Chapter 90

### Abstract

1. Nonketotic hyperglycinemia (NKH) is an inborn error of glycine degradation in which large quantities of glycine accumulate in all body tissues, including the central nervous system. The diagnosis is established by calculating the cerebrospinal fluid/plasma glycine concentration ratio. A value of greater than 0.08 is diagnostic. Confirmation of the diagnosis requires measurement of the activity of the glycine cleavage system in liver tissue.

2. Most patients have the neonatal phenotype, presenting in the first few days of life with lethargy, hypotonia, and myoclonic jerks, and progressing to apnea, and often to death. Those who regain spontaneous respiration develop intractable seizures and profound mental retardation.

3. A minority of NKH patients develop symptoms somewhat later in life. In the infantile form, patients present with seizures and have various degrees of mental retardation after a symptom-free interval and seemingly normal development for up to 6 months. In the mild-episodic form, patients present in childhood with mild mental retardation and episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late onset form, patients present in childhood with progressive spastic diplegia and optic atrophy, but intellectual function is preserved and seizures have not been reported.

4. Transient NKH has been described in six newborns with symptoms indistinguishable from those of the neonatal phenotype. Plasma and CSF glycine concentrations initially are identical to those seen in neonatal NKH, but return to normal by 8 weeks of age. Five of the six infants had no neurologic sequelae after 6 months to 13 years of followup. One had severe developmental delay at age 9 months.

5. Glycine is a neurotransmitter. It is inhibitory in the spinal cord and brain stem, which effect is probably responsible for the apnea and hiccuping seen early in the disease course. Glycine is excitatory in the cortex at the N-methyl-D-aspartate receptor channel complex. Excessive stimulation at this site probably explains the intractable seizures and brain damage seen in this disorder.

6. The primary biochemical defect in NKH is in the glycine cleavage system, an intramitochondrial enzyme complex with four components: the P protein (a pyridoxal phosphate-dependent glycine decarboxylase); the H protein (a lipoic acid containing hydrogen-carrier protein); the T protein (a tetrahydrofolate-dependent protein), and the L protein (lipoamide dehydrogenase). Defects in the P, H, and T proteins have been identified in NKH. Over 80 percent of patients with the neonatal phenotype have a defect in the P protein. Later onset cases are more likely to have defects in the H or T proteins.

7. The gene for the human P protein, GLDC (MIM 238300), maps to chromosome 9p13 or 9p23–24 and consists of 25 exons spanning over 135 kb. It encodes an mRNA of 3783 nt and a protein of 1020 amino acids. The human H protein gene, GCSH (MIM 238330), encodes a mRNA of 1192 nt and a precursor protein of 173 amino acids, which is cleaved to mature protein of 125 amino acids. Three pseudogenes for H protein are known, but none ...

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