Triheptanoin - Novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency.

Mitochondrial malate dehydrogenase (MDH2) deficiency (MDH2D) is an ultra-rare disease with only three patients described in literature to date. MDH2D leads to an interruption of the tricarboxylic acid (TCA) cycle and malate-aspartate shuttle (MAS) and results in severe early onset encephalopathy. Affected infants suffer from psychomotor delay, muscular hypotonia and frequent seizures. Laboratory findings are unspecific, including elevated lactate in blood and cerebrospinal fluid. Brain magnetic resonance imaging reveals delayed myelination and brain atrophy. Currently there is no curative therapy to treat this devastating disease. Here, we present a female patient diagnosed with MDH2D after a stroke-like episode at 18 months. Trio-whole exome sequencing revealed compound heterozygous missense variants in the MDH2 gene: c.398C>T, p.(Pro133Leu) and c.445delinsACA, p.(Pro149Hisfs*22). MDH2 activity assay and oxygraphic analysis in patient's fibroblasts confirmed the variants were pathogenic. At the age of 36 months, a drug trial with triheptanoin was initiated and well tolerated. The patient's neurologic and biochemical phenotype improved and she had no further metabolic decompensations during the treatment period suggesting a beneficial effect of triheptanoin on MDH2D. Further preclinical and clinical studies are required to evaluate triheptanoin treatment for MDH2D and other TCA cycle and MAS defects.

A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood.

BACKGROUND: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. RESULTS: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated. CONCLUSIONS: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.