Review Article

The Role of Mutations in Genes PMP22, MPZ, LITAF, EGR2, NEFL, MFN2, KIF1B, RAB7A, LMNA, TRPV4, BSCL2, GARS, HSPB1, GDAP1, HSPB8, DNM2, PRX, MTMR2, SH3TC2, SBF2, NDRG1, FGD4, FIG4, YARS, GJB1, PRPS1, in Charcot-Marie-Tooth Syndrome

Shahin Asadi1,2*

1Director of the Division of Medical Genetics and Molecular Optogenetic Research, Medical Genetics-Harvard University, USA

2Division of Medical Genetics and Molecular Pathology Research, Harvard University, Boston Children’s Hospital, USA

*Corresponding author: Shahin Asadi, Director of the Division of Medical Genetics and Molecular Optogenetic Research, Medical Genetics-Harvard University, USA.

Received Date: 06 Feb, 2020 ; Accepted Date: 17 Feb, 2020 ; Published Date: 21 Feb, 2020

Abstract

Charcot-Marie-Tooth Disease (CMT; Charcot-Marie-Tooth) involves a large group of different forms of inherited motor (sensory) and sensory (sensory) neuropathies. The molecular basis of different CMT subtypes has been identified over the past 20 years. Because muscle weakness and sensory dysfunction that progresses slowly and slowly, the main characteristic of these syndromes is the goal of treatment, to improve movement and sensory impairments to improve patients’ abilities. CMT drug trials are rare. Gene mutations that cause Charcot-Marie-Tooth syndrome affect the function of these proteins, but their mechanism of action is poorly understood. However, these mutations are likely to damage axons that disrupt the transmission of nerve waves or impair the production of myelin cells.

Keywords

Charcot-Marie-Tooth Syndrome; Genetics Mutations; Progressive genetic disorders

Overview of Charcot-Marie-Tooth Syndrome

Charcot-Marie-Tooth Syndrome is a group of progressive genetic disorders that affect the peripheral nerves. Peripheral nerves connect the brain and spinal cord to sensitive muscles and cells that recognize emotions such as touch, pain, heat and sound. Damage to peripheral nerves can lead to loss of sensation and atrophy of leg, thigh and hands muscles [1].

Clinical signs and symptoms of Charcot- Marie-Tooth Syndrome

Charcot-Marie-Tooth disease usually develops in adolescence or early adulthood, but onset may occur at any time from early childhood to late adulthood. The severity of symptoms of Charcot-Marie-Tuth disease varies even among members of a family. Some people never realize they have the disorder, but often have moderate physical disabilities. A small percentage of people experience severe weakness or other problems that in rare cases can be life threatening. But in most cases, Charcot-Marie-Tooth syndrome does not affect patients’ life expectancy [1].

Typically, the first symptoms of Charcot-Marie-Tooth syndrome include problems with balance and weakness in the leg muscles. As the disease progresses, the leg and thigh muscles usually weaken, but foot and thigh problems rarely lead to wheelchairs. Injured people may also have weakness in the hands, causing problems in daily activities such as writing, closing the shirt buttons, and turning the knobs. People with this disorder usually experience tenderness, heat, and cold in the legs and thighs, but sometimes they feel warm or burning. In some cases, people with Charcot-Marie-Tooth Syndrome experience progressive hearing loss, hearing loss, or vision loss [1].

There are several types of Charcot-Marie-Tooth syndrome. Charcot-Marie-Tooth type 1 (CMT1) syndrome is characterized by abnormalities in myelin, a type of fat white matter that covers and protects nerve cells (neurons). CMT1 syndrome is caused by abnormalities in the myelin sheath of some nerves. This type of Charcot-Marie-Tooth disease is characterized by myelin sheath damage in the peripheral nerves. Muscle weakness and atrophy, loss of sensation and slowed nerve conduction velocities of up to 2 m / s are symptoms of CMT1 syndrome (normally greater than 1 to 2 m/s) [1,2].

The progression of the disease is gradual and symptoms appear between the ages of 2 and 4 years. Less than 2% of patients become wheelchair dependent. The disease usually does not shorten the life span. There are 4 types of CMT1 that are similar in clinical presentation and are only separated by molecular genetic testing [1,2].

Charcot-Marie-Tooth type 2 (CMT2) syndrome: is caused by abnormalities in peripheral nerve cell axons. In this type of CMT, peripheral nerve axonal cells are affected. It is clinically similar to type 1 but less likely to decrease neuronal conduction. CMT2 has fifteen subgroups whose clinical signs are similar and are subtracted by molecular genetic testing [1,2].

Although the gene involved in most of these subgroups has been identified, in some cases only the chromosome carrying this gene has been identified and therefore its molecular testing is not yet available in vitro [1,2].

Note: Charcot-Marie-Tooth Intermediate type: In this type of CMT syndrome, phenotypic manifestations of myelin axons and cells are observed [1,2].

Charcot-Marie-Tooth Syndrome Type 3 (CMT3) is a severe neuropathy that begins in the neonatal period. Infants with CMT3 syndrome develop muscle atrophy, weakness, and sensory problems [1,2].

Charcot-Marie-Tooth Syndrome Type 4 (CMT4): Symptoms of leg cramps in childhood and adolescence. It is very difficult for these patients to walk.

Charcot-Marie-Tooth Type 5 (CMT5 or CMTX): This syndrome is caused by a mutation in a gene on the X chromosome. This gene mutation affects Schwann cell communication with axons [1,2].

Other variants of Charcot-Marie-Tooth syndrome are classified as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1 [1,2].

The Etiology of Charcot-Marie-Tooth Syndrome

Charcot-Marie-Tooth syndrome is caused by mutations in different genes. These genes provide instructions for the synthesis of proteins that are involved in the function of peripheral nerves in the legs, thighs and hands. Gene mutations that cause Charcot-Marie-Tooth syndrome affect the function of these proteins, but their mechanism of action is poorly understood. However, these mutations are likely to damage axons that disrupt the transmission of nerve waves or impair the production of myelin cells. As a result, peripheral nerve cells slowly lose the ability to stimulate muscles and transmit sensory signals to the brain [1,3].

CMT1 syndrome is caused by mutations in the genes NEP, PMP22, MPZ, LITAF, EGR2. It is worth noting that the PMP22 gene also causes CMT1A and CMT1E syndromes. The MPZ gene also causes CMT1B syndrome. The LITAF gene also causes CMT1C syndrome. The EGR2 gene also causes CMT1D syndrome. The NEFL gene also causes CMT1F syndrome. The PMP22 gene is located on the short arm of chromosome 17 as 17p12. The MPZ gene is located on the long arm of chromosome 1 as 1q23.3. The LITAF gene is located on the short arm of chromosome 16 at 16p13.13. The EGR2 gene is located on the long arm of chromosome 10 as 10q21.3. The NEFL gene is located on the short arm of chromosome 8 at 8p21.2 [1,3].

CMT2 syndrome can be caused by the mutation of the MFN2 gene and the KIF1B gene located on the short arm of chromosome No. 1p36.22, the RAB7A gene located on the long arm of chromosome No. 3q21.3, the LMNA gene on the long arm of chromosome No. 1 is located at 1q22, the TRPV4 gene is located on the long arm of chromosome 12 at 12q24.11, the BSCL2 gene is located at the long arm of chromosome No. 11 at 11q12.3, the GARS gene at the short arm of chromosome No. 7 is 7p14. 3 is located, the NEFL gene is located on the short arm of chromosome number 8p21.2, the HSPB1 gene is located on the long arm of chromosome number 7q11.23, the MPZ gene is located on the long arm of chromosome 7 Saw 1 is located at 1q23.3, the GDAP1 gene is located on the long arm of chromosome 8 at 8q21.11 and the HSPB8 gene is located at the long arm of chromosome 12 at 12q24.23. In addition, some mutations in the DNM2 gene, located on the short arm of chromosome 19 as 19p13.2, also cause a form of CMT2 syndrome [1,4].

MFN2 and KIF1B genes also cause CMT2A syndrome. The RAB7A gene also causes CMT2B syndrome. The LMNA gene also causes CMT2B1 syndrome. The TRPV4 gene also causes CMT2C syndrome. BSCL2 and GARS genes also cause CMT2D syndrome. The NEFL gene also causes CMT2E syndrome. The HSPB1 gene also causes CMT2F syndrome. The MPZ gene also causes CMT2I and CMT2J syndromes. The GDAP1 gene also causes CMT2K syndrome. The HSPB8 gene also causes CMT2L syndrome [1,4].

CMT3 syndrome is caused by mutations of MPZ, PMP22, PRX, EGR2 genes. The PRX gene is located on the long arm of chromosome 19 as 19q13.2.

CMT4 syndrome is caused by mutation of MTMR2 gene located on long arm of chromosome number 11q21, SBF2 gene located on short arm of chromosome number 11p15.4, SH3TC2 gene located on long arm of chromosome number 5q32 gene. NDRG1 is located on the long arm of chromosome 8 at 8q24.22, FGD4 is located at the short arm of chromosome 12 at 12p11.21, the FIG4 gene is located at long arm of chromosome 6 at 6q21 and the genes GDAP1, EGR2 , PRX is created. The GDAP1 gene also causes CMT4A syndrome. The MTMR2 gene also causes CMT4B1 syndrome. The SBF2 gene also causes CMT4B2 syndrome. The SH3TC2 gene also causes CMT4C syndrome. The NDRG1 gene also causes CMT4D syndrome. The EGR2 gene also causes CMT4E syndrome. The PRX gene also causes CMT4F syndrome. The FGD4 gene also causes CMT4H syndrome. The FIG4 gene also causes CMT4J syndrome [1,5].

Medium Charcot-Marie-Tooth syndrome is caused by a YARS gene mutation located on the short arm of chromosome 1 at 1p35.1 and the genes DNM2, MPZ, and GDAP1.

CMT5 syndrome (CMTX) is caused by the mutation of the GJB1 gene located on the long arm of the X chromosome Xq13.1, and the PRPS1 gene located on the long arm of the X chromosome Xq22.3. The GJB1 gene also causes CMTX1 syndrome and the PRPS1 gene also causes CMTX5 syndrome [1,5].

CMT1 syndrome and most cases of CMT2 and most intermediate forms of the syndrome follow the dominant autosomal inherited pattern. Therefore, a copy of the mutated genes mentioned in the text (whether father or mother) is needed to create these forms of Charcot-Marie-Tooth syndrome and the chance of having a child with these forms of Charcot-Marie-Tooth syndrome In the autosomal dominant state, there is a 50% chance of any pregnancy [1,5].

CMT3 syndrome can follow an autosomal dominant and recessive inheritance pattern. Therefore, autosomal dominant syndrome requires a copy of the MPZ, PMP22, PRX, and EGR2 genes (including parents) and the chance of having a child with this CMT3 syndrome in autosomal dominant state for any possible pregnancy. 50%. It is also required to produce CMT3 syndrome in autosomal recessive state, two copies of the aforementioned genes (one father and one mother), and the chance of having a child with autosomal recessive syndrome is 25% for each possible pregnancy [1,6].

CMT4 syndrome and several subsets of CMT2 syndrome and some forms of intermediate Charcot-Marie-Tooth syndrome follow an autosomal recessive inheritance pattern. Therefore, two copies of the relevant genes mentioned in the book (one father and one mother) are required for the development of these syndromes and the chance of having a child with these syndromes in autosomal recessive state for any possible pregnancy It is 25% [1,7].

CMT5 syndrome, or CMTX, follows the dominant X-linked inheritance pattern. Therefore, a copy of the GJB1 and PRPS1 mutant genes (whether father or mother) is required to develop the syndrome, and the chance of having a child with this syndrome in the predominant X-linked state is 50% for each possible pregnancy. Be it. It should be noted that despite having two sex X chromosomes mutations in a single set of these genes cause the syndrome, and men with CMTX syndrome experience more severe symptoms than women. The inherited characteristic of X is that fathers cannot transfer X-related traits to their son’s offspring [1,8].

It is worth noting that some cases of Charcot-Marie-Tooth syndrome are caused by new mutations without a family history [1,9].

Frequency of Charcot-Marie-Tooth Syndrome

Charcot-Marie-Tooth syndrome is the most common hereditary genetic disorder that affects the peripheral nerves. The prevalence of the syndrome worldwide is about 1 in 2,500 people. It is estimated that Charcot-Marie-Tooth syndrome has so far affected approximately 150,000 people in the United States [1,10].

Diagnosis of Charcot-Marie-Tooth Syndrome

Charcot-Marie-Tooth syndrome is diagnosed on the basis of clinical and physical findings of patients and some pathological and neurological tests. The most accurate method for detecting this syndrome is molecular genetic testing of all the genes listed in the text to determine the presence of possible mutations [1,11].

The therapeutic pathways of Charcot-Marie-Tooth Syndrome

The strategy of treatment and management of Charcot-Marie-Tooth syndrome is symptomatic and supportive. Treatment may be coordinated with a team of specialists including an orthopedist, a neurologist, a physiotherapist, an ophthalmologist, an ear specialist, and other health care professionals. There is no cure for this syndrome and all clinical measures are to alleviate the suffering of the patients. Genetic counseling is also needed for all parents who want a healthy child [1,12].

Discussion and Conclusion

Hereditary Charcot Marie Tooth Neuropathy (CMT) known as Hereditary Motor and Sensory Neuropathy (HMSN), Hereditary Sensory Neuropathic Hereditary Neuropathy (HSMN) as well as peroneal muscular atrophy That affects the peripheral nerves. The name of Charcot- Marie-Tooth comes from the names of three neurologists who first described the disease in the 19th century. The disease affects the sensory and motor nervous system, which is caused by the gradual disruption of the structure and function of the peripheral nerves (neuropathy). This disorder occurs symmetrically in the organs, especially the legs and in the advanced stages of the hands. Charcot-Marie-Tooth with the prevalence of about 1 in every 33,000 people is the most common hereditary neuropathy. Symptoms of illness usually manifest in the first to third decade of life as muscle weakness and atrophy. Some sources have described the disease as painless. But this neuropathy can also be associated with pain. Arched feet and hammer-toes are signs of the disease. Mutations in genes involved in the development of peripheral nerves cause the disease. The inherited pattern of these genes is different. Accordingly, the disease is classified (Table 1) [1-12].

Classifying these genes is not so easy because there have been cases where different mutations in one gene cause a different inherited pattern of disease. Each of the diseases listed in Table 1 is divided into several diseases based on the damaged gene and the protein product produced [1-12].

Charcot-Marie-Tooth type I (CMT1): This type of Marie-tooth disease is characterized by myelin sheath damage in the peripheral nerves. Muscle weakness and atrophy, loss of sensation and slowed nerve conduction speeds of up to 5 to 30 meters per second are symptoms of the disease (normally greater than 40 to 45 meters per second). The progression of the disease is gradual and symptoms appear between the ages of 5 and 25 years. Less than 5% of patients become wheelchair dependent. The disease usually does not shorten the life span. There are 6 types of CMT1 that are similar in clinical manifestations and can only be separated by genetic testing. The gene involved and the mutations created in the subgroups of this disease are listed in (Table 2) [1-12].

History of Charcot-Marie-Tooth Syndrome

Charcot-Marie-Tooth syndrome was first reported in 1886 by Dr. Jean-Martin Charcot, Pierre Marie, and Howard Henry Tooth [1,13].

 

Figure 1: Human foot image of Charcot-Marie-Tooth syndrome with skeletal disorder.

Figure 2: Images of related skeletal disorders in Charcot-Marie-Tooth syndrome.

Figure 3: Another view of skeletal disorders in the legs and arms of patients with Charcot-Marie-Tooth syndrome.

Figure 4: Images of bone disorders in Charcot-Marie-Tooth syndrome.

Figure 5: Overview of Skeletal Disorders in the Legs and Hands of Patients with Charcot-Marie-Tooth syndrome.

Figure 6: Schematic overview of chromosome 17 where the PMP22 gene is located in the short arm of chromosome 17p12.

Figure 7: Schematic overview of chromosome 1 where the MPZ gene is located on the long arm of chromosome 1q23.3.

Figure 8: Schematic of the MPZ protein package structure.

Figure 9: Schematic overview of chromosome 16 where the LITAF gene is located in the short arm of chromosome 16p13.13.

Figure 10: Schematic overview of chromosome 10 where the EGR2 gene is located on the long arm of chromosome 10q21.3.

Figure 11: Schematic of the closed structure of the EGR2 protein.

Figure 12: Schematic overview of chromosome 8 where the NEFL gene is located in the short arm of chromosome 8p21.2.

Figure 13: Schematic overview of chromosome 1 where the MFN2 and KIF1B genes are located in the short arm of chromosome 1p36.22.

Figure 14: Schematic of the KIF1B protein package structure.

Figure 15: Schematic overview of chromosome 3 where the RAB7A gene is located on the long arm of chromosome 3q21.3.

 

Figure 16: Schematic of the closed structure of the RAB7A protein.

Figure 17: Schematic view of chromosome 1 where the LMNA gene is located in the long arm of chromosome 1q22.

Figure 18: Schematic view of the dominant autosomal inherited pattern that follows CMT1, CMT2 syndrome and CMT intermediate.

Figure 19: Schematic view of the autosomal dominant (right) and autosomal recessive (left) inheritance pattern, which also follows CMT3 syndrome.

Figure 20: Schematic view of the dominant X-linked inheritance pattern, the patient's mother (left) and the patient's father (right), who also follow CMT5 syndrome (CMTX).

Figure 21: Images of bone disorder in legs with Charcot-Marie-Tooth syndrome.

Figure 22: Pictures of Dr. Jean-Martin Charcot (left), Dr. Pierre Marie (middle photo) and Dr. Howard Henry Tooth (right) in 1886 discoverers of Charcot-Marie-Tooth Syndrome.

Table 1: Classification of CMTs by Inheritance Pattern and Type of Damaged Cell.

 

 

Disease Name

Pathology

Inheritance pattern

Incidence rate among CMTs

CMT1

Abnormal myelin

Autosomal dominant

50%

CMT2

Axonopathy

Autosomal dominant

%20-40

average type

A combination of myelinopathy and axonopathy in one person

Autosomal dominant

Rare

CMT3

Axonopathy

Autosomal recessive

Rare

CMT4

Myelinopathy

Autosomal recessive

Rare

CMTX

Axonopathy associated with myelin changes in the second stage

X linked associate

%10-20

 

Table 2: Types of Charcot-Marie-Tooth.

 

Disease Name

Incidence rate among CMT1

Damaged genes

Protein product

CMT1A

%70-80

Duplication and deletion in PMP22

Peripheral Myelin Protein 22

CMT1B

%5-10

Point mutation in MPZ

Myelin Protein P0

CMT1C

%1-2

LITAF

Alpha Factor Induce Tumor Liposaccharide

CMT1D

>%2

EGR2

Protein 2 responsive to early growth

CMT1E

>%5

Point mutation in PMP22

Peripheral Myelin Protein 22

CMT1F/2E

>%5

NEFL

Neurofilament light polypeptide

 

 

 

Citation: Shahin Asadi (2020) The Role of Mutations in Genes PMP22, MPZ, LITAF, EGR2, NEFL, MFN2, KIF1B, RAB7A, LMNA, TRPV4, BSCL2, GARS, HSPB1, GDAP1, HSPB8, DNM2, PRX, MTMR2, SH3TC2, SBF2, NDRG1, FGD4, FIG4, YARS, GJB1, PRPS1, in Charcot-Marie-Tooth Syndrome. Rev Biotechnol Biochem 1: 003. RBB-003.000003