Targeted Therapies for Leigh Syndrome: Systematic Review and Steps Towards a 'Treatabolome'

Abstract

Background: Leigh syndrome (LS) is the most frequent paediatric clinical presentation of mitochondrial disease. The clinical phenotype of LS is highly heterogeneous. Though historically the treatment for LS is largely supportive, new treatments are on the horizon. Due to the rarity of LS, large-scale interventional studies are scarce, limiting dissemination of information of therapeutic options to the wider scientific and clinical community.

Objective: We conducted a systematic review of pharmacological therapies of LS following the guidelines for FAIR-compliant datasets.

Methods: We searched for interventional studies within Clincialtrials.gov and European Clinical trials databases. Randomised controlled trials, observational studies, case reports and case series formed part of a wider MEDLINE search.

Results: Of the 1,193 studies initially identified, 157 met our inclusion criteria, of which 104 were carried over into our final analysis. Treatments for LS included very few interventional trials using EPI-743 and cysteamine bitartrate. Wider literature searches identified case series and reports of treatments repleting glutathione stores, reduction of oxidative stress and restoration of oxidative phosphorylation.

Conclusions: Though interventional randomised controlled trials have begun for LS, the majority of evidence remains in case reports and case series for a number of treatable genes, encoding cofactors or transporter proteins of the mitochondria. Our findings will form part of the international expert-led Solve-RD efforts to assist clinicians initiating treatments in patients with treatable variants of LS.

Fig. 1

PRISMA flow diagram of articles screened for treatments in Leigh syndrome.

Fig. 2

Inclusion and exclusion criteria for screening Leigh syndrome treatments.

Fig. 3

Data extraction from articles discussing treatment in Leigh syndrome to develop a FAIR-compliant dataset.

Fig. 4

Level of evidence of treatment in Leigh syndrome according to treatment, number of studies and OCEBM score (4A), Jadad score (4B), combined Jadad and OCEBM score.

Fig. 5

Clinical trials for treatment of Leigh syndrome. LTE = long-term extension.

Fig. 6

Treatments for Leigh syndrome according to causal gene. Key: + = overall positive outcome, M = mixed outcome, - = negative outcome, CoQ10 = co-enzyme Q10, EPI-743 = Vatiquinone.

Fig. 7

Schematic representation of the mitochondrial genes and proteins with their links to the other metabolic pathways. The genes where we identified relevant references on treatments are in blue circles, the potential treatments are highlighted in red. The details of the relevant treatments are explained above. Key:B1 = thiamine, TPP = thiamine pyrophosphate, TKT = transketolase, DCA = dichloroacetic acid, PPP = pentose phosphate pathway, NA = nucleic acid, PDH = pyruvate dehydrogenase, CPT1 = carnitine palmitoyltransferaseI, Actyl CoA = acetyl co-enzyme A, CoQ = coenzyme Q, TCA = tricarboxylic acid, H₂S = hydrogen sulfide, GSH = glutathione, GSSH = glutathione persulfide, SQR = sulfide:quinone oxidoreductase, Cys = cysteine, Mn = manganese, MnSOD = manganese-superoxide dismutase, ROS = reactive oxygen species.