Ketogenic diet for mitochondrial disease: a systematic review on efficacy and safety

Abstract

Background: No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge free radicals, putting ketogenic diets (KDs) on the list of management options for MD. Furthermore, KDs are well-known, safe and effective treatments for epilepsy, a frequent symptom of MD. This systematic review evaluates efficacy and safety of KD for MD.

Methods: We searched Pubmed, Cochrane, Embase and Cinahl (November 2020) with search terms linked to MD and KD. From the identified records, we excluded studies on Pyruvate Dehydrogenase Complex deficiency. From these eligible reports, cases without a genetically confirmed diagnosis and cases without sufficient data on KD and clinical course were excluded. The remaining studies were included in the qualitative analysis.

Results: Only 20 cases (14 pediatric) from the 694 papers identified met the inclusion criteria (one controlled trial (n = 5), 15 case reports). KD led to seizure control in 7 out of 8 cases and improved muscular symptoms in 3 of 10 individuals. In 4 of 20 cases KD reversed the clinical phenotype (e.g. cardiomyopathy, movement disorder). In 5 adults with mitochondrial DNA deletion(s) related myopathy rhabdomyolysis led to cessation of KD. Three individuals with POLG mutations died while being on KD, however, their survival was not different compared to individuals with POLG mutations without KD.

Conclusion: Data on efficacy and safety of KD for MD is too scarce for general recommendations. KD should be considered in individuals with MD and therapy refractory epilepsy, while KD is contraindicated in mitochondrial DNA deletion(s) related myopathy. When considering KD for MD the high rate of adverse effects should be taken into account, but also spectacular improvements in individual cases. KD is a highly individual management option in this fragile patient group and requires an experienced team. To increase knowledge on this-individually-promising management option more (prospective) studies using adequate outcome measures are crucial.

Keywords: Adverse event; Complex I; Epilepsy; High fat diet; Management; Mitochondrial DNA deletion; Mitochondrial myopathy; Modified Atkins diet; OXPHOS; Treatment.

Fig. 1

Metabolic pathways of carbohydrates, fat and ketone bodies in energy metabolism. ATP adenosine triphosphate, C respiratory chain complex, PDHC pyruvate dehydrogenase complex, PC pyruvate carboxylase, TCA Cycle Tricarboxylic acid cycle also called citric acid cycle

Fig. 2

PRISMA flowchart. This figure detailing the search strategy

Fig. 3

Summary of positive and negative effects of ketogenic diet in 20 cases with genetically proven mitochondrial disease. This figure visualises the negative effects and adverse events on the left and the positive effects (on the right) of ketogenic diet in 20 cases with genetically proven mitochondrial disease. *temporary effect **cases with reported treatment-withdrawal effect. B/B bladder and bowel, CPEO chronic progressive external ophthalmoplegia, del deletions, HC head control, mult multiple deletions in mitochondrial DNA, MRI magnetic resonance imaging, mtDNA mitochondrial DNA, SLE stroke like episodes, SM skeletal muscle, TD tonus dysregulation