PSAT1 – Neu-Laxova Syndrome

Neu-Laxova syndrome (NLS) is a rare, lethal congenital disorder characterized by severe intrauterine growth retardation, ichthyosis, craniofacial anomalies, limb contractures, and early postnatal lethality. Biallelic pathogenic variants in PSAT1, encoding phosphoserine aminotransferase 1, have been identified as one of three genetic causes of NLS, alongside PHGDH and PSPH. The autosomal recessive inheritance and recurrent observation of PSAT1 variants in unrelated families firmly establish PSAT1 as a causal gene in NLS.

Genetic studies have described at least 17 probands with NLS harboring PSAT1 variants across five independent reports (17 probands; [PMID:35885441]; [PMID:31903955]; [PMID:25152457]; [PMID:37964427]; [PMID:39638571]). These include homozygous and compound heterozygous missense (e.g., c.296C>T (p.Ala99Val)) and loss-of-function alleles (nonsense and frameshift) fully segregating with disease in at least six consanguineous families ([PMID:25152457]). No reports have contradicted these findings.

The variant spectrum in PSAT1–related NLS encompasses missense (e.g., p.Ala99Val), nonsense (e.g., p.Ser179Ter), and frameshift changes, consistent with a loss-of-function mechanism. Founder effects have been suggested for some alleles in specific populations (e.g., c.734G>A (p.Cys245Tyr) in an Egyptian cohort) ([PMID:39638571]). Population prevalence estimates are unavailable, reflecting the ultra-rare nature of NLS.

Functional assays support the pathogenicity of PSAT1 variants. A yeast-based complementation assay quantitatively measured the impact of 200 missense alleles, correlating loss of function with clinical severity ([PMID:32077105]). Enzyme activity studies in patient fibroblasts confirmed reduced phosphoserine aminotransferase activity for selected variants ([PMID:17436247]). These concordant results demonstrate that PSAT1 dysfunction leads to L-serine deficiency and the NLS phenotype.

Mechanistically, loss of PSAT1 disrupts de novo L-serine synthesis in the phosphorylated pathway, impairing downstream sphingolipid and phosphatidylserine production critical for skin barrier function and neurodevelopment. Reduced ceramides in the stratum corneum of NLS patients further link PSAT1 deficiency to ichthyosis and barrier defects ([PMID:30348640], PHGDH study).

In summary, robust genetic and experimental data classify PSAT1–Neu-Laxova syndrome as a strong gene–disease association. Clinical genetic testing for PSAT1 variants enables definitive prenatal or postnatal diagnosis of NLS and informs family counseling. Early identification may guide consideration of L-serine supplementation, although efficacy in NLS remains to be established.

References

• Diagnostics (Basel, Switzerland) • 2022 • Prenatal Diagnosis of Neu-Laxova Syndrome PMID:35885441
• European journal of dermatology : EJD • 2019 • Novel and recurrent PHGDH and PSAT1 mutations in Chinese patients with Neu-Laxova syndrome PMID:31903955
• American journal of human genetics • 2014 • Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway PMID:25152457
• Prenatal diagnosis • 2023 • Neu Laxova syndrome and megacystis in the first trimester: Broadening the fetal phenotype PMID:37964427
• Prenatal diagnosis • 2025 • Fetal Phenotyping and Whole Exome Sequencing for 12 Egyptian Families With Serine Biosynthesis Defect: Novel Clinical and Allelic Findings With a Founder Effect PMID:39638571
• Journal of inherited metabolic disease • 2020 • A yeast-based complementation assay elucidates the functional impact of 200 missense variants in human PSAT1 PMID:32077105
• American journal of human genetics • 2007 • Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway PMID:17436247

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