Treatment of Mitochondrial Cytopathies

, MD and , Section of Pediatric Neurology, Cleveland Clinic Foundation, Cleveland, Ohio. 

Semin Neurol. 2001;21(3) 

In This Article

Vitamins and Supplements


Coenzyme Q10 (CoQ10), also known as ubiquinone, is a lipid soluble antioxidant that is synthesized from tyrosine and mevalonic acid by animal cells. Multiple vitamins and trace elements are required for its biosynthesis. Ubiquinones are components of all cell membranes, including mitochondrial membranes.

Normal CoQ10 levels are maintained by endogenous synthesis and dietary sources, which include primarily animal products. This compound can also be administered as an exogenous supplement. Normal muscle mitochondria, blood, and fibroblast levels have been established at 1811 ± 99 ng/mg (n = 10), 637 ± 84 ng/mL (n = 8), and 48 ± 1.3 ng/mg (n = 5) respectively.[24] Ubiquinone also exists in a partially reduced form (ubisemiquinone) and a fully reduced form (ubiquinol).

The role of CoQ10 in energy metabolism is well documented. Large amounts of CoQ10 are found in the mitochondrial inner membrane where it acts as a mobile electron carrier. Specifically, CoQ10 shuttles electrons from ETC complex I to complex III and from complex II to complex III. In addition, CoQ10 absorbs free radicals, which are probably generated to the greatest extent at the level of complex I, thereby acting as an antioxidant and preventing propagation of lipid peroxidation. CoQ10 also assists in regenerating active vitamin E from the tocopheroxyl radical.

Deficient CoQ10 occurs in a wide range of human diseases and may occur due to insufficient dietary intake, impaired biosynthesis either due to endogenous causes or exogenous toxins, disproportionate utilization, or any combination of these.

Given its hydrophobic nature and large particle size, oral administration results in inconsistent absorption, requiring oil-based liquid preparations or suspension in oil. Typical dosing begins at 4 mg per kg per day but may require dosages as high as 15 mg per kg per day to achieve clinical efficacy.

CoQ10 is the most widely recognized supplement used in the treatment of mitochondrial cytopathies. Reported beneficial effects have included decrease in serum lactate, improved exercise tolerance, increased muscle strength, and magnetic resonance spectroscopy improvements. As a cellular antioxidant, its role is theoretically important, as free radical production is known to increase in mitochondrial disease.

A number of primarily anecdotal reports suggest a favorable effect of CoQ10 in disorders of energy metabolism. A 17-year-old girl with MELAS had symptoms unresponsive to intravenous betamethasone, oral nicotinamide, oral CoQ10 (150 mg per day), and intravenous cytochrome c. Following initiation of CoQ10 at a dose of 300 mg per day she demonstrated improvement of her ophthalmologic symptoms, increased exercise tolerance, and decreased serum lactate (both before and after exercise).[25] A 19-year-old girl with Kearns-Sayre syndrome and low serum CoQ10 was treated with 120 mg per day of CoQ10. Serum CoQ10 increased to normal with concomitant lowering of fasting and postexercise lactate and improved ocular movements.[26] Seven patients with mitochondrial cytopathy and lactic acidosis were treated with 120 mg per day of CoQ10. Five of the seven patients had low serum CoQ10. Serum lactate following exercise was significantly diminished (P <0.05) in four of the patients. Monthly neurologic exams revealed improved muscle strength in all but one patient. No echocardiographic improvements were noted. There were no reported harmful side effects related to this treatment regimen.[27] Abe et al[28] reported on a patient with MELAS whose CSF lactate and pyruvate decreased, with noted improvement in seizures and myopathy following treatment with CoQ10.

In a double-blinded placebo-controlled crossover trial of CoQ10 at 160 mg per day for 1 month, improved muscle strength and reduced fatigability were observed for those patients whose CoQ10 levels were lower than controls prior to initiation of treatment. Following 3 months of therapy, there was a statistically significant increase in overall muscle strength testing (P <0.05) but strength of specific proximal and distal musculature did not demonstrate significant improvement. The mean serum CoQ10 levels increased to above normal range within 2 months of treatment with no significant change thereafter. These investigators did not find any significant change in the metabolism of lactate while patients were on CoQ10. The global MRC score was the only significant improvement observed in this study.[29]

Chan et al[30] sought to determine clinically valuable metabolic parameters of patients with mitochondrial encephalomyopathies treated with CoQ10 (150 mg per day) under exercise conditions. Nine patients were evaluated with bicycle ergometry prior to, during (3 months), and following treatment for 6 months. At rest, only two patients demonstrated elevated serum lactate levels, whereas, following exercise, seven patients had elevations of the same. In addition, the lactate-to-pyruvate ratio was abnormal at rest in eight patients and in all patients following exercise. At 3 months following onset of therapy, no clear change was noted in these biochemical parameters. At 6 months, however, there was a decrease in the lactate-to-pyruvate ratio at rest and in association with exercise (P <0.05 for male patients, n = 4) in six of the patients.

There are several additional reports of patients who either showed equivocal changes or did not seem to demonstrate improvements while receiving CoQ10. In a multicenter trial, 44 patients with mitochondrial myopathy were treated for 6 months exclusively with CoQ10 at a dose of 2 mg per kg per day. Sixteen of the 44 patients showed a 25% decrease of postexercise lactate levels. All patients demonstrated statistically significant increases in muscle strength. These 16 patients were subsequently studied an additional 3 months in a blinded study of CoQ10 and placebo. Serum lactate levels were not further decreased in this time interval in those treated with CoQ10, although those receiving placebo developed worsening of postexercise lactate. Muscle strength did not improve during the second treatment period. No change was noted in terms of cardiac conduction abnormalities or ophthalmologic findings during the study period of 6 months.[31]

Two patients with mitochondrial myopathies were treated for 1 year with either 100 mg or 50 mg daily of CoQ10. Neither of these patients had abnormal (low) CoQ10 levels. Following 1 year of treatment, neither patient demonstrated improvement of their ophthalmologic symptoms, quantitative isometric strength testing revealed no significant improvement, and CoQ10 levels remained essentially unchanged. It must be noted that the dose of administered CoQ10 in this study is less than is generally used to treat most adults.[32]

Sixteen patients with varied mitochondrial cytopathies were treated with CoQ10 in addition to vitamins K3 and C, riboflavin, thiamine, and niacin. This open study, using 300 mg per day over a 2-month time period, did not show any benefit. The parameters evaluated included resting and postexercise serum lactate, phosphorous magnetic resonance spectroscopy, and regular follow-up of clinical symptoms.[33]

The reliance on clinical and biochemical parameters exclusively in the evaluation of patients with mitochondrial cytopathies who undergo an experimental treatment may not provide an entirely accurate sense of effectiveness of therapy. [31] P magnetic resonance spectroscopy can be utilized to evaluate energy parameters in the specific tissue of interest, providing a noninvasive, quantitative measure of brain and/or muscle metabolism. In the presence of disordered mitochondrial metabolism one might expect to see a low concentration of phosphocreatine, a high concentration of inorganic phosphate, and a high calculated ADP.[34] Muscle can be evaluated at rest, during exercise, and during immediate postexercise recovery. In disorders of mitochondrial respiration, a decrease in the phosphocreatine/inorganic phosphate (PCr/Pi) ratio can be observed at rest. There is delayed replenishment of phosphocreatine following exercise. In some patients with mitochondrial cytopathy there may be no abnormality on 31P MRS, likely indicating that skeletal muscle mitochondria are not involved.[35] Again, with utilization of this technique, conflicting reports exist as to the effectiveness of CoQ10 therapy.

Eight patients and 18 healthy controls were treated with 150 mg of CoQ10 per day for 6 months and evaluated by 31P MRS of the calf muscle at rest, during exercise, and during the postexercise recovery period. MRS was performed at the beginning of treatment and following 3 and 6 months of therapy. The mean PCr/Pi was significantly higher for controls prior to treatment and did not significantly change throughout the supplementation period. By 3 months of treatment, there was a nonsignificant repletion of phosphocreatine in the patient population. One patient had a dramatic improvement of the PCr/Pi at rest in addition to increased repletion of phosphocreatine postexercise following 3 months of treatment.[36]

Barbiroli et al[37] utilized in vivo phosphorous magnetic resonance spectroscopy to evaluate the effectiveness of CoQ10 on improving brain and skeletal muscle mitochondrial respiration. Ten patients with mitochondrial cytopathies were evaluated by 31P MRS prior to and 6 months following treatment with 150 mg per day of CoQ10. There were 36 age-matched, healthy controls. Prior to treatment all patients demonstrated low concentrations of phosphocreatine and high ADP, indicative of mitochondrial dysfunction. There was a significant increased (P <0.02) brain concentration of phosphocreatine following treatment with CoQ10, in addition to a significant decrease (P <0.01) of brain concentration of inorganic phosphorous. With regards to the skeletal muscle evaluation, the 31P MRS spectra were not significantly different at rest either prior to or following treatment when compared with controls. Despite this, all patients did demonstrate a faster recovery of phosphocreatine following treatment and some (those with CPEO) reported increased strength.

Two patients with mitochondrial encephalomyopathy were treated with 150 mg per day of CoQ10 and evaluated by bicycle ergometry and 31P nuclear magnetic resonance (NMR) spectroscopy prior to and 10 months after initiation of treatment. In both patients before treatment there was a low PCr/Pi at rest, in addition to a high resting serum lactate. Acidosis occurred during the exercise phase, followed by a delay in recovery after exercise. Furthermore, the bicycle ergometer test revealed a lowering of the ventilatory threshold as well as reduction of the maximum oxygen uptake. Pretreatment 31P NMR spectroscopy demonstrated the following abnormalities: twofold decrease of ATP concentration and abnormally low PCr/Pi ratio. Following 10 months of treatment, there was significant improvement during the exercise test along with a decrease in resting lactate, increase in oxygen consumption, increase in maximal load, and ventilatory threshold reached normal range. 31P NMR spectroscopy (performed on flexor digitorum superficialis muscle) corroborated these findings in that there was a significant increase from the baseline PCr/Pi ratio at rest in addition to improved recovery of all measured parameters. The decreased ATP concentration was still present, thought to a lesser degree. The postexercise PCr/Pi ratio was essentially unchanged for one patient but demonstrated a fourfold increase for the second patient. These results lend support to the efficacy of high-dose administration of CoQ10.[38]

The literature suggests significant controversy regarding the efficacy of CoQ10 supplementation. Regardless, many patients report improved function, and the side effects associated with its use are rare. The majority of treating clinicians will administer a therapeutic trial in escalating doses (4 to 15 mg per kg per day) to determine its efficacy in an individual patient.

Idebenone is an analog of CoQ10 and acts both as a free radical scavenger as well as stimulating ATP formation by functioning as a mobile electron carrier. It is currently not available in the United States.

A patient with LHON and myopathy was treated with oral idebenone (45 mg three times per day with increase by 135 mg per day every 2 days) following the onset of marked spasticity and weakness. By the sixth day of treatment (135 mg three times per day), the patient was able to walk, run, and climb stairs. On neurologic examination, there was marked reduction of spasticity of the lower extremities in addition to improved strength. Following observation of this improvement, idebenone was continued at a maximum of 405 mg per day for an additional 3 months, during which the patient remained clinically stable. Following withdrawal of idebenone, the patient again demonstrated weakness of the lower extremities and spastic paraparesis. Idebenone was reinitiated and within 2 weeks clinical improvement was again observed. This patient was additionally evaluated by brain and muscle 31P MRS. Following approximately 3 months of treatment there was an increase in phosphocreatine concentration and a decrease from baseline of inorganic phosphate toward reference values. When reimaged following withdrawal of idebenone, these parameters were markedly worsened and did not markedly improve following reinstitution of medication. In addition, 3 weeks following initiation of treatment, muscle studies showed an increased rate of recovery of phosphocreatine and inorganic phosphate. Though similar worsening of variables were observed following discontinuation of this medication, once resumed there was no return to the previously observed recovery levels.[39]

A 10-year-old boy with LHON due to homoplasmic 11778 mutation was treated with oral idebenone (90 mg per day) after presenting with early-onset symptoms. After 7 months of treatment, visual acuity was improved slightly (6/90 bilaterally to 6/6).[40] However, spontaneous improvement in visual acuity is frequently reported in LHON.

A patient with MELAS was treated with CoQ10 augmented by the addition of idebenone. Following 8 months of treatment with 210 mg per day of CoQ10, the patient demonstrated some improvement in terms of amelioration of sensory disturbance, ataxia, and muscle weakness. Serum lactate decreased slightly. Electroencephalogram (EEG) and Wechsler Adult Intelligence Scale (WAIS) testing remained unchanged when compared to prior to treatment. Motor and sensory conduction velocities normalized. Following the addition of 90 mg of idebenone, muscle strength improved further. Her EEG revealed marked improvement from baseline and from during treatment with CoQ10 alone. Her WAIS scores increased by 14 points. CSF protein decreased from 64 mg/dL to 45 mg/dL. The idebenone dose was then increased to 180 mg per day for an additional 11 months. CSF lactate decreased. The improvements were maintained for a follow-up time of 20 months.[41]

The experience with idebenone may be too limited to draw any definitive conclusions. Further investigations may elucidate a role for this agent in a subset of patients with mitochondrial disease.

Endogenous levo-carnitine (beta-hydroxy-gamma-trimethylammonium butyrate), found in many human tissues, is an amino acid derivative. It is synthesized in the liver and kidney from protein-bound lysine (supplemental oral lysine cannot improve carnitine synthesis) and methionine. It is a water-soluble compound that exhibits biologic activity only when in the levo isoform. Several enzymes and cofactors (iron, ascorbic acid, niacin, and pyridoxine) are involved in its biosynthesis, and only one matrix mitochondrial enzyme is involved in the pathway. Of note, skeletal and heart muscle are unable to synthesize carnitine, and these tissues are therefore dependent on uptake of carnitine from blood.

Normal plasma and tissue levels are maintained by both de novo synthesis and exogenous dietary sources. Meat and milk products contain the highest concentrations of dietary carnitine whereas plant products are poor sources. Normal plasma carnitine concentrations are about 25 umol/L in infants and 54 umol/L in adults.[42] The highest concentration of carnitine is found in skeletal muscle (98%), although distribution is shared with heart, kidney, liver, and brain.[43]

Carnitine is present in tissues and physiologic fluids as either free carnitine or as the acylcarnitine ester. In normal circumstances, approximately 85 to 90% is present in the free state. The majority of plasma acylcarnitine is represented by acetylcarnitine, which is often nonpathologically elevated in the fasting state. The ratio between acylcarnitine to free carnitine varies with timing of the last meal, composition of that meal, nutritional status, exercise, and disease conditions and is quite sensitive to changes in mitochondrial metabolism. A ratio of 0.25 is considered to be normal, whereas greater than 0.4 is abnormal and is indicative of carnitine insufficiency or insufficient carnitine in light of the metabolic demands.[44]

Carnitine is necessary for transporting long-chain fatty acids across the inner mitochondrial membrane for the process of beta-oxidation. This occurs mainly in skeletal muscle, heart, and liver and is carried out by carnitine palmitoyltransferase I (CPT I), acylcarnitine translocase, and CPT II. A second major task of carnitine is to maintain intracellular homeostasis of acyl-CoA. Carnitine transesterifies the acyl-CoA esters that arise during beta-oxidation through the action of carnitine-acyltransferases. The acylcarnitine can then cross the mitochondrial membrane in exchange for free carnitine, thus allowing for restoration of free CoA within the mitochondria. In addition to these major functions, carnitine may also play some role in altering the physiologic properties of cell membranes, such as membrane stabilization.[45] In the setting of inborn errors of metabolism, carnitine serves to detoxify the poisonous metabolic intermediates by forming a less toxic ester.

A number of pathologic conditions have been associated with abnormal metabolism of carnitine, the most frequent of which is carnitine deficiency. Carnitine deficiency can be defined as a state where the concentration is not adequate to meet the body's normal carnitine requirement. Systemic carnitine deficiency can be primary but may occur in many disease states, including disorders of oxidative phosphorylation, beta-oxidation, organic acidurias, malnutrition, valproate, and zidovudine use and in those receiving total parenteral nutrition without adequate carnitine replacement. Many metabolic disorders lead to elevated levels of acyl-CoA intermediates, which impair the function of adenine nucleotide translocase, the enzyme that exchanges ADP for ATP across the inner mitochondrial membrane. Carnitine forms an ester linkage with the acyl-CoA, forming the relatively nontoxic acylcarnitine, which is excreted in the urine. Elevated levels of acyl-CoA intermediates over time can lead to a secondary carnitine deficiency. Likewise, a carnitine deficiency itself can result in increased toxicity of the accumulated acyl-CoA compounds.

Clinical manifestations of a carnitine-deficient state are varied, including but not limited to cardiomyopathy, acute encephalopathy, myopathy, cognitive delay, central nervous system dysfunction, gastrointestinal dysmotility, and recurrent incidences of metabolic decompensation.

Treatment with levo-carnitine should be considered for any person with a primary or secondary carnitine deficiency. The role of carnitine therapy in mitochondrial disease is threefold. As already discussed, carnitine plays a role in reestablishing homeostasis of acyl groups, a process that is aberrant when mitochondrial dysfunction exists, leading to inhibition of respiratory enzymes. In addition, secondary carnitine deficiency exists in the setting of mitochondrial cytopathies; thus, carnitine replacement is essential. Finally, carnitine may provide improved integrity of the mitochondrial membrane, thus adding to membrane stabilization.[46]

The typical dose of levo-carnitine is 100 mg per kg per day for children and 2 to 4 grams per day for adults in three divided doses. In the nonacute setting, levo-carnitine is available as a liquid or tablet, but it is also available as an intravenous preparation. The intravenous dose is the same as the oral dose. Prior to initiation of carnitine therapy in any patient, plasma and urine carnitine and acylcarnitine profiles should be obtained. The primary adverse effects include diarrhea and nausea, though carnitine is usually well tolerated at typical doses. It should be noted that oral absorption is variable, and as little as 15% of the oral dose may actually be absorbed.

Of 48 patients studied by Campos et al,47 four had both total and free plasma carnitine deficiency (both defined as <30 mmol/L with normals in the low to mid 50s) with carnitine insufficiency (defined as ratio of esterified to free carnitine >0.25 with normal 0.13 ± 0.016), and 17 had isolated carnitine insufficiency. All 21 patients with carnitine deficiency or insufficiency were treated with 50 to 200 mg per kg per day of levo-carnitine. The following improvements were observed following initiation of treatment: 20 of 21 patients with muscle weakness demonstrated subjective improvement in muscle tone, four of eight patients with failure to thrive showed growth acceleration, and eight of eight patients with cardiomyopathy demonstrated improved echocardiographic findings and clinical improvement. The average treatment duration was 11 months (range 1 to 24 months). Plasma carnitine levels 10 days after initiation of treatment were normal or above normal. Many additional reports have demonstrated the beneficial effects of carnitine in the setting of cardiomyopathy due to underlying metabolic etiologies, including mitochondrial abnormalities.

Creatine is an amino acid produced endogenously in the liver from arginine and glycine, and it is also found in meat products. Creatine phosphate is synthesized from creatine and ATP, and it is catalyzed by creatine kinase (CK). Unlike ATP, which the body is unable to store, creatine phosphate can be stored to a limited degree in tissues, allowing for a supply of the high-energy phosphate bond, which can be utilized when needed. The hydration of phosphocreatine to creatine and ATP thereby allows the ATP to be utilized by the tissue. Creatine is found in highest concentrations in skeletal muscle and to lesser degrees in cardiac muscle, smooth muscle, brain, sperm, and kidney.

Intramuscular phosphocreatine may be reduced in patients with mitochondrial cytopathies. Supplemental creatine seems to be most effective at increasing phosphocreatine and creatine in this setting. Harris et al demonstrated that administration of creatine to healthy subjects resulted in a greater effect for those patients whose initial total creatine concentration was low. There were no side effects from supplementation with doses ranging from 70 g to 330 g with maximum treatment time of 21 days.[48]

The rationale for using creatine is to increase the tissue concentrations and possibly increase the ability of muscle (or other organs) to accumulate creatine phosphate. Tarnopolsky et al have shown that creatine monohydrate (at doses of 5 g twice per day for 2 weeks followed by 2 g twice per day for 1 week) improved strength for high-intensity anaerobic and aerobic activities and lean muscle mass in patients with neuromuscular diseases, including those with mitochondrial myopathy. Both trials were based on short-term results, and the long-term beneficial effects of creatine remain to be proven. Regardless, the use of creatine in critical situations seems to be reasonable.[49,50]

In one study of nine healthy men provided with either oral creatine (as creatine monohydrate, 20 g dose) or placebo demonstrated no effect on performance for maximum exercise or on phosphocreatine levels. However, the supplement was only administered over a
3-day period and was in a setting of likely normal muscle creatine levels; therefore, its relevancy to those with mitochondrial disease is not known.[51]

Numerous pharmacologic agents have been used in the treatment of mitochondrial cytopathies, including antioxidants. Antioxidants may improve enzyme function or slow the process of oxidative damage, although the benefit over time is not possible to measure. The more commonly employed antioxidants (and the typical daily dosages) for patients with mitochondrial disease include selenium (50 to 100 mcg), vitamin C (250 to 4000 mg in divided dosages), vitamin E (400 to 1200 IU in divided dosages), and lipoic acid (200 to 600 mg in divided dosages). Given the vast clinical presentation of the mitochondrial cytopathies and the fact that these agents have not systematically been studied in this setting, it is not possible to state that there are proven benefits. Despite this, they are routinely used in patients with these diseases.

Riboflavin (vitamin B2) is a precursor to flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are cofactors of ETC complexes I and II, respectively. Riboflavin has been proposed to act therapeutically by one of several potential mechanisms including inhibition of the breakdown of complex I by providing more resistance to proteolysis or stabilizing the mitochondrial membrane. It has been used with some success in some patients with mitochondrial disease without any apparent side effects.

A 33-year-old patient with MELAS and complex I deficiency was administered a combination of riboflavin (100 mg three times per day) and nicotinamide (1 g four times per day) in a double-blinded, randomized fashion. In conjunction with this treatment, there was cessation of this patient's encephalopathic and myopathic symptoms. The spectroscopic findings were equivocal: resting PCr/Pi did not show any treatment effect, whereas high-energy phosphate recovery deteriorated upon withdrawal of nicotinamide (but not riboflavin). Sural nerve sensory testing revealed a drop in amplitude once therapy was withdrawn with recovery following the reinitiation of treatment (P = 0.00007 right, 0.017 left).[52]

A 10-month-old infant girl with a partial defect of complex I was treated with increasing doses of riboflavin (beginning at 3 mg per kg). It was observed that lactate levels normalized and muscle weakness improved at the maximal dose of 13 mg per kg.[53] Riboflavin was given to five patients with mitochondrial myopathy due to complex I deficiency in dosages ranging from 9 to 60 mg per day. Patients presented with either pure myopathic symptoms or encephalomyopathy. One patient had stabilization of the previously regressive disease and three showed clinical improvement, especially in the myopathic component. There was normalization of complex I activity in three of the patients in addition to improved lactate levels or muscle histopathology.[54] A 13-year-old girl with progressive exercise intolerance, severe lactic acidosis, and complex I deficiency was treated with 100 mg of oral riboflavin daily. There was remarkable and persistent clinical improvement with an increase in exercise tolerance. Exercise parameters (maximal work capacity, O2 uptake, and base excess) also improved.[55] A 6-year-old boy with a defect of complex I and myopathy presenting as slowly progressive weakness was successfully treated with riboflavin and carnitine. Clinically, muscle strength and motor conduction velocities were improved. In addition, the complex I activity and carnitine levels normalized 7 months after the start of treatment.[56] More recently, Ogle et al[57] report on a 21/2-year-old patient with complex I deficiency, mitochondrial DNA mutation, and myopathy and who had persistent response to riboflavin therapy (20 to 25 mg twice daily) over a 3-year period. Despite persistent lactic acidosis, this patient demonstrated improvements in terms of overall muscle strength and endurance.

Riboflavin is not always effective, as demonstrated by the case of a 4-month-old infant with severe congenital lactic acidosis and complex I deficiency, who underwent a trial of riboflavin at a dose of 100 mg daily. The child's serum lactate and ratio to pyruvate remained significantly elevated, and the patient continued to demonstrate features of severe myopathy and cardiomyopathy until his death.[58] Four patients with MELAS in association with complex I deficiency treated with riboflavin, other supplements, and the ketogenic diet did not show improvement.[59] Another large trial of riboflavin in combination with other supplements found no significant therapeutic success.[33]

The results of treatment with riboflavin, with a large variation in doses and treatment duration in this diverse population, are not uniform but demonstrate that those with complex I deficiency and pure myopathy may benefit from supplemental riboflavin, with or without other supplements. Of course, the clinical course of these diseases remains variable such that any improvement observed may not be due to therapeutic interventions.

The PDH complex catalyzes the thiamine-dependent decarboxylation of pyruvate. Thiamine pyrophosphate, the physiologically active form of thiamine, acts as a coenzyme for this decarboxylation. The use of thiamine has been established in the treatment of some forms of PDH deficiency, although its use in disorders involving more distal components of energy metabolism, such as electron transport chain disorders, is not established. There are no reported side effects with administration.

Following treatment over a several week period with thiamine at 300 mg three times per day, three patients with Kearns-Sayre syndrome were found to have normalization of previously abnormal lactate and pyruvate levels. There was some change in overall level of fatigue, but clinical improvement in general was trivial.[60] Another patient, a 23-year-old with mitochondrial myopathy, cardiomyopathy, and lactic acidosis, was treated with thiamine (100 mg two times per day) in combination with prednisone (60 mg per day). Over a 3-week period, the patient demonstrated progressive improvement in overall strength. The previously life-threatening episodes of lactic acidosis also ceased, a finding that persisted over a 7-year follow-up period.[61]

One larger study of patients with mitochondrial cytopathies failed to demonstrate efficacy of treatment at doses of 100 mg per day for 2 months.[33]


In vitro studies show that in the presence of complex I inhibitors, vitamin K3 (menadione) stimulates oxygen utilization in mitochondria, resulting in an increase of NADH oxidation.[62] One group of investigators utilized 31P nuclear magnetic resonance to assess the response to treatment with menadione (40 to 80 mg per day) and ascorbate (4 g per day) of a 19-year-old patient with mitochondrial myopathy associated with complex III deficiency. This treatment approach resulted in both clinical and metabolic improvement that persisted at 1-year follow-up. She was no longer wheelchair-bound though overall her weakness remained unchanged. The clinical improvements were supported by 31P NMR data, which revealed an increase in phosphocreatine concentration at rest and postexercise. A doubling of the initial dose of K3 improved the phosphorous NMR spectra even further without apparent side effects. Symptoms deteriorated with withdrawal of treatment with recovery of function once reinstated.[63,64]

Toscano et al[65] treated a 16-year-old girl with ataxia, myoclonus, lactic acidosis, and complex III deficiency with vitamins K3 (40 mg per day) and C (4 g per day). There was no significant change in lactic acidosis but there was mild improvement of her ataxia. After 5 months of therapy, the brain 31P-MRS indices were restored to normal. Skeletal muscle evaluation, though, revealed only slight improvement of mitochondrial bioenergetics.

One larger trial in which patients were treated with 60 mg per day of menadione and 2 g per day of vitamin C (in addition to multiple other supplements) did not substantiate the therapeutic benefit seen by these other investigators.[33]

K3 is known to cause hemolytic anemia, hyperbilirubinemia, and kernicterus and is therefore contraindicated for neonates, pregnant females, or those being treated with coumadin. It is also difficult to find, and K1, the common form of vitamin K, may have no benefit. As a practical alternative, CoQ10 may provide the same benefit.

A 23-year-old woman with Kearns-Sayre syndrome on phenytoin for a seizure disorder was found to have diminished CSF and plasma folate levels in addition to low free carnitine. She was treated with folate (40 mg per kg of body weight or 15 mg per day), D, levo-carnitine (10 g per day), and methionine (500 mg per day). Plasma folate increased to normal with supplementation but CSF folate remained unchanged. She also demonstrated clinical improvement to the point of being able to ambulate after having been bedridden.[66]

Uridine will soon be under investigation as a treatment for mitochondrial disorders. Uridine is a pyrimidine nucleotide, required for synthesis of RNA and DNA. Normal cell and organ function rely on adequate synthesis, transport, and interconversions of pyrimidines. The synthetic pathway for uridine synthesis involves the mitochondrial dehydrogenation of dihydrooroate to oroate, which is intimately linked with CoQ10 recycling and normal electron transport chain function. Any process that interferes with CoQ10 recycling or electron transport chain function can impair oroate formation. The process of uridine synthesis concludes with condensing orotic acid with phosphoribosyl pyrophosphate (PRPP) to form uridine monophosphate. Disordered oxidative phosphorylation will impede the de novo synthesis of pyrimidines and further exacerbate cellular dysfunction. The theoretical argument for treating with exogenous uridine is to overcome the relative deficit due to impaired synthesis leading to improved cellular health.

Hereditary orotic aciduria produces a primary uridine deficiency and results in a syndrome of failure to thrive, megaloblastic anemia, orotic aciduria, congenital malformations, transient immunoglobulin deficiency, immune deficiency, and developmental delays. Lifelong supplemental uridine is required and may reverse some of the manifestations of this deficient state. Postulated beneficial effects of uridine are based primarily on animal research and include: appetite stimulation, anticonvulsant effects, prevention of lactic acid overproduction, antidepressant, cardioprotective, and prevention of cerebral edema, among others. Human trials are planned. Side effects have been reported and more commonly include a transient increase in seizure activity upon initiation of therapy, nausea, vomiting, and/or diarrhea (Robert Naviaux, personal communication, 2001).


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