PHGDH deficiency

PHGDH deficiency is an autosomal recessive metabolic disorder that falls under the serine deficiency syndromes. It is caused by mutations in the PHGDH gene, which impair an enzyme involved in serine biosynthesis, a critical process for brain development. The infantile form typically presents with congenital microcephaly, psychomotor retardation, and intractable seizures, while the juvenile form is characterized by absence seizures, moderate developmental delay, and behavioral disorders. This condition is very rare, affecting fewer than 1 in 1 million people.

The clinical presentation of PHGDH deficiency varies with age. In the infantile form, affected children often exhibit congenital microcephaly, significant psychomotor retardation, and severe, intractable seizures that draw attention early in life. The juvenile form may include absence seizures, moderate developmental delays, and behavioral disturbances. Additional features reported in affected individuals include feeding difficulties, spasticity, and various neuroimaging abnormalities such as delayed myelination and cerebral white matter atrophy. Not all individuals experience every feature, and severity varies considerably.

PHGDH deficiency results from pathogenic variants in the PHGDH gene, which encodes an enzyme essential for the biosynthesis of the amino acid serine. Disruption of this enzyme affects proper brain development and function. The disorder is inherited in an autosomal recessive pattern, meaning that an affected individual receives one mutated copy of PHGDH from each parent. This condition is more common when parents share a common ancestor, as both are more likely to carry the rare variant, and each child of two carriers has a 25% chance of being affected. Genetic counseling is recommended to help families understand these risks. Associated genes include PHGDH.