Serine biosynthesis disorders (PHGDH, PSAT1, PSPH)
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A term infant has congenital microcephaly, seizures beginning in the first weeks that do not respond to standard antiseizure medication, and profound developmental delay. Plasma amino acids are read as normal. Paired fasting CSF and plasma amino acids show low CSF serine and low CSF glycine.
- Autosomal recessive. Three enzymes in the same pathway:
- PHGDH (3-phosphoglycerate dehydrogenase), the most common
- PSAT1 (phosphoserine aminotransferase)
- PSPH (phosphoserine phosphatase)
- Serine is a non-essential amino acid, which is exactly the problem: the brain cannot import enough across the blood-brain barrier and depends on making its own
- Neu-Laxova syndrome is the severe end of this same spectrum, not a separate condition: it is a lethal fetal presentation of PHGDH, PSAT1, or PSPH deficiency with ichthyosis, marked IUGR, microcephaly, contractures, and craniofacial anomalies
- Congenital microcephaly that is present at birth and progresses
- Intractable seizures, often starting in the first weeks to months, frequently including infantile spasms
- Severe developmental delay, spastic quadriparesis
- Cataracts, hypertonia, irritability
- Brain MRI shows hypomyelination and reduced white matter volume
- CSF amino acids are the diagnostic test, not plasma. Plasma serine can be normal or only borderline low, particularly if the sample is not fasting, so a normal plasma amino acid panel does not exclude this
- Collect paired fasting CSF and plasma; the CSF serine and glycine are both low, and the CSF-to-plasma ratio is what makes the case
- Confirm with sequencing of PHGDH, PSAT1, and PSPH
- Not detected by newborn screening
- Oral L-serine, with glycine added in some protocols. Seizure control often improves substantially, and head growth can partially recover
- Outcome depends almost entirely on how early treatment starts. Started in the neonatal period it can prevent the severe phenotype; started after established encephalopathy it improves seizures but not the cognitive outcome
- Prenatal maternal L-serine has been reported to prevent the Neu-Laxova phenotype in a subsequent affected pregnancy
- Sibling testing and early treatment of an affected newborn before symptoms appear
- This is one of the very few treatable causes of congenital microcephaly, which is why it is worth remembering despite being rare. Microcephaly plus intractable seizures should prompt CSF amino acids before the workup broadens.
- A normal plasma amino acid panel is the trap. The deficiency is compartmental, so only CSF reveals it.
- Low CSF serine and low CSF glycine together is the pattern; glycine is made from serine, so it falls with it. Isolated low glycine points elsewhere.