REVIEW Special Focus Clinical variability in glycine encephalopathy Julia B Hennermann Glycine encephalopathy (GCE) is an autosomal recessive error of glycine degradation, Otto Heubner Center for resulting in a poor outcome with severe mental retardation, intractable seizures and Pediatric & Adolescent Medicine, Charité spasticity. Milder variants with a significantly better outcome have been reported, but an Universitätsmedizin Berlin early prediction of the long-term outcome is not yet possible. With regard to the long-term Augustenburger Platz 1, outcome, the data reported in the literature of children with different GCE forms were 13353 Berlin, Germany compared. Determination of cerebrospinal fluid and plasma glycine concentrations at the Tel.: +49 304 5066 6191; Fax: +49 304 5056 6918; time of diagnosis were not useful in differentiating mild and severe outcomes. By contrast, [email protected] several clinical parameters correlate with a poor outcome: spastic quadriparesis, truncal hypotonia, typical electroencephalography patterns, congenital and cerebral malformations (e.g., corpus callosum hypoplasia). Hyperactivity, behavioral problems and choreiform movement disorders are associated with a milder outcome. Thus, prediction of the outcome of GCE may be facilitated by searching for selected clinical parameters. In addition, early neuroimaging may be a valuable tool in predicting the outcome of GCE. Glycine encephalopathy ([GCE]; synonym: intracellular free calcium accumulation resulting nonketotic hyperglycinemia; Online Mendelian in neuronal injury, with subsequent cell death Inheritance in Man [OMIM] 605899) is an and intractable seizures [1,5]. Furthermore, gly- autosomal recessive inborn error of glycine deg- cine is a neurotransmitter on the glycinergic radation resulting in an excessive accumulation receptors, located in the spinal cord and the of glycine in all tissues, particularly in the CNS. brain stem. Stimulation of these receptors has an Patients may be diagnosed biochemically by the inhibitory effect due to an enhanced chloride typical combination of an increase of glycine in permeability in the postsynaptic neurons, and is plasma and cerebrospinal fluid (CSF), with an likely to be involved in muscular hypotonia, neo- increased CSF–plasma glycine ratio. The under- natal apnea and hiccupping in children with lying defect is a deficiency of the glycine cleavage GCE [1]. The excitatory effect of these receptors system (GCS), an intramitochondrial enzyme on neural progenitor cells could be involved in complex made up of four different protein com- the malformations sometimes observed in ponents: the P-protein (a pyridoxal phosphate- patients with GCE [6]. dependent glycine decarboxylase [GLDC]), the As far as is predictable, the prevalence of GCE T-protein (a tetrahydrofolate-dependent protein seems to be approximately 1 in 60,000 [1,7]. Most [AMT]), the H-protein (a lipoic acid containing patients suffer from the severe neonatal form (clas- hydrogen-carrier protein [GCSH]), and the sic GCE), presenting in the first few days of life L-protein (lipoamide dehydrogenase) [1]. with muscular hypotonia, seizures, lethargy and Approximately 65–80% of children with GCE apnea, leading to an early death or severe global have a defect in the P-protein, with the rest hav- mental retardation, intractable seizures and spastic ing a defect in the T-protein. A defect in the quadriparesis. Patients with milder forms of GCE H-protein has been described in one single show variable degrees of mental retardation and Keywords: atypical patient. Abnormalities in the L-protein have not seizures, behavioral problems and choreoiform nonketotic hyperglycinemia, been reported in GCE [1–4]. movement disorders. Patients with transient GCE glycine cleavage system, Glycine functions both as an inhibitory and have rarely been described, mimicking the clinical glycine decarboxylase, glycine encephalopathy, hydrogen excitatory neurotransmitter. It acts as a neuro- and biochemical features of classic GCE during carrier protein, nonketotic modulator with an excitatory effect at the the neonatal period, but resulting in a good hyperglycinemia, outcome, N-methyl-D-aspartate (NMDA) receptor chan- neurological outcome with no, or only slight, neu- symptoms, tetrahydrofolate- dependent protein nel complex located in the cortex and the fore- rological sequelae [1,4]. An early prediction of the brain. GCS deficiency causes an accumulation of outcome of GCE at the time of manifestation is glycine in the synaptic cleft, leading to an over- not yet possible. In addition, an effective stimulation of the NMDA receptor at the gly- treatment does not exist. Current therapy is cine modulatory site. This causes an increased directed at decreasing the glycine concentration 10.2217/14796708.1.5.621 © 2006 Future Medicine Ltd ISSN 1479-6708 Future Neurol. (2006) 1(5), 621–630 621 REVIEW – Hennermann and at blocking the effect of glycine at neuro- outcome with a developmental quotient (DQ) of transmitter receptors. Glycine plasma concentra- less than 10. They have a developmental age of tions may be reduced by benzoate treatment and approximately 6 weeks old and may learn to by a low protein diet. The optional treatment smile, but only occasionally learn to grasp objects with NMDA receptor agonists includes dex- and/or to sit [10]. In contrast to children with mild trometorphane, ketamine and felbamate. Addi- GCE, they seldom show hyperactivity and/or tionally, combined anticonvulsive treatment is behavioral problems (Table 1). Approximately necessary in most children with GCE, mainly in 30% die during the neonatal period [9–10]. those with classic GCE. To facilitate the classifica- Long-term problems in patients with classic tion and prognosis of children with GCE findings GCE variably include feeding difficulties, bile on clinical symptoms, laboratory results, electro- stones, gastroesophageal reflux and esophagitis, encepholography (EEG) and neuroimaging of all some of which represent side effects of patients with a mild or transient form of GCE treatment [8]. Some children require gastric tube reported in the literature were compared with sur- feeding. Further problems involve the skeletal veys on children with classic GCE, this was system, including hip dislocation, scoliosis and mainly the survey performed by our group [8]. osteoporosis [1]. Females had been reported to show a more devastating course of the disease [9], Clinical course which was not confirmed by our data [8]. Classic glycine encephalopathy The typical clinical picture of GCE is that of chil- Mild glycine encephalopathy variants dren with classic GCE, which starts early in the All children with GCE have an impaired DQ of neonatal period with ensuing poor outcome. varying degrees, but 15–20% of them, termed During the first 3 days of life, at least two thirds mild GCE, show a significantly better clinical of the children present with muscular hypotonia, outcome, reaching a DQ of 25–80 [9–10]. They apnea and coma [8,9]. Seizures may occur during learn to walk and show some motor skills, but the neonatal period but also later during the first predominantly manifest severe speech retarda- 3 months of life. Some children show congenital tion. In contrast to classic GCE, children with malformations, including clump feet, cleft mild GCE are hyperactive and may develop lip/cleft palate, dysplastic ears, congenital hernias choreiform movement disorders and behavioral and cryptorchism; and children also frequently problems, mainly aggressive behavior. In the fol- show brain malformations. The occurrence of lowing, the clinical data of all patients with a these malformations always associates with a poor mild or transient form of GCE reported in the clinical course [4,10]. Patients develop spastic literature are compared with those of surveys on quadriparesis before 6 months of age, truncal children with classic GCE (Table 1). Enzymatic hypotonia, intractable seizures, severe global assays have been performed in only some children retardation, frequent hiccuping and microcephaly with mild GCE, these revealed a significantly (Table 1). Children with classic GCE show a poor reduced, but not null activity of GCS in liver Table 1. Clinical symptoms in different glycine encephalopathy forms, as reported in the literature. Clinical symptoms Mild neonatal GCE* Mild infantile GCE‡ Late onset GCE§ Classic GCE¶ Mental retardation 16/16 100% 23/25 92% 8/13 62% 23/23 100% including speech delay Muscular (truncal) 13/16 81% 14/25 56% 0/13 0% 23/23 100% hypotonia Spasticity# 3/16 19% 1/25 4% 5/13 38% 23/23 100% Seizures 11/16 69% 11/25 44% 1/13 8% 23/23 100% Choreoiform movement 7/16 44% 7/25 28% 3/13 23% 3/23 13% disorders Behavioral problems 10/16 63% 10/25 40% 6/13 46% 4/23 17% *[8,11–16]; ‡[8,13–15,17–28]; §[14,22,30–36]; ¶[8]; #Spasticity in late-onset GCE is described as a spastic diplegia caused by a progressive spinocerebellar degeneration [30–32]. Data of all patients with a mild or transient form of GCE reported in the literature are pooled and compared with those of surveys on children with classic GCE. GCE: Glycine encephalopathy. 622 Future Neurol. (2006) 1(5) Clinical variability in glycine encephalopathy – REVIEW tissue in all children tested. Therefore, mild GCE directly [35]. In conclusion, late onset GCE forms seem to be associated with a certain appears to display a different clinical entity of residual GCS activity. GCE, but GCS deficiency has never been proved Children with mild