Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels

Abstract

Background Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. Aim We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. Methods Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). Results Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. Conclusion KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.

Deep postnatal phenotyping of a new mouse model of nonketotic hyperglycinemia

“…Epilepsy is a key symptom of NKH in human patients, which partially improves upon reducing glycine using benzoate therapy or ketogenic diet. 6,28 While we did not observe signs of epilepsy in our mice, there was an increase in the spontaneous rate of electrographic spikes on EEG, and this increase was significantly exacerbated with glycine challenge. Determination of the epileptic threshold could be a next step.…”

“…3,19 Most past hypotheses of the pathophysiology have focused primarily on neurotoxicity caused by excess glycine, [20][21][22] or on end-product deficiency of glycine derived one-carbon units to folate via 5,10methylene-THF. [23][24][25] Current therapy is exclusively focused on mitigating the effects of excess glycine and comprises glycine reduction strategies using benzoate or ketogenic diet [26][27][28] and dextromethorphan to decrease putative excessive neurotransmission at the N-methyl-D-aspartate receptor. 29,30 Early treatment moderately improves outcomes in attenuated NKH, 31 but this treatment is ineffective in changing the outcome in severe NKH, even when initiated neonatally.…”

“…3,6 Glycine reduction through benzoate or through a ketogenic diet increases wakefulness, thus providing a link to the reduction of glycine to diminish the encephalopathic effect. 26,28,75 Female J129 mice, who have higher brain cortex glycine levels, appeared to have a lower alpha/delta band intensity ratio on EEG in the left cortex, reflecting a greater encephalopathic effect. Functionally, they moved slower and traveled less in the Open Field test, explored the Y-maze test less, and had worse initial performance on the Radial Arm Water Maze.…”

The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype

“…Current treatment consists of glycine reduction and mitigation of purported glycine toxicity. There are two glycine-reduction strategies aimed at normalizing plasma glycine levels to 120-300 µM [ 2 ], which reduces but does not normalize brain glycine levels [ 13 ]. First, benzoate is given, which conjugates with glycine and is excreted in the urine as hippurate thus lowering plasma glycine levels [ 3 , 14 , 15 ].…”

“…First, benzoate is given, which conjugates with glycine and is excreted in the urine as hippurate thus lowering plasma glycine levels [ 3 , 14 , 15 ]. Second, ketogenic diet results in glycine lowering by use of glycine as a gluconeogenic precursor [ 13 ]. Both glycine lowering treatments result in increased alertness and improved seizure control, but the effect on behavior is not reported.…”