Serine deficiency disorders

SUMMARY

Serine deficiency disorders comprise a relatively new group of neurometabolic disorders and are caused by defects in the biosynthesis of the amino acid L-serine. Patients suffer from severe neurological symptoms such as microcephaly, psychomotor retardation and seizures, symptoms that underscore the roles of the L-serine pathway in brain development and function. In contrast to many neurometabolic disorders, serine deficiency disorders are treatable disorders, albeit that prompt recognition and treatment are of outmost importance. In this chapter, I will discuss the cellular functions of the L-serine pathway, the clinical and biochemical findings as well as the genetic defects associated with serine deficiency.

INTRODUCTION

Serine deficiency disorders are relatively new inborn errors of metabolism. Only in 1996, Jaeken and colleagues reported for the first time patients with a defect in the L-serine synthetic pathway¹. These patients suffered from severe neurological symptoms and were identified because of low plasma and CSF serine concentrations upon routine amino acid analysis. The molecular defect in these patients affected the first step in the L-serine synthetic pathway, namely the enzyme 3-phosphoglycerate dehydrogenase (3-PGDH). In recent years patients have been identified with defects in the three enzymes of the L-serine pathway and almost invariably they presented with serious neurological symptoms consisting of psychomotor retardation, microcephaly and seizures. In this chapter an overview of serine metabolism and serine deficiency disorders will be given, disorders that can be classified as treatable neurometabolic disorders. The fact that to date only a limited number of patients have been recognized with defects in amino acid synthetic pathways might indicate that these disorders are very rare disorders indeed. However, it might also be true that these patients disorders are under diagnosed, because most diagnostic procedures are aimed at the detection of elevated amino acid concentrations instead of decreased amino acid values. Awareness of serine deficiency disorders is important given the potential therapeutic consequences.

L-SERINE SYNTHESIS

Historically two pathways of L-serine synthesis were identified: a phosphorylated pathway involving 3-phosphoglycerate, phospho-hydroxypyruvate, phosphoserine and L-serine, and a non-phosphorylated pathway involving D-glycerate, hydroxypyruvate and L-serine (Figure 119-1). It was subsequently shown that the non-phosphorylated pathway is not a synthetic route at all, but is in fact an L-serine catabolic pathway involved in gluconeogenesis and that only the phosphorylated pathway is the primary route of L-serine synthesis². The reason that the phosphorylated pathway can not contribute to gluconeogenesis is due to the irreversibility of the final step, the dephosphorylation of phosphoserine. Beyond the fact that L-serine is being synthesised through the phosphorylated pathway, L-serine is also of course a normal constituent of dietary protein and some dietary products such as gelatine are particularly rich in L-serine. Other sources of L-serine are the conversion from glycine via serine hydroxymethyltransferases and L-serine becomes available after protein and phospholipid degradation. Limited data is available on the regulation of the L-serine synthetic ...