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【Summary】 Primary Mitochondrial Disease, Scientific Basis for 4 Treatment Methods

Tuesday, June 1, 2021

Primary Mitochondrial Disease

Scientific Basis for the Treatment of Primary Mitochondrial Disease

Primary mitochondrial disease is a condition in which the mitochondria in the cells are dysfunctional, and various methods of treatment have been tried.

This article will summarize the results of research limited to nutrients that can be ingested.

Evidence for Alpha Lipoic Acid

The health benefits of ALA in the treatment of PMD are based on limited evidence.

A case report published in 1995 described the effects of one month of oral ALA supplementation (200 mg three times a day) on brain and skeletal muscle energy metabolism in patients with CPEO.

Results showed an increase in brain energy availability after one month and further improvement was reported after seven months of supplementation. Supplementation also had a positive effect on muscle mitochondrial activity during exercise, with patients reporting an overall improvement characterized by decreased eye pain and discomfort and improved muscle strength after supplementation.

The standard dose is 50-200 mg / day.

Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medical Society.Genet Med2014.[ PubMed abstract ].

Evidence for arginine.

Studies suggest that arginine supplementation may reduce the severity and frequency of stroke-like episodes.

Thereby, it has been used in patients with mitochondrial encephalomyopathy (MELAS) by stimulating vasodilation. However, there are no RCTs that have tested this hypothesis, and evidence for the efficacy of arginine in MELAS is based on small, open-label studies (6-15 patients) of 12-24 months. Furthermore, no studies have evaluated the use of arginine supplementation to treat other PMDs.

Oral administration of 150-300 mg/kg/day of arginine for 12-24 months significantly reduced the frequency and severity of stroke-like episodes.

Patients did not have major stroke-like seizures such as hemiconvulsions or hemiparesis (temporary muscle weakness on one side of the body) after arginine supplementation.

Carr DS. Treatment of mitochondrial electron transfer chain disorders: a review of clinical trials over the past decade. Mol Genet Metab 2010; 99: 246-55.[ PubMed abstract ].

Koga Y, Ishibashi M, Ueki I, Yaga S, Fukiyama R, Akita Y, et al. Effect of L-arginine on the acute phase of stroke in three patients with MELAS. Neurology 2002; 58: 827-8.[ PubMed abstract ].

Evidence for carnitine.

A small, randomized, double-blind, controlled crossover study evaluated the effect of 3 g/day oral carnitine supplementation on exercise tolerance in 12 patients with mitochondrial myopathy and CPEO.

After 8 weeks of carnitine treatment and 8 weeks of placebo treatment, patients were divided in a 4-week washout period and There was no change after carnitine supplementation or placebo in peripheral muscle strength, which was initially low compared to values in healthy controls.

However, after carnitine supplementation, inspiratory capacity (a measure of lung function) and aerobic performance during strenuous sedentary exercise improved significantly compared to placebo.

The study did not measure plasma or muscle carnitine levels, so it is unclear whether the patients had carnitine deficiency.

An open-label study evaluated the effects of carnitine supplementation (50-200 mg / kg / day in 2-4 oral doses) for 1-24 months in 21 patients with CPEO, KSS, MELAS, mitochondrial encephalomyopathy, mitochondrial myopathy, or Leigh's disease.

Carnitine supplementation normalized plasma carnitine levels in all patients after 10 days, and improved symptoms in 20 patients.

Muscle strength and muscle power improved subjectively in 19 of 20 patients with muscle weakness.

Growth improved after supplementation in 4 of 8 patients with growth failure, and clinical and laboratory evaluations showed improvement in 8 patients with cardiomyopathy based on echocardiographic assessment. Ten percent of patients experienced side effects, primarily nausea and diarrhea.

El-Hattab AW, Scaglia F. Impaired carnitine biosynthesis and transport.Mol Genet Metab 2015; 116: 107-12.[ PubMed abstract ].

Campos Y, Huertas R, Lorenzo G, Bautista J, Gutierrez E, Aparicio M, et al. Plasma carnitine deficiency and efficacy of L-carnitine therapy in patients with mitochondrial myopathy. Muscle Nerve 1993; 16: 150-3.[ PubMed abstract ].

Hsu CC, Chuang YH, Tsai JL, Jong HJ, Shen YY, Huang HL, et al. Overlap of CPEO and carnitine deficiency in MEEO syndrome. Acta Neurol Scand 1995; 92: 252-5.[ PubMed abstract ]

Evidence for creatine.

There are small open-label studies, results of which have been investigated in randomized, double-blind, crossover trials with conflicting results.

Two prospective studies found that creatine supplementation had a positive effect on muscle symptoms in patients with PMD.

The first randomized, double-blind, crossover study provided creatine monohydrate for three weeks (2g, twice daily, for two weeks) or placebo for three or five weeks.

Creatine supplementation resulted in a significant increase in ischemic isometric handgrip strength and an overall 11% increase in non-ischemic, isometric, dorsiflexion torque compared to placebo.

A second open-label study evaluated the effects of creatine monohydrate supplementation of 0.08-0.35 g/kg/day for 9 months to about 4 years in 5 patients (7-19 years) with KSS, MELAS, or NARP.

Skeletal muscle strength analysis showed a mean increase in maximal muscle performance of 12% in all patients.

Self-reported muscle symptoms and coordination improved, but cognitive function (i.e., school performance) did not change.

Two randomized controlled crossover trials found that creatine supplementation (150 mg/kg/day or 20 g/day) or placebo for 4 to 6 weeks, with a 4-week washout period in between, did not affect clinical outcomes such as skeletal

Komura K, Hovey-Brunken E, Wilichski EK, Hanefeld FA. Efficacy of creatine monohydrate in mitochondrial encephalomyopathy. Pediatr Neurol 2003; 28: 53-8.[ PubMed abstract ].

Tarnopolsky MA, Roy BD, MacDonald JR. A randomized controlled trial of creatine monohydrate in patients with mitochondrial cytotoxicity. Muscle Nerve 1997; 20: 1502-9.[ PubMed abstract ].

Klopstock T, Querner V, Schmidt F, Gekeler F, Walter M, Hartard M et al. A placebo-controlled crossover trial of creatine in mitochondrial disease. Neurology 2000; 55: 1748-51.[ PubMed abstract ].

Kornblum C, Schroder R, Muller K, Vorgerd M, Eggers J, Bogdanow M et al. Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with mitochondrial single DNA deletions: a placebo-controlled double-blind 31P-MRS crossover study. Eur J Neurol 2005; 12: 300-9.[ PubMed abstract ].

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