
The objective of this study was to elucidate the anti-oxidative roles of coenzyme Q (CoQ) and alpha-tocopherol in mitochondrial membranes by determining whether CoQ directly scavenges peroxyl- and alkoxyl-radicals or indirectly regenerates alpha-tocopherol during autooxidation of mitochondrial membranes. A comparison of the interaction between alpha-tocopherol and CoQ during autooxidation was made between bovine and rat heart mitochondria, which differ approximately 15-fold in their alpha-tocopherol content. Autooxidation of both bovine and rat heart mitochondria resulted in the formation of thiobarbituric-acid-reactive substances and protein carbonyls; however, the differences in the autooxidizability of mitochondria between rat and bovine heart mitochondrial membranes were relatively minor. Supplementation of rat heart mitochondria with succinate caused reduction of CoQ to ubiquinol while alpha-tocopherol concentration remained unaffected during autooxidation. In contrast, in the absence of succinate, CoQ was present in the oxidized form (ubiquinone) and the mitochondrial membranes were depleted of alpha-tocopherol. CoQ concentrations remained unchanged over time irrespective of the presence or absence of succinate. In the absence of succinate, autooxidation of bovine SMPs, supplemented with different amounts of alpha-tocopherol, was inversely related to the amount of alpha-tocopherol, whereas in the presence of succinate autooxidation was greatly reduced. Results of this study indicate that during autooxidation of mitochondria, alpha-tocopherol acts as the direct radical scavenger, whereas ubiquinol regenerates alpha-tocopherol.
Article
The respiratory-chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis. We assessed respiratory-chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q10 content. Clinical follow-up and detailed biochemical investigations of respiratory chain activity were carried out over the 3 years of oral quinone administration. Deficiency of coenzyme Q10-dependent respiratory-chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy. Particular attention should be paid to multiple quinone-responsive respiratory-chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone.
Article
To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency. Muscle CoQ10 deficiency has been reported only in a few patients with a mitochondrial encephalomyopathy characterized by 1) recurrent myoglobinuria; 2) brain involvement (seizures, ataxia, mental retardation), and 3) ragged-red fibers and lipid storage in the muscle biopsy. Having found decreased CoQ10 levels in muscle from a patient with unclassified familial cerebellar ataxia, the authors measured CoQ10 in muscle biopsies from other patients in whom cerebellar ataxia could not be attributed to known genetic causes. The authors found muscle CoQ10 deficiency (26 to 35% of normal) in six patients with cerebellar ataxia, pyramidal signs, and seizures. All six patients responded to CoQ10 supplementation; strength increased, ataxia improved, and seizures became less frequent. Primary CoQ10 deficiency is a potentially important cause of familial ataxia and should be considered in the differential diagnosis of this condition because CoQ10 administration seems to improve the clinical picture.
Article
Two brothers with myopathic coenzyme Q10 (CoQ10) deficiency responded dramatically to CoQ10 supplementation. Muscle biopsies before therapy showed ragged-red fibers, lipid storage, and complex I + III and II + III deficiency. Approximately 30% of myofibers had multiple features of apoptosis. After 8 months of treatment, excessive lipid storage resolved, CoQ10 level normalized, mitochondrial enzymes increased, and proportion of fibers with TUNEL-positive nuclei decreased to 10%. The authors conclude that muscle CoQ10 deficiency can be corrected by supplementation of CoQ10, which appears to stimulate mitochondrial proliferation and to prevent apoptosis.
Article
Coenzyme Q (CoQ(10)) is a component of the mitochondrial electron transport chain and also a constituent of various cellular membranes. It acts as an important in vivo antioxidant, but is also a primary source of O(2)(-*)/H(2)O(2) generation in cells. CoQ has been widely advocated to be a beneficial dietary adjuvant. However, it remains controversial whether oral administration of CoQ can significantly enhance its tissue levels and/or can modulate the level of oxidative stress in vivo. The objective of this study was to determine the effect of dietary CoQ supplementation on its content in various tissues and their mitochondria, and the resultant effect on the in vivo level of oxidative stress. Rats were administered CoQ(10) (150 mg/kg/d) in their diets for 4 and 13 weeks; thereafter, the amounts of CoQ(10) and CoQ(9) were determined by HPLC in the plasma, homogenates of the liver, kidney, heart, skeletal muscle, brain, and mitochondria of these tissues. Administration of CoQ(10) increased plasma and mitochondria levels of CoQ(10) as well as its predominant homologue CoQ(9). Generally, the magnitude of the increases was greater after 13 weeks than 4 weeks. The level of antioxidative defense enzymes in liver and skeletal muscle homogenates and the rate of hydrogen peroxide generation in heart, brain, and skeletal muscle mitochondria were not affected by CoQ supplementation. However, a reductive shift in plasma aminothiol status and a decrease in skeletal muscle mitochondrial protein carbonyls were apparent after 13 weeks of supplementation. Thus, CoQ supplementation resulted in an elevation of CoQ homologues in tissues and their mitochondria, a selective decrease in protein oxidative damage, and an increase in antioxidative potential in the rat.
Article
A 31-year-old woman had encephalopathy, growth retardation, infantilism, ataxia, deafness, lactic acidosis, and increased signals of caudate and putamen on brain magnetic resonance imaging. Muscle biochemistry showed succinate:cytochrome c oxidoreductase (complex II-III) deficiency. Both clinical and biochemical abnormalities improved remarkably with coenzyme Q10 supplementation. Clinically, when taking 300mg coenzyme Q10 per day, she resumed walking, gained weight, underwent puberty, and grew 20cm between 24 and 29 years of age. Coenzyme Q10 was markedly decreased in cerebrospinal fluid, muscle, lymphoblasts, and fibroblasts, suggesting the diagnosis of primary coenzyme Q10 deficiency. An older sister has similar clinical course and biochemical abnormalities. These findings suggest that coenzyme Q10 deficiency can present as adult Leigh's syndrome.
Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects
  • Matthews