PHGDH – Neu-Laxova syndrome

Neu-Laxova syndrome (NLS) is a rare, lethal autosomal recessive disorder characterized by severe prenatal growth restriction, microcephaly, ichthyosis, edema, limb hypoplasia, arthrogryposis and perinatal lethality. Biallelic loss-of-function variants in PHGDH, encoding the first enzyme of de novo L-serine biosynthesis, underlie the most severe end of serine deficiency disorders, representing extreme phenotypic variability within the serine synthesis continuum.

Initial positional mapping and whole-exome sequencing in consanguineous families identified PHGDH mutations in >70 probands across >20 unrelated families, establishing an autosomal recessive inheritance pattern ([PMID:24836451]). Case reports describe a homozygous nonsense variant c.1297C>T (p.Gln433Ter) in a fetus with the most severe NLS phenotype to date, confirming genotype–phenotype correlations between the degree of PHGDH inactivation and clinical severity ([PMID:25913727]).

The spectrum of pathogenic alleles includes nonsense (e.g., p.Gln433Ter), frameshift (e.g., p.Leu259fs), splice‐site and missense changes (e.g., p.Arg163Trp), with >25 distinct variants documented ([PMID:24836451]). Affected individuals are homozygous or compound heterozygous, while heterozygous carriers remain asymptomatic, demonstrating clear segregation in multiplex sibships.

Functional assays show that missense and nonsense mutations markedly reduce PHGDH enzymatic activity in patient fibroblasts and yeast complementation systems ([PMID:11055895]). Phgdh knockout mice recapitulate human microcephaly and embryonic lethality, with marked central nervous system growth retardation and serine deficiency ([PMID:18228065]). Stratum corneum analyses in NLS patients reveal reduced ceramide levels, linking serine shortage to skin barrier defects ([PMID:30348640]).

The pathogenic mechanism involves loss of PHGDH function, leading to systemic L-serine deficiency that impairs neurogenesis, extracellular matrix integrity and fetal development. Concordant animal and cellular models validate haploinsufficiency as the key driver of the NLS phenotype.

No conflicting evidence has been reported. Together, genetic and functional data fulfill ClinGen criteria for a definitive gene–disease relationship, supporting clinical genetic testing for PHGDH in suspected NLS cases. Early diagnosis enables prenatal counseling and consideration of L-serine supplementation as a potential therapeutic strategy.

References

• American journal of human genetics • 2014 • Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH PMID:24836451
• American journal of medical genetics. Part A • 2015 • Identification of a premature stop codon mutation in the PHGDH gene in severe Neu-Laxova syndrome-evidence for phenotypic variability PMID:25913727
• Journal of lipid research • 2018 • Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency PMID:30348640
• American journal of human genetics • 2000 • Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis PMID:11055895
• Functional & integrative genomics • 2008 • Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: changes in gene expression and associated regulatory networks resulting from serine deficiency PMID:18228065

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