Phosphoserine Aminotransferase Deficiency: A Novel Disorder of the Serine Biosynthesis Pathway

Abstract

We present the first two identified cases of phosphoserine aminotransferase deficiency. This disorder of serine biosynthesis has been identified in two siblings who showed low concentrations of serine and glycine in plasma and cerebrospinal fluid. Clinically, the index patient presented with intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation and died at age 7 mo despite supplementation with serine (500 mg/kg/d) and glycine (200 mg/kg/d) from age 11 wk. The younger sibling received treatment from birth, which led to a normal outcome at age 3 years. Measurement of phosphoserine aminotransferase activity in cultured fibroblasts in the index patient was inconclusive, but mutational analysis revealed compound heterozygosity for two mutations in the PSAT1 gene--one frameshift mutation (c.delG107) and one missense mutation (c.299A-->C [p.Asp100Ala])--in both siblings. Expression studies of the p.Asp100Ala mutant protein revealed a V(max) of only 15% of that of the wild-type protein.

Amino acid synthesis deficiencies

“…While enzymatic assays are available for the three L-serine synthesis enzymes, enzyme testing is being replaced more and more by DNA diagnostics. This is due to problems in the availability of the substrate required for the 3-PGDH assay and the debated sensitivity of the other assays (Hart et al 2007).…”

“…No progress, or only very limited progress, in psychomotor development has been observed during (long term) treatment follow-up (de Koning et al 2002;Brassier et al 2016;personal observations). However, treatment can be successful when amino acid therapy is initiated before symptoms arise, either as antenatal Lserine therapy given to the mother or as immediate postnatal therapy on the first day of life in still asymptomatic patients (de Koning et al 2004;Hart et al 2007).…”

Discovery and Analysis of Cofactor-dependent Phosphoglycerate Mutase Homologs as Novel Phosphoserine Phosphatases in Hydrogenobacter thermophilus

“…Furthermore, PSAT activity has also been detected biochemically (14), and we confirmed the existence of phosphoserine by metabolome analysis. 3 However, because H. thermophilus and other members of Aquificales lack an ortholog of dPSP (Table 1), we hypothesized that H. thermophilus may possess a novel type of PSP.…”

Cilostazol Promotes the Migration of Brain Microvascular Endothelial Cells

“…PSAT1 has some important metabolic functions such as PSAT1 deficiency results in intractable seizures and acquired microcephaly [8], and reduced expression in diabetic mice [36]. However, there was no previous information regarding PSAT1 expression and function in endothelial migration.…”