Successful anticonvulsive therapy with D/L 3-hydroxybutyrate and ketogenic diet in a boy with agininosccinate lyase deficiency and status epileptics minor

Ketogenic Diet is indicated in pharmacoresistent epilepsy, but seems to be contraindicated in urea cycle defects, because metabolic changes are comparable to a fast. Alternatively, administration of 3-β-Hydroxybutyrate (BHB) is discussed. D/L BHB is successfully used in few patients with hypoketotic neurometabolic disorders like Glutaric aciduria type II.

The 6 years old with argininosuccinate lyase deficiency (ASL) was diagnosed as neonate with hyperammonemia. In the next years, receiving standard treatment, he showed psychomotor retardation. Seizures, starting at 2 years, were treated with Phenobarbital and Oxcarbazepin. With 4 years myoclonic seizures started and he had loss of acquired functions, discharging into episodes of deep somnolenz. EEG revealed bioelectric status. Therapy was performed with Diazepam, Phenytoine, Clonazepam, Topiramate, Gabapentine and repeated Methylpedrnisolone pulses without response. Felbamate disrupted status epilepticus but status relapsed within 4 month. While ketogenic diet was contraindicated, treatment with D/L BHB was started to mimic the metabolic effects of ketogenic diet. D/L BHB (Sigma Aldrich) was administered 6 times per day with increasing dosage up to 2g/kg. BHB concentrations in Plasma were 0.6–1 mmol/l. Clinical status of the boy improved and EEG improved. After 4 month of treatment the boy was hospitalized due to increasing vomiting. Plasma and urine amino acid profile showed very high amounts of β-aminobutyric- and β-aminoisobutyric acid, which we discussed to be a side effect of the BHB therapy. Vomiting resolved stopping the BHB therapy and amino acid pattern normalized. Because status minor relapsed, ketogenic diet was started with a 2:1 fat: carbohydrate/protein ration and was clinically effective at BHB concentrations between 0.6–1 mmol/l. Higher ketosis worsened the situation. Clinical status was stable for subsequent 1 year without metabolic decompensation and neurological function significantly improved.

This case report demonstrates that treatment with D/L BHB can be effective in the sense of a ketogenic diet, but may lead to an accumulation of recemic derivatives with signs of intoxication, because only D-BHB can be metabolized. However, ketogenic diet, against general concerns, was successfully performed resulting in disruption of status minor and neurological improvement. Pharmacoresistent epilepsy in ASL is common and its ethiology remains unclear, but ketogenic diet should be discussed.