Phosphoglycerate dehydrogenase deficiency is a condition characterized by an unusually small head size (microcephaly); impaired development of physical reactions, movements, and speech (psychomotor retardation); and recurrent seizures (epilepsy). Different types of phosphoglycerate dehydrogenase deficiency have been described; they are distinguished by their severity and the age at which symptoms first begin. Most affected individuals have the infantile form, which is the most severe form, and are affected from infancy. Symptoms of the juvenile and adult types appear later in life; these types are very rare.

In phosphoglycerate dehydrogenase deficiency there is a progressive loss of brain cells leading to a loss of brain tissue (brain atrophy), specifically affecting the fatty tissue known as myelin that surrounds nerve cells (hypomyelination). Frequently, the tissue that connects the two halves of the brain (corpus callosum) is small and thin, and the fluid-filled cavities (ventricles) near the center of the brain are enlarged. Because development of the brain is disrupted, the head does not grow at the same rate as the body, so it appears that the head is getting smaller as the body grows (progressive microcephaly). Poor brain growth leads to an inability to achieve many developmental milestones such as sitting unsupported and speaking. Many affected infants also have difficulty feeding.

The seizures in phosphoglycerate dehydrogenase deficiency can vary in type. Recurrent muscle contractions called infantile spasms are typical early in the disorder. Without early treatment, seizures may progress to tonic-clonic seizures, which involve a loss of consciousness, muscle rigidity, and convulsions; myoclonic seizures, which involve rapid, uncontrolled muscle jerks; or drop attacks, which are sudden episodes of weak muscle tone.

Individuals with the infantile form of phosphoglycerate dehydrogenase deficiency develop many of the features described above. Individuals with the juvenile form typically have epilepsy as well as mild developmental delay and intellectual disability. Only one case of the adult form has been reported; signs and symptoms began in mid-adulthood and included mild intellectual disability; difficulty coordinating movements (ataxia); and numbness, tingling, and pain in the arms and legs (sensory neuropathy).

This condition is likely a rare disorder, but its prevalence is unknown. At least 15 cases have been described in the scientific literature.

Mutations in the PHGDH gene cause phosphoglycerate dehydrogenase deficiency. The PHGDH gene provides instructions for making the parts (subunits) that make up the phosphoglycerate dehydrogenase enzyme. Four PHGDH subunits combine to form the enzyme. This enzyme is involved in the production of the protein building block (amino acid) serine. Specifically, the enzyme converts a substance called 3-phosphoglycerate to 3-phosphohydroxypyruvate in the first step in serine production. Serine is necessary for the development and function of the brain and spinal cord (central nervous system). Serine is a part of chemical messengers called neurotransmitters that transmit signals in the nervous system. Proteins that form cell membranes and myelin also contain serine. Serine can be obtained from the diet, but brain cells must produce their own serine because dietary serine cannot cross the protective barrier that allows only certain substances to pass between blood vessels and the brain (the blood-brain barrier).

PHGDH gene mutations result in the production of an enzyme with decreased function. As a result, less 3-phosphoglycerate is converted into 3-phosphohydroxypyruvate than normal and serine production is stalled at the first step. The lack of serine likely prevents the production of proteins and neurotransmitters in the brain and impairs the formation of normal cells and myelin. These disruptions in normal brain development lead to the signs and symptoms of phosphoglycerate dehydrogenase deficiency.

Genetic Testing Information

• Genetic Testing Registry: PHGDH deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY; PHGDHD

Scientific Articles on PubMed

• PubMed

• de Koning TJ, Klomp LW, van Oppen AC, Beemer FA, Dorland L, van den Berg I, Berger R. Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet. 2004 Dec 18-31;364(9452):2221-2. doi: 10.1016/S0140-6736(04)17596-X. Citation on PubMed
• de Koning TJ, Klomp LW. Serine-deficiency syndromes. Curr Opin Neurol. 2004 Apr;17(2):197-204. doi: 10.1097/00019052-200404000-00019. Citation on PubMed
• Kraoua I, Wiame E, Kraoua L, Nasrallah F, Benrhouma H, Rouissi A, Turki I, Chaabouni H, Briand G, Kaabachi N, Van Schaftingen E, Gouider-Khouja N. 3-Phosphoglycerate dehydrogenase deficiency: description of two new cases in Tunisia and review of the literature. Neuropediatrics. 2013 Oct;44(5):281-5. doi: 10.1055/s-0033-1338133. Epub 2013 Apr 6. Citation on PubMed
• Tabatabaie L, de Koning TJ, Geboers AJ, van den Berg IE, Berger R, Klomp LW. Novel mutations in 3-phosphoglycerate dehydrogenase (PHGDH) are distributed throughout the protein and result in altered enzyme kinetics. Hum Mutat. 2009 May;30(5):749-56. doi: 10.1002/humu.20934. Citation on PubMed
• Tabatabaie L, Klomp LW, Berger R, de Koning TJ. L-serine synthesis in the central nervous system: a review on serine deficiency disorders. Mol Genet Metab. 2010 Mar;99(3):256-62. doi: 10.1016/j.ymgme.2009.10.012. Epub 2009 Oct 25. Citation on PubMed
• Tabatabaie L, Klomp LW, Rubio-Gozalbo ME, Spaapen LJ, Haagen AA, Dorland L, de Koning TJ. Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency. J Inherit Metab Dis. 2011 Feb;34(1):181-4. doi: 10.1007/s10545-010-9249-5. Epub 2010 Nov 27. Citation on PubMed or Free article on PubMed Central
• van der Crabben SN, Verhoeven-Duif NM, Brilstra EH, Van Maldergem L, Coskun T, Rubio-Gozalbo E, Berger R, de Koning TJ. An update on serine deficiency disorders. J Inherit Metab Dis. 2013 Jul;36(4):613-9. doi: 10.1007/s10545-013-9592-4. Epub 2013 Mar 6. Citation on PubMed