Effect of valine on propionate metabolism in control and hyperglycinemic fibroblasts and in rat liver.

Measurement of methylmalonyl-CoA mutase and propionyl-CoA carboxylase activities in lysates from fibroblasts derived from control, nonketotic hyperglycinemia, propionic acidemia, and both vitamin B12-responsive and -nonresponsive variants of methylmalonic acidemia showed only one abnormality: a 59% decrease in carboxylase activity in the nonketotic hyperglycinemic lysates (P less than 0.01). When fibroblasts from all cell types were grown on valine-supplemented (24 mM) media, mutase activity was generally inhibited. As for carboxylase activity, control lines were inhibited 35% as compared to controls without valine and propionic acidemia activity was undetectable. On the other hand, carboxylase activity in both methylmalonic acidemia variants was increased 40% and nonketotic hyperglycinemia carboxylase activity was increased 80% (P less than 0.01) when grown on valine-supplemented media. Isoleucine could not substitute for valine in producing increased carboxylase activity in these mutants. Glycine cleavage activity in fresh rat liver homogenates (11.1 micronmol/gm protein/90 min) did not vary significantly when 24 mM valine was added to the reaction (9.9 micronmol/mg protein/90 min). Therefore, the hyperglycinemia observed in both ketotic and nonketotic forms is probably not caused by a direct effect of valine on the glycine cleavage reaction. These data suggest that the presence of increased amounts of propionic acid in serum or urine does not necessarily rule out the possibility of nonketotic hyperglycinemia due to the decreased activity of the carboxylase enzyme.     

Glycine transport by human diploid fibroblasts--absence of a defect in cells from patients with nonketotic hyperglycinemia.

Glycine transport in human diploid fibroblasts was shown to be by a single sodium-dependent system. Glycine transport does not appear to exhibit transstimulation or transinhibition. Transport appears to be similar to the A transport system of other mammalian cell lines, as defined by competition patterns. Normal and nonketotic hyperglycinemia (NKH) fibroblasts could not be distinguished on the basis of accumulation or initial rates. A distribution ratio of 15 to 30 was reached by both types of cells. The normal lines have slightly lower apparent Kms (1.1-1.3 mM) than the NKH lines (1.8 to 2.4 mM). The values for the Vmax of the normal cells (11.4-12.9 nmole/mg/min) and the NKH cells (7.0-16.7 nmole/mg/min) overlapped. There were no measurable differences in either the long-term incorporation into protein of leucine and glycine or the oxidation of glycine in normal and NKH fibroblasts.     

Studies on the valine sensitivity in non-ketotic hyperglycinemia.

An oral loading test with L-valine (100 mg/kg body weight) in 3 patients with non-ketotic hyperglycinemia was accompanied by drowsiness and hyperreflexia of the patients. Metabolic studies revealed a slightly lower rate of disappearance of valine from blood in 2 of the patients. In a third patient, the curve was not different from controls. Gas chromatographic analysis for short-chain fatty acids in serum carried out during the valine loading test did not show increased concentrations. Urine collected during the valine loading test did not show excretion of N-acylglycine derivatives. As neither of the branched chain amino acid transaminases proved to be inhibited by glycine, inhibition by glycine of the uptake of valine by the tissues became likely. This uptake has been measured in rat liver slices. Glycine was found to be a competitive inhibitor of valine uptake, with a Ki of 4.9 mM. It is concluded that the tendency to a decreased rate of valine disappearance from blood in non-ketotic hyperglycinemia could be due to an inhibition of valine uptake by the high plasma glycine concentration. The relationship of the inhibited valine uptake in liver slices of rats with the clinical symptoms in non-ketotic hyperglycinemia patients after a valine load remains to be established.     

Acute neonatal nonketotic hyperglycinemia: normal propionate and methylmalonate metabolism.

Propionyl-CoA carboxylase and combined methylmalonyl-CoA (MMA-CoA) racemase and -mutase activities were studied in liver and fibroblasts of two patients with the acute neonatal form of nonketotic hyperglycemia. In all experiments, these enzyme activities studied in tissues of the patients were within the range of healthy control subjects, whereas no propionyl-CoA carboxylase activity was measurable in the fibroblasts of a patient with propionic acidemia. Subcellular fractionation of liver and fibroblasts indicated that the normal amounts of MMA-CoA found after incubation of whole tissue homogenate were formed by propionyl-CoA carboxylase, a mitochondrial enzyme, and not be acetyl-CoA carboxylase, which theoretically could also be involved in the carboxylation of propionyl-CoA. From the above data as well as from clinical and biochemical observations in three patients, it was concluded that there exists a true nonketotic hyperglycinemia which is not related etiologically to the different disorders of the ketotic hyperglycinemia syndrome. True nonketotic hyperglycinemia is not associated with ketoacidosis even after loading with propionate- and MMA precursors. It must be distinguished by exclusion from mild forms of the ketotic hyperglycinemia syndrome which may present clinically as hyperglycinemia without ketosis.     

The effectiveness of benzoate in the management of seizures in nonketotic hyperglycinemia

Patients with nonketotic hyperglycinemia generally have intractable seizures that are poorly responsive to anticonvulsant medication. No effective treatment has been consistently reported. In three patients with nonketotic hyperglycinemia, the oral administration of sodium benzoate in dosages designed to lower the cerebrospinal fluid concentration of glycine was followed by an abrupt change from frequent major seizures before treatment to no seizures, or only occasional minor ones, after treatment. This attenuation of seizures was associated with a decrease in the concentrations of glycine in both plasma and cerebrospinal fluid. There was no evident change in psychomotor development.     

Dextromethorphan and high-dose benzoate therapy for nonketotic hyperglycinemia in an infant.

To test the hypothesis that nonketotic hyperglycinemia causes overstimulation of the excitatory N-methyl-D-aspartate receptor by allosteric glycine activation, and that reduction of glycine and blocking of the cation channel coupled to the receptor would be beneficial, we administered benzoate and dextromethorphan, a blocker of the N-methyl-D-aspartate channel to an infant with nonketotic hyperglycinemia. Therapy with benzoate, 500 mg/kg per day, was started on day 5, and the dosage was increased to 750 mg/kg per day on day 8, with prompt normalization of the neurologic and electroencephalographic findings. The glycine concentrations in both plasma and cerebrospinal fluid were substantially reduced. Dextromethorphan was added to the regimen on day 12. The electroencephalogram remained normal until the infant was 8 months of age, when diffuse slowing became apparent. Serial brain magnetic resonance imaging showed delayed myelination. At 12 months of age, physical examination findings and growth were normal except for hypotonia. The developmental quotient was approximately 60, and the child was free of seizures. This outcome, although not ideal, is better than that typical for nonketotic hyperglycinemia. Our results suggest that trials with additional patients and other N-methyl-D-aspartate cation channel blockers are warranted.     

Neonatal form of a nonketotic hyperglycinemia in consanguinous parents]

This is a report of the neonatal form of nonketotic hyperglycinemia with rapid progressing neurological symptoms, respiratory distress and seizures. The EEG pattern is characteristic, the ratio of cerebrospinal fluid to plasma glycine abnormally high. The result of cranial computerized tomography demonstrates also in our patient that nonketotic hyperglycinemia joins a growing list of inborn errors of metabolism associated with brain malformations. The consanguinity of parents supports the known autosomal recessive form of inheritance.     

Enzymatic diagnosis of nonketotic hyperglycinemia with lymphoblasts.

We developed a new enzymatic assay for the glycine cleavage system that used Epstein-Barr virus-transformed lymphoblasts instead of liver biopsy specimens. Patients with nonketotic hyperglycinemia from a deficiency of P-protein could be clearly distinguished from control subjects by activities in their lymphoblasts, suggesting the clinical usefulness of this method.     

Nonketotic hyperglycinemia presenting as pulmonary hypertensive vascular disease and fatal pulmonary edema in response to pulmonary vasodilator therapy

The association of pulmonary hypertensive vascular disease with nonketotic hyperglycinemia is rare. We describe 5?infants diagnosed with nonketotic hyperglycinemia, in whom pulmonary hypertensive vascular disease was the?main presenting feature, and who developed severe pulmonary edema in response to pulmonary vasodilators.     

Neurologic sequelae in transient nonketotic hyperglycinemia of the neonate.

We report a neonate with the transient form of nonketotic hyperglycinemia manifested by extreme hypotonia, lethargy, apnea, and myoclonic and generalized convulsions in early neonatal life. Despite normalization of the biochemical values, severe neurologic sequelae were observed. This case suggests that the transient form of nonketotic hyperglycinemia sometimes causes severe brain damage.     

Hyperglycinuria and hyperglycinemia in two siblings with mild developmental delays.

Two preschool-age siblings with similar histories of encephalopathy were examined for developmental retardation and found to have elevated levels of urinary and blood glycine. Their inability to convert glycine into serine in the absence of elevated blood and urinary ketone levels was suggestive of a defect in the glycine-cleavage enzyme system (or serine hydroxymethyl transferase). These patients differ significantly from the majority of reported cases of nonketotic hyperglycinemia in that they did not manifest life-threatening neonatal illness, severe mental retardation, or neurological deficits. However, during an oral glycine load, alterations in the electroencephalographic pattern occurred that suggested a relationship between elevated blood glycine levels and pathological involvement of the central nervous system. The ratio of CSF-blood glycine was found to be in the range expected for nonketotic hyperglycinemia.     

Mild variant of nonketotic hyperglycinemia with typical neonatal presentations: mutational and in vitro expression analyses in two patients

In neonatal-onset nonketotic hyperglycinemia, severe psychomotor retardation is the expected uniform outcome. We report two patients with typical neonatal presentation who showed far better developmental outcomes. The in vitro expression analysis of the identified GLDC mutations revealed considerable residual enzyme activity, suggesting prognostic and enzymatic heterogeneity even in neonatal-onset nonketotic hyperglycinemia.     

Nonketotic hyperglycinemia. Clinical, biochemical and therapeutic aspects.

A patient exhibiting progressive cerebral depression from the first days of life is described. The diagnosis of nonketotic hyperglycinemia was established on the typical clinical presentation, elevated glycine concentrations in body fluids and diminished glycine cleavage activity in liver tissue. A series of therapeutic trials, including strychnine treatment, was tried on this patient without apparent effect on the clinical course.     

Nonketotic hyperglycinemia: Analyses of glycine cleavage system in typical and atypical cases

The molecular nature of the glycine cleavage system was investigated in eight patients 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.     

NONKETOTIC HYPERGLYCINEMIA Clinical, Biochemical and Therapeutic Aspects

Abstract. A patient exhibiting progressive cerebral depression from the first days of life is described. The diagnosis of nonketotic hyperglycinemia was established on the typical clinical presentation, elevated glycine concentrations in body fluids and diminished glycine cleavage activity in liver tissue. A series of therapatic trials, including strychnine treatment, was tried on this patient without apparent effect on the clinical course.     

Neonatal nonketotic hyperglycinemia

Nonketotic hyperglycinemia has variable phenotypic expressions and a poor prognosis. We report a case of severe neonatal nonketotic hyperglycinemia, who started convulsing immediately after birth. His glycine index was 0.38 and he did not respond to treatment with sodium benzoate and dextromethorphan. Hypotonia, transient hyperammonemia and metabolic acidosis were associated findings.     

Nonketotic hyperglycinemia treated with strychnine, a glycine receptor antagonist.

A 6 1/2-month-old boy suffering from nonketotic hyperglycinemia has been treated for at least 12 months with oral strychnine. The drug caused improvement of muscle tone, motoricity, vigilance and social behavior. Glycine is one of the putative neurotransmitters of postsynaptic inhibition, particularly at the spinal and reticular levels, strychnine its antagonist at the postsynaptic membrane. Strychnine improved the patient's motoricity presumably by blocking the excessive glycine-mediated inhibition of motoneurons. The beneficial effect of strychnine on vigilance and social behavior is more difficult to explain but may have been related to its antagonism of glycine inhibition of brainstem reticular neurons.     

Dysplasia of the Corpus Callosum in Identical Twins with Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia (NKH) is an autosomal recessively inherited disorder of the glycine degradation pathway leading to accumulation of glycine in body fluids and tissues. Identical twins with nonketotic hyperglycinemia and dysplasia of the corpus callosum are described in support of the hypothesis that some patients with NKH have a genetic defect of the glycine degradation pathway resulting in abnormal corpus callosal development. It is important to screen for metabolic defects whenever similar structural defects are present.     

Nonketotic hyperglycemia: Clinical,biochemical, and therapeutic considerations

The salient features of nonketotic hyperglycinemia include apnea, feeding difficulties, lethargy, seizures, abnormal muscle tone and reflex activity, significant developmental delay, and, in most instances, early death. The pathogenesis of the biochemical defect leading to increased glycine concentration in blood, urine, and CSF is likely to concern derangements of the glycine cleavage enzyme and/or transport mechanisms of glycine. Our current state of knowledge of this disorder is incomplete. Therapeutic attempts, as described in Table 2, have been largely unsuccessful.Further basic research on the underlying biochemical perturbation, including additional documentation of the glycine cleavage enzyme deficiency patterns, of substrate inhibition of key metabolic pathways, and of glycine transport aberrations, as well as investigations of new pharmacologic approaches, will be a challenge for investigators in this field. It is hoped that new knowledge in these areas will eventually lead to reduction of morbidity and mortality in children with nonketotic hyperglycinemia.     

新生儿非酮症性高甘氨酸血症1例

本文报道了一例新生儿非酮症性高甘氨酸血症,并简单介绍了该病的发病机制、临床表现、诊断和鉴别诊断以及治疗。