Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most commonly inherited neurological disorder, affecting about one in 2,500 people. It is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and the Briton Howard Henry Tooth (1856–1925).
Internexin, alpha-internexin, is a Class IV intermediate filament approximately 66 KDa. The protein was originally purified from rat optic nerve and spinal cord. The protein copurifies with other neurofilament subunits, as it was originally discovered, however in some mature neurons it can be the only neurofilament expressed. The protein is present in developing neuroblasts and in the central nervous system of adults. The protein is a major component of the intermediate filament network in small interneurons and cerebellar granule cells, where it is present in the parallel fibers.
Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks, but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.
Neurofilaments (NF) are classed as type IV intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring 10 nm in diameter and many micrometers in length. Together with microtubules (~25 nm) and microfilaments (7 nm), they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. The proteins that form neurofilaments are members of the intermediate filament protein family, which is divided into six types based on their gene organization and protein structure. Types I and II are the keratins which are expressed in epithelia. Type III contains the proteins vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP). Type IV consists of the neurofilament proteins NF-L, NF-M, NF-H and α-internexin. Type V consists of the nuclear lamins, and type VI consists of the protein nestin. The type IV intermediate filament genes all share two unique introns not found in other intermediate filament gene sequences, suggesting a common evolutionary origin from one primitive type IV gene.
Giant axonal neuropathy is a rare, autosomal recessive neurological disorder that causes disorganization of neurofilaments. Neurofilaments form a structural framework that helps to define the shape and size of neurons and are essential for normal nerve function. A distinguishing feature is its association with kinky, or curly, hair; in such cases it has been called Giant axonal neuropathy with curly hair.
Myelin protein zero is a single membrane glycoprotein which in humans is encoded by the MPZ gene. P0 is a major structural component of the myelin sheath in the peripheral nervous system (PNS). Myelin protein zero is expressed by Schwann cells and accounts for over 50% of all proteins in the peripheral nervous system, making it the most common protein expressed in the PNS. Mutations in myelin protein zero can cause myelin deficiency and are associated with neuropathies like Charcot–Marie–Tooth disease and Dejerine–Sottas disease.
Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.
Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the GJB1 gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulates and controls the transfer of communication signals across cell membranes, primarily in the liver and peripheral nervous system. However, the protein is expressed in multiple organs, including in oligodendrocytes in the central nervous system.
Glycine—tRNA ligase also known as glycyl–tRNA synthetase is an enzyme that in humans is encoded by the GARS1 gene.
Peripheral myelin protein 22 (PMP22), also called Growth arrest-specific protein 3 (GAS-3), is a protein which in humans is encoded by the PMP22 gene. Mutations in PMP22 cause changes in the expression of peripheral myelin protein 22 which can result in several neuropathies.
Neurofilament medium polypeptide (NF-M) is a protein that in humans is encoded by the NEFM gene.
Lipopolysaccharide-induced tumor necrosis factor-alpha factor is a protein that in humans is encoded by the LITAF gene.
Ganglioside-induced differentiation-associated protein 1 is a type of protein that in humans is encoded by the GDAP1 gene.
Gigaxonin also known as kelch-like protein 16 is a protein that in humans is encoded by the GAN gene.
Myotubularin-related protein 2 also known as phosphatidylinositol-3,5-bisphosphate 3-phosphatase or phosphatidylinositol-3-phosphate phosphatase is a protein that in humans is encoded by the MTMR2 gene.
Hereditary neuropathy with liability to pressure palsy (HNPP) is a peripheral neuropathy, a condition that affects the nerves. Pressure on the nerves can cause tingling sensations, numbness, pain, weakness, muscle atrophy and even paralysis of the affected area. In normal individuals, these symptoms disappear quickly, but in sufferers of HNPP even a short period of pressure can cause the symptoms to occur. Palsies can last from minutes or days to weeks or even months.
Neurofilament, heavy polypeptide (NEFH) is a protein that in humans is encoded by the NEFH gene.
EnCor Biotechnology is a United States company that manufactures monoclonal and polyclonal antibodies with a focus on reagents targeting neural proteins. EnCor was founded in 1999 as a spin-off from the University of Florida by Gerry Shaw, a British scientist initially a professor in the Department of Neuroscience, University of Florida, and now professor emeritus. The company is based in Gainesville, Florida and markets high quality and very well characterized antibody reagents at reasonable prices.
Several biomarkers for diagnosis of multiple sclerosis, disease evolution and response to medication are under research. While most of them are still under research, there are some of them already well stablished:
Autosomal dominant Charcot–Marie–Tooth disease type 2 with giant axons is a rare subtype of hereditary motor and sensory neuropathy of the axons which is characterized by symptoms similar to those from Charcot–Marie–Tooth disease and autosomal dominant inheritance.
