Coenzyme Q10 deficiency and isolated myopathy

Three unrelated, sporadic patients with muscle coenzyme Q10 (CoQ10) deficiency presented at 32, 29, and 6 years of age with proximal muscle weakness and elevated serum creatine kinase (CK) and lactate levels, but without myoglobinuria, ataxia, or seizures. Muscle biopsy showed lipid storage myopathy, combined deficiency of respiratory chain complexes I and III, and CoQ10 levels below 50% of normal. Oral high-dose CoQ10 supplementation improved muscle strength dramatically and normalized serum CK.     

Cytochromec oxidase and coenzyme Q in neuromuscular diseases: a histochemical study

Summary Cytochromec oxidase (CCO) has been histochemically studied in 250 muscle biopsies from patients with different neuromuscular diseases. The results were compared with those obtained on serial sections stained with Gomori's trichrome and with the methods for NADH tetrazolium reductase, succinate dehydrogenase and lactate dehydrogenase. In 58 selected cases serial sections were also stained with a method demonstrating coenzyme Q (CoQ) activity. Demonstration of structural alterations was as good with CCO as with the methods for other oxidative enzymes: particularly evident were alterations of the distribution of mitochondria, such as core areas in central core and multiminicore diseases. Unstained fibers were observed in mitochondrial myopathies, in Becker, Emery-Dreifuss, limb-girdle, facio-scapulo-humeral muscular dystrophies, muscle infarction, polymyositis, motor neuron diseases and neuropathies. The histochemical method for CoQ showed only low specificity, since partial staining was also present in areas devoid of mitochondria, such as cores. CoQ deficiency was not observed in any of the 19 mitochondrial myopathies examined.     

Muscle coenzyme Q: a potential test for mitochondrial activity and redox status

The aim of this study is to determine whether coenzyme Q (CoQ) muscle concentrations and redox state are associated with pathologic changes in muscle biopsy specimens. Skeletal muscle biopsies were collected (January 2002-February 2004) and underwent pathologic evaluation. Quadriceps specimens (n = 47) were stratified accordingly: Group 1, controls without evidence of pathologic abnormalities; Group 2, type I myofiber predominance; Group 3, type II myofiber atrophy; Group 4, lower motor unit disease; and Group 5, muscular dystrophy. Ubiquinol-10, ubiquinone-10, total coenzyme Q10 (CoQ10), coenzyme Q9 (CoQ9), total CoQ (CoQ9+CoQ10) concentrations were analyzed in biopsy muscle by high-performance liquid chromatography. Ubiquinone-10, total CoQ10, and total CoQ concentrations were significantly decreased in Group 5. Significant positive correlations (r congruent with 0.40) were found between muscle ubiquinone-10, total CoQ10, and total CoQ concentrations vs the percentage of myofibers having subsarcolemmal mitochondrial aggregates. CoQ redox ratio and the fraction CoQ9/total CoQ were negatively correlated with subsarcolemmal mitochondrial aggregates. A significant correlation (r = 0.328) also occurred between ubiquinol-10 concentration and citrate synthase activity. This study suggests that total CoQ concentration provides a new method for estimating mitochondrial activity in biopsy muscle; and that the muscle CoQ test is feasible and potentially useful for diagnosing CoQ deficiency states.     

Exercise intolerance and the mitochondrial respiratory chain

The syndrome of exercise intolerance, cramps, and myoglobinuria is a common presentation of metabolic myopathies and has been associated with several specific inborn errors of glycogen or lipid metabolism. As disorders in fuel utilization presumably impair muscle energy production, it was more than a little surprising that exercise intolerance and myoglobinuria had not been associated with defects in the mitochondrial respiratory chain, the terminal energy-yielding pathway. Recently, however, specific defects in complex I, complex III, and complex IV have been identified in patients with severe exercise intolerance with or without myoglobinuria. All patients were sporadic cases and all harbored mutations in protein-coding genes of muscle mtDNA, suggesting that these were somatic mutations not affecting the germ-line. Another respiratory chain defect, primary coenzyme Q10 (CoQ10) deficiency, also causes exercise intolerance and recurrent myoglobinuria, usually in conjunction with brain symptoms, such as seizures or cerebellar ataxia. Primary CoQ10 deficiency is probably due to mutations in nuclear gene(s) encoding enzymes involved in CoQ10 biosynthesis.     

Familial cerebellar ataxia with muscle coenzyme Q10 deficiency

OBJECTIVE: To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Kearns-Sayre syndrome: mitochondrial encephalomyopathy caused by deficiency of the respiratory chain

We report the cases of a 46 year old woman and of a 18 year-old boy who met the criteria for Kearns-Sayre syndrome. Additional atypic features were present in one case: family history, psychosis and acute respiratory failure. In both cases histoenzymatic analysis of the muscle biopsy and biochemical studies of mitochondria isolated from the muscle sample demonstrated mitochondrial myopathy associated with combined partial deficiency of complexes I and IV of the electron transfer chain. Although there is no correlation between clinical and biological data in the mitochondrial myopathies our cases confirm that such defects are involved in Kearns-Sayre syndrome. Improvement with coenzyme Q10 therapy in these patients is reported.     

Cerebellar ataxia with coenzyme Q10 deficiency: diagnosis and follow-up after coenzyme Q10 supplementation

Our aim was to report a new case with cerebellar ataxia associated with coenzyme Q10 (CoQ) deficiency, the biochemical findings caused by this deficiency and the response to CoQ supplementation. PATIENT: A 12-year-old girl presenting ataxia and cerebellar atrophy. BIOCHEMICAL STUDIES: Coenzyme Q10 in muscle was analysed by HPLC with electrochemical detection and mitochondrial respiratory chain (MRC) enzyme activities by spectrophotometric methods. CoQ biosynthesis in fibroblasts was assayed by studying the incorporation of radiolabeled 4-hydroxy[U 14C] benzoic acid by HPLC with radiometric detection. RESULTS: Mitochondrial respiratory chain enzyme analysis showed a decrease in complex I + III and complex II + III activities. CoQ concentration in muscle was decreased (56 nmol/g of protein: reference values: 157-488 nmol/g protein). A reduced incorporation of radiolabeled 4-hydroxy[U- 14C] benzoic acid was observed in the patient (19% of incorporation respect to the median control values). After 16 months of CoQ supplementation, the patient is now able to walk unaided and cerebellar signs have disappeared. CONCLUSIONS: Cerebellar ataxia associated with CoQ deficiency in our case might be allocated in the transprenylation pathway or in the metabolic steps after condensation of 4-hydroxybenzoate and the prenyl side chain of CoQ. Clinical improvement after CoQ supplementation was remarkable, supporting the importance of an early diagnosis of this kind of disorders.     

Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency

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.     

Long-term coenzyme Q10 therapy for a mitochondrial encephalomyopathy with cytochrome c oxidase deficiency: a 31P NMR study

For 2 years we administered high doses of coenzyme Q10 (CoQ) to a patient having mitochondrial encephalomyopathy with cytochrome c oxidase deficiency. Abnormal elevation of the serum lactate per pyruvate ratio and the increased concentration of serum lactate plus pyruvate induced by exercise decreased with CoQ treatment. This therapeutic effect continued for 2 years. 31P nuclear magnetic resonance spectroscopy showed acceleration of the postexercise recovery of the ratio of phosphocreatine to inorganic phosphate in muscle during CoQ treatment. These observations support the beneficial effect of CoQ on the impaired mitochondrial oxidative metabolism in muscle. Also, impaired central and peripheral nerve conductivities consistently improved during CoQ treatment. These results indicate that CoQ has clinical value in the long-term management of patients with mitochondrial encephalomyopathies, even though there are clinical limitations to the effects of this therapy.     

Delayed manifestation of mitochondrial myopathy--complex I and IV deficiency of the mitochondrial respiratory chain with progressive paresis]

We describe a 53-year-old patient with a progressive mitochondrial myopathy of late-onset, restricted to skeletal muscle only without external ophthalmoplegia. The myopathy developed at the age of 46 years initially with exercise intolerance and subsequently progressive permanent muscle weakness. Muscle biopsy revealed severe myopathic changes, ragged red fibers, and a marked multifocal cytochrome-c-oxidase deficiency. Biochemical analysis showed a deficiency of complexes I and IV of the mitochondrial respiratory chain. Genetic analysis of mitochondrial DNA revealed no deletions. Mitochondrial myopathies restricted to skeletal muscle have to be considered in the differential diagnosis of late-onset progressive myopathies.     

Muscle coenzyme Q10 level in statin-related myopathy

BACKGROUND: Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce the level of cholesterol by inhibiting the synthesis of mevalonate, an intermediary in the cholesterol biosynthetic pathway. Use of statin drugs has been associated with a variety of skeletal muscle-related complaints. Coenzyme Q10 (CoQ10), a component of the mitochondrial respiratory chain, is also synthesized from mevalonate, and decreased muscle CoQ10 concentration may have a role in the pathogenesis of statin drug-related myopathy. OBJECTIVES: To measure the CoQ10 concentration and respiratory chain enzyme activities in muscle biopsy specimens from 18 patients with statin drug-related myopathy and to look for evidence of apoptosis using the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) assay. DESIGN: An open-labeled study of CoQ10 concentration in muscle from patients with increased serum creatine kinase concentrations while receiving standard statin drug therapy. SETTING: Neuromuscular centers at 2 academic tertiary care hospitals. RESULTS: Muscle structure was essentially normal in 14 patients and showed evidence of mitochondrial dysfunction and nonspecific myopathic changes in 2 patients each. Muscle CoQ10 concentration was not statistically different between patients and control subjects, but it was more than 2 SDs below the normal mean in 3 patients and more than 1 SD below normal in 7 patients. There was no TUNEL positivity in any patients. CONCLUSION: These data suggest that statin drug-related myopathy is associated with a mild decrease in muscle CoQ10 concentration, which does not cause histochemical or biochemical evidence of mitochondrial myopathy or morphologic evidence of apoptosis in most patients.     

Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Q10

We tested the efficacy of coenzyme Q10 (ubidecarenone, CoQ10) therapy in patients with Kearns-Sayre syndrome and other mitochondrial myopathies with chronic progressive external ophthalmoplegia (CPEO). We treated seven patients for 1 year with daily oral administration of 120 mg of CoQ10. Throughout the treatment most of our patients showed a progressive reduction of serum lactate and pyruvate levels following standard muscle exercise and generally improved neurologic functions. The ECG and echocardiogram showed no significant changes in our patients. None of our patients showed any improvement in ptosis and CPEO.     

Congenital or late-onset myopathy in patients with the T14709C mtDNA mutation

Three patients with different clinical phenotypes harbored the same point mutation at nucleotide 14709 (T14709C) in the tRNAGlu gene of mitochondrial DNA (mtDNA). The first patient was a 21-month-old child with severe congenital myopathy, respiratory distress and mild mental retardation. Muscle biopsy showed about 12% cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs), and markedly decreased activities of mitochondrial respiratory chain complexes I, III and IV. The other two patients were 51- and 55-year-old siblings with slowly progressive myopathy and diabetes mellitus. Muscle biopsy showed focal COX-negative RRFs and decreased activities of complexes I, III and IV. In all three patients, the T14709C mutation was abundant in muscle but present at lower levels in accessible tissues. Previously described patients with the same mutation also showed congenital or late-onset myopathy. Diabetes is frequently associated with both phenotypes and is a clinical clue to the molecular diagnosis.     

Coenzyme Q in serum and muscle of 5 patients with Kearns-Sayre syndrome and 12 patients with ophthalmoplegia plus

Summary Coenzyme Q₁₀ (CoQ) was measured in serum and muscle of 17 patients with ophthalmoplegia plus (including 5 patients with Kearns-Sayre syndrome), in muscle of 9 patients with neurogenic atrophies, 5 patients with myositis, and 5 patients with progressive muscular dystrophies (including 1 patient with oculopharyngeal dystrophy), and in serum and muscle of normal controls. CoQ was markedly decreased in serum and muscle of 1 patient with Kearns-Sayre syndrome and treatment with CoQ resulted in a significant clinical improvement. The other 4 patients with Kearns-Sayre syndrome and the patients with ophthalmoplegia plus exhibited normal concentrations of CoQ in serum and muscle. CoQ levels in muscle of patients with progressive muscular dystrophies, myositis or neurogenic atrophies were within the normal range. Concentrations of CoQ in serum and muscle of normal controls were independent of age and showed no sex difference. The data indicate that CoQ deficiency might be the specific cause of mitochondrial encephalomyopathy in 1 patient but it was not the underlying defect common to all cases with Kearns-Sayre syndrome and ophthalmoplegia plus, although the possibility of a focal CoQ deficiency affecting only single muscle fibres cannot be excluded.Dedicated to the late Dr. Saburo Ogasahara     

Coenzyme Q10, exercise lactate and CTG trinucleotide expansion in myotonic dystrophy.

Steinert's myotonic dystrophy (DM) is a genetic autosomal dominant disease and the most frequent muscular dystrophy in adulthood. Although causative mutation is recognized as a CTG trinucleotide expansion on 19q13.3, pathogenic mechanisms of multisystem involvement of DM are still under debate. It has been suggested that mitochondrial abnormalities can occur in this disease and deficiency of coenzyme Q 10 (CoQ10) has been considered one possible cause for this. The aim of this investigation was to evaluate, in 35 DM patients, CoQ10 blood levels and relate them to the degree of CTG expansion as well as to the amount of lactate production in exercising muscle as indicator of mitochondrial dysfunction. CoQ10 concentrations appeared significantly reduced with respect to normal controls: 0.85 +/- 0.25 vs. 1.58 +/- 0.28 microg/ml (p < 0.05). Mean values of blood lactate were significantly higher in DM patients than controls (p < 0.05) both in resting conditions (2.9 +/- 0.55 vs. 1.44 +/- 1.11 mmol/L) and at the exercise peak (6.77 +/- 1.79 vs. 4.90 +/- 0.59 mmol/L), while exercise lactate threshold was anticipated (30-50% vs. 60-70% of the predicted normal maximal power output, p < 0.05). Statistical analysis showed that serum CoQ10 levels were significantly (p < 0.05) inversely correlated with both CTG expansion degree and lactate values at exercise lactate threshold level. Our data indicates the occurrence of reduced CoQ10 levels in DM, possibly related to disease pathogenic mechanisms associated with abnormal CTG trinucleotide amplification.     

Mitochondrial complex I deficiency in a female with multiplex arthrogryposis congenita

A 10-year-old female with arthrogryposis multiplex congenita is presented. Clinical, neurophysiologic, and histologic findings suggested a mild myopathy. The analysis of enzymatic activity in the homogenate and of mitochondrial function in saponin-permeabilized fibers from the muscle biopsy revealed an approximately twofold-decreased specific activity of the NADH:CoQ oxidoreductase (complex I of the mitochondrial respiratory chain) that was compensated for by an increased number of mitochondria. The complex I deficiency was also detected in cultivated skin fibroblasts of the patient. The observed defect of mitochondrial oxidative phosphorylation in arthrogryposis multiplex congenita may be of pathogenetic relevance.     

Late-onset cerebellar ataxia with hypogonadism and muscle coenzyme Q10 deficiency

Two brothers had late-onset progressive ataxia, cerebellar atrophy, and hypergonadotropic hypogonadism associated with coenzyme Q10 (CoQ10) deficiency in skeletal muscle. Both patients improved on high-dose CoQ10 supplementation, stressing the importance of CoQ10 deficiency in the differential diagnosis of cerebellar ataxia, even when onset is late.     

Partial deficiency of complexes I and IV of the mitochondrial respiratory chain in skeletal muscle of two patients with mitochondrial myopathy

Summary Respiratory chain enzymes were studied in isolated mitochondria of two patients with mitochrondrial myopathy. Both patients had been suffering from chronic progressive external ophthalmoplegia and abnormal muscular fatigability since late childhood. One of the patients exhibited the complete triad of symptoms characteristic of Kearns-Sayre syndrome. Venous lactate levels at rest and during minimal exercise were increased in both patients. Histochemical examination of muscle revealed ragged red fibres and intermingled fibres negative for cytochrome c oxidase. Biochemical studies showed decreased activities of complex I and complex IV of the respiratory chain in both patients. Reduced minus oxidized spectra of mitochondrial cytochromes revealed a decreased content of cytochrome aa₃ in only one patient, but a normal content in the other. A combined deficiency of complexes I and IV in muscle might either be due to a deficiency of a single subunit common to both complexes or to a coincidental deficiency of both complexes expressed either in the same or in different fibres.     

A novel nonsense mutation (Q352X) in the mitochondrial cytochrome b gene associated with a combined deficiency of complexes I and III.

We identified a novel mitochondrial cytochrome b mutation in a patient with progressive exercise intolerance, muscle cramps and lactic acidosis. A marked reduction of the enzymatic activities of respiratory chain complexes I and III was found in muscle biopsy. The mutation was a heteroplasmic C15800T transition, determining a stop-codon at amino acid position 352 (Q352X). Mutant mtDNA was approximately 45% of total genomes in muscle, while it was absent in all of the other examined tissues of the patient and in lymphocytes of the patient's mother. Clinical presentation and laboratory findings strongly support the hypothesis that this mutation is the primary cause of the disease in our patient.     

Progressive myopathy with a combined respiratory chain defect including Complex II

Biochemical defects in the respiratory chain are mostly associated with deficiencies in Complexes I, III and IV, caused by nuclear or mitochondrial DNA mutations. Combined defects including Complex II have been reported very rarely and have muscular symptoms as the main manifestation, including muscle weakness, exercise intolerance and myoglobinuria. We report a patient with a fatal progressive myopathy and muscle biopsy showing diffuse reduction in succinate dehydrogenase activity, ragged red fibers and intense lipid accumulation. Cytochrome c oxidase (COX) histochemistry demonstrated 30% of fibers with increased subsarcolemmal staining while 27% were COX negative. Western blotting analysis showed reduction in the expression of the 39 kDa subunit of Complex I, subunit II of Complex IV and the 70 kDa subunit of Complex II. Our findings suggest that the patient had a complex pattern of mitochondrial dysfunction affecting multiple respiratory chain complexes (I, II and IV) and fatty acid metabolism. This report adds a new histological pattern associated to combined deficiencies of respiratory chain with involvement of Complex II and shows that this disease may be fatal with a rapid progression.