Mitochondrial and Inherited Genetic Diseases

MEDLINE EXPRESS (R) 10/97-11/97 2 of 45
TI: Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects.
AU: Shults-CW; Haas-RH; Passov-D; Beal-MF
SO: Ann-Neurol. 1997 Aug; 42(2): 261-4
AB: The activities of complex I and complex II/III in platelet mitochondria are reduced in patients with early, untreated Parkinson's disease. Coenzyme Q10 is the electron acceptor for complex I and complex II. We found that the level of coenzyme Q10 was significantly lower in mitochondria from parkinsonian patients than in mitochondria from age- and sex-matched control subjects and that the levels of coenzyme Q10 and the activities of complex I and complex II/III were significantly correlated.

MEDLINE EXPRESS (R) 10/97-11/97 7 of 45
TI: Coenzyme Q10 treatment in mitochondrial encephalomyopathies. Short-term double-blind, crossover study.
AU: Chen-RS; Huang-CC; Chu-NS
SO: Eur-Neurol. 1997; 37(4): 212-8
AB: We report a short-term double-blind, crossover study of CoQ10 in 8 patients with mitochondrial encephalomyopathies. Four patients had myoclonus epilepsy with ragged-red fibers syndrome, 3 had mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome, and 1 had chronic progressive external ophthalmoplegia with myopathy. A trend of effectiveness of CoQ10 in several parameters was noted. Fatigability of daily activities was alleviated. The endurance to muscle exercise was augmented. Global muscle strength scored by Medical Research Council scale was increased. The extent of elevation in serum lactate and pyruvate levels after exercise was decreased. However, only the global MRC index score had a statistical significance (p  MEDLINE EXPRESS (R) 10/97-11/97 8 of 45

TI: Brain and skeletal muscle bioenergetic failure in familial hypobetalipoproteinaemia.
AU: Lodi-R; Rinaldi-R; Gaddi-A; Iotti-S; D'Alessandro-R; Scoz-N; Battino-M;  Carelli-V; Azzimondi-G; Zaniol-P; Barbiroli-B
SO: J-Neurol-Neurosurg-Psychiatry. 1997 Jun; 62(6): 574-80
AB: OBJECTIVE: To determine whether a multisystemic bioenergetic deficit is an underlying feature of familial hypobetalipoproteinaemia. METHODS: Brain and skeletal muscle bioenergetics were studied by in vivo phosphorus MR spectroscopy (31P-MRS) in two neurologically affected members (mother and son) and in one asymptomatic member (daughter) of a kindred with familial  hypobetalipoproteinaemia. Plasma concentrations of vitamin E and coenzyme Q10 (CoQ10) were also assessed. RESULTS: Brain 31P-MRS disclosed in all patients a reduced phosphocreatine (PCr) concentration whereas the calculated ADP concentration was increased. Brain phosphorylation potential was reduced in the members by about 40%. Skeletal muscle was studied at rest in the three members and during aerobic exercise and recovery in the son and daughter. Only the mother showed an impaired mitochondrial function at rest. Both son and daughter showed an increased end exercise ADP concentration whereas the rates of postexercise recovery of PCr and ADP were slow in the daughter. The rate of inorganic phosphate recovery was reduced in both cases. Plasma concentration of vitamin E and CoQ10 was below the normal range in all members. CONCLUSIONS: Structural changes in mitochondrial membranes and deficit of vitamin E together with reduced availability of CoQ10 can be responsible for the multisystemic bioenergetic deficit. Present findings suggest that CoQ10 supplementation may be important in familial hypobetalipoproteinaemia.

MEDLINE EXPRESS (R) 1/97-9/97 17 of 45

TI: Mitochondrial encephalomyopathy with coenzyme Q10 deficiency.
AU: Sobreira-C; Hirano-M; Shanske-S; Keller-RK; Haller-RG; Davidson-E; Santorelli-FM; Miranda-AF; Bonilla-E; Mojon-DS; Barreira-AA; King-MP; DiMauro-S
SO: Neurology. 1997 May; 48(5): 1238-43
AB: 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.

MEDLINE EXPRESS (R) 1/97-9/97 28 of 45

TI: Energy metabolism defects in Huntington's  disease and effects of coenzyme Q10.
AU: Koroshetz-WJ; Jenkins-BG; Rosen-BR; Beal-MF
SO: Ann-Neurol. 1997 Feb; 41(2): 160-5
AB: We investigated whether the Huntington's disease (HD) gene mutation may produce either primary or secondary effects on energy metabolism. 31P magnetic resonance spectroscopy demonstrated a significant decrease in the phosphocreatine to inorganic phosphate ratio in resting muscle of 8 patients as compared with 8 control subjects. The cerebrospinal fluid  lactate-pyruvate ratio was significantly increased in 15 patients as compared with 13 control subjects. Lactate concentrations assessed using 1H magnetic resonance spectroscopy are increased in Huntington's disease cerebral cortex. Treatment with coenzyme Q10, an essential cofactor of the electron transport chain, resulted in significant decreases in cortical lactate concentrations in 18 patients, which reversed following withdrawal of therapy. These findings provide evidence for a  generalized energy defect in Huntington's disease, and suggest a possible therapy.

MEDLINE EXPRESS (R) 1/97-9/97 44 of 45

TI: [Benign infantile mitochondrial myopathy caused by reversible cytochrome c oxidase deficiency]
AU: Wada-H; Nishio-H; Nagaki-S; Yanagawa-H; Imamura-A; Yokoyama-S; Sano-T; Woo-M; Matsuo-M; Itoh-H; Nakamura-H
SO: No-To-Hattatsu. 1996 Sep; 28(5): 443-7
AB: A 2-month-old girl had generalized weakness, profound muscular hypotonia,  hepatomegaly and severe lactic acidosis. She needed ventilatory support. Muscle specimen taken at 2 months showed ragged-red fibers, abnormal mitochondria, and reduced cytochrome c oxidase (CCO) staining Biochemical analysis showed CCO activity to be reduced to about 16% of the normal mean. She received carnitine and coenzyme Q10 supplementation from the age of 3 months and abnormal blood lactate values declined to near normal values during the first three weeks. Gradually her condition  started to improved: she held her head at 9 months, and walked alone at 15 months. The second biopsy specimen at 3 years and 8 months showed almost normal CCO staining and she was free of clinical signs. This case is an example of a rare benign infantile mitochondrial myopathy caused by CCO deficiency. Early diagnosis is crucial to provide intensive treatment until spontaneous clinical improvement appears. We concluded that carnitine and coenzyme Q10 supplementation was a useful treatment for clinical improvement in patients with a benign infantile mitochondrial myopathy caused by CCO deficiency.

MEDLINE EXPRESS (R) 1/97-2/97 3 of 40
TI: Assessment of coenzyme Q10 tolerability in Huntington's disease.
AU: Feigin-A; Kieburtz-K; Como-P; Hickey-C; Claude-K; Abwender-D; Zimmerman-C; Steinberg-K; Shoulson-I
SO: Mov-Disord. 1996 May; 11(3): 321-3
AB: We performed a 6-month open-label trial to evaluate the tolerability and efficacy of coenzyme Q10 (CoQ) in 10 patients with Huntington's disease (HD). Subjects were evaluated at baseline, 3 months, and 6 months using the HD Rating Scale (HDRS), the HD Functional Capacity Scale (HDFCS), and standardized neuropsychological measures. Adverse events (AEs) were assessed by telephone interview every month. CoQ doses ranged from 600 to 1,200 mg per day. All subjects completed the study, although four subjects reported mild AEs, including headache, heartburn, fatigue, and increased involuntary movements. There was no significant effect of the treatment on the clinical ratings. The good tolerability of CoQ suggests that it is a good candidate for evaluation in long-term clinical trials designed to slow the progression of HD.

MEDLINE EXPRESS (R) 1/97-2/97 12 of 40
TI: The influence of Coenzyme Q10 on total serum calcium concentration in two patients with Kearns-Sayre Syndrome and hypoparathyroidism.
AU: Papadimitriou-A; Hadjigeorgiou-GM; Divari-R; Papagalanis-N;  Comi-G; Bresolin-N
SO: Neuromuscul-Disord. 1996 Jan; 6(1): 49-53
AB: Two patients with Kearns-Sayre Syndrome and hypoparathyroidism were treated with alfacalcidol (1a-OH D3) and total serum calcium concentration remained within normal range for a long period. After two months of combined therapy with Coenzyme Q10 (CoQ10), hypercalcemia was noticed and as a result, 1a-OHD3 was gradually discontinued. Normal total serum calcium concentration was obtained with CoQ10 monotherapy while the  replacement of CoQ10 with placebo led to hypocalcemia. The mechanism of action of CoQ10 is difficult to explain. Since the parathormone level remained unchanged during CoQ10 or placebo therapy, we speculate that the capacity of producing an active form of vitamin D in mitochondria of proximal tubules was restored by CoQ10 therapy.

MEDLINE EXPRESS (R) 1/96-11/96 1 of 25
TI: Could coenzyme Q10 and L-carnitine be a treatment for diabetes secondary to 3243 mutation of mtDNA?  [letter]
AU: Silvestre-Aillaud-P; BenDahan-D; Paquis-Fluckinger-V; Pouget-J; Pelissier-JF; Desnuelle-C; Cozzone-PJ; Vialettes-B
SO: Diabetologia. 1995 Dec; 38(12): 1485-6

MEDLINE EXPRESS (R) 1/96-11/96 2 of 25
TI: Abnormal evoked potentials of Kearns-Sayre syndrome.
AU: Nakamura-Y; Takahashi-M; Kitaguchi-M; Yorifuji-S; Nishikawa-Y; Imaoka-H; Tarui-S
SO: Electromyogr-Clin-Neurophysiol. 1995 Oct; 35(6): 365-70
AB: We examined eight patients with  Kearns-Sayre syndrome (KSS) to investigate a dysfunction in the central nervous system (CNS) using PTN-SEP, MN-SEP and BAEP. We found a significant increase in the P37 latency of PTN-SEPs and the central conduction time of MN-SEPs, and interpeak latencies of BAEPs. Delayed SEPs or BAEPs were caused by a dysfunction of the somatosensory or lateral lemniscus pathways which could be related to mitochondrial abnormalities in the CNS. Long-term therapy with CoQ showed an improvement of the  latencies of SEPs after about half a year from the start of CoQ therapy in our patients. The improvement of the latencies of SEPs were preserved during CoQ therapy. It could be demonstrated that CoQ therapy had the beneficial effects on abnormal functions of the CNS in patients with KSS.

MEDLINE EXPRESS (R) 1/96-10/96 7 of 469
TI: Insulin edema in diabetes mellitus associated with the 3243 mitochondrial tRNA(Leu(UUR)) mutation; case reports.
AU: Suzuki-Y; Kadowaki-H;  Taniyama-M; Kadowaki-T; Katagiri-H; Oka-Y; Atsumi-Y; Hosokawa-K; Tanaka-Y; Asahina-T; et-al
SO: Diabetes-Res-Clin-Pract. 1995 Aug; 29(2): 137-42
AB: We encountered a patient with diabetes mellitus due to the 3243 mitochondrial tRNA mutation(DM-Mt3243), who developed insulin edema and hepatic dysfunction after starting insulin. Such a rare phenomenon was unlikely to be a fortuitous coincidence in mitochondrial diabetes, as none in 197 non-mutant NIDDM patients had same episode. Moreover,  similar leg edema was noticed in another DM-Mt3243 patient, and other two DM-Mt3243 patients had leg edema which responded to coenzyme Q10. These observations suggest further a role of mitochondrial function on leg edema. The mechanism of his insulin edema may involve vasomotor changes induced by the rapidly glycemic control, because our case of insulin edema had a prominent increase of strong succinate dehydrogenase reactive vessels. Alternatively, myocardial dysfunction might have produced leg edema and hepatic dysfunction, because he had subclinical myocardial dysfunction, judged by imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid. The third explanation is that a rapid improvement of glycemic control might have induced hepatic reoxygenation and the production of reactive oxygen species in the liver that contributed to cell damage. Thus, although we cannot draw definite conclusion, our experiences here suggest that mitochondrial dysfunction is important in the etiology of insulin edema.

MEDLINE EXPRESS (R) 1991-1995 24 of 469
TI: A case of diabetic amyotrophy associated with 3243 mitochondrial tRNA(leu; UUR) mutation and successful therapy with coenzyme Q10.
AU: Suzuki-Y; Kadowaki-H; Atsumi-Y; Hosokawa-K; Katagiri-H; Kadowaki-T; Oka-Y; Uyama-K; Mokubo-A; Asahina-T; et-al
SO: Endocr-J. 1995 Apr; 42(2): 141-5
AB: We report the case of 71-year-old male who was once diagnosed as having diabetic amyotrophy, because of pronounced wasting in proximal muscles, massive weight loss, and development of paresthesia in his legs. Afterwards, ragged red fibers and mitochondrial tRNA mutation at position 3243 were documented in muscle biopsy. He had diabetes mellitus associated with 3243 mitochondrial DNA mutation, suggesting that clinically, diabetic amyotrophy may be overlapped with mitochondria-related disease entities in some parts. Coenzyme Q10 administration was effective in relieving the symptoms in his legs,  fatigue, and residual urine in his bladder. These were confirmed with the improvement in neurological parameters. In conclusion, this case gives important help in understanding myopathy in diabetes. It would be important to check on the 3243 mitochondrial tRNA mutation in patients with diabetic amyotrophy and/or diabetic neuropathic symptoms.

MEDLINE EXPRESS (R) 1991-1995 32 of 469
TI: Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies.
AU: Folkers-K; Simonsen-R
SO: Biochim-Biophys-Acta. 1995 May 24; 1271(1): 281-6
AB: Coenzyme Q10 (vitamin Q10) is biosynthesized in the human body and is functional in bioenergetics, anti-oxidation reactions, and in growth control, etc. It is indispensable to health and survival. The first double-blind trial was with twelve patients, ranging from 7-69 years of age, having diseases including the Duchenne, Becker, and the limb-girdle  dystrophies, myotonic dystrophy. Charcot-Marie-Tooth disease, and the Welander disease. The control coenzyme Q10 (CoQ10) blood level was low and ranged from 0.5-0.84 microgram/ml. They were treated for three months with 100 mg daily of CoQ10 and a matching placebo. The second double-blind trial was similar with fifteen patients having the same categories of disease. Since cardiac disease is established to be associated with these muscle diseases, cardiac function was blindly monitored, and not one mistake was made in assigning CoQ10 and placebo to the patients in both trials. Definitely improved physical performance was recorded. In retrospect, a dosage of 100 mg was too low although effective and safe. Patients suffering from these muscle dystrophies and the like, should be treated with vitamin Q10 indefinitely.

MEDLINE EXPRESS (R) 1991-1995 33 of 469
TI: The treatment of mitochondrial myopathies and encephalomyopathies.
AU: Peterson-PL
SO: Biochim-Biophys-Acta. 1995 May 24; 1271(1): 275-80
AB: This paper briefly summarizes the results of a long-term, open pharmacotherapy trial in 16 patients with well-characterized mitochondrial disease. Outcome measures included repeated clinical evaluation, 31P-NMR spectroscopy and near-infrared spectroscopy. Treated patients appeared to survive longer with less functional disability and medical complications than typically seen in clinical practice.

MEDLINE EXPRESS (R) 1991-1995 34 of 469
TI: The universality of bioenergetic disease and amelioration with redox therapy.
AU: Linnane-AW; Degli-Esposti-M; Generowicz-M; Luff-AR; Nagley-P
SO: Biochim-Biophys-Acta. 1995 May 24; 1271(1): 191-4
AB: Overt mitochondrial diseases associated with mitochondrial DNA mutations are characterized by a decline in mitochondrial respiratory function. Similarly, a progressive decline in mitochondrial respiratory function associated with  mitochondrial DNA mutations is clearly evidenced in aged human subjects. This communication is concerned with the development of a rat model for the study of bioenergy decline associated with the ageing process and overt mitochondrial diseases. The model involves the treatment of young rats with AZT to induce skeletal and cardiac myopathies. It has shown that there is a decline in soleus muscle function in vivo and that this decline is mirrored in the capacity of heart sub-mitochondrial  particles to maintain bioenergy function. Coenzyme Q10 and several analogs were administered with AZT as potential therapeutics for the re-energization of affected tissues. Coenzyme Q10 and especially decyl Q were found to be therapeutically beneficial by both in vivo improvement in soleus muscle function and in vitro cardiac mitochondrial membrane potential capacity. Sub-mitochondrial particles were also prepared from heart mitochondria of young and aged rats. The particles prepared from the  aged rats were found to have a decreased ability to maintain membrane potential as compared to those derived from the young rats.

MEDLINE EXPRESS (R) 1991-1995 39 of 469
TI: [Genetic diagnosis of diabetes mellitus]
AU: Suzuki-S
SO: Rinsho-Byori. 1995 May; 43(5): 463-7
AB: NIDDM is likely to have a major genetic component in view of the different prevalence between ethnic groups, the familial clustering, and the high concordance in monozygotic twins. Linkage  analysis of extended pedigrees of patients with maturity-onset diabetes of the young (MODY) identified the glucokinase gene mutations. Specific phenotypes have also led to the discovery of the insulin gene mutations in patients with high insulin or proinsulin levels, to the insulin receptor mutations in patients with marked insulin resistance, and to the mutations in mitochondrial DNA associated with deafness and maternal inheritance. These four types of diabetogenic gene mutations account for only a minor proportion of NIDDM. Direct screening for mutations in candidate genes with single-strand conformation polymorphism or heteroduplex screening or with direct sequencing in the diabetic patients with the appropriate pathophysiological abnormality can be a successful strategy. Genetic diagnosis provides clear definite diagnosis and specific therapies, such as IGF-1 for the insulin receptor mutations and coenzyme Q10 for the mitochondrial gene mutations.

MEDLINE EXPRESS (R) 1991-1995 42 of 469
TI: Free radicals, lipid peroxides and antioxidants in blood of patients with myotonic dystrophy.
AU: Ihara-Y; Mori-A; Hayabara-T; Namba-R; Nobukuni-K; Sato-K; Miyata-S; Edamatsu-R; Liu-J; Kawai-M
SO: J-Neurol. 1995 Feb; 242(3): 119-22
AB: We studied the levels of free radicals, lipid peroxides and antioxidants, as well as superoxide dismutase (SOD) activity in the blood of six patients with myotonic dystrophy (MyD) (mean age 52.8, SD 5.0 years) and seven controls (mean age 48.8, SD 6.3 years). Electron spin resonance was used to assess the free radicals by the spin-trapping method using 5,5-dimethyl-1-pyrroline-1-oxide. The levels of C centre radical (P  MEDLINE EXPRESS (R) 1991-1995 43 of 469
TI: MELAS syndrome: peripheral neuropathy and cytochrome C-oxidase deficiency: a case report and review of the literature.
AU: Barak-Y; Arnon-S; Wolach-B; Raz-Y; Ashkenasi-A; Glick-B; Shapira-Y
SO: Isr-J-Med-Sci. 1995 Apr; 31(4): 224-9
AB: A 4-year-old boy presented with developmental delay, aggressive behavior, and incoordination. His EEG showed a diffuse encephalopathy. At age 10 he developed convulsions and severe migraine-like headaches. Muscle wasting, arreflexia, and lactic acidemia following exercise were noted. Electromyography was myopathic and nerve conduction studies revealed a peripheral neuropathy. Muscle biopsy demonstrated variation in fiber size and an excess of lipid droplets. He than had several stroke-like episodes and periods of unconsciousness, associated with severe metabolic acidosis. Muscle cytochrome C oxidase was abnormally low. This boy displayed the classical clinical and biochemical features of MELAS syndrome, namely Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes. Treatment included carnitine, vitamin C, vitamin K, riboflavin, coenzyme Q10, and corticosteroids. He died at the age of 14 years following  an episode of seizures, coma, and gastrointestinal hemorrhage. This is the first reported case of MELAS syndrome in Israel.

MEDLINE EXPRESS (R) 1991-1995 50 of 469
TI: [Mitochondrial encephalopathies with late disclosure and predominant involvement of central nervous system]
AU: Drouet-A; Pellissier-JF; Desnuelle-C; Valance-J
SO: Rev-Neurol-Paris. 1994 Oct; 150(10): 689-99
AB: We report three cases of mitochondrial encephalomyopathy affecting predominantly the  central nervous system; two patients had the MELAS syndrome and one had "ophthalmoplegia plus". Histoenzymatic analysis of muscle biopsy and biochemical studies of muscle mitochondria demonstrated myopathy associated with partial deficiency of complex I of the electron transfer chain in three cases, complex IV in two cases and complex III in one case. Molecular analysis of mtDNA in the first case did not revealed any abnormality. Coenzyme Q10 therapy improved exercise tolerance but  not the central nervous signs.

MEDLINE EXPRESS (R) 1991-1995 79 of 469
TI: [Redox therapy in mitochondrial diseases using coenzyme Q10]
AU: Gvozdjakova-A; Kucharska-J; Gvozdjak-J
SO: Bratisl-Lek-Listy. 1994 Oct; 95(10): 443-51
AB: BACKGROUND: The biochemical and genetic analysis served as the basis for the definition of the following mitochondrial diseases (mt diseases) and the diseases of the mitochondrial deoxyribonucleic acid (mtDNA diseases): mitochondrial  myopathy, encephalomyopathy, and cardiomyopathy. The therapy of mitochondrial diseases (in both practice and experiment) belongs to the current trends of research. AIM: The study does not present any new experimental results but in their literary review the authors indicate: a) new trend in biochemical studies of mitochondrial diseases, b) some current knowledge on mtDNA diseases, c) the current trend of mitochondrial disease "redox therapy" by CoQ10, d) significance of the therapeutic task of CoQ10 in four experimental models of the myocardial mitochondria impairment (by ageing, smoking, alcohol, ischemia). SIGNIFICANCE FOR PRACTICE AND RESEARCH DEVELOPMENT: The authors indicate a new perspective for the studies of mitochondrial diseases (mt diseases) and the diseases of the mitochondrial deoxyribonucleic acid (mtDNA diseases) and their therapy not only under experimental conditions, but also in the blood and bioptic samples of patients. (Tab. 3, Fig. 2, Ref.  43.)

MEDLINE EXPRESS (R) 1991-1995 80 of 469
TI: Neurochemistry and toxin models in Huntington's disease.
AU: Beal-MF
SO: Curr-Opin-Neurol. 1994 Dec; 7(6): 542-7
AB: Huntington's disease (HD) is a prototypical neurodegenerative disease characterized by selective loss of neurons in the basal ganglia. Although the gene defect has recently been identified, the mechanism by which it leads to neuronal degeneration remains unknown. We have hypothesized that a defect in oxidative phosphorylation may lead to slow, excitotoxic neuronal degeneration in this illness. Evidence for such a defect is reviewed here, including our recent studies using magnetic resonance imaging spectroscopy that show elevated lactate levels in the basal ganglia and cerebral cortex of patients with HD. If a defect in energy metabolism is responsible for neuronal degeneration in HD, it should be possible to mimic the neurodegenerative process with mitochondrial toxins. Our recent  studies with 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase, show that it can produce striking similarities to the neuropathologic and neurochemical features of HD in both rodents and primates. If such a mechanism is indeed relevant to the pathogenesis of HD, then agents that can improve oxidative phosphorylation might prove to be efficacious. We found that both coenzyme Q10 and nicotinamide can ameliorate striatal lesions produced by mitochondrial toxins in vivo.  Furthermore, they reduced elevated lactate concentrations when administered to patients with HD. This finding raises the possibility that such an approach might prove useful in trying to slow the neurodegenerative process.

MEDLINE EXPRESS (R) 1991-1995 81 of 469
TI: Improvement of Kearns-Sayre syndrome with controlled carbohydrate intake and coenzyme Q10 therapy [letter; comment]
AU: Berio-A; Piazzi-A
SO: Ophthalmologica. 1994; 208(6): 342-3

MEDLINE EXPRESS (R) 1991-1995 82 of 469
TI: Benign mitochondrial myopathy with decreased succinate cytochrome C reductase activity.
AU: Arpa-J; Campos-Y; Gutierrez-Molina-M; Cruz-Martinez-A; Arenas-J; Caminero-AB; Palomo-F; Morales-C; Barreiro-P
SO: Acta-Neurol-Scand. 1994 Oct; 90(4): 281-4
AB: In most of the cases previously described, the defect on complex II was suggested by low activity of succinate cytochrome C reductase (SCCR). The clinical pattern of the previous 10  cases is heterogeneous and may be limited to one particular tissue or be of a more general nature. We report a 22-year-old-woman, daughter of consanguineous parents, with generalized muscle weakness, easy fatigability and benign course, who showed a decrease of SCCR activity in mitochondria of muscle fibers. Free carnitine (FC) concentration was decreased in muscle as well. The muscle biopsy showed a mild variation in fiber size, with fiber type I predominance, subsarcolemmal oxidative DPNH  accumulations, excess of neutral lipids and abnormally large mitochondria with paracrystalline inclusions. A possible inheritance pattern is discussed. Coenzyme Q10 therapy in this patient induced a significant increase of global MRC index score and a decrease of the turns-mean amplitude ratio in the automatic analysis of the EMG.

MEDLINE EXPRESS (R) 1991-1995 84 of 469
TI: [Circulating levels of CoQ10 in hypo- and hyperthyroidism]
 AU: Pandolfi-C; Ferrari-D; Stanic-I; Pellegrini-L
SO: Minerva-Endocrinol. 1994 Sep; 19(3): 139-42
AB: Coenzyme Q10 (CoQ10) plays an essential physiologic role in oxidative phosphorylation and its plasma and tissue concentration has been evaluated in various pathologic conditions, both endocrine and non endocrine; among the latter particularly in cardiac failure. Plasma CoQ10 determination has been reported in the literature an a useful diagnostic tool in differential diagnosis of  thyroid diseases. In the present study we have evaluated CoQ10 circulating levels both in hypo- and hyperthyroidism. For this purpose plasma CoQ10, fT3-fT4 and TSH concentrations have been determined (HPLC, RIA and IRMA respectively) in a group of hypothyroid patients, hyperthyroid and control subjects. No patient was harbouring cardiovascular, metabolic or systemic disease. CoQ10 has resulted 0.97 +/- 0.46 mcg/ml in the hypothyroid group, 0.51 +/- 0.35 in hyperthyroid and 0.73 +/- 0.16 in  control group, with a significative difference between first and second group only; more, the prevalence of high levels has appeared greater in hypo- towards hyperthyroid patients and that of low levels in the latter greater than in the former. Finally an inverse relation of CoQ10 with fT3 and tT3, but not with fT4 and tT4, has been shown. In conclusion, plasma CoQ10 levels have not given in this study a sharp distinction between euthyroidism on a side and hypo- and hyperthyroidism on the  other, but necessity of longitudinal studies after therapy is outlined, both to know time of normalization of plasma concentrations and to verify the opportunity of exogenous administration of CoQ10 in hyperthyroid patients with risk factors for heart failure.

MEDLINE EXPRESS (R) 1991-1995 90 of 469
TI: [Free radical, lipid peroxide and antioxidant in mitochondrial encephalomyopathy]
AU: Ihara-Y; Hayabara-T; Namba-R; Nobukuni-K; Mori-A
SO: Rinsho-Shinkeigaku. 1994 Jun; 34(6): 593-5
AB: We studied free radical, lipid peroxide (LPO) and antioxidant levels of blood in three cases with mitochondrial encephalomyopathy. Case 1 was a 17-year-old man with MELAS. Serum vitamin E levels were decreased and LPO levels were increased after stroke-like episodes in case 1. Case 2 was a 68-year-old woman with MELAS and a maternal elder aunt of case 1. She showed an elevated serum LPO levels (6.58 nmol/ml) in the absence of stroke-like episode and serum CoQ10 level was 0.54 microgram/ml before therapy. By CoQ10, idebenone and tocopherol nicotinate therapy, serum LPO levels decreased gradually in parallel with the decrease of lactate and pyruvate levels. Free radicals were measured in case 2 and controls by spin trapping method. Hydroxyl radical and C center radical were increased and H radical was normal in blood. But these free radicals in serum were all normal. Her serum antioxidants revealed an elevated percent  inhibition of SOD and a decreased transfferin level. Case 3 was a 52-year-old woman with MERRF. She showed an elevation of serum LPO (12.8 nmol/ml). Her serum antioxidants revealed an elevated vitamin E and ceruloplasmin levels and percent inhibition of SOD.

MEDLINE EXPRESS (R) 1991-1995 119 of 469
TI: [Anesthesia and intensive therapy for a patient with mitochondrial myopathy]
AU: Breucking-E; Mortier-W; Lampert-R; Brandt-L
SO: Anaesthesist. 1993 Oct; 42(10): 719-23
AB: Since 1983 we have been involved in the diagnostic work-up and emergency treatment of a female patient now 48 years old who has a mitochondrial myopathy resembling Luft's disease. The syndrome was first described in 1959, and in more detail in 1962, by Luft and et al., who reported a picture of hypermetabolism with high temperature, extreme sweating, tachycardia, dyspnoea at rest, polydipsia, polyphagia and irritability but normal thyroid function. In 1971 and 1976 Haydar and Di Mauro presented a second case and proposed treatment with chloramphenicol. Our patient has the third case of the syndrome reported so far: her case was initially published in 1987. CASE REPORT. Since her 17th year of life the patient had suffered from episodes of fever, tachycardia and sweating. At the age of 32 these attacks worsened, leading to unconsciousness and apnoea. The patient then had to be intubated, ventilated and sometimes resuscitated.  The diagnosis of MH susceptibility and Luft's disease was made on biochemical grounds after the first muscle biopsy in 1983. Therapy with chloramphenicol failed. Therapy with beta blockers, vitamin C and K or E, coenzyme Q10 and a high-caloric diet was started in 1985. The patient was registered with an emergency service, which flew her to our ICU whenever she had a severe crisis. For milder episodes she was supplied with an oxygen breathing mask at home. Myalgia increased with the episodes starting in 1988, and the patient needed dantrolene infusions and analgesics at home. To facilitate venepuncture a Port-A-Cath system was implanted in 1987, which had to be removed four times due to infection and sepsis. A muscle biopsy was taken in Rotterdam, which revealed differences in mitochondrial function from the biochemical findings recorded in 1983 and not in keeping with Luft's disease. Unfortunately, the patient was not able to undergo further metabolic investigations or  therapeutic trials. ANAESTHESIA. The patient received three local and six general anaesthetics in our clinic. The muscle biopsies, two in 1983 and one in 1985, were performed under local infiltration with procaine and were uneventful. The general anaesthetics were carried out without MH trigger substances following pretreatment with dantrolene for the following surgical procedures: the repair of an extensive arterio-venous fistula between the brachiocephalicus trunk and the right jugular and  subclavian vein, revision of the sternum cerclage, implantations and explanations of infectious Port-A-Cath systems. We used etomidate, propofol and fentanyl or alfentanil with nitrous oxide and oxygen for induction and maintenance of anaesthesia. Muscle relaxation was induced with vecuronium or atracurium. All cardiovascular, respiratory, metabolic and temperature measurements stayed in normal ranges. After the extensive vascular repair (av fistula) the patient had to be mechanically  ventilated for some hours until normal body temperature was restored. At the end of all other periods of anaesthesia she was extubated in the operating theatre. In five cases the postoperative period was uneventful. Only once she developed a crisis with hyperthermia, tachycardia, sweating and dyspnoea. INTENSIVE CARE. From 1985 to 1992 the patient was treated in our ICU 21 times. On 11 occasions she was already intubated and being ventilated by the emergency service on arrival. Extubation was usually possible within 2-20 h. During the crisis, heart rate was about 160-190 per minute and temperature above 40 degrees C. Serum values of CK, glucose, BUN, electrolytes, lactate and thyroid hormones were always in the normal ranges. Blood gas controls showed a constant respiratory alkalosis, arterial pCO2 values decreasing to 20 mm Hg or less. In addition to mechanical ventilation, treatment consisted in dantrolene infusions and droperidol injections, supplemented from 1989 onward with piritramide injections because of the increased severity of myalgia. In 1991 we gave propofol by

MEDLINE EXPRESS (R) 1991-1995 142 of 469
TI: Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease.
AU: Matthews-PM; Ford-B; Dandurand-RJ; Eidelman-DH; O'Connor-D; Sherwin-A; Karpati-G; Andermann-F; Arnold-DL
SO: Neurology. 1993 May; 43(5): 884-90
AB: We followed 16 patients with a variety of mitochondrial diseases over  one to four periods of treatment (2 months each) with coenzyme Q10 plus vitamins K3 and C, riboflavin, thiamine, and niacin, using independent measures of oxidative metabolism to assess efficacy. There were large (> threefold) increases in serum coenzyme Q10 concentrations with treatment, but no measure of oxidative metabolism showed significant improvement with treatment for the group, nor did any individual patient show significant, reproducible, objective clinical improvement. The  results suggest that coenzyme Q10 plus vitamin therapy does not significantly improve mitochondrial oxidative metabolism in patients with mitochondrial disease in general. Any clinical benefit that may follow from short-term administration appears slight.

MEDLINE EXPRESS (R) 1991-1995 149 of 469
TI: Coenzyme Q10, iron, and vitamin B6 in genetically-confirmed Alzheimer's disease [letter] [see comments]
AU: Imagawa-M; Naruse-S; Tsuji-S; Fujioka-A; Yamaguchi-H
SO: Lancet. 1992 Sep 12; 340(8820): 671

MEDLINE EXPRESS (R) 1991-1995 150 of 469
TI: [Ptosis and asthenia manifesting a mitochondrial myopathy]
AU: Disdier-P; Harle-JR; Figarella-Branger-D; Cherif-AA; Desnuelle-C; Weiller-PJ
SO: Rev-Med-Interne. 1992 Sep-Oct; 13(5): 381-3
AB: We report a case of mitochondrial myopathy discovered in a 55-year old woman who was being investigated for the cause of her asthenia. Physical examination showed ptosis of the upper eyelid and proximal muscle deficit. Histological examination of a muscle biopsy disclosed rare fibres with mitochondrial aggregates. Biochemical exploration of muscle tissue revealed a double enzyme deficit involving complexes I and IV of the respiratory chain. Clinical improvement was obtained after the patient was put on coenzyme Q10. We conclude that a diagnosis of mitochondrial myopathy must be considered in patients, including middle-aged adults, presenting with muscular asthenia.

MEDLINE EXPRESS (R) 1991-1995 181 of 469
TI: 31P NMR spectroscopy and ergometer exercise test as evidence for muscle oxidative performance improvement with coenzyme Q in mitochondrial myopathies [see comments]
AU: Bendahan-D; Desnuelle-C; Vanuxem-D; Confort-Gouny-S; Figarella-Branger-D; Pellissier-JF; Kozak-Ribbens-G; Pouget-J; Serratrice-G; Cozzone-PJ
SO: Neurology. 1992 Jun; 42(6): 1203-8
AB: Two patients with mitochondrial encephalomyopathy due to complexes I and IV deficiencies received 150 mg/d of coenzyme Q10 (CoQ). We studied them with a bicycle ergometer exercise test and 31P NMR spectroscopy before and after 10 months of treatment. Before treatment, we observed a low phosphocreatine/inorganic phosphate (PCr/P(i)) resting value along with abnormally high resting lactate concentration. During exercise, there was a pronounced acidosis with delayed kinetics of postexercise recovery for blood lactate, pH, PCr, and PCr/P(i) ratio. Oxygen uptake during exercise was reduced while the lowering of the ventilatory threshold indicated an early activation of glycolysis. After treatment, the bicycle ergometer exercise test indicated a significant improvement with a decrease in resting blood lactate level, an increase in oxygen consumption during exercise, and an increase in the kinetics of lactate disappearance during the recovery period. A shift of the ventilatory threshold to higher workload was present. 31P NMR spectroscopy confirmed the  improvement, showing a significant increase in the PCr/P(i) ratio at rest and in the kinetics of recovery for pH, PCr, and PCr/P(i) ratio following exercise in patient 1. For patient 2, we observed a less pronounced acidosis correlated with a lesser amount of Pi produced during exercise. These observations indicate an improvement of mitochondrial function and a shift from high to low glycolytic activity in both patients consequent to CoQ treatment.

MEDLINE EXPRESS (R) 1991-1995 201 of 469
TI: Multicenter trial with ubidecarenone: treatment of 44 patients with mitochondrial myopathies.
AU: Scarlato-G; Bresolin-N; Moroni-I; Doriguzzi-C; Castelli-E; Comi-G; Angelini-C; Carenzi-A
SO: Rev-Neurol-Paris. 1991; 147(6-7): 542-8
AB: Fourty four patients with mitochondrial myopathies were treated with Ubidecarenone (CoQ10) for six months in an open multicentric trial. No side effects due to the drug administration were observed.  Sixteen patients showing at least 25% decrease of post exercise lactate levels were selected as responders. Responsiveness was apparently not related to CoQ10 level in serum and platelets or to the presence or absence of mtDNA deletions. The responders were further treated for 3 months with CoQ10 or placebo in the second blind part of the trial; no significant differences between the 2 groups were observed. It is not clear why CoQ10 had therapeutic effects in some patients and not in others with the same clinical presentation and biochemical defect, and we failed to identify candidate responders before treatment. At the dosage of CoQ10 used in the study (2 mg/kg/day) the therapy requires long administration time before a response is demonstrable.