Novel Report of Phosphoserine Phosphatase Deficiency in an Adult with Myeloneuropathy and Limb Contractures

Abstract

Serine is a nonessential amino acid that plays a vital role in proper development and functioning of the central nervous system (CNS). Serine deficiency leads to microcephaly, intellectual disability, seizures, and psychomotor retardation in children and severe axonal neuropathy in adults. Serine deficiency syndrome is due to a deficiency of one of three enzymes in the endogenous serine biosynthesis pathway: phosphoglycerate dehydrogenase, phosphoserine transaminase, or, most rarely, phosphoserine phosphatase. Of critical importance to clinical care, serine deficiency syndrome is treatable. Herein, we describe the novel presentation of phosphoserine phosphatase deficiency in an adult. The patient had intrauterine growth restriction, lifelong intellectual disability, childhood onset epilepsy, and borderline microcephaly. In adulthood, she developed progressively severe lower extremity hypertonia, axonal neuropathy, and hand contractures. Neuropathy was complicated by non-healing wounds. Fasting plasma amino acids showed low serine and glycine. Molecular analysis revealed compound heterozygous mutations in phosphoserine phosphatase (PSPH). Treatment with oral serine resulted in improvement of plasma serine levels, decreased neuropathic pain, and subjective improvement in energy level. Although the first case of phosphoserine phosphatase deficiency was described nearly 20 years ago, only eight cases have been reported, all in children. This is the first report of phosphoserine phosphatase deficiency in an adult.

The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders

“…Patients with phosphoglycerate dehydrogenase or phosphoserine aminotransferase manifest with severe intellectual disability, spastic tetraparesis, severe microcephaly and epilepsy [8]. A deficiency of 3-phosphoserine phosphatase was identified in one patient with moderate intellectual disability who also had Williams's syndrome [15] and in another patient with intrauterine growth restriction, intellectual disability, childhood onset epilepsy, and borderline microcephaly who developed progressive lower extremity hypertonia, axonal neuropathy, and hand contractures in adulthood [4].…”

Deoxysphingolipid precursors indicate abnormal sphingolipid metabolism in individuals with primary and secondary disturbances of serine availability

“…Patients or their guardians gave written, informed consent. PSD patient 1, enrolled in the NIH Undiagnosed Diseases Program [12–14], had PSAT deficiency, while PSD patient 2 (previously reported [15]) has PSPH deficiency. Plasma samples were obtained when the patients were not receiving serine or glycine supplementation.…”

The first insight into the genetic structure of the population of modern Serbia

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted December 20, 2020. ; https://doi.org/10.1101/2020.12.18.423408 doi: bioRxiv preprint family, a phosphoserine phosphatase involved in the biosynthesis of serine [38]. A recent study by Jia et al [39] showed that the PSPH loci is associated with the glycine level, while Byers et al [40] showed that these substitutions affect the PSPH protein functions, while molecular mechanisms underlying this disturbance were predicted to be associated with phosphorylation and cleavage of the PSPH protein ( Table 2). Thus far, there is no information about the effect of these variants at the level of metabolites affected by PSPH, but their proximity to the already described glycine decreasing variant [40] can lead to the assumption of the same effect.…”

“…A recent study by Jia et al [39] showed that the PSPH loci is associated with the glycine level, while Byers et al [40] showed that these substitutions affect the PSPH protein functions, while molecular mechanisms underlying this disturbance were predicted to be associated with phosphorylation and cleavage of the PSPH protein ( Table 2). Thus far, there is no information about the effect of these variants at the level of metabolites affected by PSPH, but their proximity to the already described glycine decreasing variant [40] can lead to the assumption of the same effect. Since glycine was shown to have antihypertensive and atheroprotective properties, as well as, to reduce risk of acute myocardial infarction [41,42], gene variants lowering the glycine level in blood might increase susceptibility to various cardiovascular diseases.…”