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.

Currently, management of PHGDH deficiency focuses on supportive care and symptom management, as there are no FDA-approved treatments specifically for this condition. Treatment is highly individualized and typically involves a multidisciplinary team to address issues such as seizures, developmental delays, and feeding difficulties. Regular surveillance is an essential part of long-term care, helping to identify potential complications early so that interventions can be timely initiated. Genetic counseling is also recommended to assist families in understanding their options and to support family planning discussions.

The long-term outlook for individuals with PHGDH deficiency is variable, with outcomes depending on the severity of symptoms, age at diagnosis, and access to specialized care. While many individuals face significant neurodevelopmental challenges, modern approaches to supportive care and multidisciplinary management can help optimize quality of life. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with multidisciplinary specialists familiar with this condition for ongoing guidance and support.

Clinical trials are underway exploring new treatment approaches for PHGDH deficiency. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.