Dr. M Shakiba Subspecialist of pediatric Endocrinology and metabolism

 Mitochondrial cytopathies are clinically and biochemically heterogeneous disorders affecting energy production.  Because of the heterogeneity of disorders, the large number of biochemical and genetic defects, and wide spectrum of clinical course, there are limited data about proven effective therapies.  Treatments for mitochondrial cytopathies are intended to augment energy production and reduce the production of free radicals and other toxic metabolites that further limit the generation of cellular energy.  Treatment can be aimed at increasing respiratory chain activity by supplementing relative deficiencies of cofactors required for proper functioning.

dietary management supplemental vitamins and cofactors specific medications aimed at a particular symptom

MedicationMechanism of actionDose Coenzyme Q10Bypass complex I and II2-5 mg/kg/d(5-15)/3 div doses Coenzyme Q10COQ10 deficiency mg/kg/d CreatinAlternative energy source, neuroprotection 100mg/kg/d ThiamineCofactor for PDH3-9 mg/kg/d RiboflavinBypass complex I ( via II)3-5 mg/kg/d( ) Vitamin EAntioxidant5-10 mg/kg/d Vitamin CAntioxidant5-10 mg/kg/d L-carnitineTreat secondary deficiency30-50 mg/kg/d SuccinateBypass complex I defects30-70 mg/kg/d α-Lipoic acidAntioxidant, Component of mitochondria 3-5 mg/kg/d DichloroacetateActivate PDH and reduce lactate 25 mg/kg/d

 The clinical benefits for cofactor and vitamin therapy can include improved strength and endurance, although patients report a variety of benefits.  The use of creatine has been shown to improve strength in patients with mitochondrial myopathies, although its long- term use should be be consider with caution Because of the potential for renal toxicity.  Benefit of Triacetyluridine and magnesium orotate is contravercial

 The use of antioxidants.(á-lipoic acid, vitamin E, vitamin C, â-carotene, selenium, vitamin K and N- acetylcysteine) to lessen free radical damage to the mitochondrial membrane has a scientific rationale, but again proof of effectiveness does not exist.  The other B vitamins have been used, with reports of effectiveness in small numbers of patients, likely those with a rare but specific vitamin-responsive syndrome.  Treatment with Dichloroacetate associate with some degree of improvement in several studies. It is recommended during attacks with high level of lactate (>10 mmol/l) for short time. Long time usage associate with peripheral neuropathy

 In critical situations, when lactic acid and ammonia levels are extremely elevated, the use of continuous infusion insulin ( U/kg/h), using very frequent glucose monitoring, may help reverse catabolism, decrease circulating toxic free fatty acids, and lower lactic acid and ammonia levels.  The use of sodium benzoate, phenylbutyrate, and sodium phenylacetate can bind conjugate ammonia in the case of severe hyperammonemia.  Enteral use of lactulose also can help lower ammonia levels.

 There are no genetic therapies  Exercise:  - with endurance and resistance type exercise showing evidence of efficacy especially in sporadic mitochondrial mutation  - They must work within their limit and in play based exercise  - There are some reports of nausea, vomiting, vertigo and and even exercise induced deafness  - avoidance from vigorous exercise during intercurrent illness and migraine like headache  - Activities such as Tai Chi, Karate, Ballet are helpful in patients with dyscoordination and ataxia

 Dietary management for mitochondrial disorders remains largely trial and error.  A low-carbohydrate, high fat diet is helpful for some patients with complex I deficiency but others do better on a high-carbohydrate, low-fat diet.  Patients with PDH deficiency should be treated with a ketogenic diet.  The use of frequent, small-volume feedings is generally well tolerated.  For children with primary and secondary gluconeogenetic defects, avoidance of fasting is recommended.

 from an anesthetic perspective, the most important issue is to avoid prolonged periods of fasting.  avoidance from anesthetic drugs that predispose to malignant hypertermia (propofol+local anesthetics(ELMA cream))

 Peripheral neuropathy and other types of neurogenic pain can be a feature of mitpochondrial cytopathy  Gabapentin is one of the first line of therapy  Pregabalin had success in patient who can not tolerate Gabapentin  Another choice is a combination of capsicin and ELMA(50/50)

 Valprovate sodium should not be used because it may trigger Rey like syndrome  Topomax is particularly sedating in children with mitochondrial cytopathy

 In GI problem particularly in MNGIE syndrome TPN, Simethicone,Buscopcan  Lactolose and glycerin and high fluid and fiber diets can be helpful  Mineral oil do not be recommended

 Psychologic support  for patients family and  for patients