Editing Microcephaly (section)

==Pathophysiology==

Microcephaly generally is due to the diminished size of the largest part of the human brain, the [[cerebral cortex]], and the condition can arise during embryonic and fetal development due to insufficient [[neural stem cell]] proliferation, impaired or premature [[neurogenesis]], the death of neural [[stem cells]] or [[neurons]], or a combination of these factors.<ref>{{cite journal|last1=Jamuar|first1=SS|last2=Walsh|first2=CA|title=Genomic variants and variations in malformations of cortical development.|journal=Pediatric Clinics of North America|date=June 2015|volume=62|issue=3|pages=571–85|pmid=26022163|doi=10.1016/j.pcl.2015.03.002|pmc=4449454}}</ref> Research in animal models such as rodents has found many genes that are required for normal brain growth. For example, the [[Notch pathway]] genes regulate the balance between stem cell proliferation and [[neurogenesis]] in the stem cell layer known as the [[ventricular zone]], and experimental mutations of many genes can cause microcephaly in mice,<ref>{{cite journal|last1=Rash|first1=BG|last2=Lim|first2=HD|last3=Breunig|first3=JJ|last4=Vaccarino|first4=FM|title=FGF signaling expands embryonic cortical surface area by regulating Notch-dependent neurogenesis.|journal=The Journal of Neuroscience|date=26 October 2011|volume=31|issue=43|pages=15604–17|pmid=22031906|doi=10.1523/jneurosci.4439-11.2011|pmc=3235689}}</ref> similar to human microcephaly.<ref>{{cite journal|last1=Shen|first1=J|last2=Gilmore|first2=EC|last3=Marshall|first3=CA|last4=Haddadin|first4=M|last5=Reynolds|first5=JJ|last6=Eyaid|first6=W|last7=Bodell|first7=A|last8=Barry|first8=B|last9=Gleason|first9=D|last10=Allen|first10=K|last11=Ganesh|first11=VS|last12=Chang|first12=BS|last13=Grix|first13=A|last14=Hill|first14=RS|last15=Topcu|first15=M|last16=Caldecott|first16=KW|last17=Barkovich|first17=AJ|last18=Walsh|first18=CA|title=Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.|journal=Nature Genetics|date=March 2010|volume=42|issue=3|pages=245–9|pmid=20118933|doi=10.1038/ng.526|pmc=2835984}}</ref><ref>{{cite journal|last1=Alkuraya|first1=FS|last2=Cai|first2=X|last3=Emery|first3=C|last4=Mochida|first4=GH|last5=Al-Dosari|first5=MS|last6=Felie|first6=JM|last7=Hill|first7=RS|last8=Barry|first8=BJ|last9=Partlow|first9=JN|last10=Gascon|first10=GG|last11=Kentab|first11=A|last12=Jan|first12=M|last13=Shaheen|first13=R|last14=Feng|first14=Y|last15=Walsh|first15=CA|title=Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected].|journal=American Journal of Human Genetics|date=13 May 2011|volume=88|issue=5|pages=536–47|pmid=21529751|doi=10.1016/j.ajhg.2011.04.003|pmc=3146728}}</ref> Mutations of the [[ASPM (gene)|abnormal spindle-like microcephaly-associated (ASPM) gene]] are associated with microcephaly in humans and a knockout model has been developed in [[ferret]]s that exhibits severe microcephaly.<ref name="JohnsonSun2018">{{cite journal|last1=Johnson|first1=Matthew B.|last2=Sun|first2=Xingshen|last3=Kodani|first3=Andrew|last4=Borges-Monroy|first4=Rebeca|last5=Girskis|first5=Kelly M.|last6=Ryu|first6=Steven C.|last7=Wang|first7=Peter P.|last8=Patel|first8=Komal|last9=Gonzalez|first9=Dilenny M.|last10=Woo|first10=Yu Mi|last11=Yan|first11=Ziying|last12=Liang|first12=Bo|last13=Smith|first13=Richard S.|last14=Chatterjee|first14=Manavi|last15=Coman|first15=Daniel|last16=Papademetris|first16=Xenophon|last17=Staib|first17=Lawrence H.|last18=Hyder|first18=Fahmeed|last19=Mandeville|first19=Joseph B.|last20=Grant|first20=P. Ellen|last21=Im|first21=Kiho|last22=Kwak|first22=Hojoong|last23=Engelhardt|first23=John F.|last24=Walsh|first24=Christopher A.|last25=Bae|first25=Byoung-Il|title=Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size|journal=Nature|volume=556|issue=7701|year=2018|pages=370–5|doi=10.1038/s41586-018-0035-0|pmid=29643508|pmc=6095461|bibcode=2018Natur.556..370J}}</ref> In addition, viruses such as [[cytomegalovirus]] (CMV) or [[Zika]] have been shown to infect and kill the primary stem cell of the brain—the [[radial glial cell]], resulting in the loss of future daughter neurons.<ref>{{cite journal|last1=Nowakowski|first1=TJ|last2=Pollen|first2=AA|last3=Di Lullo|first3=E|last4=Sandoval-Espinosa|first4=C|last5=Bershteyn|first5=M|last6=Kriegstein|first6=AR|title=Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells.|journal=Cell Stem Cell|date=5 May 2016|volume=18|issue=5|pages=591–6|pmid=27038591|pmc=4860115|doi=10.1016/j.stem.2016.03.012}}</ref><ref>{{cite journal|last1=Li|first1=C|last2=Xu|first2=D|last3=Ye|first3=Q|last4=Hong|first4=S|last5=Jiang|first5=Y|last6=Liu|first6=X|last7=Zhang|first7=N|last8=Shi|first8=L|last9=Qin|first9=CF|last10=Xu|first10=Z|title=Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice.|journal=Cell Stem Cell|date=7 July 2016|volume=19|issue=1|pages=120–6|pmid=27179424|doi=10.1016/j.stem.2016.04.017|doi-access=free}}</ref> The severity of the condition may depend on the timing of infection during pregnancy.{{citation needed|date=January 2021}}

Microcephaly is a feature common to several different genetic disorders arising from a deficiency in the cellular [[DNA damage (naturally occurring)|DNA damage]] response.<ref>{{cite journal |vauthors=O'Driscoll M, Jeggo PA |title=The role of the DNA damage response pathways in brain development and microcephaly: insight from human disorders |journal=DNA Repair (Amst) |volume=7 |issue=7 |pages=1039–50 |date=July 2008 |pmid=18458003 |doi=10.1016/j.dnarep.2008.03.018 }}</ref> Individuals with the following DNA damage response disorders exhibit microcephaly: [[Nijmegen breakage syndrome]], ATR-[[Seckel syndrome]], [[MCPH1]]-dependent primary microcephaly disorder, [[XPA|xeroderma pigmentosum complementation group A]] deficiency, [[Fanconi anemia]], [[LIG4 syndrome|ligase 4 deficiency syndrome]] and [[Bloom syndrome]]. These findings suggest that a normal DNA damage response is critical during [[development of the nervous system|brain development]], perhaps to protect against induction of [[apoptosis]] by DNA damage occurring in [[neuron]]s.<ref>{{cite journal |vauthors=Ribeiro JH, Altinisik N, Rajan N, Verslegers M, Baatout S, Gopalakrishnan J, Quintens R |title=DNA damage and repair: underlying mechanisms leading to microcephaly |journal=Front Cell Dev Biol |volume=11 |issue= |pages=1268565 |date=2023 |pmid=37881689 |pmc=10597653 |doi=10.3389/fcell.2023.1268565 |doi-access=free }}</ref>