Thursday, February 11, 2016

Mitochondrial cocktails

I posted:

For patients with disorders of oxidative metabolism who may be treated with CoQ10, levocarnitine, riboflavin, etc., how are others convincing themselves of actual benefit to the patient? The Cochrane Review for the treatment of mitochondrial disorders in 2006 states: "There is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches." Obviously, when a patient is started on a supplement or supplements and there is a striking and convincing clinical change in the patient's performance, there is much less reason to raise the question, although, for example, depending on the preparation, CoQ10 may be expensive and uncovered by insurance. There may also be biochemical evidence, for example, a decrease in lactate. Dr. Shoffner at Medical Neurogentics measures resting metabolic rate. What if the numbers are better, but the patient is seemingly not? If a patient is on a supplement and there is neither evidence of clinical or biochemical improvement, should the supplement be increased? Should another supplement be tried? If so, instead of or in combination with the first one or ones? I have struggled with such issues in many patients and have made a variety of management decisions, but, as I reflect on that experience, I do not feel that the algorithm has become clearer.

A reply:

I would like to add my "hear, hear!" to this. The more I use these the more doubts I have about what I am really accomplishing.

Another reply:

Cochrane papers are great if you are trying to address the use of daily aspirin in 50+ year old men, or the value of mammography in the diagnosis of breast cancer ---an illness that is diagnosed in 200,000 women each year in the USA. Cochrane cannot address the common question of: which works better in epilepsy - Keppra or Tegretol -- an issue with 1000x the experience/exposure than we have with mitochondrial disorders. I agree with the 2006 Cochrane report but it, is irrelevant when it comes to treating the child in your office. There are very few properly conducted Randomized Clinical Trials --- and of course there is not one mitochondrial disorder to test, there are 100s (so grouping results is difficult even if you choose to study one genotype). Those of us up to our eyeballs in this issue address these issues as n of 1 trials; and the decision whether to start all supplements at once or one at a time is the art, not science, of medicine. We do the best we can with the limited resources. The NAMDC (North American Mitochondria) Disease Consortium) is re-applying for NIH funding, and one of the goals of this organization (Michio Hirano is the PI) is to develop trials (in addition to biobanking, standardizing testing protocols, etc.).

I do not think anyone should be critical of a doctor suggesting CoQ10 in a child with a mitochondrial disorder. I do not think anyone should be critical of stopping CoQ10 if it is not working, however we determine efficacy. Finally the authors of this paper understand the frustration from patients and their doctors for all the reasons stated, and it can take on a life of its own. There is a lot to learn and Sumit's paper adds clarity to this subject.

I posted:

At a time when I was more involved in decisions regarding supplementation for mitochondria! patients than I currently seem to be, there was considerable hullabaloo made in certain quarters regarding the preparation of the supplement. Coenzyme Q10 was a prime example. There was insistence that the Tishcon brand be utilized, which had financial and convenience consequences for the family. From those who are currently more active in this domain, what is the advice given to parents regarding the source of such supplements?

A reply (same source as "another reply" above):

CoQ10 has the consistency and water solubility of soft wax. 100 mg of a blob of CoQ10 will not be absorbed. The Tishcon product (I have no COI with any of the supplement companies) has a particle size that allows it to be nearly completely absorbed, based on PD studies. You can find the Tishcon brand and Ubiquinol (reduced CoQ10) at Costco and Sam's Club most if the time and it is price about 1/2 the usual cost. There are several "mito" supplements that have easier delivery systems (g-tube safe and tasteless or tasty) at After that, most us us recommend name brands. Sumit Parikh will be publishing soon a Delphi-document about this issue. Having said that, there is only one relevant randomized controlled crossover trial published in 2007 (Mark Tarnopolsky) suggesting some benefit to Coq10, alpha lipoic acid and creatine in an adult population. Most of us have reservations about the global benefit in most patients. We use them, but with limited expectations. There is A huge difference between me saying to my patient: 'yes the symptoms of Leigh syndrome in your child is very stable so let's continue the supplements' AND 'the medical literature supports the use of supplements in Leigh syndrome.'


  1. Chinnery P, Majamaa K, Turnbull D, Thorburn D. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004426. Review. Update in: Cochrane Database Syst Rev. 2012;4:CD004426. PubMed PMID: 16437486.



    Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. They present with central and peripheral neurological features usually in association with other organ involvement including the eye, the heart, the liver, and kidneys, diabetes mellitus and sensorineural deafness. Current treatment is largely supportive and the disorders progress relentlessly causing significant morbidity and premature death. Vitamin supplements, pharmacological agents and exercise therapy have been used in isolated cases and small clinical trials, but the efficacy of these interventions is unclear.


    To determine whether there is objective evidence to support the use of current treatments for mitochondrial disease.


    We searched the Cochrane Neuromuscular Disease Group trials register (searched September 2003), the Cochrane Central Register of Controlled Trials, MEDLINE (January 1966 to October 3 2003), EMBASE (January 1980 to October 3 2003) and the European Neuromuscular Centre (ENMC) clinical trials register, and contacted experts in the field.


    We included randomised controlled trials (including crossover studies) and quasi-randomised trials comparing pharmacological treatments, and non-pharmacological treatments (vitamins and food supplements), and physical training in individuals with mitochondrial disorders. The primary outcome measures included an improvement in muscle strength and/or endurance, or neurological clinical features. Secondary outcome measures included quality of life assessments, biochemical markers of disease and negative outcomes.


    Details of the number of randomised patients, treatment, study design, study category, allocation concealment and patient characteristics were extracted. Analysis was based on intention to treat data. We planned to use meta-analysis, but this did not prove necessary.


    Six hundred and seventy-eight abstracts were reviewed, and six fulfilled the entry criteria. Two trials studied the effects of co-enzyme Q10 (ubiquinone), one reporting a subjective improvement and a significant increase in a global scale of muscle strength, but the other trial did not show any benefit. Two trials used creatine, with one reporting improved measures of muscle strength and post-exercise lactate, but the other reported no benefit. One trial of dichloroacetate showed an improvement in secondary outcome measures of mitochondrial metabolism, and one trial using dimethylglycine showed no significant effect.


    There is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches.

  2. Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol. 2009 Nov;11(6):414-30.


    The treatment of mitochondrial disease varies considerably. Most experts use a combination of vitamins, optimize patients' nutrition and general health, and prevent worsening of symptoms during times of illness and physiologic stress. We agree with this approach, and we agree that therapies using vitamins and cofactors have value, though there is debate about the choice of these agents and the doses prescribed. Despite the paucity of high-quality scientific evidence, these therapies are relatively harmless, may alleviate select clinical symptoms, and theoretically may offer a means of staving off disease progression. Like many other mitochondrial medicine physicians, we have observed significant (and at times life-altering) clinical responses to such pharmacologic interventions. However, it is not yet proven that these therapies truly alter the course of the disease, and some experts may choose not to use these medications at all. At present, the evidence of their effectiveness does not rise to the level required for universal use. Based on our clinical experience and judgment, however, we agree that a therapeutic trial of coenzyme Q10, along with other antioxidants, should be attempted. Although individual specialists differ as to the exact drug cocktail, a common approach involves combinations of antioxidants that may have a synergistic effect. Because almost all relevant therapies are classified as medical foods or over-the-counter supplements, most physicians also attempt to balance the apparent clinical benefit of mitochondrial cocktails with the cost burden that these supplements pose for the family.

  3. Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R; Mitochondrial
    Medicine Society Clinical Directors Working Group; Clinical Director's Work Group. Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management. Mitochondrion. 2013 Nov;13(6):681-7.


    Mitochondrial medicine is a young subspecialty. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted. We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care.

  4. Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, Anselm I,
    Cohen BH, Falk MJ, Greene C, Gropman AL, Haas R, Hirano M, Morgan P, Sims K, Tarnopolsky M, Van Hove JL, Wolfe L, DiMauro S. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015 Sep;17(9):689-701.



    The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients.


    The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve.


    Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease.


    The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.

  5. from the reference in the prior comment

    Treatment with vitamins and xenobiotics

    Multiple vitamins and cofactors are used in the treatment of mitochondrial disease, although such therapies are not standardized and multiple variations of treatments exist. Despite empiric rationale for the use of such vitamins or xenobiotics, few trials have explored the clinical effects of these treatments.145 There is a general lack of consensus regarding which agents should be used, although most physicians prescribe CoQ10, L-carnitine, creatine, α-lipoic acid (ALA), and certain B-vitamins. A Cochrane review of mitochondrial therapies has found little evidence supporting the use of any vitamin or cofactor intervention.

    CoQ10 in its various forms is the most commonly used nutritional supplement in mitochondrial disease and is an antioxidant that also has many other functions. The evidence base supporting the use of CoQ10 in mitochondrial diseases other than primary CoQ10 deficiency is sparse, with few placebo-controlled studies available. Most of the supportive data come from either anecdotal open-label treatment or treatment in combination with other cofactors, with minimal benefit reported with CoQ10 alone.

    ALA is relatively commonly used in mitochondrial disease therapy, but no controlled clinical trial has evaluated its use as monotherapy. A single randomized study used ALA in conjunction with creatine and CoQ10. Case reports have also described the use of ALA in conjunction with other therapies, including ubiquinone, riboflavin, creatine, and vitamin E, with some clinical benefit.

    Although B-vitamins alone or as a multivitamin tablet (e.g., vitamin B50) are commonly recommended for mitochondrial disease patients in clinical practice, no randomized trials have explored the efficacy of this treatment. Riboflavin use has also been seen to improve clinical and biochemical features in other small, open-label studies. Riboflavin as part of a combination of vitamins has been used in an open-label study of 16 children who did not demonstrate clear clinical benefit.

    There have been no clinical trials exploring the use of L-carnitine for the treatment of mitochondrial disease, although L-carnitine supplementation is commonly used in this patient population. L-Carnitine supplementation has also been used for the treatment of a number of neurometabolic disorders, including organic acidemias and some fatty-acid oxidation disorders; however, even in these conditions, no randomized, controlled trials have been performed. L-Carnitine was used as a therapy in case studies, typically combined with other vitamins.

    Patients with mitochondrial disease, especially those with mtDNA deletion syndromes such as KSS, have potentially low CSF 5-methyltetrahydrofolate, and folinic acid supplementation is relatively common in patients with mitochondrial disease and neurologic signs or symptoms. There have been no clinical trials using folinic acid for mitochondrial disease therapy.(continued)

  6. (continued) Many other compounds were reviewed and the data can be found in the online summaries. The consensus was that further research regarding these compounds is needed.

    Consensus recommendations for vitamin and xenobiotic use

    1. CoQ10 should be offered to most patients with a diagnosis of mitochondrial disease and not exclusively used for primary CoQ10 deficiency.

    a. Reduced CoQ10 (ubiquinol) is the most bioavailable form and, when used, dosing should be appropriately modified.

    b. Plasma and/or leukocyte CoQ10 levels are helpful in monitoring absorption and adherence to treatment. Plasma levels are more variable and less reflective of tissue levels.

    2. ALA and riboflavin should be offered to mitochondrial disease patients.

    3. Folinic acid should be considered in mitochondrial disease patients with central nervous system manifestations and routinely administered to those with documented CSF deficiency or with disease states known to be associated with deficiency.

    4. L-Carnitine should be administered to mitochondrial disease patients when there is a documented deficiency and levels should be monitored during therapy.

    5. When beginning supplement therapy, one should begin one at a time when possible, taking into account a patient’s clinical status.

    6. There is no evidence to suggest that one can adjust a person’s diet on the basis of ETC results.

    7. Goal levels for most vitamin therapy used are not yet known; it is prudent to replace deficiency states.