Serine is obtained from diet and is synthesized endogenously starting from the glycolytic intermediate 3- phosphoglycerate in three steps using the enzymes phosphoglycerate dehydrogenase (gene PHGDH ), phosphoserine aminotransferase ( PSAT1 ), and phosphoserine phosphatase ( PSPH ). Three disorders of serine biosynthesis are known affecting each of the steps in this serine biosynthetic pathway (Tabatabaie et al. 2010). Characteristic for all three disorders is the decreased biosynthesis of serine resulting in serine deficiency. Serine is an essential component of phosphatidylserine, sphingolipids, and ceramides and is necessary for myelin development (de Koning et al. 2003). -Serine is converted through the racemase to d-serine, which is an NMDA receptor activator. Through the serine hydroxymethyltransferase enzyme, serine is converted into glycine and provides methylene- tetrahydrofolate which is important for thymidine synthesis.
3-Phosphoglycerate dehydrogenase deficiency (PHGDH) is an autosomal recessive condition and the most frequently reported cause of serine deficiency syndrome. In the severe infantile form, it presents in the neonatal period with congenital microcephaly, intractable seizures starting shortly after birth, and severe psychomotor retardation. A wide variation of seizure types are reported including West syndrome. The EEG patterns include hypsarrhythmia, multifocal epilepsy, and Lennox-Gastaut syndrome. They develop spastic tetraparesis, with adducted thumbs, and hyperexcitability. Variable symptoms observed in some patients include cataracts, hypogonadism, megaloblastic anemia, and nystagmus. The MRI of the brain shows a striking reduction in the volume of the white matter and very delayed to absent myelination. The cerebral white matter on T2 has a higher signal intensity than the cortex, indicative of a lack of myelin. There is also cortical and subcortical atrophy. MRS shows a decreased level of N -acetylaspartate/ creatine and increased choline /creatine in the white matter
Phosphoserine aminotransferase defi ciency (PSAT1) was reported in a single family (Hart et al. 2007). They had acquired microcephaly, intractable seizures since early infancy, and hypertonia. Brain MRI showed generalized atrophy, a hypoplastic cerebellar vermis, and poor white matter development. Serine and glycine were defi cient in plasma and CSF. Diagnosis was confi rmed by sequencing, as the enzyme assay was not defi cient. Phosphoserine phosphatase defi ciency (PSPH) has been reported in a single patient who also had Williams syndrome (Jaeken et al. 1997). The child had growth and psychomotor retardation, but no seizures. His fasting plasma serine levels were low–normal, and his CSF serine levels were low. He was homozygous for a missense mutation that decreased the enzyme activity.
This text is an extract from “Physician´s Guide to the Diagnosis, Treatment and Follow-Up of Inherited Metabolic Diseases”, Editors: Nenad Blau, Marinus Duran, K. Michael Gibson, Carlos Dionisi-Vici, Publisher: Springer
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de Koning TJ, Snell K, Duran M et al (2003) l-Serine in disease and development. Biochem J 137:653–661
Hart CE, Race V, Achouri Y et al (2007) Phosphoserine aminotransferase defi ciency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 80:931–937
Jaeken J, Detheux M, Fryns JP et al (1997) Phosphoserine phosphatase defi ciency in a patient with Williams syndrome. J Med Genet 34: 594–596