Management of Diseases



Disclaimer: The following information is for education purposes only. The reader is advised to consult your physician regarding treatment issues. Despite a number of drugs that have been tried in mitochondrial disorders, there are no successful long term trials (Chinnery et al 2006).

Please consult your metabolic specialist regarding specific therapies for mitochondrial disorders.

Like many genetic diseases, the day to management patients with mitochondrial disorders remains a challenge. Although continuous research is being done, there is unfortunately no cure today for mitochondrial diseases. The primary goal is of symptom control and improvement in the quality of life as much as possible for patients. Unfortunately there are few randomized and controlled studies evaluating the various treatment options for mitochondrial disorders to develop clear and definite evidence based guidelines.

Mitochondrial disorders can manifest as single organ dysfunction or as multisystem disease involving the nervous system, eyes, ears, endocrine organs, heart, intestines, kidneys, bone marrow or skin etc.   (General symptoms)

Assessments

  1. Baseline: Complete medical assessment should be carried out.
  2. Vision and Hearing assessment (to rule out ophthalmological involvement0 and hearing loss
  3. Cardiac assessment to rule out cardiomyopathy and arrhythmias
  4. Swallowing assessment
  5. Cognitive and developmental assessment
  6. Renal assessment
  7. Physiotherapy assessment

Therapeutic aspects for mitochondrial disorders

Even though there are presently no permanent cures that can be offered for mitochondrial disorders, the individual patient and family members who are affected can benefit from several therapeutic measures outlined below.

Symptomatic therapy

The symptomatic therapies can be divided into:

  • Nutrition
  • Drugs-(Symptomatic therapy)
  • Drugs-affecting the mitochondrial function
  • Avoidance of drugs
  • Invasive measures
  • Miscellaneous
  • Future therapies

 

 Nutrition

Though most specific diets have been found to be ineffective, overall general good nutrition is encouraged with avoidance of fasting. For some of the specific disorders such as pyruvate dehydrogenase deficiency, a ketogenic diet has been found to be useful. Some patients with MELAS and non specific mitochondrial disorders might benefit from relatively high-fat content in the diet.

If there are swallowing issues, a formal feeding and swallowing assessment should be carried out. Some patients may require gastrostomy  or G Tube inserted directly into the stomach through the abdominal wall for feeding purposes.  The procedure for insertion will usually require the services of a surgeon or interventional radiologist and a feeding team.

 Drugs (Symptomatic  therapy)

Antiepileptics:  traditional anticonvulsant drugs are generally prescribed; however, special precautions should be taken to avoid the drug “valproic acid or sodium valproate, which can inhibit the carnitine uptake and may cause hyperammonemia.

Muscle relaxants: such as Baclofen or botulinum toxin can be considered for spasticity /dystonia (local or generalized) under supervision.

Pain: Gabapentin, Pregabalin, Carbamazepine or Lamotrigine can be used for neuropathic pain.

Cardiac drug therapy: is required in case of rhythm abnormalities or heart failure.

Gastrointestinal: Domperidone or cisapride may be useful if there is generalized dysmotility along with vomiting.

Renal: Electrolyte replacements (sodium and potassium) are required in when kidney function is compromised or in situations such as  hypoaldosteronism where salt and fluid balance is affected.

Blood: In case of anemia or pancytopenia iron, transfusions or hematopoietic cell stimulators may be beneficial.

Endocrine: If there are endocrine disturbances along with mitochondrial disorders then patients may benefit from substitution of hormones for hypopituitarism, hypocorticism, hypogonadism etc.

 
Drugs-affecting the mitochondrial function

Respiratory chain proteins are responsible in the transference and electrochemical reactions which eventually lead to production of ATP, the body’s energy currency, as the end result. Vitamins help to make this transfer more efficient. The exact ingredients in the vitamin cocktail are determined by the physician and the success of the treatment varies from patient to patient.  The important components of this cocktail include riboflavin, Coenzyme Q and vitamins E, C, etc.

       Coenzyme Q (Quinones): This is most frequently prescribed supplement for mitochondrial disorders. Quinones not only have an antioxidant effect but also act as electron donor/acceptor respiratory chain. Coenzyme Q also known as coenzyme Q10, ubiquinone is a fat-soluble vitamin vital to a number of activities related to energy metabolism.  CoQ is vital for the transfer of electrons from complex 1 and II to III. CoQ increases ATP production, has antioxidant properties and is an indirect stabilizer of calcium channels.  Although uncommon, potential side effects of CoQ include gastrointestinal discomfort and low blood pressure. CoQ (300-1500 mg/day) is highly effective in CoQ deficiency states presenting as exercise intolerance and lactic acidosis. CoQ substitution and vitamin E have been effective in Friedrich ataxia as well.

Idebenone- Only limited experiences exist for idebenone      

Other supplements

Vitamin E (Alpha-tocopherol) is usually used in combination with other supplements. There are no well-designed studies to evaluate its role on its own in mitochondrial disorders.

Alpha Lipoic acid is an essential cofactor for mitochondrial bioenergetics enzymes.  It has been used in neuropathic pain in mitochondrial disorders with polyneuropathy.

Vitamin C acts as an important antioxidant and protects mitochondria from oxidative injury.

Riboflavin may be effective in secondary riboflavin deficiency. Riboflavin also has donor/acceptor  properties. Riboflavin has been used in combination with other supplements. High dose riboflavin has been tried in headache and migraines with MELAS patients.  

Succinate has been tried in some MELAS patients

Creatine-monohydrate Beneficial effect concerning muscle strength has been reported in some studies although not confirmed in others.  

L- Arginine- Recent studies have shown that L-arginine , a nitric oxide precursor, may improve endothelial functions in patients with MELAS. L-arginine may be particularly beneficial in stroke- like events. Both intravenous administration (for acute episode) and oral arginine supplements for prevention have been tried with some success. Long term studies with use of arginine will be very helpful.

L-Carnitine- is highly effective in primary carnitine deficiency. Carnitine supplements are also helpful when there is secondary carnitine deficiency.  L-Carnitine should also be given when valproate use is unavoidable.

Thiamine- Some patients with sideroblastic anemia may find thiamine useful. Patients with Pyruvate dehydrogenase deficiency may respond to thiamine.

Folic acid-has been found to be useful in Kearns Sayre syndrome (KSS) as CSF folic acid concentration is decreased.

Other vitamins such as Niacin, Pyridoxal phosphate, or vitamin K –only anecdotal reports are available.

Lactate lowering agents

Bicarbonate -Buffering of lactate is possible with bicarbonate but carries only a transient effect.

Dichloroacetate- decreases lactate by inhibiting pyruvate dehydrogenase enzyme complex. Side effects include peripheral neuropathy.  Dichloroacetate does not reverse long term complications of lactic acidosis

Avoidance of Drugs

More important than administration is the avoidance of drugs which are detrimental to the mitochondrial function.

Avoid drugs such as:

  • ifosamide, carboplatin (inhibit mitochondrial replication)
  • zidouvidine – reduces respiratory chain complexes 1/IV activity
  • interferon (impair mitochondrial DNA transcription)
  • carvedilol , bupivacaine (block respiratory chain 1 complex)
  • acetyl salicylic acid (inhibit the electron transport chain)
  • statins (decrease endogenous coenzyme Q)
  • tetracyclins and amiodarone (inhibit beta oxidation)
  • barbiturates, chloramphenicol (reduce mitochondrial protein synthesis)
  • doxorubicin and valproate (decrease carnitine and reduce Respiratory chain/oxphos activity)
  • metformin (biguanides) (cause lactic acidosis)
  • avoid Propofol (anesthetic agent) (prolonged use can cause bradycardia, rhabdomyolysis, hyperlipidemia, metabolic and lactic acidosis)

DO NOT USE RINGERS LACTATE PRIOR TO OR DURING SURGICAL PROCEDURES

Invasive measures

  • Blood transfusions for Pearson syndrome
  • Use of erythropoietin and transfusion of platelets may be helpful in Pearson syndrome
  • Implantation of pacemaker in patients with KSS syndrome.
  • Implantable cardioverter defibrillator may be needed in case of hypertrophic cardiomyopathy.
  • Ptosis has been corrected surgically although the effects of the repair may only be temporary.
  • Cataracts due to mitochondrial disorders may require surgical removal.
  • Cochlear implants may be helpful to overcome hearing problems.
  • Pseudo obstruction in MNGIE or MELAS may require emergency surgical resection of part of intestine. Bone marrow transplantation has been tried as well for MNGIE.
  • Gastrostomy (percutaneous) may be required for swallowing problems, recurrent vomiting and diarrhea.

Miscellaneous

Mitochondrial patients should avoid stress, extremes of temperature, alcohol, nicotine (Smoking).

They should get adequate sleep and should perform physical activity to below their maximum ability

Future Therapies

Stem cell therapy has been used in patients with MNGIE. Gene therapy is challenging due to heteroplasmy. Manipulation of heteroplasmy levels (gene shifting). Shifting of the level of heteroplasmy towards wild type (normal) mitochondrial DNA is being pursued. This is being done by induction of muscle regeneration among other procedures. The easiest approach is exercise or endurance training which may improve muscle oxidative capacity.

Conclusion:

With better understanding of the biology of mitochondrial function we hope that newer and more effective therapies will be developed. In the interim, it is important for patients to ensure proper nutrition, to avoid agents that can be harmful, to avoid smoking and alcohol. Exercise under proper supervision can be extremely helpful.  Each patient should preferably have their own specific treatment protocol which can be used in event of emergencies. The patient and his/her family should get to know about their disease so that they can be active participants in their medical care. Genetic counselling is very important for the management. Prenatal diagnosis is still very challenging for mitochondrial disorders. A referral to an appropriate genetics clinic and an appointment with a geneticist and genetic counsellor can be very helpful.

Please see the mitochondrial support groups which may be of help.

References

Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhaupl KM, Arnold G.

High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol. 2004 Jul;11(7):475-7.

Kubota M, Sakakihara Y, Mori M, Yamagata T, Momoi-Yoshida M.Beneficial effect of L-arginine for stroke-like episode in MELAS. Brain Dev. 2004 Oct;26(7):481-3; discussion 480. 

Robert McFarland MRCPCH, Prof Robert W Taylor PhD and Prof Douglass M Turnbull FRCP, A neurological perspective on mitochondrial disease. The Lancet Neurology  Volume 9, Issue 8, August 2010, Pages 829-840

Koga Y, Pvalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T. MELAS and L-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci. 2010 Jul;1201:104-10.

Kerr DS. Treatment of mitochondrial electron transport chain disorders: a review of clinical trials over the past decade. Mol Genet Metab. 2010 Mar;99(3):246-55. Epub 2009 Nov 26.

Shoffner JM, Wallace DC. Oxidative phosphorylation diseases and mitochondrial DNA mutations: diagnosis and treatment. Annu Rev Nutr. 1994;14:535-68.

Finsterer J. Treatment of mitochondrial disorders. European Journal of Paediatric Neurology 14. 2010 29-44.

P Chinnery, K Majamaa, D Turnbull and D Thorburn, Treatment for mitochondrial disorders, Cochrane Database Syst Rev 1 (2006) CD004426..

Online resources

http://www.ncbi.nlm.nih.gov/books/NBK1224/

Finsterer J. Treatment of Mitochondrial Disorders. Eur J Paediatr Neurol. 2010;

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Last Updated June 10, 2011 | © 2007, LHSC, London Ontario Canada