Serine deficiency disorders are rare autosomal-recessive metabolic diseases caused by impaired synthesis of L-serine. They are most commonly associated with biallelic variants in PHGDH, PSAT1 or PSPH.
The neurological spectrum ranges from lethal prenatal disease to infantile, juvenile and adult-onset forms. Epilepsy is especially important in the infantile and juvenile phenotypes.
Infantile-onset disease
Infantile serine deficiency typically causes early seizures, microcephaly, developmental delay, severe intellectual disability and spasticity.
Seizures can begin in the first weeks or months of life.
Seizure types
Reported seizure types include infantile spasms, myoclonic, tonic, atonic, gelastic and tonic-clonic seizures.
Epilepsy is often highly drug resistant before the metabolic cause is recognised.
Infantile spasms
About one third of described infantile cases have presented with infantile spasms syndrome.
Hypsarrhythmia may be present on EEG.
Biochemical diagnosis
Very low cerebrospinal-fluid serine is a characteristic finding.
Plasma serine can also be reduced, but CSF assessment is particularly informative in neurological disease.
Genetic diagnosis
Diagnosis is confirmed by biallelic pathogenic variants in PHGDH, PSAT1 or PSPH.
The disorder is inherited in an autosomal-recessive pattern.
L-serine is targeted therapy
L-serine supplementation is the disease-specific treatment.
GeneReviews reports major seizure improvement in many treated individuals, with some becoming seizure free and no longer needing chronic antiseizure medication.
Why early treatment matters
Serine is important for neuronal proliferation, membrane lipid synthesis and neurotransmitter pathways.
Neurological injury that occurs before diagnosis may not be fully reversible, so early recognition is important.
Glycine supplementation
Glycine may be added in selected cases when response to L-serine alone is incomplete.
Dosing requires specialist metabolic supervision.
MRI
Infantile disease can show hypomyelination, white-matter abnormalities or delayed myelination.
Juvenile and adult-onset forms may have normal MRI.
Development beyond seizures
Even when seizure control improves, microcephaly, spasticity, motor disability and intellectual disability can persist.
Therapy therefore includes rehabilitation, communication support and nutritional care.
Newborn relatives
When a family diagnosis is known, apparently unaffected newborn siblings should be evaluated promptly because pre-symptomatic treatment may prevent severe neurological injury.
Worldwide access
Serine deficiency is easily missed because the symptoms resemble many genetic developmental epilepsies.
Availability of CSF amino-acid testing and genomic diagnosis varies widely.
The central point
Serine deficiency is one of the metabolic epilepsies where correcting the biochemical defect can dramatically change seizure control.
Related reading
Sources
Medical note: L-serine therapy requires metabolic specialist supervision and should not be self-prescribed.
Evidence checked: September 2026.