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.     

Clinical and radiologic improvements in mitochondrial encephalomyelopathy following sodium dichloroacetate therapy

We administered sodium dichloroacetate (DCA), which reduces the circulating lactate and pyruvate concentrations by stimulating the activity of the pyruvate dehydrogenase complex (PDHC), to three children with mitochondrial encephalomyelopathy. Significant clinical, biochemical and radiologic improvements were obtained following DCA therapy (approximately 30 mg/kg per day, divided into three doses). All three patients had non-pyruvate dehydrogenase complex (PDHC) deficiencies: two exhibited Leigh syndrome (complex I deficiency and unknown etiology), and one abnormal myelination (multienzyme deficiency), demonstrated on magnetic resonance imaging (MRI). The lactic and pyruvic acid concentrations in serum and cerebrospinal fluid (CSF) were decreased significantly by the oral DCA treatment. The lactic acid peak on MR spectroscopy also markedly decreased in parallel with the CSF level. In addition, the brain lesions observed on MRI were improved in all patients. No exacerbation was observed in any of the patients, who have been followed-up more than 21 months following the DCA therapy. These results suggest that DCA therapy should be considered in all patients with a mitochondria-related enzyme deficiency.     

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.     

Defects in citric acid cycle and the electron transport chain in progressive poliodystrophy

Abstract– We will present 8 children with progressive infantile or juvenile poliodystrophy (Alpers' disease), associated with a defect in pyruvate metabolism. Laboratory studies showed elevated levels of lactate in CSF and, in 4 children, elevated levels in serum. Histopathologic studies revealed lipid storage in liver and/or muscle tissue, sometimes myopathy with abnormal mitochondria and slight axonal degeneration in the peripheral nerve. Autopsy showed the characteristics of progressive poliodystrophy with degeneration and loss of neurons. Electron microscopy of cerebral cortex showed no mitochondrial abnormalities in neurons or astroglia. Biochemical studies in muscle and/or liver and/or cerebral tissue showed different deficiencies in pyruvate metabolism: in the pyruvate dehydrogenase complex, in the second part of the citric acid cycle (after the oxoglutarate dehydrogenase complex), in the NADH oxidation, in cytochrome aa ₃ and in pyruvate carboxylase.     

Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy

We used a standardized bicycle ergometry protocol with a stepwise increasing workload (30–100 W) to evaluate various metabolic factors for the diagnosis and metabolic monitoring of mitochondrial encephalomyopathies. All patients (n = 9) showed pathological venous lactate/pyruvate (L/P) ratios, which normalized in three patients after 6 months of coenzyme Q₁₀ (CoQ) therapy. Thus, the L/P ratio proved to be the clinically most useful parameter in the evaluation and monitoring of mitochondrial diseases, showing higher sensitivity than lactate measurements only. CoQ may exert a favourable effect in some patients with mitochondrial diseases. Received: 15 October 1997 Received in revised form: 6 February 1998 Accepted: 20 March 1998     

Basal ganglia calcification in Kearns-Sayre syndrome

The Kearns-Sayre syndrome (KSS) appears to be a distinctive disorder characterized by progressive external ophthalmoplegia, pigmentary degeneration of the retina, heart block, and elevated CSF protein levels. Recent reports have suggested that abnormalities of muscle mitochondria may also be a consistent finding in KSS. We recently examined a patient with KSS whose skeletal muscle contained abnormal mitochondria. In addition, a computerized tomographic scan of the head showed cerebellar and brain stem atrophy, as well as calcification in the region of the basal ganglia.     

The effects of acute cerebrovascular disease on serum and cerebrospinal fluid parameters

In order to evaluate the effects due to acute cerebrovascular disease on serum and cerebrospinal fluid (CSF) parameters, biochemical data from 312 patients were studied. In serum, CK, LD and alpha 1 protein fraction showed a moderately close relationship to the severity of stroke. In CSF there could not be observed any relation between enzymatic activities (LD, ASAT, CK) and the severity of the disease. The same result was found for CSF protein and the ratio CSF albumin/serum albumin, parameters which are indicative for Blood Brain Barrier (BBB) disturbances. Substances from the intermediate metabolism in the Central Nervous System (CNS) (lactate and pyruvate) were evidently raised in CSF and there was a clear relation between the CSF concentration and the severity of stroke. No indication for IgG immunoglobulin abnormalities in CSF was found. The concentration of neurotransmitter metabolite 5HIAA in CSF was significantly higher in (in)completed stroke than in Transient Ischaemic Attack.     

Mitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme Q10 and idebenone

Two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and strokelike episodes (MELAS) in one family are reported. Pathological examination of case 1 showed ragged-red fibers, with 7% of the fibers being unstained by cytochrome c oxidase stain, peripheral nerve damage, multiple areas of softening in the cerebrum and midbrain, and spongy changes in the cerebrum, optic nerve and pons. Electron microscopic examination revealed abnormal accumulations of mitochondria in the skeletal muscle, smooth muscle and cardiac muscle. The activity of cytochrome c oxidase in the brain and liver showed a tendency to decrease. In case 2 (maternal aunt of case 1), muscular weakness and peripheral nerve damage improved by treatment with coenzyme Q₁₀. By adding idebenone to the coenzyme Q₁₀ therapy, the EEG and Wechsler's Adult Intelligence Scale (WAIS) improved. Furthermore, in the cerebral spinal fluid (CSF), the protein, lactate, and pyruvate decreased, and the monoamines and monoamine metabolites increased.     

A case of Kearns-Sayre-Shy syndrome with abnormal signal intensity on MRI in cerebral white matter and brainstem

A 42-year-old woman was admitted for complaining of gait disturbance lasting for 2 years. She had a past history of hearing loss and bilateral ocular ptosis since her age of 21 years. Neurological examinations revealed severe external ophthalmoplegia, ptosis and muscular weakness of neck and extremities, but no dementia. Laboratory examinations showed high level of serum CK and slight elevations of CSF protein, lactate and pyruvate. The QT interval on ECG was prolonged. The EEG finding was slightly abnormal. The neurogenic pattern on EMG was noted. Muscle biopsy was performed at the quadriceps muscle. Its specimens demonstrated mixed changes of muscular atrophy and ragged red fibers. From these findings, Kearns-Sayre-Shy syndrome was diagnosed. It was noted in this case that brain MRI (T2-weighted image) revealed bilateral diffuse high signal intensity areas on cerebral white matter and brainstem. It seems that the lesions of central nervous system may progress subclinically for many years in cases of KSS, as our case shows.     

Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado-Joseph disease

To identify the metabolic alterations related to mitochondrial functions in Machado-Joseph disease (MJD), we analyzed the cerebrospinal fluid (CSF) levels of lactate, pyruvate, and citric acid cycle intermediates by high performance liquid chromatography (HPLC) in 7 Japanese patients with that disease and then measured some mitochondrial enzymes. Their mean age was 46 years. Diseased controls were matched by age to the patients studied. The CSF level of lactate was significantly elevated, pyruvate was significantly decreased, and the lactate/pyruvate (L/P) ratio was significantly elevated in the patients with MJD. There were no significant differences of citric acid cycle intermediates of the CSF between the patients and the controls. We measured the native and dichloroacetate (DCA)-activated pyruvate dehydrogenase complex (PDHC) activities, and mitochondrial electron transport activities in 3 patients with MJD, and found these activities to be normal. Therefore, the increased CSF lactate, increased lactate/pyruvate ratio, and decreased pyruvate may reflect the decreased regional cerebral blood flow rather than metabolic derangement of the mitochondria.     

An investigation of pyruvate metabolism in patients with cerebellar and spinocerebellar degeneration

This study extends previous observations of pyruvate metabolism in the spino-cerebellar degenerations by screening for abnormalities of pyruvate oxidation using the rise in blood pyruvate after an oral glucose load and examining the activity of the lipoamide dehydrogenase (LAD) moeity of the pyruvate dehydrogenase complex in the serum of 31 patients with Friedreich's ataxia, hereditary spastic ataxia and primary cerebellar degeneration. Serum LAD activity was significantly reduced in 10 Friedreich's ataxia patients when compared to controls and to 10 patients with spastic ataxia, thus confirming previous studies. Two patients with Friedreich's ataxia and 2 with primary cerebellar degeneration had abnormal blood pyruvate curves after oral glucose loading. The findings suggest that abnormal pyruvate oxidation occurs in some cases of Friedreich's ataxia and primary cerebellar degeneration and that the abnormality of pyruvate metabolism is not necessarily reflected in the serum LAD activity of these patients. The relevance of these findings to the heterogeneity of the hereditary ataxias is discussed.     

Kearns-Sayre综合征一例临床病理分析

目的探讨Kearns-Sayre综合征(KSS)的临床与病理形态学表现,旨在提高对该病的认识。方法对1例KSS患者的临床和病理特点进行分析。结果该患者表现为视物不清、双上睑下垂、慢性进行性眼外肌瘫痪、视网膜色素变性,眼底色素改变呈"椒盐状"、晕厥发作、心脏传导阻滞、小脑性共济失调、不育、脑脊液蛋白升高、脑脊液叶酸/血清叶酸比值降低。肌肉活检MGT染色发现有不整红边纤维(RRF),出现比例为11.6%。电镜观察表现为线粒体数目增多,形态异常,嵴排列紊乱等,可见线粒体内类结晶状包涵体。结论本例提示尽管KSS的临床表现多样,但对不明原因的单侧或双侧上睑下垂、眼球运动障碍伴视网膜色素变性和晕厥等症状的患者,应想到KSS的诊断,进行肌肉活检、遗传咨询和采取必要的措施,防止威胁生命的事件发生。     

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system

Objective: To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). Methods: We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n = 49). Results: Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9 mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40 mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). Conclusions: Our study suggests that that CSF lactate level > 19.9 mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20–40 mg/dl), lactate CSF/blood ratio > 0.91 may also provide diagnostic information.     

Brain energy metabolism and intracranial pressure in idiopathic adult hydrocephalus syndrome

BACKGROUND: The symptoms in idiopathic adult hydrocephalus syndrome (IAHS) are consistent with pathology involving the periventricular white matter, presumably reflecting ischaemia and CSF hydrodynamic disturbance. OBJECTIVE: To investigate whether a change in intracranial pressure (ICP) can affect energy metabolism in deep white matter. METHODS: A microdialysis catheter, a brain tissue oxygen tension probe, and an ICP transducer were inserted into the periventricular white matter 0-7 mm from the right frontal horn in 10 patients with IAHS. ICP and intracerebral Ptio2 were recorded continuously during lumbar CSF constant pressure infusion test. ICP was raised to pressure levels of 35 and 45 mm Hg for 10 minutes each, after which CSF drainage was undertaken. Microdialysis samples were collected every three minutes and analysed for glucose, lactate, pyruvate, and glutamate. RESULTS: When raising the ICP, a reversible drop in the extracellular concentrations of glucose, lactate, and pyruvate was found. Comparing the values during baseline to values at the highest pressure level, the fall in glucose, lactate, and pyruvate was significant (p < 0.05, Wilcoxon sign rank). There was no change in glutamate or the lactate to pyruvate ratio during ICP elevation. Ptio2 did not decrease during ICP elevation, but was significantly increased following CSF drainage. CONCLUSIONS: Raising intracranial pressure induces an immediate and reversible change in energy metabolism in periventricular white matter, without any sign of ischaemia. Theoretically, frequent ICP peaks (B waves) over a long period could eventually cause persisting axonal disturbance and subsequently the symptoms noted in IAHS.     

Chronic progressive external ophthalmoplegia (CPEO) with deleted mitochondrial DNA

A 19-year-old man with chronic progressive external ophthalmoplegia with deleted mitochondrial DNA was reported. Neurological examination revealed bilateral external ophthalmoplegia, hearing loss of sensorineural type, short stature, mental retardation, muscle atrophy and weakness in the proximal muscles. Lactate and pyruvate levels were elevated in both serum and cerebrospinal fluid (CSF). Protein concentration was slightly increased in CSF. Electromyogram showed myopathic changes on all the muscles examined. Ragged-red fibers were found in biopsied rectus femoris muscle, stained with modified Gomori trichrome. Scattered cytochrome c oxidase deficient fibers were encountered. The computed tomography of the brain showed mild cerebral and cerebellar atrophy without any abnormal calcification or hypo-lucency. Southern blot analysis of the mitochondrial DNA (mtDNA) extracted from the patient's muscle revealed mixed population of mtDNA, consisting of the normal one and partially deleted one. The size of the deletion was about 4.5-kilobase. The region included the sequences coding for at least four subunits of Complex I, one subunit of Complex IV, two subunits of Complex V and five tRNAs. There may be a "hot area" on the mitochondrial genome that is more prone to be deleted than other regions of mtDNA. Southern blot analysis is usefull for the diagnosis of KSS or CPEO.     

Lesch-Nyhan syndrome: a study of motor behavior and cerebrospinal fluid neurotransmitters

We studied 5 boys, 2 to 10 years old, with marked or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase and Lesch-Nyhan syndrome with varying degrees of mental retardation, dysarthria, chorea, dystonia, spasticity, and ataxia. Four patients had marked reduction of homovanillic acid in the cerebrospinal fluid (CSF) and all showed low CSF 3-methoxy-4-hydroxy phenylethylene glycol, indicating reduced dopamine and norepinephrine turnover. Three patients showed high CSF 5-hydroxyindoleacetic acid, suggesting increased serotonin turnover. Some patients improved with carbidopa-levodopa, but others benefited from tetrabenazine, a monoamine-depleting agent. This study provides support for the theory of abnormal central monoamine metabolism in Lesch-Nyhan syndrome.     

Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial

Riboflavin, which improves energy metabolism similarly to coenzyme Q10 (CoQ10), is effective in migraine prophylaxis. We compared CoQ10 (3 x 100 mg/day) and placebo in 42 migraine patients in a double-blind, randomized, placebo-controlled trial. CoQ10 was superior to placebo for attack-frequency, headache-days and days-with-nausea in the third treatment month and well tolerated; 50%-responder-rate for attack frequency was 14.4% for placebo and 47.6% for CoQ10 (number-needed-to-treat: 3). CoQ10 is efficacious and well tolerated.     

Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome.

Localized proton magnetic resonance spectroscopy (MRS) was performed to study the metabolic changes in the brain of a patient with Leigh syndrome, who had a T-->G point mutation at nt 8993 of mitochondrial DNA. In this patient, sodium dichloroacetate therapy normalized the lactate and pyruvate levels in both blood and cerebrospinal fluid (CSF). However, his psychomotor retardation did not improve and magnetic resonance imaging showed progressive cerebral atrophy. In the patient's spectra, elevation of brain lactate was observed throughout the brain with regional variations, predominantly in the basal ganglia and brainstem with an abnormal MRI appearance. Although the lactate/creatine ratio observed on proton-MRS was related to the CSF lactate level, the ratio did not completely parallel the CSF lactate level, i.e. brain lactate was detected even when the CSF lactate level had become normalized. Furthermore, proton-MRS revealed a decrease in the N-acetylaspartate/creatine ratio and an increase in the choline/creatine ratio, representing neuronal loss and breakdown of membrane phospholipids. The clinical and MRI findings were well related to the changes in spectroscopically determined brain metabolites. These results indicate that the brain metabolites observed on proton-MRS are useful indicators of a response to therapy and prognosis in Leigh syndrome.     

Intracerebral microdialysis and CSF hydrodynamics in idiopathic adult hydrocephalus syndrome

BACKGROUND: In idiopathic adult hydrocephalus syndrome (IAHS), a pathophysiological model of "chronic ischaemia" caused by an arteriosclerotic process in association with a CSF hydrodynamic disturbance has been proposed. OBJECTIVE: To investigate whether CSF hydrodynamic manipulation has an impact on biochemical markers related to ischaemia, brain tissue oxygen tension (PtiO(2)), and intracranial pressure. METHODS: A microdialysis catheter, a PtiO(2) probe, and an intracerebral pressure catheter were inserted into the periventricular white matter 0-7 mm from the right frontal horn in 10 patients with IAHS. A subcutaneous microdialysis probe was used as reference. Intracranial pressure and intracerebral PtiO(2) were recorded continuously. Samples were collected for analysis between 2 and 4 pm on day 1 (baseline) and at the same time on day 2, two to four hours after a lumbar CSF hydrodynamic manipulation. The concentrations of glucose, lactate, pyruvate, and glutamate on day 1 and 2 were compared. RESULTS: After CSF drainage, there was a significant rise in the intracerebral concentration of lactate and pyruvate. The lactate to pyruvate ratio was increased and remained unchanged after drainage. There was a trend towards a lowering of glucose and glutamate. Mean intracerebral PtiO(2) was higher on day 2 than on day 1 in six of eight patients. CONCLUSIONS: There is increased glucose metabolism after CSF drainage, as expected in a situation of postischaemic recovery. These new invasive techniques are promising tools in the future study of the pathophysiological processes in IAHS.