Novel Treatment Approach for Ultrarare MDH2D Detailed in Patient Case

To date, just 3 previous reports have detailed cases of mitochondrial malate dehydrogenase deficiency (MDH2D), and there are no known cures.

A recent case report is putting a spotlight on a new approach to treating mitochondrial malate dehydrogenase deficiency (MDH2D): triheptanoin. The treatment, according to the researchers writing in Molecular Genetics and Metabolism Reports, elicited improvements in both the patient’s medical condition and their social ability.

MDH2D is an ultrarare disease that causes an undersupply of energy to organs that require high allotments of energy, like the brain and muscles, due to enzyme and transporter deficiencies of the tricarboxylic acid (TCA) cycle and the malate-aspartate shuttle (MAS). As a result, infants with the disease often experience psychomotor delay, muscular hypotonia, and seizures. To date, just 3 previous reports have detailed cases of MDH2D, and there are no known cures.

“A therapeutic strategy to attenuate the effects of MDH2D is to increase the amount of available substrates in the mitochondria to ensure a proper flux of energy through the TCA cycle and to improve the intracellular NADH/NAD+ homeostasis by bypassing the MAS,” wrote the researchers. “Using [medium-chain triglycerides] as a treatment for MAS defects has been suggested. Therefore, a clinical trial with the odd-chain triglyceride triheptanoin known for its anaplerotic effect was introduced and well tolerated by our patient.”

In the current report, the researchers outline the case of a 4-year-old girl—diagnosed with MDH2D at age 18 months—who began receiving triheptanoin at 36 months. According to the researchers, there were no adverse events reported, with the exception of frequent hiccups. While on treatment, the patient did not experience any metabolic decompensation; prior to treatment, there were 6 instances in which the patient either had emergency consultations or was hospitalized for metabolic decompositions.

Although the patient’s head remained smaller than expected, her weight normalized. Her manual skills remained stable and her gross motor function improved slightly. More detailed findings showed that her movements, such as reaching and grasping, became more purposeful, and her verbal skills and functional play improved.

“While it is difficult to differentiate between the effects of triheptanoin treatment and the spontaneous remission the patient might have undergone during the observation period, it is impressive how her medical condition improved,” noted the researchers. “Most strikingly during the entire treatment period she did not suffer from any metabolic decompensation unlike the 6 metabolic decompensations she experienced prior to treatment with triheptanoin. From a biochemical point of view the most striking result was a significant decrease in plasma lactate levels in response to triheptanoin.”

The researchers note that more research into the treatment for MDH2D and how it impacts the disease is needed to better determine its effectiveness.


Laemmle A, Steck A, Schaller A, et al. Triheptanoin – novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency. Mol Genet Metab Rep. 2021;29:100814. doi:10.1016/j.ymgmr.2021.100814