Treatment for mitochondrial disorders.

Systematic review of randomized and cross-over trials in children and adults with confirmed primary mitochondrial disorders. Included phenotypes spanned MELAS, PEO/KSS, LHON, MERRF, NARP, MNGIE, Leigh syndrome, and other respiratory chain or mtDNA-related disorders.

This review evaluated multiple active regimens used in primary mitochondrial disorders, including coenzyme Q10, creatine monohydrate, dimethylglycine, and a whey-based cysteine supplement, compared with placebo or other inactive comparators in randomized or cross-over trials. Doses ranged from CoQ10 600 mg orally twice daily for 60 days to creatine monohydrate 20 g/day for 4 weeks, 150 mg/kg/day for 6 weeks, or a multicomponent cocktail containing creatine, dextrose, alpha-lipoic acid, and coenzyme Q10.

Overall, there was no clear evidence supporting any of the reviewed pharmacological or nutritional interventions for meaningful clinical benefit in mitochondrial disorders. Some studies showed biochemical or surrogate improvements, such as increased CoQ10 levels with lower lactate at 1 minute of cycle ergometry, creatine-associated gains in handgrip strength by 19% and NIDFT by 11%, and DCA-associated reductions in lactate and brain MRS ratios, but these effects were inconsistent and did not reliably translate into clinical improvement. The larger DCA trial found no significant differences in GATE or secondary outcomes and was stopped because of peripheral nerve toxicity, with 15 DCA withdrawals in the first 24 months versus 4 placebo withdrawals. The review also noted no significant effect for dimethylglycine and no consistent benefit from whey-based cysteine supplementation.

Evidence was limited by small sample sizes, heterogeneous mitochondrial phenotypes, and frequent use of cross-over designs. Many outcomes were biochemical or surrogate rather than clinically meaningful, follow-up was short, and the trials were underpowered to detect important patient-centered effects. Adverse-event reporting and generalizability were also limited, and one key DCA study was discontinued for toxicity.