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Neu-Laxova syndrome (NLS) is a term that unifies the independent reports by Neu and Laxova of a lethal multiple congenital anomaly syndrome (1). The main features of NLS involve defective somatic growth and the disturbed development of the central nervous system and skin, as well as many other anomalies that might present primarily as malformations or a malformation sequence (1). In 2014, mutations in PHGDH, which encodes phosphoglycerate dehydrogenase (PHGDH), were found in autosomal recessive cases of NLS (1). In addition, mutations in PSAT1, which encodes phosphoserine aminotransferase 1, and PSPH, which encodes phosphoserine phosphatase, were identified in several autosomal recessive cases of NLS (2). NLS is a genetically heterogeneous disorder that can be caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH (Fig. 1). l-Serine is a nonessential amino acid that is synthesized de novo from the glycolytic intermediate 3-phosphoglycerate through three steps that are respectively catalyzed by PHGDH, phosphoserine aminotransferase, and phosphoserine phosphatase (3). PHGDH deficiency, which is a congenital error of serine metabolism, was first described in 1996, before NLS was proposed as a syndrome (4). PHGDH is the first enzyme in the de novo biosynthesis of serine from carbohydrates. A reduced ability to synthesize l-serine has potentially serious consequences for cellular metabolism (5). Serine is Abstract Neu-Laxova syndrome (NLS) is a very rare autosomal recessive congenital disorder characterized by disturbed development of the central nervous system and the skin and caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH. l-Serine is essential for the biosynthesis of phosphatidylserine and sphingolipids. The extracellular lipid of the stratum corneum, of which sphingolipid constitutes a significant part, plays a primary role in skin barrier function. Here, we describe a Japanese NLS pedigree with a previously unreported nonsense mutation in PHGDH and a unique inversion of chromosome 1. In addition, the levels of 11 major ceramide classes in the tapestripped stratum corneum of the NLS patient's skin were assessed by LC/MS. Notably, lower amounts of ceramides of all classes were found in the patient's stratum corneum than in those of controls. This is the first report to demonstrate the reduction of ceramides in the stratum corneum of an NLS patient due to PHGDH mutations. The clinical findings and a detailed analysis of ceramides from the stratum corneum in the family extend the spectrum of clinical anomalies and give us a clue to the pathomechanisms of ichthyosis in NLS patients with phosphoglycerate dehydrogenase deficiency.-Takeichi, T.

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Background: Redness of the facial skin is an important cosmetic concern. Although qualitative and quantitative modifications of sebum on the skin surface are major pathogenic factors of chronic inflammatory skin conditions, the relationship between skin redness, sebum, and mild inflammation on the cheeks of healthy subjects remains elusive. Aims:We aimed to explore the correlation between cheek redness and sebum and inflammatory cytokines in the stratum corneum (SC) of healthy subjects. We also examined the effects of representative sebum lipids on the gene expression of inflammatory cytokines in cultured keratinocytes.Patients/Methods: This study included 198 healthy participants. Skin sebum was analyzed using flow injection analysis, and skin redness was assessed using a spectrophotometer. Inflammatory cytokines in tape-stripped SC were measured using enzyme-linked immunosorbent assay.Results: Cheek redness parameters positively correlated with the amount of skin sebum and the proportion of monounsaturated free fatty acids (C16:1 and C18:1) in the sebum. They also positively correlated with the interleukin (IL)-36γ/IL-37 ratio in the SC. Among the representative sebum lipids examined, oleic acid (C18:1, cis-9) dose-and time-dependently regulated the mRNA expression of IL-36γ and IL-37 in cultured keratinocytes, and this effect was attenuated by the N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonist, MK801.Conclusions: Skin surface sebum may be related to cheek redness in healthy subjects, and oleic acid-induced IL-36γ through NMDA-type glutamate receptors may be a link | 2309 KAWAMOTO et al.