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 ... 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.
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 ... 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.