Alternative titles; symbols
ORPHA: 583595, 79351; DO: 0050722;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p12 | Phosphoglycerate dehydrogenase deficiency | 601815 | Autosomal recessive | 3 | PHGDH | 606879 |
A number sign (#) is used with this entry because of evidence that 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 (NLS1; 256520), an allelic disorder with a more severe phenotype that usually results in neonatal death.
Phosphoglycerate dehydrogenase deficiency (PHGDHD) 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).
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 (CSF) 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.
El-Hattab et al. (2016) described a 2-month-old male infant with intrauterine growth retardation, generalized ichthyotic skin lesions, microcephaly, and distinctive facial features including hypertelorism, depressed nasal bridge, and micrognathia. He developed poor feeding and anemia requiring blood transfusion. He had low serine and glycine in plasma and CSF. Benke et al. (2017) reported that this patient had severe developmental delay and spasticity and that serine supplementation resulted in no improvement in development.
Benke et al. (2017) reported sibs from 2 unrelated families with PHGDHD. In family 1, 2 sisters had low serine and glycine in CSF and plasma. PHGDH enzyme activity was low in fibroblasts. One sister had severe developmental delay, spasticity, athetosis, cortical blindness, microcephaly, and failure to thrive. Neuroimaging showed small cerebral hemispheres, hypoplasia of the corpus callosum, and hypomyelination. The other sister had severe developmental delay, spasticity, microcephaly, and failure to thrive. Serine supplementation in both sibs resulted in some improvement in spasticity and responsiveness. In family 3, 3 sisters, born to consanguineous Arab parents, were affected. The youngest sib had microcephaly and cataracts at birth. She was able to walk at 2.5 years of age, but lost the ability to walk due to spasticity at age 5 years. She developed seizures at age 2 years. Her plasma serine was low-normal and plasma glycine was normal. The middle sib had microcephaly at birth, and normal development until age 1 year when spasticity was diagnosed. At age 4 years she started having seizures, and learning difficulties were noticed when she started school. At age 8, developmental regression started and she was nonambulatory due to spasticity at age 10. The oldest sister had cataracts and microcephaly at birth and started having seizures at age 6 months. She developed spasticity during the second year of life. At age 12 she became nonambulatory due to spasticity. All 3 sibs were noted to have pleasant personalities. The sibs had improvement in seizures, spasticity, mobility, and speech after supplementation with 400 mg/kg/d of oral serine.
Fu et al. (2023) reported 2 brothers, born to consanguineous Chinese parents, with PHGDHD. Both had a normal prenatal and perinatal course with no obvious symptoms during the period after birth. The brothers both had microcephaly and seizure onset at age 4 years. EEGs showed multifocal epileptiform discharges in both sibs. Although development was initially normal, cognitive impairment was noted later in childhood. Brain MRI showed widened cerebellar sulci in one boy and slightly enlarged ventricles in the other. Ichthyosiform scaling was seen on the leg of one of the boys. Biochemical analyses done in one of the brothers showed a low serine level and a normal glycine level.
Brassier et al. (2016) reported a boy with a prenatal history of intrauterine growth retardation and progressive microcephaly. Hypertonia was noted at birth. At 10 months of age, he had severe psychomotor retardation and intractable seizures. Brain MRI at 4.5 years of age showed hypomyelination and corpus callosum atrophy. The patient had very low plasma and CSF serine.
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.
Benke et al. (2017) reported the outcome of treatment with oral serine and oral glycine in the patients they reported with PGDHD. In 8- and 4-year-old sisters (family 1), treatment with serine 500 mg/kg/d and glycine 250 mg/kg/d normalized serine and glycine levels in the CSF. Both sibs had some improvement in spasticity and responsiveness, but no change in developmental progress. In a 6-month-old male infant (family 2), previously reported by El-Hattab et al. (2016), who was treated with serine 500 mg/kg/d and glycine 250 mg/kg/day, no improvement in development was observed. In 3 sisters (family 3), aged 13, 19, and 21 years, treatment with serine 400 mg/kg/d resulted in resolution of seizures and improvement in spasticity, ambulation, and verbal communication.
The transmission pattern of PHGDHD in the families reported by Klomp et al. (2000) was consistent with autosomal recessive inheritance.
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.
In a 2-month-old boy, born to parents who came from the same area in the United Arab Emirates, with PHGDH deficiency, El-Hattab et al. (2016) identified a homozygous missense mutation in the PHGDH gene (G429V; 606879.0011).
In 5 members from 2 unrelated families with PHGDHD, Benke et al. (2017) identified homozygous or compound heterozygous mutations in the PHGDH gene (606879.0005 and 606879.0012). Studies in patient fibroblasts showed decreased PHGDH enzyme activity compared to control. Serine and glycine were low in patient plasma and CSF. By metabolomic analysis in plasma from these sisters and the boy previously reported by El-Hattab et al. (2016), Glinton et al. (2018) found low glycerophospholipids including low phosphatidylcholine, suggesting that PHGDH may play a role in CNS development.
In 2 brothers, born to consanguineous Chinese parents, with PHGDHD, Fu et al. (2023) identified homozygosity for a novel missense mutation in the PHGDH regulatory domain (V404D; 606879.0014). Both parents were heterozygous for the variant, which was confirmed by Sanger sequencing. The variant was not present in the gnomAD and ExAC databases, and was classified as likely pathogenic. The authors reviewed the literature on pathogenic variants in the PHGDH gene; they noted 17 variants, mostly located in the regulatory domain, associated with PHGDHD.
In a boy with PHGDHD, Brassier et al. (2016) identified compound heterozygous mutations in the PHGDH gene (R135W; 606879.0004 and R163W 606879.0015). The mutations were identified by sequencing of a 3-gene panel associated with serine deficiency. The R135W mutation was inherited from the mother; DNA from the father was not available for testing.
Benke, P. J., Hidalgo, R. J., Braffman, B. H., Jans, J., van Gassen, K. L. I., Sunbul, R., El-Hattab, A. W. Infantile serine biosynthesis defect due to phosphoglycerate dehydrogenase deficiency: variability in phenotype and treatment response, novel mutations, and diagnostic challenges. J. Child Neurol. 32: 543-549, 2017. [PubMed: 28135894] [Full Text: https://doi.org/10.1177/0883073817690094]
Brassier, A., Valayannopoulos, V., Bahi-Buisson, N., Wiame, E., Hubert, L., Boddaert, N., Kaminska, A., Habarou, F., Desguerre, I., Van Schaftingen, E., Ottolenghi, C., de Lonlay, P. Two new cases of serine deficiency disorders treated with l-serine. Europ. J. Paediat. Neurol. 20: 53-60, 2016. [PubMed: 26610677] [Full Text: https://doi.org/10.1016/j.ejpn.2015.10.007]
De Koning, T. J., Duran, M., Van Maldergem, L., Pineda, M., Dorland, L., Gooskens, R., Jaeken, J., Poll-The, B. T. Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. J. Inherit. Metab. Dis. 25: 119-125, 2002. [PubMed: 12118526] [Full Text: https://doi.org/10.1023/a:1015624726822]
de Koning, T. J., Klomp, L. W. J., van Oppen, A. C. C., Beemer, F. A., Dorland, L., van den Berg, I. E. T., Berger, R. Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. (Letter) Lancet 364: 2221-2222, 2004. [PubMed: 15610810] [Full Text: https://doi.org/10.1016/S0140-6736(04)17596-X]
El-Hattab, A. W., Shaheen, R., Hertecant, J., Galadari, H. I., Albaqawi, B. S., Nabil, A., Alkuraya, F. S. On the phenotypic spectrum of serine biosynthesis. J. Inherit. Metab. Dis. 39: 373-381, 2016. [PubMed: 26960553] [Full Text: https://doi.org/10.1007/s10545-016-9921-5]
Fu, J., Chen, L., Su, T., Xu, S., Liu, Y. Mild phenotypes of phosphoglycerate dehydrogenase deficiency by a novel mutation of PHGDH gene: case report and literature review. Int. J. Dev. Neurosci. 83: 44-52, 2023. [PubMed: 36308023] [Full Text: https://doi.org/10.1002/jdn.10236]
Glinton, K. E., Benke, P. J., Lines, M. A., Geraghty, M. T., Chakraborty, P., Al-Dirbashi, O. Y., Jiang, Y., Kennedy, A. D., Grotewiel, M. S., Sutton, V. R., Elsea, S. H., El-Hattab, A. W. Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling. Molec. Genet. Metab. 123: 309-316, 2018. [PubMed: 29269105] [Full Text: https://doi.org/10.1016/j.ymgme.2017.12.009]
Jaeken, J., Detheux, M., Van Maldergem, L., Foulon, M., Carchon, H., Van Schaftingen, E. 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch. Dis. Child. 74: 542-545, 1996. [PubMed: 8758134] [Full Text: https://doi.org/10.1136/adc.74.6.542]
Klomp, L. W. J., de Koning, T. J., Malingre, H. E. M., van Beurden, E. A. C. M., Brink, M., Opdam, F. L., Duran, M., Jaeken, J., Pineda, M., van Maldergem, L., Poll-The, B. T., van den Berg, I. E. T., Berger, R. Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis. Am. J. Hum. Genet. 67: 1389-1399, 2000. [PubMed: 11055895] [Full Text: https://doi.org/10.1086/316886]
Tabatabaie, L., de Koning, T. J., Geboers, A. J. J. M., van den Berg, I. E. T., Berger, R., Klomp, L. W. J. Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Hum. Mutat. 30: 749-756, 2009. [PubMed: 19235232] [Full Text: https://doi.org/10.1002/humu.20934]