An Examination of Serum Acylcarnitine and Amino Acid Profiles at Different Time Point of Ketogenic Diet Therapy and Their Association of Ketogenic Diet Effectiveness

Background: This study aimed to identify metabolic parameters at different time points of ketogenic diet therapy (KDT) and investigate their association with response to KDT in pediatric drug-resistant epilepsy (DRE). Methods: Prospectively, twenty-nine patients (0.67~20 years old) with DRE received classic ketogenic diet with non-fasting, gradual KD initiation protocol (GRAD-KD) for 1 year were enrolled. A total of 22 patients remaining in study received blood examinations at baseline, 3rd, 6th, 9th, and 12th months of KDT. β-hydroxybutyrate, free carnitine, acylcarnitines, and amino acids were compared between responders (seizure reduction rate ≥ 50%) and non-responders (seizure reduction rate < 50%) to identify the effectiveness of KDT. Results: The 12-month retention rate was 76%. The responders after 12 months of KDT were 59% (13/22). The free carnitine level decreased significantly at 9th months (p < 0.001) but increased toward baseline without symptoms. Propionyl carnitine (C3), Isovaleryl carnitine (C5), 3-Hydroxyisovalerylcarnitine (C5:OH) and methylmalonyl carnitine (C4-DC) decreased but 3-hydroxybutyrylcarnitine (C4:OH) increased significantly at 12th months of KDT. The glycine level was persistently higher than baseline after KDT. KDT responders had lower baseline C3 and long-chain acylcarnitines, C14 and C18, as well as lower C5, C18, and leucine/isoleucine. Conclusions: KDT should be avoided in patients with non-ketotic hyperglycemia. Routine carnitine supplementation is not recommended because hypocarnitinemia was transient and asymptomatic during KDT. Better mitochondrial βoxidation function associates with greater KDT response.

Effect of intravenous glutamine on duodenal mucosa protein synthesis in healthy growing dogs

To determine whether glutamine acutely stimulates protein synthesis in the duodenal mucosa, five healthy growing dogs underwent endoscopic biopsies of duodenal mucosa at the end of three 4-h primed, continuous intravenous infusions ofl-[1-13C]leucine on three separate days, while receiving intravenous infusion of 1) saline, 2)l-glutamine (800 μmol ⋅ kg−1 ⋅ h−1), and 3) isonitrogenous amounts of glycine. The three infusions were performed after 24 h of fasting, a week apart from each other and in a randomized order. Glutamine infusion induced a doubling in plasma glutamine level, and glycine caused a >10-fold rise in plasma glycine level. During intravenous infusions of [13C]leucine, the plasma leucine labeling attained a plateau value between 3.22 and 3.68 mole % excess (MPE) and [13C]ketoisocaproate ([13C]KIC) of 2.91–2.84 MPE; there were no significant differences between glutamine, glycine, and saline infusion days. Plasma leucine appearance rate was 354 ± 33 (SE), 414 ± 28, and 351 ± 35 μmol ⋅ kg−1 ⋅ h−1(not significant) during glycine, saline, and glutamine infusion, respectively. The fractional synthetic rate (FSR) of duodenal mucosa protein was calculated from the rise in protein-bound [13C]leucine enrichment in the biopsy sample, divided by time and with either plasma [13C]KIC or tissue free [13C]leucine as precursor pool enrichment. Regardless of the precursor pool used in calculations, duodenal protein FSR failed to rise significantly during glutamine infusion (65 ± 11%/day) compared either with saline (84 ± 18%/day) or glycine infusion days (80 ± 15%/day). We conclude that 1) plasma [13C]KIC and tissue free [13C]leucine can be used interchangeably as precursor pools to calculate gut protein FSR; and 2) short intravenous infusion of glutamine does not acutely stimulate duodenal protein synthesis in well-nourished, growing dogs.

Efficacy of Tryptophan for the Treatment of Nonketotic Hyperglycinemia: A New Therapeutic Approach for Modulating the N-Methyl-D-aspartate Receptor

Nonketotic hyperglycinemia (NKH) is a rare inherited disease caused by a defect of the glycine cleavage enzyme.1 Especially in the neonatal type, neurological symptoms such as muscular hypotonia, seizures, respiratory distress, and lethargy develop rapidly, and the prognosis is unfavorable.1 Elevation of glycine in the cerebrospinal fluid (CSF) is thought to be responsible for these symptoms. However, management is quite difficult, because it is not well understood how elevation of glycine causes these symptoms. Lowering of the glycine level in CSF with sodium benzoate is not enough to avoid severe psychomotor and mental retardation. The N-methyl-D-aspartate (NMDA) receptor, which is one of the excitatory amino acid receptors, has a glycine binding site.2

Metabolic Effects of Prostatectomy

Transurethral resection syndrome (TURS), complicating transurethral resection of the prostate (TURP) has been ascribed to hyponatraemia but reports have indicated that hyperammonaemia following metabolism of glycine can be the main cause. Prospective data has been collected on 96 prostatectomy patients (82 TURP and 14 retropubic). The retropubic group showed no significant postoperative change in the serum sodium or plasma ammonia. Of the TURP group, no TURS occurred although hyponatraemia was noted in 32 patients. The weight of prostate resected, the volume of glycine used, the time taken and the plasma ammonia levels were not significantly different in the normonatraemic or hyponatraemic groups. In severely hyponatraemic patients (13 out of 32 with a 10mmol/l, or greater, decrease in serum sodium) there was a significant rise (P≤0.05) in plasma ammonia, 1 or 4 h post TURP, which had decreased by 24 h. There was a highly significant increase in serum glycine level in the hyponatraemic compared with the normonatraemic group (P≤0.001). There was no correlation between serum glycine and plasma ammonia levels in the normonatraemic or hyponatraemic group. There were nine patients with post TURP plasma ammonia levels ≥ 100 μmol/l (mean 254) who experienced no mental confusion: six of these patients were hyponatraemic. The weight of prostrate resected (mean 26 g), volume of glycine used (mean 181) and operation time (mean 39 min) were all relatively low. Subsequently, TURS has occurred in a patient, with severe hyponatraemia and hyperglycinaemia but no hyperammonaemia. This study shows that hyperammonaemia does not always correlate with hyponatraemia or hyperglycinaemia, and high plasma ammonia levels can occur in the absence of TURS.

Failure of Strychnine Treatment during the Neonatal Period in Three Finnish Children with Nonketotic Hyperglycinemia

Three Finnish infants with a severe neonatal-onset-type of nonketotic hyperglycinemia were treated with strychnine nitrate in a daily dosage of 0.2 to 0.9 mg/kg, given orally in four doses. In order to lower the plasma and CSF-glycine concentrations concomitant exchange transfusions (200 to 300 ml/kg of heparinized blood) were carried out in two of these infants. Although the strychnine therapy was started at ages 15, 40, and 62 hours, the strychnine produced no clinical effect, and the exchange transfusion caused only a transient decrease in the plasma glycine level. Despite treatment, the clinical course was the same as in the majority of children with the severe form of the disease—all died within the first ten days of life. Impressive effects of strychnine treatment initiated in two infants at ages 5 and 6½ months, and given in addition to sodium benzoate and anticonvulsants, have been reported. These cases, however, probably represent a less severe type of nonketotic hyperglycinemia. Nevertheless, the therapeutic failure in the present cases probably indicates that strychnine treatment does not solve the therapeutic problems of severe forms of NKH.