Phosphoglycerate Dehydrogenase Deficiency

A number sign (#) is used with this entry because phosphoglycerate dehydrogenase deficiency (PHGDHD) is caused by homozygous or compound heterozygous mutation in the PHGDH gene (606879) on chromosome 1p12.

See also Neu-Laxova syndrome (NLS; 256520), an allelic disorder with a much more severe phenotype that usually results in neonatal death.

Description

Phosphoglycerate dehydrogenase deficiency is an autosomal recessive inborn error of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures (summary by Jaeken et al., 1996).

Clinical Features

Jaeken et al. (1996) described the clinical and biochemical features of 2 Turkish brothers who had a defect in the first enzyme of serine biosynthesis (phosphoglycerate dehydrogenase). The sibs were born from a first-cousin union. The authors noted that serine cerebrospinal fluid concentrations were markedly decreased, as were, to a lesser extent, glycine levels. Both sibs exhibited postnatal growth retardation, congenital microcephaly, hypogonadism, and hypertonia, and later showed profound psychomotor retardation and epilepsy. Magnetic resonance imaging of the brain showed evidence of 'dysmyelination.' Symmetric growth retardation at birth and bilateral congenital cataracts were present in 1 brother. Notably, plasma serine and glycine values were occasionally in the normal value range, as were urine organic acids and amino acids. Ophthalmologic examination of the second brother was normal. Decreased activity of phosphoglycerate dehydrogenase in fibroblasts was noted in both sibs (22% and 13% when compared to controls). Neither the parents nor the normal sibs were tested. Jaeken et al. (1996) noted that although serine is a nonessential amino acid, as it can be synthesized de novo from phosphoglycerate as well as glycine, it appears essential for normal brain function as it plays a role in the biosynthetic reactions of brain constituents such as protein, glycine, cysteine, serine phospholipids, sphingomyelins, and cerebrosides. The authors compared this enzyme deficiency to other 'anabolic' aminoacidopathies such as arginase deficiency (207800) in the urea cycle, homocysteinemia, and phenylketonuria (261600) and contrasted it with the more common 'catabolic' defects of amino acid metabolism.

Clinical Management

Jaeken et al. (1996) found that treatment with oral serine significantly increased cerebrospinal fluid serine concentrations in a dose-dependent manner and was coincident with the cessation of seizures (at a dose of 200 mg/kg/day divided into 3 doses) in 1 affected sib.

De Koning et al. (2002) reported the follow-up data of amino acid therapy in 5 patients with 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency followed for 3 to 7.5 years. Different treatment regimes were used, but a favorable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; 2 patients became seizure free. Amino acids were well tolerated, with no adverse effects documented. The progress of psychomotor development was only observed in 1 patient, diagnosed early, and treated with a high dose of L-serine.

De Koning et al. (2004) reported the prenatal diagnosis of an affected fetus with the V90M mutation (606879.0001) in the PHGDH gene. Ultrasound assessment showed a reduction of fetal head circumference in the 75th percentile at 20 weeks' gestation to the 29th percentile at 26 weeks' gestation. L-serine at 190 mg/kg per day in 3 divided doses was given to the mother which resulted in an fetal head circumference increase to the 76th percentile at 31 weeks' gestation. At birth, the girl's head circumference was normal. Within 12 hours after birth, the serine concentration in plasma dropped to a severely deficient value of 33 micromol/l, and serine was also depleted in cerebrospinal fluid. MRI was normal, but EEG showed discrete seizure activity. After initiation of L-serine treatment of 400 mg/kg per day, seizure activity diminished to normal within 1 week. At 4 years of age the girl had normal growth and psychomotor development, with follow-up MRI scans at 12 and 14 months showing no brain abnormalities. Since the consanguineous couple had 2 severely affected children born with congenital microcephaly prior to this child, de Koning et al. (2004) concluded that PHGDH deficiency is an inborn metabolic error that can be successfully treated antenatally.

Molecular Genetics

To investigate the molecular basis of PHGDH deficiency, Klomp et al. (2000) characterized the PHGDH mRNA sequence and analyzed it for variations in 6 patients from 4 families with this disorder. Five patients in 3 different families were homozygous for a single nucleotide substitution predicted to change valine at position 490 to methionine (606879.0001). The sixth patient was homozygous for a valine-to-methionine substitution at position 425 (606879.0002). Both mutations were located in the C terminus of the PHGDH gene. In vitro expression of these mutant proteins resulted in significant reduction of PHGDH enzyme activities. RNA blot analysis indicated abundant expression of PHGDH in adult and fetal brain tissue. Taken together with the severe neurologic impairment in these patients, the data suggested an important role for PHGDH activity and L-serine biosynthesis in the metabolism, development, and function of the central nervous system.

In 3 Dutch patients, including a brother and sister, and 2 unrelated Turkish patients, who presented with congenital microcephaly, psychomotor retardation, and seizures, Tabatabaie et al. (2009) identified compound heterozygosity or homozygosity for 5 mutations in the PHGDH gene, respectively (see, e.g., 606879.0003-606879.0006). Studies in patient fibroblasts, transient overexpression in HEK293 cells, and molecular modeling onto the partial crystal structure of 3-PGDH suggested that missense mutations associated with 3-PGDH deficiency, including the previously identified V490M and V425M substitutions, either primarily affect substrate binding or result in very low residual enzymatic activity.