3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis.

Abstract

Serine concentrations were markedly decreased in the cerebrospinal fluid of two brothers with congenital microcephaly, profound psychomotor retardation, hypertonia, epilepsy, growth retardation, and hypogonadism. The youngest boy also had congenital bilateral cataract. Magnetic resonance imaging of the brain showed evidence of dysmyelination. Plasma serine as well as plasma and cerebrospinal fluid glycine concentrations were also decreased but to a lesser extent. Treatment with oral serine in the youngest patient significantly increased cerebrospinal fluid serine and abolished the convulsions. In fibroblasts of both patients, a decreased activity was demonstrated of 3-phosphoglycerate dehydrogenase, the first step of serine biosynthesis ( 22% and 13% of the mean control value). This is an unusual disorder as the great majority of aminoacidopathies are catabolic defects. It is a severe but potentially treatable inborn error of metabolism that has not been previously reported in man.(Arch Dis Child 1996;74:542-545 Case reports The patients, two brothers, were from a Turkish family. The parents were first cousins. They were healthy and had a normal height and head circumference.Their first child was healthy and showed normal plasma amino acid concentrations. The third child (case 1) was born after a normal term pregnancy with weight of 2130 g (3rd centile 2600 g), length 43 cm (3rd centile 47 cm), and head circumference 29 cm (3rd centile 33 cm). At the age of 3.5 months he was admitted for investigation of congenital bilateral cataracts and feeding difficulties. Weight was 3700 g (3rd centile 5100 g), length 50.5 cm (3rd centile 58 cm), and head circumference 34.2 cm (3rd centile 39 cm). He was severely retarded, hypertonic, and hyperexcitable. Tendon reflexes were normal. There was adduction of the thumbs and pes calcaneovalgus. He also had small testes. At the age of 1 year he developed epilepsy. Laboratory investigation could not demonstrate intrauterine infection. Chromosomal analysis was normal. Plasma amino acid analysis by ion exchange chromatography and fluorescence detection revealed low fasting concentrations of serine (29 and 55; normal range for age 70-187 rnol/l) and low to normal fasting concentrations of glycine (77 and 97; 80-341 jimol/l). In the cerebrospinal fluid, protein was normal, serine was severely decreased (6; 35-80 gmol/l), and glycine was also decreased but less so (2.8; 3.6-9.0

Cloning, sequencing and expression of rat liver 3-phosphoglycerate dehydrogenase

“…In the opposite direction, the enzyme displayed a K m of 20-25 µM for NADH, and was inhibited by elevated concentrations of 3-phosphohydroxypyruvate ( Figure 4A). As previously reported by Jaeken et al [4], this inhibition was released by 100-400 mM KCl. The data obtained in the present study at low substrate concentrations indicate that the salt displaced the saturation curve to the right, inhibiting enzyme activity at low concentrations of substrate and stimulating activity at elevated concentrations.…”

“…The activity of this enzyme was indeed markedly decreased (to 13 and 22 % of the normal value) in fibroblasts from two patients with a decreased concentration of serine in the plasma and cerebrospinal fluid [4]. Furthermore, E. coli 3-phosphoglycerate dehydrogenase was shown to catalyse the reduction of 2-oxoglutarate to both the -and -isomers of 2-hydroxyglutarate, suggesting that a mutation of the human enzyme may contribute to the neurometabolic diseases -and -hydroxyglutaric aciduria [11].…”

“…In rat liver, its activity depends strongly on nutritional status, being low in animals fed a normal diet and increasing more than 10-fold upon ingestion of a lowprotein, carbohydrate-rich diet [2,3]. When measured in the nonphysiological direction, the enzyme present in human fibroblasts is inhibited by concentrations of the substrate 3-phosphohydroxypyruvate above 10 µM, and this inhibition is released by salts [4]. Similar properties have been described for bovine liver -glycerate dehydrogenase, the inhibitory substrate being hydroxypyruvate in this case [5,6], but were not observed with 3-phosphoglycerate dehydrogenases from bacteria [7] or plants [8].…”

Oral Administration of L-serine Modifies Amino Acid Metabolism in the Brain of Rats

“…Serine-deficiency syndrome, a congenital disease associated with an inborn error generally in the L-serine biosynthetic enzyme 3-phosphoglycerate dehydrogenase, was reported [1]. Patients of this syndrome were identified because of very low concentrations of serine and glycine in the plasma and cerebrospinal fluid.…”

Alterations in Plasma Levels of Amino Acids after Intracerebroventricular Administration of L-Serine or D-Serine in Conscious and Freely Moving Rats

“…Thus, we considered that it would be of great interest to examine the potential use of the blood levels of these amino acids as biological markers for neuropsychiatric diseases.. L-Serine has been shown to play a role in cellular proliferation, as it is a precursor for nucleotide synthesis [15][16][17]. In addition, after the first reports of serine deficiency disorders (3-phosphoglycerate dehydrogenase (3-PGDH) deficiency and 3-phosphoserine phosphatase (3-PSP) deficiency)), it also became clear that L-serine and L-serinederived metabolites are important for brain development and function [17][18][19][20][21][22][23][24][25]. In contrast, D-serine, an isomer of Lserine, plays a role as a key co-agonist for NMDA receptors [26][27][28][29][30][31][32].…”