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Charcot-Marie-Tooth disease

The Charcot-Marie-Tooth disease is a hereditary peripheral neuropathy disease that can

be traced back in the 19th century (Boutary et al. 1). Charcot-Marie-Tooth or otherwise CT

occurs worldwide and is estimated to have a prevalence rate of 1 in 2,500 people. Charcot-

Marie-Tooth is considered clinically and genetically to be a heterogeneous class of sensorimotor

peripheral neuropathies. Therefore, it represents perhaps the most recurrent cause of hereditary

pathologies that affect the human nervous system (Larrea et al. 1782). CMT is falls under

category of neuromuscular disorders that are characterized by having lengthy, dependent and

progressive deterioration of peripheral nerves. The nerve degeneration usually leads to muscle

weakness and wasting that occurs in limbs, hands, and feet. The onset of CMT varies from

childhood up to late adulthood (Lee et al. 728). Charcot-Marie-Tooth disorder regularly becomes

seemingly obvious during early adulthood or adolescence. The clinical severity often varies from

austere to mild or acute between different patients.

The symptoms of CMT vary according to severity of infection and age of onset. In other

people they don’t realize they have the disorder since they might experience mild symptoms,

however, most patients have a form of disability (Wang et al. 974). The earliest signs of CMT

causes muscle atrophy mostly in the feet. Some patients show signs of severe weakness which

could be dangerous. The individuals start to have foot challenges or abnormalities such as flat

feet, curled toes, and high arches. They find it hard to walk on foot’s heel and flex their feet. The
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challenges can result to making abnormal steps (steppage gait) hence, increasing chances of

tripping and ankle injuries (Pipis et al. 644). Consequently, as the disease worsens the muscles

located in the lower end of the legs start to weaken, making motions difficult. The hands can

become weak causing more challenges in performing daily activities such as turning doorknobs,

fastening buttons, and writing. People suffering from Charcot-Marie-Tooth syndrome

characteristically experience a lessened sensitivity to cold, heat, and touch, especially in lower

legs. In rare instances, the affected individuals can experience visual impairment or steady

hearing loss which can lead to one becoming deaf (Duan et al. 1). The resultant of

neuropathological and neurophysiological defects in sensory and motor nerves create deformities

and those affected will depend on specialized equipment such as wheelchairs to make

movements possible.

Figure 1: Symptoms of CMT

Image source: https://www.cmtausa.org/understanding-cmt/what-is-cmt/

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The ancillary diagnosis which encompasses electrophysiological studies as well as nerve

biopsy can be used for diagnosis of patients with Charcot-Marie-Tooth disease. Skin biopsy and

peripheral nerve MRI are also other techniques that have been used lately as diagnostic tools

especially in inherited neuropathies (Edgar et al. 1). Electrophysiological studies differentiate

two key types of neuropathies, one being demyelinating forms that are characterized by

symmetrically decelerated nerve transmission speed and abridged composite muscle action

potential. Depending on the neurophysiological findings and the age of onset, quite a few clinical

phenotypes can be described (Pareyson et al. 55). The in vitro experiments have clarified the

mechanisms by which mutations occurring in genes lead to certain gene diseases. They have also

described the pathways embroiled especially in peripheral neuropathy disease through molecular

diagnosis. Applying population-based units instigated the influence of individual genes to

causing disease, permitting evidence-based prioritizing of gene testing.

Charcot-Marie-Tooth disease may be hereditary particularly in autosomal recessive,

autosomal dominant, or the X-linked dominant way. The genetic pathologies can be determined

by using a combination of genes for a specific characteristic that are found on the chromosomes

acquired form the mother or the father (Stone et al. 423). Recessive genetic disorders are known

to occur when the individual receives similar abnormal genes of the identical trait from the

parents. When an individual acquires one gene associated with the disease and one normal gene,

the person becomes a carrier of the disease (Benoy et al. 673). However, the individual might not

show symptoms associated to the disease. There is a 25 percent chance that two carrier parents to

pass the imperfect gene to the child. The risk increases to 50 percent of having a child who is a

carrier of the disease same as the parents with subsequent pregnancy (Boutary et al. 1). The

probability of a child to acquire normal genes from the parents and end to be genetically normal
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for a specific trait is 50 percent. The risk of having the disease is equal in both females and

males.

The dominant genetic disorders happen only if a single print of the anomalous gene is

essential for advent of the disease. The anomalous gene can be as a result of gene change or gene

mutation in affected person or can be passed from the parents (Larrea et al. 1782). The risk is

much higher, 50 percent, of passing the gene from parents to the offspring in each pregnancy

irrespective of gender of the resultant child. The X-associated dominant genetic syndromes are

instigated by an anomalous X-chromosome. Females having this anomalous gene are affected by

CMT (Lee et al. 728). Males having the anomalous gene are hard-hit that their female

counterparts.

Grouping of Charcot-Marie-Tooth syndrome as hereditary sensory and motor

neuropathies is done in several categories CMT type 1, CMT type 2, CMT type 3, CMT type 4

and CMT type X. CMT type I is more common and is where nerve transmission speed is very

slow (Wang et al. 974). It is caused by having abnormal genes participating in structuring and

determining functionality of myelin. CMT1D, CMT1C, CMT1B, CMT1A, and CMT1X fall

under CMT type 1 and classification is done according to gene anomalies (Pipis et al. 644). CMT

type 2 is the autosomal dominant form which leads to nerve conditions where transmissions are

marginally lower than normal. The anomaly in genes involved in structuration and functionality

of axons causes CMT type 2. It has been further divided to 2MT2A-2L with CMT2A being the

most common (Duan et al. 1). Dominant Intermediate CMT is one which the transmission

velocities are uncertain regarding if their neuropathy is demyelinating or primary axonal caused

by mutation in YARS and genes (…). CMT3 is gradually considered not important genetic

designation since individuals show gene mutation in genes that lead to either CMT1A, CMT1D,
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CMT4, or CMT1B (Edgar et al. 1). Autosomal recessive Form of CMT is CMT4 and can be

classified into CMT4A, CMT4B1-B2, and CMT4C-4F. Lastly, CMTX is due to X-linked

dominant gene (Pareyson et al. 55). The forms of CMTX are infrequent and can be characterized

by spastic paraplegia, hearing loss and optic atrophy.

Figure 2: Charcot–Marie–Tooth disease genetic classification and associated peripheral

neuropathies
Image source: https://www.nature.com/articles/ejhg200931/tables/1

Recent documentation of genes that are mutating in different ways paved way for more

understanding of CMT. The discovery also put forward exceptional comprehensions into the

biology of neurons and Schwan cells (Stone et al. 423). Granting that genes are mutating in

CMTs encode proteins that participate in numerous cellular processes, there are other emergent

insights that matter in further study of CMT. The axonal characteristics of CMT normally impact

the spinal motor neurons and the dorsal root ganglion sensory neurons (Benoy et al. 673). The

two neuronal cells become extremely polarized and the axons become extended by at least by 1

meter away from the somas of the sensory receptors in skin or muscles. They extend towards the
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neuromuscular junctions within the skeletal muscles (Boutary et al. 1). Since most of the

neuronal proteins are created in cell body, therefore, the cellular design necessitates intensive

transport of proteins to happen between the axonal extremity and the soma. Since there are

mutations that affect the DYNC1H1 genes which participates in encoding the heavy cytoplasmic

dynein sequence 1 protein, which is a crucial category of the dynein 1 liable for axonal

retrograde conveyance leading to Charcot-Marie-Tooth syndrome (Larrea et al. 1782).

Furthermore, both neurofilament encoding protein (NEFL) and the encoding lamin A/C (LMNA)

are constituents that participate in neurofilament homeostasis (Lee et al. 728). When it is

disrupted, it impedes axonal transport.

Figure 3: Schematic diagram indicating the Charcot-Marie-Tooth disease related genes and paths
found in peripheral nerve.
Image source: https://www.mdpi.com/1422-0067/21/19/7419/htm

HSPB8 and HSPB1 (small heat shock protein Beta-1 and B8) that mimic ATP-

autonomous protectors during protein folding have a critical role in structure or framework of

cytoskeleton (Wang et al. 974). Mitochondria are the most energetic organelles in a cell and their

functionality relies majorly on appropriate axonal transport. Besides dominant, X-linked and
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recessive CMT types, there can be mutations which occur in isolated individuals. Recently, it

was determined that some CMT phenotype was related to a flaw present in MT-ATP6A gene

that is encoded by mitochondrial DNA (Duan et al. 1). Mutations in two dissimilar genes

associated with mitochondrial functions GDAP1 and MFN2 cause CMT. When mitochondrial

axonal transport is interfered by MFN2 by associating with adaptor Milton or Miro complexes

where kinesin leads to mitochondrial attachment to microtubules (Pipis et al. 644). Conversely,

GDAP1 is considered as an aspect of mitochondrial fission and is directly tangled in leading to

adaptation of various sized mitochondria depending on requirements of the cell. Additionally, the

mutations happening in genes that participate in protein turnover and protein synthesis;

(LRSAM1, AARS, GARS), gene expression (MED25) calcium homeostasis (TRPV4)

endocytosis DNM2, RAB, and myelin assembly (MPZ) (Edgar et al. 1). They all lead to axonal

forms of Charcot-Marie-Tooth syndrome.

Larger axons which have a diameter greater than 1 μm are enveloped within the myelin

sheath. The sheath is a specific cell membrane that has high lipid-protein ratio, with lipids having

a higher share of around 7o percent of myelin membranes dry weight (Pareyson et al. 55). The

occurrence of myelin near the axonal segments have a significant role in insulating axons by

increasing their axonal resistance, as well as participating in mechanisms that ultimately lead to

axon ion channels grouping at the nodes of Ranvier (Stone et al. 423). Myelinating Schwann

cells are also important in ensure proper electrical properties and structuration framework of

axons. By doing so they allow for a significant increase in more than 100 fold of nerve

transmission speed and lessening the energy consumed during those transmissions (Benoy et al.

673). The significance of correct assembly and alignment of myelin membranes is because the

mutations happening in PRX, MPZ, and PMP22 genes, which all partake in the gathering of
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myelin often lead to development of CMT (Boutary et al. 1). The observational changes that

occur in myelin proteins gene doses often lead to development of CMT (Larrea et al. 1782). The

evidence presented in the study of mutations of the EGR2 genes, which is a transcription factor

that governs gene myelin expression can likewise be a basis leading to CMT phenotypes. It is

estimated that there is a 6,500-fold rise in number of membrane surface that occurs during the

process of myelination. The more polarized Schwann cells give an impression that membrane

transport, assembly, and maintenance are important activities for optimal functionality of

Schwann cells (Lee et al. 728). Therefore, the mutations that do happen in NDRG1, FIG4,

SBF2/MTMRI1, and MTMR2 genes which encode the proteins necessary for membrane

trafficking. SH3TC2 genes participate in remodeling of cytoskeleton which support the

phenomenon and provides further understanding in molecular mechanisms that participate in

processes of myelin membrane homeostasis.

The intermediate modes of CMT are anticipated to impact both the neuronal and glial

functions and identify the close relationship that exist between the two cells. Mutation that often

impacts the genes participating in protein encoding partaking in skeletal remodeling DNM2 and

INF2, myelin assembly GJB1 and MPZ, nucleotide synthesis PRPSI, and protein synthesis

YARS, cause deformities in Schwann cells and the axons involved (Wang et al. 974). Onion bulb

formation and demyelination are occurrences that are seen in CMT1 patients. CMTIA is

triggered by point mutation and replication of PMP22 genes. Almost 70 to 80 percent of CMT1

cases are associated with PMP22 mutations. The three-point mutation happening in PMP3 gene

responsible for myelin P2 coding protein were associated with autosomal dominance. P2 genes

are mostly expressed by Schwann cells found in PNS (Pipis et al. 644). It is found in compact

myelin where it stabilizes the multifaceted lipid membrane gathering. P2 is a small and is one of
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the classes of the fatty acid-binding proteins (FABPs), therefore, it can transport fatty acids to

and from lipid membranes (Duan et al. 1). It achieves transportation by applying a collision

transmission mechanism, demonstrating a useful role especially in myelin lipid homeostasis.

Missense mutation happening in the gene encoding the RAB7 causes CMT2B.

neuropathy. RAB7 is an abundant protein that governs the transfer to late lysosomes and

endosomes particularly in endocytic path (Edgar et al. 1). The protein is also important in

neurons particularly in signaling the neurotrophins, endosomal trafficking and, reversing axonal

transport. The mutation happening on this protein makes them show altered koff rates and

ultimately end in the GTP bound form and attach more strongly to the RAB7 effector protein

(Pareyson et al. 55). The expression due to CMT2B leading to RAB7 mutant protein severely

constrain neurite outgrowth in numerous cell lines and change nerve growth factor mode of

trafficking and signaling. RAB7 has a significant role in neuronal cells and the CMT2B leading

to RAB7 mutation changes neurological specific pathways.

The diversity seen in molecular and cellular roles of proteins that are linked with the

different types of Charcot-Marie-Tooth disease show that classification of gene disease is very

important, particularly when seeking to get an understanding the biology of peripheral nervous

system and pathophysiology of the syndrome (Stone et al. 423). Therefore, whereas more data is

available on characterization of several CMT types have produced a list of probable pathways

that can be selectively compromised in affected patients (Benoy et al. 673) There is no

substantial evidence that can completely ignore other biological frameworks or biochemical

reactions which are still important in understanding CMT molecular pathology.

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Works cited

Benoy, Veronick, et al. "HDAC6 is a therapeutic target in mutant GARS-induced Charcot-

Marie-Tooth disease." Brain 141.3 (2018): 673-687.
Boutary, Suzan, et al. "Squalenoyl siRNA PMP22 nanoparticles are effective in treating mouse
models of Charcot-Marie-Tooth disease type 1 A." Communications biology 4.1 (2021):
1-14.
Duan, Xiaohui, et al. "Characterization of genotype–phenotype correlation with MORC2
mutated Axonal Charcot–Marie–Tooth disease in a cohort of Chinese
patients." Orphanet Journal of Rare Diseases 16.1 (2021): 1-15.
Edgar, James R., et al. "A dysfunctional endolysosomal pathway common to two sub-types of
demyelinating Charcot–Marie–Tooth disease." Acta Neuropathologica
Communications 8.1 (2020): 1-16.
Larrea, Delfina, et al. "MFN2 mutations in Charcot–Marie–Tooth disease alter mitochondria-
associated ER membrane function but do not impair bioenergetics." Human molecular
genetics 28.11 (2019): 1782-1800.
Lee, Sooyeon, et al. "Elevated peripheral myelin protein 22, reduced mitotic potential, and
proteasome impairment in dermal fibroblasts from Charcot-Marie-Tooth disease type 1A
patients." The American journal of pathology 188.3 (2018): 728-738.
Pareyson, Davide, et al. "A multicenter retrospective study of charcot‐marie‐tooth disease type
4B (CMT4B) associated with mutations in myotubularin‐related proteins
(MTMRs)." Annals of neurology 86.1 (2019): 55-67.
Pipis, Menelaos, et al. "Next-generation sequencing in Charcot–Marie–Tooth disease:
opportunities and challenges." Nature Reviews Neurology 15.11 (2019): 644-656.
Stone, Elizabeth J., Atsuko Uchida, and Anthony Brown. "Charcot–Marie–Tooth disease Type
2E/1F mutant neurofilament proteins assemble into neurofilaments." Cytoskeleton 76.7-8
(2019): 423-439.
Wang, Haicui, et al. "Genotype-phenotype correlations in Charcot-Marie-Tooth disease due to
MTMR2 mutations and implications in membrane trafficking." Frontiers in
neuroscience 13 (2019): 974.