P 605. Epileptic Encephalopathy Caused by Mitochondrial MPC-1 Deficiency Can Benefit from Ketogenic Diet—Significance of Early Genetic Testing for a Targeted Therapy

Background: The mitochondrial pyruvate carrier (MPC) complex, a heterodimer composed of the subunits MPC1and MPC2, is located in the mitochondrial inner membrane importing pyruvate into the mitochondrial matrix. Pyruvate is the final product of glycolysis as well as the main substrate of the tricarboxylic acid cycle. Therefore, it serves as key metabolite linking catabolic pathways to the anabolic pathways of lipid and amino acid biosynthesis as well as gluconeogenesis.¹

Up to today, three consanguineous families have been described carrying biallelic variants in MPC1. Patients present with lactate acidosis, developmental delay, muscular hypotonia, and epileptic encephalopathy.^2,3 MPC deficiency is lethal in a mouse model: MPC-deficient mouse pups only survive gestation when the pregnant dams were fed a ketogenic diet.⁴

Aims: We present a MPC1 deficiency in a 2016 born boy (consanguineous parents of Syrian origin. Mother primipara, primigravida, no family history of known mitochondriopathy: birth via primary cesarean due to breech presentation after 38 + 4 weeks of gestation in an external maternity clinic. Referral to neonatal intensive care unit due to difficulties with respiratory adaptation and elevated lactate levels. Initial onset of myoclonic seizures at 2.5 months. Start on anticonvulsive medication which soon proves to be pharmacoresistant. Subsequently, myoclonic seizures shift to infantile spasms and evidence of hypsarrhythmia. Meanwhile, a severe combined developmental delay becomes apparent.

Primary Question: What is the significance of an early genetic testing for a targeted therapy of epileptic encephalopathy in mitochondrial diseases?

Methods: Further metabolic analysis pointed to a disorder of mitochondrial metabolism (cerebrospinal fluid [CSF]: elevated lactate, diminished glucose CSF/blood ratio; blood: lactate acidosis, hyperammonia, elevated alanine/lysine ratio; urine organic acids: elevated excretion of lactate and pyruvate, as well as further metabolites of citrate cycle). Cerebral imaging in September 2017 showed a characteristic magnetic resonance imaging pattern which was initially interpreted as evidence for a neurometabolic disorder (progredient deficit of supratentorial white matter substance, marked enlargement of inner and outer subarachnoidal space, delayed myelinization, symmetric signal alterations of both pallidum and median thalamic nucleus with diffusion impairment. No lactate peak in spectroscopy).

Exome sequencing at 10 months revealed a not as yet published homozygous missense variation c.85A>G, p.(Lys29Glu) in MPC1 (NM_001270879.1), both parents being heterozygous carriers.

Results: According to findings in the mouse model, we started an individualized therapy with ketogenic diet in a 2.5:1 ratio. The comedication with vigabatrine and lamotrigine was continued. This resulted in the cessation of hypsarrhythmia and infantile spasms. The little boy became more alert and showed interaction with his parents. Currently, he is 21 months old and is on ketogenic diet for 8 months now. Seizure situation is stable after a relapse which was successfully treated with increase of ketogenic diet ratio to 4:1 and an add-on medication of topiramate. Severe developmental delay is still present.

Conclusion: Ketogenic diet led to an improvement of epileptic encephalopathy in a toddler with MPC-1 deficiency. Comparison with the mouse model suggests that an early start of ketogenic diet is crucial for a treatment at the best possible rate. This example illustrates once more the importance of an early genetic diagnosis for a targeted therapy.

References

1. Bender T, Martinou JC. The mitochondrial pyruvate carrier in health and disease: to carry or not to carry? Biochim Biophys Acta 2016;1863(10):2436–2442

2. Brivet M, Garcia-Cazorla A, Lyonnet S, et al. Impaired mitochondrial pyruvate importation in a patient and a fetus at risk. Mol Genet Metab 2003;78(3):186–192

3. Bricker DK, Taylor EB, Schell JC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science 2012;337(6090):96–100

4. Vanderperre B, Herzig S, Krznar P, et al. Embryonic lethality of mitochondrial pyruvate carrier 1 deficient mouse can be rescued by a ketogenic diet. PLoS Genet 2016;12(5):e1006056