Editing Serine (section)

== Clinical significance ==
Serine deficiency disorders are rare defects in the biosynthesis of the amino acid <small>L</small>-serine. At present three disorders have been reported:

* [[3-phosphoglycerate dehydrogenase deficiency]]
* [[3-phosphoserine phosphatase deficiency]]
* [[Phosphoserine aminotransferase deficiency]]

These enzyme defects lead to severe neurological symptoms such as congenital microcephaly and severe psychomotor retardation and in addition, in patients with 3-phosphoglycerate dehydrogenase deficiency to intractable seizures. These symptoms respond to a variable degree to treatment with <small>L</small>-serine, sometimes combined with glycine.<ref>{{cite journal| author = de Koning TJ| title = Treatment with amino acids in serine deficiency disorders | journal= [[Journal of Inherited Metabolic Disease]]| volume = 29| issue = 2|  pages = 347–351|date=April 2006|pmid = 16763900| doi=10.1007/s10545-006-0269-0| s2cid = 25013468 }}</ref><ref>{{cite journal|author1=Tabatabaie L |author2=Klomp LW |author3=Berger R |author4=de Koning TJ | title = L-Serine synthesis in the central nervous system: a review on serine deficiency disorders| journal = [[Mol Genet Metab]]| volume = 99| issue = 3|  pages = 256–262|date=March 2010| doi= 10.1016/j.ymgme.2009.10.012| pmid = 19963421}}</ref>
Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, as well as for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial [[International Working Group on Neurotransmitter Related Disorders]] (iNTD).<ref>{{cite web|title=Patient registry|url=http://intd-online.org/}}</ref>

Besides disruption of serine biosynthesis, its transport may also become disrupted. One example is [[spastic tetraplegia, thin corpus callosum, and progressive microcephaly]], a disease caused by mutations that affect the function of the [[neutral amino acid transporter A]].

=== Research for therapeutic use ===
The classification of <small>L</small>-serine as a non-essential amino acid has come to be considered as conditional, since vertebrates such as humans cannot always synthesize optimal quantities over entire lifespans.<ref name="MetcalfDunlop2017">{{cite journal|last1=Metcalf|first1=J. S.|last2=Dunlop|first2=R. A.|last3=Powell|first3=J. T.|last4=Banack|first4=S. A.|last5=Cox|first5=P. A.|title=L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential|journal=Neurotoxicity Research|volume=33|issue=1|year=2017|pages=213–221|issn=1029-8428|doi=10.1007/s12640-017-9814-x|pmid=28929385|s2cid=20271849}}</ref> Safety of <small>L</small>-serine has been demonstrated in an FDA-approved human phase I clinical trial with Amyotrophic Lateral Sclerosis, [[ALS]], patients (ClinicalTrials.gov identifier: NCT01835782),<ref>{{cite journal | vauthors = Dunlop RA, Cox PA, Banack SA, Rodgers KJ | title = The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation | journal = PLOS ONE | year = 2013 | volume = 8 | issue = 9 | pages = e75376 | pmid = 24086518 | pmc = 3783393 | doi = 10.1371/journal.pone.0075376 | bibcode = 2013PLoSO...875376D | doi-access = free }}</ref><ref>{{cite journal|last1=Levine|first1=Todd D.|last2=Miller|first2=Robert G.|last3=Bradley|first3=Walter G.|last4=Moore|first4=Dan H.|last5=Saperstein|first5=David S.|last6=Flynn|first6=Lynne E.|last7=Katz|first7=Jonathan S.|last8=Forshew|first8=Dallas A.|last9=Metcalf|first9=James S.|last10=Banack|first10=Sandra A.|last11=Cox|first11=Paul A.|date=2017-01-02|title=Phase I clinical trial of safety of L-serine for ALS patients|journal=Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration|language=en|volume=18|issue=1–2|pages=107–111|doi=10.1080/21678421.2016.1221971|pmid=27589995|s2cid=4584977|issn=2167-8421|doi-access=free}}</ref> but treatment of ALS symptoms has yet to be shown. A 2011 meta-analysis found adjunctive [[sarcosine]] to have a medium effect size for negative and total symptoms of schizophrenia.<ref>{{cite journal | vauthors = Singh SP, Singh V | title = Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia | journal = CNS Drugs | volume = 25 | issue = 10 | pages = 859–885 | date = Oct 2011 | pmid = 21936588 | doi = 10.2165/11586650-000000000-00000 | s2cid = 207299820 }}</ref> There also is evidence that <small>L</small>‐serine could acquire a therapeutic role in diabetes.<ref name="HolmBuschard2019">{{cite journal|last1=Holm|first1=Laurits J.|last2=Buschard|first2=Karsten|title=L-serine: a neglected amino acid with a potential therapeutic role in diabetes|journal=APMIS|year=2019|volume=127|issue=10|pages=655–659|issn=0903-4641|doi=10.1111/apm.12987|pmid=31344283|pmc=6851881|doi-access=free}}</ref>
 
<small>D</small>-Serine is being studied in rodents as a potential treatment for schizophrenia.<ref>{{cite journal | vauthors = Balu DT, Li Y, Puhl MD, Benneyworth MA, Basu AC, Takagi S, Bolshakov VY, Coyle JT | title = Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 26 | pages = E2400–E2409 | date = Jun 2013 | pmid = 23729812 | doi = 10.1073/pnas.1304308110 | pmc=3696825| bibcode = 2013PNAS..110E2400B | doi-access = free }}</ref> <small>D</small>-Serine also has been described as a potential biomarker for early [[Alzheimer's disease]] (AD) diagnosis, due to a relatively high concentration of it in the [[cerebrospinal fluid]] of probable AD patients.<ref>{{cite journal | vauthors = Madeira C, Lourenco MV, Vargas-Lopes C, Suemoto CK, Brandão CO, Reis T, Leite RE, Laks J, Jacob-Filho W, Pasqualucci CA, Grinberg LT, Ferreira ST, Panizzutti R | title = D-Serine levels in Alzheimer's disease: implications for novel biomarker development | journal = Translational Psychiatry | volume = 5 | issue = 5 | pages = e561 | date = May 5, 2015 | pmid = 25942042 | doi = 10.1038/tp.2015.52 | pmc=4471283}}</ref> D-serine, which is made in the brain, has been shown to work as an antagonist/inverse co-agonist of ''t''-NMDA receptors mitigating neuron loss in an animal model of [[temporal lobe epilepsy]].<ref name=":3">{{cite journal |last1=Beesley |first1=Stephen |last2=Sullenberger |first2=Thomas |last3=Crotty |first3=Kathryn |last4=Ailani |first4=Roshan |last5=D'Orio |first5=Cameron |last6=Evans |first6=Kimberly |last7=Ogunkunle |first7=Emmanuel O. |last8=Roper |first8=Michael G. |last9=Kumar |first9=Sanjay S. |date=2020-10-02 |title=D-serine mitigates cell loss associated with temporal lobe epilepsy |journal=Nature Communications |volume=11 |issue=1 |pages=4966 |doi=10.1038/s41467-020-18757-2 |issn=2041-1723 |pmc=7532172 |pmid=33009404|bibcode=2020NatCo..11.4966B }}</ref>

<small>D</small>-Serine has been theorized as a potential treatment for sensorineural hearing disorders such as [[hearing loss]] and [[tinnitus]].<ref name="Wang 2021">{{cite journal | last1=Wang | first1=Jing | last2=Serratrice | first2=Nicolas | last3=Lee | first3=Cindy J. | last4=François | first4=Florence | last5=Sweedler | first5=Jonathan V. | last6=Puel | first6=Jean-Luc | last7=Mothet | first7=Jean-Pierre | last8=Ruel | first8=Jérôme | title=Physiopathological Relevance of D-Serine in the Mammalian Cochlea | journal=Frontiers in Cellular Neuroscience | publisher=Frontiers Media SA | volume=15 | date=17 December 2021 | page=733004 | issn=1662-5102 | doi=10.3389/fncel.2021.733004| pmid=34975405 | pmc=8718999 | doi-access=free }}</ref>