Neu-Laxova Syndrome, an Inborn Error of Serine Metabolism, Is Caused by Mutations in PHGDH

Abstract

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by severe fetal growth restriction, microcephaly, a distinct facial appearance, ichthyosis, skeletal anomalies, and perinatal lethality. The pathogenesis of NLS remains unclear despite extensive clinical and pathological phenotyping of the >70 affected individuals reported to date, emphasizing the need to identify the underlying genetic etiology, which remains unknown. In order to identify the cause of NLS, we conducted a positional-mapping study combining autozygosity mapping and whole-exome sequencing in three consanguineous families affected by NLS. Surprisingly, the NLS-associated locus identified in this study was solved at the gene level to reveal mutations in PHGDH, which is known to be mutated in individuals with microcephaly and developmental delay. PHGDH encodes the first enzyme in the phosphorylated pathway of de novo serine synthesis, and complete deficiency of its mouse ortholog recapitulates many of the key features of NLS. This study shows that NLS represents the extreme end of a known inborn error of serine metabolism and highlights the power of genomic sequencing in revealing the unsuspected allelic nature of apparently distinct clinical entities.

Amino acid synthesis deficiencies

“…In 2014, two different groups published mutations in serine synthesis genes in patients with this Neu-Laxova syndrome (Acuna-Hidalgo et al 2014, Shaheen et al 2014). From this it was obvious that defects in all three genes can give rise to the same clinical phenotype.…”

Serine biosynthesis and transport defects

“…In serine biosynthesis defects, a deficiency in one of the three serine biosynthesis enzymes, PGDH, PSAT, or PSP, results in the impairment of the de novo serine biosynthetic pathway which serves as the major source of this nonessential amino acid. Therefore, a deficiency of serine in all organs including the brain occurs despite the fact that serine can still be derived from diet, degradation of protein and phospholipids, and direct synthesis from glycine, because these alternative sources cannot compensate for defects in the serine biosynthesis pathway [6,2,23,24]. On the other hand, in serine transport defect, dysfunctional ASCT1 results in impaired serine transport to neurons leading to neuronal serine deficiency [4,3].…”

“…Homozygous mutations in the PHGDH gene were identified in these three families indicating that Neu-Laxova syndrome can be due to PGDH deficiency [23]. That finding paved the way for the identification of additional affected individuals with Neu-Laxova syndrome and biallelic mutations in the PHGDH gene [24,25].…”

“…In PGDH deficiency, the enzyme activity has been reported to be reduced to 10-25% of normal activity in both infantile and childhood phenotypes. Although enzyme assay in individuals with Neu-Laxova has not been performed, it is expected to be lower than the range seen in the milder infantile and childhood phenotypes [23,24].…”

“…The variability in the phenotypes associated with serine biosynthesis defects has been suggested to result from the degree of the residual enzyme activity [23,24]. In PGDH deficiency, the enzyme activity has been reported to be reduced to 10-25% of normal activity in both infantile and childhood phenotypes.…”