Brief clinical and laboratory observation

Progressive neurodegenerative disorder in a patient with nonketotic hyperglycinemia†

Clinical symptoms in atypical nonketotic hyperglycinemia (NKH) are heterogeneous, in sharp contrast to uniform severe neurological symptoms in the classical NKH. A review of the literature of atypical NKH cases reveals three forms: neonatal, infantile, and late onset. The presentation in the neonatal form is similar to the classical one but the subsequent outcome is significantly better. Mental retardation and behavioral abnormalities are prevalent in both infantile and late onset forms although the phenotype in late onset atypical NKH is more heterogeneous. Patients with the atypical NKH tend to have a lower CSF/plasma glycine ratio when compared with the classical form, but overlap occurs. Hyperglycinemia in the neonatal and infantile atypical NKH, similar to the classical form, is caused by a deficient glycine cleavage system, whereas the cause of hyperglycinemia in late onset atypical NKH is unknown. A mutation of the T-protein AMT gene and several mutations of P-protein GLDC gene have been identified in homozygous or compound heterozygous state. Some of the GLDC mutations are associated with residual glycine decarboxylase activity when expressed in COS7 cells and early therapeutic intervention may be crucial to improve the outcome in patients harboring such mutations. Identification of more mutations causing atypical NKH and information about the mutations’ effect on enzyme activity may help to predict patients with a milder phenotype as well as those who may respond to early therapeutic intervention.

Eight novel mutations were found in the P-protein (glycine decarboxylase) gene (GLDC) of the glycine cleavage system (EC 2.1.1.10) by screening five exons of the gene in patients with glycine encephalopathy (NKH). The mutations identified were of eight single base changes: a one-base deletion 1054del A, a splice site mutation IVS18-2A→G and six amino acid substitutions A283P, A313P, P329T, R410K, P700A, and G762R.

A 16-year-old boy had intermittent chorea, delirium, and vertical gaze palsy precipitated by febrile illness. Nonketotic hyperglycinemia was confirmed by measurement of liver and lymphoblast glycine cleavage enzyme activity. Deficient but residual enzyme activity was demonstrated in both tissues, possibly accounting for the mild phenotype. Confirmation of an atypical variant of nonketotic hyperglycinemia with residual glycine cleavage enzyme activity has important implications for diagnosis and treatment. (J PEDIATR 1996;128:243-6)

A 13-year old girl with early-onset, mild, slowly progressive mental retardation caused by nonketotic hyperglycinemia is described. The plasma and cerebrospinal fluid glycine concentrations were elevated, but the cerebrospinal fluid/plasma glycine ratio was only midly elevated. The diagnosis was confirmed by demonstration of a detect in the activity of the glycine cleavage system in cultured lymphoblasts.

The molecular nature of the glycine cleavage system was investigated in eightpatients with typical (neonatal) and two patients with atypical (late onset) nonketotic hyperglycinemia (NKH). The overall activity of the glycine cleavage system was found to be decreased in all of the liver and brain tissue studied, but it was undetectable or extremely low in typical NKH, whereas there was some residual activity in atypical NKH. Six patients with typical NKH had a specific defect in the P protein, and one a defect in the T protein; the activity of the T protein was defective in one patient with atypical NKH.