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

Alexander Laemmle; Andrea Lisa Steck; André Schaller; Sandra Kurth; Eveline Perret Hoigné; Andrea Deborah Felser; Nedelina Slavova; Claudia Salvisberg; Mariana Atencio; Fanny Mochel; Jean-Marc Nuoffer; Matthias Gautschi

doi:10.1016/j.ymgmr.2021.100814

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

Mol Genet Metab Rep. 2021 Oct 19:29:100814. doi: 10.1016/j.ymgmr.2021.100814. eCollection 2021 Dec.

Authors

Alexander Laemmle^{1

2}, Andrea Lisa Steck², André Schaller³, Sandra Kurth¹, Eveline Perret Hoigné², Andrea Deborah Felser^{1

2}, Nedelina Slavova^{4

5}, Claudia Salvisberg², Mariana Atencio⁶, Fanny Mochel^{6

7}, Jean-Marc Nuoffer^{1

2}, Matthias Gautschi^{1

2}

Affiliations

¹ Institute of Clinical Chemistry, Inselspital, University Hospital Bern, Bern, Switzerland.
² Department of Pediatrics, Inselspital, University Hospital Bern, Bern, Switzerland.
³ Department of Human Genetics, Inselspital, University Hospital Bern, Bern, Switzerland.
⁴ Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁵ University Institute of Diagnostic and Interventional Neuroradiology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland.
⁶ Paris Brain Institute (ICM), Sorbonne University UMR S 1127, Inserm U1127, CNRS UMR 7225, Paris, France.
⁷ AP-HP, Pitié-Salpêtrière University Hospital, Department of Genetics and Reference Center for Neurometabolic Diseases, Paris, France.

Abstract

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.

Keywords: Encephalopathy; Inborn errors of the tricarboxylic acid cycle; Malate-aspartate shuttle; Mitochondrial malate dehydrogenase deficiency; Triheptanoin.