Nonketotic Hyperglycinemia: Insight into Current Therapies

Abstract

Nonketotic hyperglycinemia (NKH) is a rare inborn error of glycine metabolism that is characterized by the accumulation of glycine in all tissues, especially in the central nervous system (CNS). Based on clinical outcomes, NKH can be divided into two forms, i.e., severe and attenuated NKH. A poor prognosis, including no developmental progress and intractable epilepsy, is typical of severe NKH, whereas patients with the attenuated form present with varied symptoms and neurodevelopmental outcomes. So far, no causal treatment of NKH is known. Currently, the therapy is based on sodium benzoate and NMDA (The N-methyl-D-aspartate receptor) receptor site antagonists (dextromethorphan, ketamine). Different clinical outcomes of the therapy raise doubts about the effectiveness of the treatment. The purpose of this review is to summarize the therapeutic potential, challenges and effectiveness of different NKH therapies.

Neonatal Status Epilepticus Secondary to Nonketotic Hyperglycinemia: Efficacy of Low-Dose Dextromethorphan

“…9 In summary, no causal treatment of NKH is known to date, and the therapy is based on sodium benzoate and NMDA receptor site antagonists such as dextromethorphan, but different clinical outcomes of the therapy raise doubts about the effectiveness of the treatment. 10 Based on the current literature, the impact of different antiepileptic drugs on outcome in NKH remains to be determined, as blinded clinical trials are not possible based on the low incidence of NKH. It is hard to know if the improvement in the patient was only related to dextromethorphan onset or due to synergistic effect of previously initiated antiepileptic drugs.…”

Endogenously produced hydrogen cyanide serves as a novel mammalian gasotransmitter

“…Glycine encephalopathy (also known as nonketotic hyperglycinemia or NKH) 32 is a devastating disease caused by mutations in the genes GLDC or AMT (genes that encode essential proteins of the glycine cleavage enzyme system), leading to a pathological buildup of glycine in the cells and blood of NKH patients. We hypothesized that NKH could also result in the cellular accumulation of endogenous intracellular cyanide, potentially contributing to cytotoxic effects.…”

Cycling back to folate metabolism in cancer

“…Glycine donates a 1C unit to THF to produce 5,10-methylene-THF in a reaction catalysed by a mitochondrial enzymic complex called the glycine cleavage system (GCS) 25 . However, the principal role of the GCS appears to be to limit glycine accumulation, with germline mutations in GLDC (a major component of the GCS) resulting in glycine encephalopathy 26 . Most recently, the 1C units produced by GCS have been suggested to drive reverse flux of SHMT2, producing serine and clearing excess mitochondrial glycine in the liver 27 .…”