Charcot-Marie-Tooth disease (CMT) and spinal muscular atrophy (SMA) are two degenerative neurological diseases that have many similar features. Both CMT and SMA are congenital (inherited) diseases that directly affect neurons (nerve cells), leading to a loss of nerve function. Although CMT and SMA can share some of the same symptoms, there are many important differences between the two.
CMT disease, also called hereditary motor and sensory neuropathy, causes progressive weakness, muscle atrophy, and loss of sensation in the distal limbs (hands, feet, lower legs, and forearms). CMT symptoms are caused by impairment of both sensory and motor function in the longer nerves of the peripheral nervous system (all the nerves outside the brain and spinal cord).
Symptoms of CMT include:
CMT diagnosis requires a thorough family medical history and physical exam. Genetic testing is not usually used to diagnose CMT because of the large number of possible gene mutations that can cause the disease. Additional tests for nerve conduction velocity are needed to help determine the type of CMT. CMT has at least eight different types with multiple subtypes. Muscle or nerve biopsy and electromyogram testing are rarely used for diagnosis.
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CMT disease and SMA are inherited neurological diseases that both cause muscle weakness and atrophy due to neuronal degeneration, but, for the most part, the similarities stop there. Despite appearing very similar on the surface, CMT and SMA each generally have a very different range of symptoms, severity, genetic causes, and pathogenesis (underlying cause of disease).
In most cases, SMA is a much more severe disease than CMT. Although both diseases can lead to significant physical impairment, the most common types of SMA cause severe and debilitating physical symptoms that affect muscles throughout the entire body. SMA not only affects the limbs, but can also cause weakness in the torso, head, and neck. Scoliosis, a condition where the spine curves sideways, is common in people with SMA.
Most types of early-onset SMA can progress to affect the muscles needed to breathe, speak, and chew. CMT rarely causes life-threatening symptoms such as difficulty breathing. The symptoms are mostly confined to the arms and legs. Foot deformities and atrophy of the peroneal muscles in the calf are common in CMT disease. Certain rare types of CMT include symptoms such as hearing loss and retinopathy (a type of eye disease).
Some rare forms of SMA share unique clinical features that are also seen in CMT. Distal spinal muscular atrophy primarily affects muscles in the hands and feet. Symptoms of SMA with lower-extremity predominance (SMA-LED) are usually limited to the legs. People with milder forms of SMA can also have symptoms limited to the extremities, such as SMA type 3 (or late-onset SMA, which develops after 11 months of age) and SMA type 4 (or adult-onset SMA).
SMA is a disease that primarily affects motor neurons that extend from the spinal cord to skeletal muscle throughout the body, but can also involve the brain and brainstem. CMT is a disease of both motor and sensory neurons — it causes both weakness and loss of sensation. CMT is also confined to the peripheral nervous system and does not directly affect the central nervous system (the brain and spinal cord).
SMA causes cell death in motor neurons that leads to a variety of symptoms, but CMT causes neuronal dysfunction in other ways. Healthy neurons have a myelin sheath, a layer of fat and protein that encases the long, thin axons that extend from the body of nerve cells to connect to other parts of the body, such as muscles. Myelin is produced by Schwann cells, which wrap around axons.
Two of the most common CMT disease types are CMT type 1 and CMT type 2. CMT type 1 and Dejerine-Sottas syndrome (CMT type 3) are caused by loss of the myelin sheath (demyelination) of peripheral nerves, and CMT type 2 is caused by dysfunction in axons. Demyelinating and axonal pathologies rarely occur together. CMT does not cause cell death in sensory and motor neurons but causes slow nerve conduction velocity — the neurons cannot transmit signals the way healthy neurons can.
SMA and CMT are inherited genetic disorders. The most common types of SMA (SMA types 0 through 4) are all caused by mutations to the same gene, SMN1. The cause of these types of SMA has been positively identified, so genetic testing can be used for diagnosis, and disease-modifying gene therapy treatments are available to treat SMA. The most common types of SMA are autosomal recessive, meaning that people must inherit a mutated gene from both parents to develop the disease (or they inherit one copy to be an asymptomatic carrier).
Rare types of SMA (such as SMA-LED and Finkel type SMA) are not caused by an SMN1 mutation, but rather by mutations in other genes. Some genes that are known to cause rare types of SMA, such as the DYNC1H1 gene in SMA-LED type 1, can also cause CMT. Not all rare types of SMA are autosomal recessive. Other gene mutations that cause SMA can be autosomal dominant, meaning that the mutated gene only needs to be inherited from one parent, or X-linked, meaning they are due to mutations in the X chromosome and have a different pattern of heritability.
CMT can be caused by many different inherited genetic mutations from your family history, or even new mutations. Patterns of inheritance can be:
The two most common types of CMT, CMT type 1 and CMT type 2, are autosomal dominant. The other most common types of CMT are CMTX, which is X-linked dominant, and CMT type 4, which is autosomal recessive. The most common gene mutations seen in CMT are in the PMP22 gene (CMT1A) or MPZ gene (CMT1B), the MFN2 gene (CMT2), and the GJB1 gene (CMTX). Mutations in these four genes are the most commonly seen in CMT, but dozens of genes have been identified that can cause CMT. Because so many different genes can cause CMT, genetic testing is not as useful for diagnosis as with SMA.
Both CMT disease and SMA can have a similar phenotype (the outward appearance of signs and symptoms), but they are caused by very different and unrelated mechanisms. SMA shares symptoms with several neurodegenerative diseases that have varied causes and respond to entirely different treatments. It is important to get a proper diagnosis with SMA and other neuromuscular and genetic disorders to make sure you receive the proper treatment.
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