D-glycerate dehydrogenase deficiency (or 3-phosphoglycerate dehydrogenase deficiency, PHGDH deficiency, PHGDHD) is a rare

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

metabolic disease where the young patient is unable to produce an enzyme necessary to convert

3-phosphoglycerate 3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. Th ...

into

3-phosphohydroxypyruvate Phosphohydroxypyruvic acid is an intermediate in the synthesis of serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biolog ...

, which is the only way for humans to synthesize

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

.This disorder is called

Neu–Laxova syndrome Neu–Laxova syndrome (NLS, also known as Neu syndrome; Neu-Povysilová syndrome; or 3-phosphoglycerate dehydrogenase deficiency, neonate form) is a rare autosomal recessive disorder characterized by severe intrauterine growth restriction and mu ...

in neonates.

Symptoms and signs

In addition significantly shortening lifespan, PHGDH deficiencies are known to cause congenital microcephaly,

psychomotor retardation Psychomotor may refer to: * Psychomotor learning, the relationship between cognitive functions and physical movement * Psychomotor retardation, a slowing-down of thought and a reduction of physical movements in an individual * Psychomotor agitatio ...

, and

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

in both humans and rats, presumably due to the essential signaling within the nervous system that serine, glycine, and other downstream molecules are intimately involved with.

Cause

Homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

or compound heterozygous mutations in 3-

phosphoglycerate dehydrogenase Phosphoglycerate dehydrogenase (PHGDH) is an enzyme that catalyzes the chemical reactions :3-phospho-D-glycerate + NAD+ \rightleftharpoons 3-phosphonooxypyruvate + NADH + H+ :2-hydroxyglutarate + NAD+ \rightleftharpoons 2-oxoglutarate + NADH + ...

(PHGDH) cause Neu-Laxova syndrome and phosphoglycerate dehydrogenase deficiency.

Mechanism

3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the

committed step In enzymology, the committed step (also known as the ''first'' committed step) is an effectively irreversible enzymatic reaction that occurs at a branch point during the biosynthesis of some molecules. As the name implies, after this step, the m ...

in the phosphorylated pathway of

L-serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

biosynthesis. It is also essential in

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

and

glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...

synthesis, which lie further downstream. 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.

Diagnosis

Treatment

Treatment typically involves oral supplementation of serine and glycine.

References

External links

{{Medical resources , ICD10 = {{ICD10, Q, 74, 8 , UMLS = C0268165 , GARD = 2836 , OMIM = 260000 Autosomal recessive disorders Congenital disorders Syndromes with cleft lip and/or palate Syndromes with craniofacial abnormalities Syndromes affecting the nervous system Syndromes with dysmelia Rare syndromes