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PHGDH deficiency(PHGDHD)

MedGen UID:
400935
Concept ID:
C1866174
Disease or Syndrome
Synonym: Phosphoglycerate dehydrogenase deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PHGDH (1p12)
 
Monarch Initiative: MONDO:0011152
OMIM®: 601815
Orphanet: ORPHA79351

Definition

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). [from OMIM]

Additional description

From MedlinePlus Genetics
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).  https://medlineplus.gov/genetics/condition/phosphoglycerate-dehydrogenase-deficiency

Clinical features

From HPO
Decreased testicular size
MedGen UID:
66027
Concept ID:
C0241355
Finding
Reduced volume of the testicle (the male gonad).
Thumbs, congenital Clasped
MedGen UID:
98140
Concept ID:
C0431886
Congenital Abnormality
In the resting position, the tip of the thumb is on, or near, the palm, close to the base of the fourth or fifth finger.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Cerebral dysmyelination
MedGen UID:
343222
Concept ID:
C1854885
Finding
Defective structure and function of myelin sheaths of the white matter of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Megaloblastic anemia
MedGen UID:
1527
Concept ID:
C0002888
Disease or Syndrome
Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Primary microcephaly
MedGen UID:
383046
Concept ID:
C2677180
Finding
Head circumference below 2 standard deviations below the mean for age and gender at birth.
Reduced 3-phosphoglycerate dehydrogenase activity
MedGen UID:
1841981
Concept ID:
C5826593
Finding
Diminished activity of the enzyme 3-phosphoglycerate dehydrogenase (PGDH), which catalyzes the first step in the pathway by converting D-3-phosphoglycerate (PGA), an intermediate in glycolysis, to phosphohydroxypyruvate concomitant with the reduction of NAD+.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPHGDH deficiency

Professional guidelines

PubMed

Han J, Yang YD, He Y, Liu WJ, Zhen L, Pan M, Yang X, Zhang VW, Liao C, Li DZ
Prenat Diagn 2020 Apr;40(5):577-584. Epub 2020 Feb 10 doi: 10.1002/pd.5653. PMID: 31994750
de Koning TJ
J Inherit Metab Dis 2006 Apr-Jun;29(2-3):347-51. doi: 10.1007/s10545-006-0269-0. PMID: 16763900

Recent clinical studies

Therapy

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
Eur J Paediatr Neurol 2016 Jan;20(1):53-60. Epub 2015 Nov 5 doi: 10.1016/j.ejpn.2015.10.007. PMID: 26610677

Prognosis

Ali A, Dhahouri NA, Almesmari FSA, Fathalla WM, Jasmi FA
Genes (Basel) 2021 May 8;12(5) doi: 10.3390/genes12050703. PMID: 34066864Free PMC Article
Klomp LW, de Koning TJ, Malingré HE, van Beurden EA, Brink M, Opdam FL, Duran M, Jaeken J, Pineda M, Van Maldergem L, Poll-The BT, van den Berg IE, Berger R
Am J Hum Genet 2000 Dec;67(6):1389-99. Epub 2000 Oct 27 doi: 10.1086/316886. PMID: 11055895Free PMC Article

Clinical prediction guides

Ali A, Dhahouri NA, Almesmari FSA, Fathalla WM, Jasmi FA
Genes (Basel) 2021 May 8;12(5) doi: 10.3390/genes12050703. PMID: 34066864Free PMC Article
Vandekeere S, Dubois C, Kalucka J, Sullivan MR, García-Caballero M, Goveia J, Chen R, Diehl FF, Bar-Lev L, Souffreau J, Pircher A, Kumar S, Vinckier S, Hirabayashi Y, Furuya S, Schoonjans L, Eelen G, Ghesquière B, Keshet E, Li X, Vander Heiden MG, Dewerchin M, Carmeliet P
Cell Metab 2018 Oct 2;28(4):573-587.e13. Epub 2018 Jul 12 doi: 10.1016/j.cmet.2018.06.009. PMID: 30017355
Klomp LW, de Koning TJ, Malingré HE, van Beurden EA, Brink M, Opdam FL, Duran M, Jaeken J, Pineda M, Van Maldergem L, Poll-The BT, van den Berg IE, Berger R
Am J Hum Genet 2000 Dec;67(6):1389-99. Epub 2000 Oct 27 doi: 10.1086/316886. PMID: 11055895Free PMC Article

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