Editing Charcot–Marie–Tooth disease (section)

== Classification ==
{{further|Charcot–Marie–Tooth disease classifications}}
Charcot–Marie–Tooth (CMT) disease is a genetically heterogeneous disorder, meaning that it can be caused by mutations in many different genes.<ref name="pmid26527893">{{cite journal | vauthors = Hoyle JC, Isfort MC, Roggenbuck J, Arnold WD | title = The genetics of Charcot-Marie-Tooth disease: current trends and future implications for diagnosis and management | journal = The Application of Clinical Genetics | volume = 8 | pages = 235–243 | year = 2015 | pmid = 26527893 | pmc = 4621202 | doi = 10.2147/TACG.S69969 | doi-access = free }}</ref> 

To date, dozens of genes have been linked to various forms of CMT, reflecting the complexity of its molecular basis. As a result, CMT is classified into several major types, such as CMT1, CMT2, CMT4, CMTX, and intermediate forms, based on the pattern of inheritance and whether the primary defect affects the myelin sheath or the axon. CMT1 involves demyelination and is most caused by duplication of the PMP22 gene, while CMT2 is primarily axonal and frequently linked to mutations in genes such as MFN2 or NEFL. X-linked and autosomal recessive forms, like CMTX and CMT4, are also recognized and often associated with more severe or early-onset symptoms.<ref name="pmid26527893" /><ref name="Lupski2010">{{cite journal |vauthors=Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L, Bainbridge M, Dinh H, Jing C, Wheeler DA, McGuire AL, Zhang F, Stankiewicz P, Halperin JJ, Yang C, Gehman C, Guo D, Irikat RK, Tom W, Fantin NJ, Muzny DM, Gibbs RA |date=April 2010 |title=Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy |journal=The New England Journal of Medicine |volume=362 |issue=13 |pages=1181–1191 |doi=10.1056/NEJMoa0908094 |pmc=4036802 |pmid=20220177}}</ref>

Each type is further divided into subtypes, defined by the specific gene that is mutated. This genetic classification helps guide diagnosis, prognosis, and, potentially, the development of targeted therapies<ref name="Lupski2010" />

=== GARS1-related axonal neuropathy (CMT2) ===
Charcot–Marie–Tooth type 2 (CMT2) is commonly classified as an axonal neuropathy due to the degeneration of nerve axons observed in affected individuals. Unlike CMT type 1, which results from damage to the myelin sheath, CMT type 2 is characterized by direct injury to the axon itself.. This axonal damage can disrupt nerve signal transmission between the brain and muscles, resulting in symptoms such as muscle weakness, atrophy, reduced sensation, and foot deformities. The onset of symptoms in CMT2 typically occurs between the ages of 5 and 25.<ref name=":0">{{Cite web |date=2015-12-23 |title=CMT2 - Types of Charcot-Marie-Tooth Disease (CMT) - Diseases |url=https://www.mda.org/disease/charcot-marie-tooth/types/cmt2 |access-date=2022-05-10 |website=Muscular Dystrophy Association |language=en}}</ref>

CMT2D is one of more than 31 recognized subtypes of Charcot–Marie–Tooth disease type 2 (CMT2) and is diagnosed when both motor and sensory deficits are present—such as loss of sensation caused by degeneration of sensory axons. In cases where only motor symptoms are observed without sensory involvement, the condition is classified as distal hereditary motor neuropathy type V (dHMN-V). The reason behind the variability in sensory involvement among patients with GARS1-related neuropathy remains unclear.<ref name=":1">{{cite journal |vauthors=Sleigh JN, Mech AM, Aktar T, Zhang Y, Schiavo G |title=Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels |journal=Frontiers in Cellular Neuroscience |volume=14 |pages=232 |date=2020 |pmid=32848623 |pmc=7431706 |doi=10.3389/fncel.2020.00232 |doi-access=free}}</ref> 

Symptoms of CMT2D typically include muscle weakness, loss of sensation, reduced reflexes, and muscle atrophy, which are similar to those seen in both CMT1 and other CMT2 variants. The severity and combination of symptoms vary widely among patients, particularly regarding the extent of sensory involvement.<ref name=":1" />

CMT2D is a result of autosomal dominant mutations in the human ''GARS''1 gene located at 7p14.3 <ref>{{Cite web |title=OMIM Entry - # 601472 - Charcot–Marie–Tooth disease, axonal, type 2D; CMT2D |url=https://omim.org/entry/601472?search=601472 |access-date=2022-05-10 | work = Online Mendelian Inheritance in Man }}</ref> and is thought to be caused by [[Mutation|aberrant gain-of-function missense mutations]].<ref name=":1" /> 

The GARS1 gene encodes the enzyme glycyl-tRNA synthetase (GlyRS), which belongs to the class II group of aminoacyl-tRNA synthetases. This enzyme is essential in the process of protein synthesis, facilitating the bonding of the amino acid glycine to its corresponding transfer RNA (tRNA). Through this process, GlyRS ensures the accurate incorporation of glycine during translation, making it essential for proper protein production.<ref>{{Cite web |title=OMIM Entry- * 600287 - Glycl-tRNA Synthetase 1; GARS1 |url=https://omim.org/entry/601472?search=601472 |access-date=2022-05-10 | work = Online Mendelian Inheritance in Man }}</ref>

Many different mutations have been found in CMT2D patients, and how mutations in GARS1 cause CMT2D remains unclear. However,  mutant glycyl-tRNA synthetase (GlyRS) is thought to interfere with transmembrane receptors, causing motor disease,<ref name="Wei2019">{{cite journal|vauthors= Wei N, Zhang Q, Yang XL|date= 2019|title= Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases|journal=J Biol Chem |volume=294|issue= 14|pages=5321–5339|doi= 10.1074/jbc.REV118.002955|pmid= 30643024|pmc= 6462521|doi-access= free}}</ref><ref name=":2">{{cite journal | vauthors = He W, Bai G, Zhou H, Wei N, White NM, Lauer J, Liu H, Shi Y, Dumitru CD, Lettieri K, Shubayev V, Jordanova A, Guergueltcheva V, Griffin PR, Burgess RW, Pfaff SL, Yang XL | title = CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase | journal = Nature | volume = 526 | issue = 7575 | pages = 710–714 | date = October 2015 | pmid = 26503042 | pmc = 4754353 | doi = 10.1038/nature15510 | bibcode = 2015Natur.526..710H }}</ref> and that mutations in the gene could disrupt the ability of GlyRS to interact with its cognate RNA, disrupting protein production. The ''GARS1'' mutations present in CMT2D cause a deficient amount of glycyl-tRNA in cells, preventing the [[Translation (biology)|elongation phase]] of [[Protein biosynthesis|protein synthesis]]. Elongation is a key step in protein production, so when a deficiency of glycyl-tRNA exists, protein synthesis is unable to continue at glycine sites. ''GARS1'' mutations also stall initiation of translation due to a stress response that is induced by glycine addition failure. By stalling elongation and initiation of translation, CMT2D mutations in ''GARS1'' cause translational repression, meaning that overall translation is inhibited.<ref>{{cite journal | vauthors = Mendonsa S, von Kuegelgen N, Bujanic L, Chekulaeva M | title = Charcot-Marie-Tooth mutation in glycyl-tRNA synthetase stalls ribosomes in a pre-accommodation state and activates integrated stress response | journal = Nucleic Acids Research | volume = 49 | issue = 17 | pages = 10007–10017 | date = September 2021 | pmid = 34403468 | pmc = 8464049 | doi = 10.1093/nar/gkab730 }}</ref>

GARS1-associated axonal neuropathy is a progressive condition that deteriorates over time. Although the precise mechanisms driving the chronic neurodegeneration caused by mutant glycyl-tRNA synthetase (GlyRS) remain unclear, one proposed theory involves disrupted vascular endothelial growth factor (VEGF) signaling. The mutant GlyRS aberrantly interacts with neuronal transmembrane receptors, such as neuropilin 1 (Nrp1) and VEGF receptors, interfering with normal signaling pathways and contributing to the development of neuropathy.<ref name=":2" /> 

GARS-CMT2D mutations alter GlyRS and allow it to bind to the Nrp1 receptor, interfering with the normal binding of Nrp1 to VEGF. While enhanced expression of VEGF improves motor function, reduced expression of Nrp1 worsens CMT2D; because Nrp1 binds to mutant GlyRS in mutant GARS1-CMT2D individuals, Nrp1 expression is reduced, in turn worsening motor function. Mice with deficient VEGF demonstrate motor neuron disease over time. Thus, the VEGF/Nrp1 pathway is considered to be targetable for CMT2D treatment.<ref name=":0" />

=== X-linked CMT ===
Main article: [[X-linked Charcot–Marie–Tooth disease]]

CMT can also be produced by X-linked mutations, in which case it is called X-linked CMT (CMTX). In CMTX, mutated [[Connexon|connexons]] create nonfunctional [[Gap junction|gap junctions]] that interrupt molecular exchange and signal transport.<ref name=":3">{{Cite journal |last1=Berger |first1=Philipp |last2=Young |first2=Peter |last3=Suter |first3=Ueli |date=2002-03-01 |title=Molecular cell biology of Charcot-Marie-Tooth disease |url=https://link.springer.com/article/10.1007/s10048-002-0130-z |journal=Neurogenetics |language=en |volume=4 |issue=1 |pages=1–15 |doi=10.1007/s10048-002-0130-z |pmid=12030326 |issn=1364-6745}}</ref><ref>{{Cite journal |last=Kleopa |first=Kleopas A. |date=2011-12-07 |title=The Role of Gap Junctions in Charcot-Marie-Tooth Disease |url=https://www.jneurosci.org/content/31/49/17753 |journal=Journal of Neuroscience |language=en |volume=31 |issue=49 |pages=17753–17760 |doi=10.1523/JNEUROSCI.4824-11.2011 |issn=0270-6474 |pmid=22159091|pmc=6634164 }}</ref><ref>{{Cite journal |last1=Szigeti |first1=Kinga |last2=Lupski |first2=James R. |date=June 2009 |title=Charcot-Marie-Tooth disease |journal=European Journal of Human Genetics |volume=17 |issue=6 |pages=703–710 |doi=10.1038/ejhg.2009.31 |issn=1476-5438 |pmc=2947101 |pmid=19277060}}</ref>The mutation can appear in the ''[[GJB1]]'' gene coding for the [[connexin 32]] protein, a gap junction protein expressed in Schwann cells. Because this protein is also present in [[oligodendrocytes]], demyelination can appear in the CNS as well.<ref>{{Cite journal |last1=Koutsis |first1=Georgios |last2=Breza |first2=Marianthi |last3=Velonakis |first3=Georgios |last4=Tzartos |first4=John |last5=Kasselimis |first5=Dimitrios |last6=Kartanou |first6=Chrisoula |last7=Karavasilis |first7=Efstratios |last8=Tzanetakos |first8=Dimitrios |last9=Anagnostouli |first9=Maria |last10=Andreadou |first10=Elisavet |last11=Evangelopoulos |first11=Maria-Eleftheria |last12=Kilidireas |first12=Constantinos |last13=Potagas |first13=Constantin |last14=Panas |first14=Marios |last15=Karadima |first15=Georgia |date=2019-02-01 |title=X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association |url=https://jnnp.bmj.com/content/90/2/187 |journal=Journal of Neurology, Neurosurgery & Psychiatry |language=en |volume=90 |issue=2 |pages=187–194 |doi=10.1136/jnnp-2018-319014 |issn=0022-3050 |pmid=30196252}}</ref>

[[Schwann cell]]s create the myelin sheath by wrapping their plasma membranes around the axon.<ref name=":3" /> These Schwann cells work together with neurons and [[fibroblast]]s to create a functional nerve. Schwann cells and neurons exchange molecular signals by way of gap junctions that regulate survival and differentiation.<ref>{{Cite journal |last1=Amiott |first1=Elizabeth A. |last2=Lott |first2=Paul |last3=Soto |first3=Jamie |last4=Kang |first4=Peter B. |last5=McCaffery |first5=J. Michael |last6=DiMauro |first6=Salvatore |last7=Abel |first7=E. Dale |last8=Flanigan |first8=Kevin M. |last9=Lawson |first9=Victoria H. |last10=Shaw |first10=Janet M. |date=May 2008 |title=Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations |journal=Experimental Neurology |volume=211 |issue=1 |pages=115–127 |doi=10.1016/j.expneurol.2008.01.010 |issn=0014-4886 |pmc=2409111 |pmid=18316077}}</ref>

Demyelinating Schwann cells cause abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction.<ref name="Krajewski" /> The myelin sheath allows nerve cells to conduct signals faster. When the myelin sheath is damaged, however, nerve signals are slower. This can be measured by a common neurological test, [[electromyography]]. When the axon is damaged, the result is a reduced compound muscle [[action potential]].<ref>{{Cite journal |last1=Yiu |first1=Eppie M. |last2=Burns |first2=Joshua |last3=Ryan |first3=Monique M. |last4=Ouvrier |first4=Robert A. |date=2008 |title=Neurophysiologic abnormalities in children with Charcot-Marie-Tooth disease type 1A |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1529-8027.2008.00182.x |journal=Journal of the Peripheral Nervous System |language=en |volume=13 |issue=3 |pages=236–241 |doi=10.1111/j.1529-8027.2008.00182.x |pmid=18844790 |issn=1529-8027}}</ref>