Chapter 139

Glycine and serine are nonessential amino acids that feed into many synthetic pathways. Both are involved in transfer of one-carbon units. Proline is a nonessential amino acid that has unique biochemical properties. While most disorders of amino acid metabolism disrupt catabolic pathways, only a few affect the synthesis of amino acids. Three of them compromise the production of serine or proline. Formation and elimination of glycine occurs through many pathways. One precursor of glycine is choline, which can be oxidized to betaine and sequentially demethylated to dimethylglycine, sarcosine, and glycine, which is finally degraded to CO2 and NH3. Four known defects in glycine metabolism lead to distinct biochemical or clinical phenotypes.

Glycine encephalopathy (GCE) is an inherited metabolic disorder in which large amounts of glycine are found in body fluids, without further metabolic abnormalities.

### Clinical Presentation

GCE typically presents with severe neonatal epileptic encephalopathy. Neonates appear normal at birth but develop myoclonic seizures, hiccough, apnea, muscular hypotonia, and unresponsiveness within the first 2 days of life. Their EEG shows a typical burst-suppression pattern. Many affected individuals die early, and survivors are severely retarded or developmentally arrested.1 Rarely, neonatal transient variants and late-onset forms have been described. These can present after an apparently asymptomatic period of months or even years with various symptoms such as mental retardation, episodes of chorea, vertical gaze palsy and delirium, or progressive spastic diplegia and optic atrophy.2,3

### Metabolic Derangement, Including Pathophysiology

GCE is caused by defects in the mitochondrial glycine cleavage system (GCS) a multiprotein complex that catalyzes the degradation of glycine to CO2 and NH3, thereby transferring a one-carbon unit onto tetrahydrofolate to form 5,10-methylenetetrahydrofolate (MeTHF). A block in the GCS leads to accumulation of glycine and a lack of MeTHF, which promotes further production of glycine from serine. The latter reaction is catalyzed by serine hydroxymethyl transferase and yields the required MeTHF (see Chapter 153, Fig. 153-1). Glycine modulates N-methyl-D-aspartate (NMDA)–mediated neurotransmission. The accumulation of glycine in GCE is most pronounced in the cerebral compartment, where its increased concentration is thought to be directly responsible for the observed neurological symptoms.

### Genetics

All forms of GCE (OMIM no. 605809) are inherited as autosomal recessive traits. The enzyme is multimeric with four distinct protein components. P protein (a pyridoxal phosphate–dependent glycine decarboxylase, 9p22), H protein (a lipoic acid–containing protein, 16q24), T protein (a tetrahydrofolate-requiring aminomethyltransferase, 3p21.2-p21.1), and L protein (a dihydrolipoamide dehydrogenase, 7q31-q32). Several mutations in the P and T genes and one in the H gene have been found, with the T protein being most commonly affected.4,5 A single mutation is responsible for most cases in Finland.6 Prenatal diagnosis can be performed by biochemical analysis of chorionic villus sample biopsies, but false negatives have been reported.7 Once a mutation is ...

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