Objective.The ketogenic diet is a well-known treatment for epilepsy. Despite decades of research, it is not yet known how the diet accomplishes its anti-seizure efficacy. One of the earliest proposed mechanisms was that the ketogenic diet is able to replenish cellular energy stores in the brain. Although several mechanisms have been suggested for how energy depletion may contribute to seizure generation and epileptogenesis, how the dynamics of energy depletion actually leads to abnormal electrical activity is not known.Approach.In this work, we investigated the behavior of the tripartite synapse using a recently developed neurochemical model, which was modified to include ketone chemistry. We ran transient, non-steady-state simulations mimicking normoglycemia and ketosis for metabolic conditions known to be clinically treated with the ketogenic diet, as well as a condition for which the ketogenic diet was not effective clinically.Main results.We found that reduction in glucose, as well as pathological decreases in the activity of glucose transporter 1, pyruvate dehydrogenase complex, monocarboxylate transporter 1 (MCT1), and mitochondrial complex I, all led to functioning of the tripartite synapse in a rapid burst-firing mode suggestive of epileptiform activity. This was rescued by the addition of the ketone D-β-hydroxybutyrate in the glucose deficit, glucose transporter 1 deficiency, and pyruvate dehydrogenase complex deficiency, but not in MCT1 deficiency or mitochondrial complex I deficiency.Significance.We demonstrated that replenishment of cellular energy stores is a feasible mechanism for the efficacy of the ketogenic diet. Although we do not rule out other proposed mechanisms, our work suggests that cellular energy repletion may be the primary action of the ketogenic diet. Further study of the contribution of energy deficits to seizure onset and even epileptogenesis may yield novel therapies for epilepsy in the future.

Monocarboxylate transporter 1 (MCT1) deficiency (OMIM# 616095), caused by variants in the SLC16A1 gene (OMIM# 600682), is responsible for the transport of monocarboxylates across the plasma membrane. This condition is recognized as a rare genetic cause of impaired ketone body utilization in extrahepatic tissues, resulting in recurrent ketoacidosis triggered by fasting and infection. To date, only 17 patients with this disorder have been identified. Individuals with homozygous variants typically present at a younger age, exhibit developmental delays, and experience more severe ketoacidosis. We describe the genotype and clinical phenotype of three Palestinian children with MCT1 deficiency from two unrelated families. In an extended consanguineous family (Family A), whole exome sequencing identified a novel homozygous missense variant, SLC16A1_p.Gly25Val, in patient 1. Patient 2 was homozygous for the same variant. In unrelated family B, exome sequencing of patient 3 revealed another novel homozygous missense variant, SLC16A1_p.Leu403Phe. The clinical phenotypes and biochemical abnormalities were similar across all three patients, characterized by acute recurrent vomiting, severe dehydration, metabolic acidosis, and hyperuricemia. MCT1 deficiency should be considered in infants and children who experience recurrent ketoacidosis. We report two novel homozygous variants in the SLC16A1 gene, further expanding the genotype-phenotype spectrum of this rare disorder.

Monocarboxylate transporter 1 (MCT1) deficiency (MIM #616095) is a relatively new identified cause of recurrent ketoacidosis triggered by fasting or infections. MCT1 was first described in 2014 by van Hasselt et al. to result from both homozygous and heterozygous mutations in the SLC16A1 gene. Patients with homozygous mutations are known to have a more severe phenotype with developmental delay and epilepsy. Thirteen patients with MCT1 deficiency with ketoacidosis have been reported in the literature to date. We describe a developmentally normal male patient with heterozygous missense variation in the SLC16A1 gene. Our patient who presented with cyclic vomiting and ketoacidosis episodes was found to have a heterozygous c.303T > G (p.Ile101Met) missense mutation. It is crucial to take early preventive measures and to minimize the harmful effects of ketoacidotic episodes. MCT1 deficiency should be considered in the differential diagnosis of ketoacidosis in patients with normal SCOT and ACAT1 activities.

Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete. The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function variation c.747_750del in homozygosity in SLC16A1 (which codes for MCT1). Persistent ketotic and lactic acidosis was accompanied by an abnormal excretion of organic acids related to redox balance disturbances. Together with an altered bioenergetic profile detected in patient-derived fibroblasts, this suggests possible mitochondrial dysfunction. Brain MRI revealed extensive, diffuse bilateral, symmetric signal alterations for the subcortical white matter and basal ganglia, together with corpus callosum agenesia. These findings suggest that the clinical spectrum of MCT1 deficiency not only involves recurrent atacks of ketoacidosis, but may also cause lactic acidosis and neuromotor delay with a distinctive neuroimaging pattern including agenesis of corpus callosum and other brain signal alterations.

Monocarboxylate transporter 1 (MCT1) deficiency was first described in 2014 by Hasselt et al. as a novel genetic cause of recurrent ketoacidosis. Patients present in the first year of life with acute episodes of ketoacidosis triggered by fasting or infections. Patients with homozygous mutations are known to have a more severe phenotype with mild to moderate developmental delay and an increased prevalence of epilepsy. There is only one recent report of the neuroimaging findings of this disorder as reported by Al-Khawaga et al. (Front Pediatr. 7:299, 2019). We report the neuroimaging abnormalities in two siblings with similar clinical presentation of recurrent ketoacidosis, seizures, and developmental delay. Whole exome sequencing in the younger sibling confirmed a known pathogenic homozygous mutation in MCT1, also known as SLC16A1 gene. Brain MRI showed a similar very distinctive pattern of signal abnormality at the gray-white matter junction, basal ganglia, and thalami in both patients. Both siblings had agenesis of the corpus callosum. Knowledge of this pattern of brain involvement might contribute to an earlier diagnosis and timely management of this rare and under recognized disorder.