Glycine encephalopathy (nonketotic hyperglycinemia): Comments and speculations

Glycine encephalopathy (nonketotic hyperglycinemia or NKH) is an autosomal recessive disorder of glycine metabolism with a birth incidence of 1:63,000 in British Columbia, Canada [Applegarth et al., 2000a]. It is caused by defects in the glycine cleavage enzyme complex, which is responsible for the catabolism of glycine to CO2 and methylene tetrahydrofolate. Patients with the disease have increased levels of the amino acid glycine in blood, cerebrospinal fluid (CSF), and brain. Blood levels of glycine can, occasionally, be only modestly increased and usually initial laboratory diagnosis is basedonmarkedly increased levels of glycine inCSF. One-third of the patients die within the first year of life [Hamosh and Johnston, 2001], many in the neonatal period, often of respiratory impairment, which can be treated by providing respiratory support. This support can often be withdrawn after a few days and the patients then, usually, can breathe unassisted. Those who survive can live for many years, but remain severely neurologically impaired and have a developmental age of about 3–6 months. Most therapies aim at reducing glycine levels by complexing glycine with metabolites such as benzoate so as to increase glycine losses in urine and by attempting to ameliorate seizures with dextromethorphan. There is no totally successful therapy. The pathophysiology of the disease is usually ascribed to the effect of postnatally high glycine levels on receptors in brain. There are inhibitory glycine receptors in the brain stem and it is their interaction with glycine, which is believed to be responsible for the early postnatal respiratory difficulties. It is not clear why this respiratory suppression appears during the first few days orweeks of life and yet is not a continuing significant problem. The longer-term pathophysiology of the disease is usually ascribed to be the result of interactions of high brain glycine levels with excitatory Nmethyl-D-aspartate (NMDA) receptors in the cerebral cortex. There is some evidence for in utero brain damage in that the patients with glycine encephalopathy often have agenesis or dysgenesis of the corpus callosum and often have inadequate de novo synthesis of myelin [Shuman et al., 1978; Brun et al., 1979]. Mothers of affected children often report reduced fetal movement and in utero hiccups [Hamosh and Johnston, 2001]. Confirmation of diagnosis is difficult in most centers. Probably the commonest presentation is of a seizing infant who, fairly soon after birth, requires ventilation, most likely at the same time as laboratory investigations are in progress. Initial diagnosis, usually made by assay of glycine in plasma and CSF and exclusion of an organic acid disease by urinary organic acid assay [Applegarth and Toone, 2001], can be quite rapid, based on results of these analyses and clinical presentation. Confirmatory testing by either, or both, enzyme or molecular diagnosis is much slower. Almost all cases of glycine encephalopathy are caused by mutations in two genes (glycine decarboxylase (GLDC) and aminomethyltransferase (AMT)), which encode two of the four proteins (Pand Tproteins) within the glycine cleavage complex. Except in Finnish patients, no common mutations are described although it is likely that deletions in the areasofGLDCexons1, 2, and3maybecommon.Most unrelated patients will be compound heterozygotes [Applegarth and Toone, 2004]. Molecular diagnosis will usually require extensive sequencingof thePand T-protein genes requiring long turnaround times for assay results.On this continent,molecular analyses are routinely available only in Vancouver and Denver in