Peripheral neuropathies encompass the set of disorders that primarily lead to peripheral nerve dysfunction. Symptoms typically include weakness of muscles at extremities, spine curvature, and loss of sensation at extremities (Kang, 2024c; UpToDate, 2024). Neuropathies may be caused by a variety of different factors, such as metabolic issues (including Fabry disease, Niemann-Pick disease, et al.) or present as a secondary symptom to another condition (such as Tangier disease) (Kang, 2024c). 

Charcot-Marie-Tooth (CMTA) disease, also known as hereditary motor sensory neuropathy, is a group of progressive disorders that affect the peripheral nerves. CMT is caused by a mutation in one of several myelin genes that result in defects in myelin structure, maintenance, or function within peripheral nerves. Charcot-Marie-Tooth disease is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States (Kang, 2024a).

Symptoms 
The neuropathy of CMT affects both motor and sensory nerves. Symptoms usually start in childhood and have a gradual progression. The severity of symptoms varies greatly among individuals and even among family members with the disease and gene mutation (Bird, 2023; NINDS, 2007, 2023). Typical symptoms include the following:

• “Weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop)
• A high-stepped gait with frequent tripping or falling
• Balance problems
• Foot deformities, such as high arches and curled toes (hammertoes)
• Lower legs may take on an "inverted champagne bottle" shape due to the loss of muscle bulk
• Reduced ability to feel heat, cold, and touch
• Weakness and atrophy may occur in the hands, causing difficulty with fine motor skills
• Decreased sense of vibration and position (proprioception)
• Curvature of the spine (scoliosis)
• Hip displacement
• Contractures (chronic shortening of muscles or tendons around joints)
• Muscle cramping
• Nerve pain” (NINDS, 2023)

Pain can range from mild to severe, and some people may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people living with CMT experience tremor, and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected (NINDS, 2023). 

Causes
CMT is caused by mutations in genes that produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. Although different proteins are abnormal in different forms of CMT disease, all mutations affect the normal function of the peripheral nerves. There is little correlation between the genotype and phenotype of CMT; it is common to see differing mutations result in various clinical phenotypes all within the same gene (Kang, 2024a).

Pattern of Inheritance
The pattern of inheritance varies with the type of CMT disease. CMT1, most cases of CMT2, and most intermediate forms are inherited in an autosomal dominant pattern. CMT4, a few CMT2 subtypes, and some intermediate forms are inherited in an autosomal recessive pattern. CMTX is inherited in an X-linked pattern. Some cases of CMT disease result from a new mutation and occur in people with no history of the disorder in their family. In rare cases the gene mutation causing CMT disease is a new mutation which occurs spontaneously in the individual's genetic material and has not been passed down through the family (Kang, 2024a).

CMT1
Charcot-Marie-Tooth disease type 1 (CMT1) is a demyelinating peripheral neuropathy characterized by distal muscle weakness and atrophy, sensory loss, and are usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop (Bird, 2023). The six subtypes of CMT1 shown in Table 1 are clinically indistinguishable and are designated solely on molecular findings (Saporta et al., 2011) 

Table 1: Molecular Genetics of CMT1 (Saporta et al., 2011)

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant disease that results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). Overexpression of this gene causes the structure and function of the myelin sheath to be abnormal. A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent demyelinating neuropathy (NINDS, 2007, 2023). 

Charcot-Marie-Tooth disease type 1B (CMT1B) is an autosomal dominant disease caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (P0), which is another critical component of the myelin sheath. Most of these mutations are point mutations. As a result of abnormalities in P0, CMT1B produces symptoms similar to those found in CMT1A (NINDS, 2007, 2023).

Other less common causes genetic causes of CMT1 result from mutations within LITAF, EGR2, PMP22, and NEFL genes, respectively (NINDS, 2023). 
CMT2 

Charcot-Marie-Tooth disease type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy. Axonal peripheral neuropathy shows extensive clinical overlap with CMT1 (Bird, 2023). In general, individuals with CMT2 tend to be less disabled and have less sensory loss than individuals with CMT1 (Bird, 2023). It is less common than CMT1. CMT2A, the most common axonal form of CMT, is caused by mutations in Mitofusin 2, a protein associated with mitochondrial fusion. Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1. Additionally, symptoms for CMT2 may have vocal cord or phrenic nerve involvement, causing speech or respiratory problems (NINDS, 2023). 

Table 2: Molecular Genetics of CMT2 (Anthony Antonellis, 2018; Bird, 2023; Peter De Jonghe, 2011; Schindler, 2014; Züchner, 2013)

CMT3 
Dejerine-Sottas disease (CMT3), is a severe demyelinating neuropathy that begins in infancy. Infants have severe muscle atrophy, weakness, and sensory problems. This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively (NINDS, 2023). 

CMT4 
Charcot-Marie-Tooth disease type 4 (CMT4) comprises several different subtypes of autosomal recessive demyelinating motor and sensory axonal neuropathies. Each neuropathy subtype is caused by a different genetic mutation, may affect a particular ethnic population, and produces distinct physiologic or clinical characteristics. Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. Several genes have been identified as causing CMT4, including GDAP1 (CMT4A), MTMR13 (CMT4B1), MTMR2 (CMT4B2), SH3TC2 (CMT4C), NDG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FDG4 (CMT4H), and FIG4 (CMT4J) (Kang, 2024a; NINDS, 2007, 2023).

Table 3: Molecular Genetics of CMT4 (Bird, 2017; Delague, 2013; Hamid Azzedine, 2015; Li, 2013)