D-glycerate dehydrogenase deficiency explained

Synonyms:	3-phosphoglycerate dehydrogenase deficiency, PHGDH deficiency, PHGDHD
D-glycerate dehydrogenase deficiency
Field:	Metabolism
Symptoms:	Congenital microcephaly, psychomotor retardation and seizures in infants, moderate developmental delay and behavioral disorders juveniles.^[1]
Onset:	Adolescent, Infancy, Childhood
Causes:	Genetic
Prevention:	N/A
Treatment:	Diet
Medication:	Serine
Prognosis:	Shortened life expectancy
Frequency:	<1 / 1 000 000

D-glycerate dehydrogenase deficiency (or 3-phosphoglycerate dehydrogenase deficiency, PHGDH deficiency, PHGDHD) is a rare autosomal metabolic disease where the young patient is unable to produce an enzyme necessary to convert 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the only way for humans to synthesize serine. This disorder is called Neu–Laxova syndrome in neonates.

Cause

Homozygous or compound heterozygous mutations in 3-phosphoglycerate dehydrogenase (PHGDH) cause Neu-Laxova syndrome^{[2] [3]} and phosphoglycerate dehydrogenase deficiency.^[4]

Mechanism

3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the committed step in the phosphorylated pathway of L-serine biosynthesis. It is also essential in cysteine and glycine synthesis, which lie further downstream.^[5] This pathway represents the only way to synthesize serine in most organisms except plants, which uniquely possess multiple synthetic pathways. Nonetheless, the phosphorylated pathway that PHGDH participates in is still suspected to have an essential role in serine synthesis used in the developmental signaling of plants.^{[6] [7]}

Treatment

Treatment typically involves oral supplementation of serine and glycine.^{[8] [9]}

References

1. Web site: Orphanet: Search by disease name. 1 December 2019.
2. Shaheen R, Rahbeeni Z, Alhashem A, Faqeih E, Zhao Q, Xiong Y, Almoisheer A, Al-Qattan SM, Almadani HA, Al-Onazi N, Al-Baqawi BS, Saleh MA, Alkuraya FS . Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH . American Journal of Human Genetics . 94 . 6 . 898–904 . Jun 2014 . 24836451 . 4121479 . 10.1016/j.ajhg.2014.04.015 .
3. Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M . Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway . American Journal of Human Genetics . 95 . 3 . 285–93 . Sep 2014 . 25152457 . 4157144 . 10.1016/j.ajhg.2014.07.012 .
4. Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E . 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis . Archives of Disease in Childhood . 74 . 6 . 542–5 . Jun 1996 . 8758134 . 1511571 . 10.1136/adc.74.6.542.
5. Web site: MetaCyc L-serine biosynthesis . biocyc.org . 2016-03-01 .
6. Ros R, Muñoz-Bertomeu J, Krueger S . Serine in plants: biosynthesis, metabolism, and functions . Trends in Plant Science . 19 . 9 . 564–9 . Sep 2014 . 24999240 . 10.1016/j.tplants.2014.06.003 . 2014TPS....19..564R . 19690197 .
7. Ho CL, Noji M, Saito M, Saito K . Regulation of serine biosynthesis in Arabidopsis. Crucial role of plastidic 3-phosphoglycerate dehydrogenase in non-photosynthetic tissues . The Journal of Biological Chemistry . 274 . 1 . 397–402 . Jan 1999 . 9867856 . 10.1074/jbc.274.1.397. free .
8. de Koning TJ, Duran M, Dorland L, Gooskens R, Van Schaftingen E, Jaeken J, Blau N, Berger R, Poll-The BT . Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency . Annals of Neurology . 44 . 2 . 261–5 . Aug 1998 . 9708551 . 10.1002/ana.410440219 . 46565109 . free .
9. de Koning TJ, Klomp LW, van Oppen AC, Beemer FA, Dorland L, van den Berg I, Berger R . 40121728 . Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency . Lancet . 364 . 9452 . 2221–2 . 2004-12-18 . 15610810 . 10.1016/S0140-6736(04)17596-X .