Nonketotic hyperglycinemia (NKH) is an inborn error of metabolism caused by deficiency or dysfunction of the glycine cleavage system (GCS), an enzyme complex expressed in liver, kidney, brain, and placental mitochondria. Affected individuals develop lethargy, apnea, and myoclonus in the first days of life. Those surviving the neonatal period develop intractable seizures and profound mental retardation. Dysfunction of the GCS leads to accumulation of glycine in plasma and all body tissues including the brain. The clinical phenotype is thought to result from glycine's role as a neurotransmitter: inhibitory in the brain stem and spinal cord when acting upon the strychnine-sensitive glycine receptor; excitatory in the forebrain when acting upon the NMDA-receptor channel complex. The role of the GCS in modulating CNS glycine concentrations is unknown as are the effects of elevated brain glycine concentration upon the inhibitory glycine receptor and upon NMDA receptor levels, subunit composition, and distribution. An animal model of NKH will facilitate a comprehensive appreciation of the pathophysiology of this disease process and provide insight into the normal biology of glycine and the GCS and potentially the pathogenic role of this system in other disorders such as idiopathic epilepsy and hypoxic-ischemic injury. The overall goal of this project is to create a mouse model for NKH and to characterize the NKH mouse phenotypically, biochemically, neuroanatomically and neurochemically. The mouse will be made by targeted disruption of the murine glycine decarboxylase gene using homologous recombination in embryonic stem cells. The quantity and distribution of glycine decarboxylase mRNA and protein will be determined by in situ hybridization, Northern blot analysis, immunocytochemistry and Western blot analysis. Quantitation of GCS activity in the brain and liver and of plasma, CSF, and tissue glycine concentrations will be performed. Phenotypic parameters include survival, growth, feeding, movements, activity level, fertility, and electroencephalographic analysis. The effect of elevated glycine concentrations upon brain development and pathology will be assessed by Nissl and hematoxylin staining of embryonic and postnatal mouse brains. The distribution and subunit composition of NMDA and other glutamate receptors will be determined by specific antibodies.
| Hamosh, A; Maher, J F; Bellus, G A et al. (1998) Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia. J Pediatr 132:709-13 |
