Anti-MAG peripheral neuropathy

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Anti-MAG peripheral neuropathy
Other namesNeuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein
Specialty Immunology, neurology

Anti-MAG peripheral neuropathy is a specific type of peripheral neuropathy in which the person's own immune system attacks cells that are specific in maintaining a healthy nervous system. As these cells are destroyed by antibodies, the nerve cells in the surrounding region begin to lose function and create many problems in both sensory and motor function. Specifically, antibodies against myelin-associated glycoprotein (MAG) damage Schwann cells. While the disorder occurs in only 10% of those afflicted with peripheral neuropathy, people afflicted have symptoms such as muscle weakness, sensory problems, and other motor deficits usually starting in the form of a tremor of the hands or trouble walking. [1] [2] There are, however, multiple treatments that range from simple exercises in order to build strength to targeted drug treatments that have been shown to improve function in people with this type of peripheral neuropathy. [3]

Contents

Background

Myelination by Schwann cells

Myelin is an important part of neuron cells and provides insulation allowing the neuron's action potential to travel faster and more consistently. In order to provide insulation, multiple layers of closely opposing membrane are wrapped around the axon. By acting as an electrical insulator, the conduction ability of the axon is sped up considerably allowing action potentials to travel at a much faster rate, about fifteen times faster in certain cases. This ability allows the nervous system to send messages faster and more accurately. Disruption of the myelin sheath on cells that are normally myelinated allows leakage of action potential much like a faulty wire will allow leakage of electricity in a circuit. This slows the messages being sent along those nerves and disrupts normal function. [4]

Schwann cells are the cells in the peripheral nervous system that create and maintain myelin sheaths on neurons. These are the glial cells of the peripheral nervous system and are located around the axons that they serve. Damage to these cells result in degeneration of the myelin sheath and inevitably lead to problems in communication for the nervous system. [4]

Myelin-associated glycoprotein

Myelin-associated glycoprotein (MAG) is a glycoprotein that is specific to Schwann cells, which create myelin for nerve cells in the peripheral nervous system. Research through cloning of the rat MAG gene has shown that it is a type I transmembrane protein meaning that it contains domains both inside the cell membrane and outside the cell membrane. Expression of this glycoprotein is very specific to myelin-forming cells and begins very early in the myelination process in order to function in the early development of axons in the central nervous system. The expression continues to be relatively high even in mature animals, however, suggesting that it is associated with not only formation but maintenance as well. [5]

Research through knockout mice, or mice with the MAG gene removed, has shown that this glycoprotein serves heavily in the formation of myelin but also show that early development of the peripheral nervous system is relatively normal even without the presence of MAG. The knockout mice generally show many motor deficits, however, as they age caused by the degeneration of the myelinated axons further suggesting the need for these glycoproteins in maintenance of the sheaths. [5]

While it is still unclear as to the exact mechanism or pathway by which MAG affects myelination, studies suggest that MAG serves in a receptor role to begin a signaling cascade begun by activation from an external source. MAG has also been shown to bind as a ligand to a receptor on the axonal surface which suggests that the external stimulus activating the creation of myelin comes from the nerve cell or cells that these glycoproteins are bound to. [5]

MAG antibodies

Antibodies are created by the body that can then attack and disrupt the function of myelin associated glycoproteins. These antibodies have been found to bind to the external domain of the glycoproteins and inhibit any other signaling to occur. As these proteins are important in various signal cascades that eventually lead to the Schwann cells creating myelin, these antibodies basically halt myelin creation leading to the neuropathy. There is still, however, much debate as to the actual cause for these antibodies to be created. There has been some research to suggest that these antibodies are linked to various forms of amyloidosis as patients with amyloidosis experience elevated anti-MAG antibodies usually leading to a form of neuropathy. This does not, however, provide any evidence as to the mechanisms behind the creation of the antibodies. [1] [5] [6]

Symptoms and signs

Common

People with this disease have shown many sensory and muscular symptoms. Most patients have a sensory ataxia, or sensory loss in various extremities, along with mild to moderate muscle weakness, usually starting in the toes and fingers and moving inward. Most patients also present a mild to moderate tremor in the extremities which increases as the disease progresses. [1]

Severe

More severe symptoms occur after the disease progresses and there is much more damage to the myelin sheaths in the peripheral nervous system. These can present as debilitating tremors that prevent patients from doing normal tasks, complete sensory loss on limbs, and, in some cases, extensive muscle atrophy. [7]

Diagnosis

Detection of this type of neuropathy has concentrated mostly on detecting presence of antibodies because the antibodies are the main cause for the disease. Anti-MAG antibodies can be readily detected in a patient's sera using various types of assays, but mainly an ELISA has been shown to be most effective. [1] [8] There are also various biological indicators, such as elevated cerebral spinal fluid proteins and elevated IgM monoclonal levels. These can also be tested either by drawing serum from a patient or by drawing spinal fluid from a spinal tap and testing using an assay or blot. [1]

Treatments

Drug and therapeutic treatments exist in order to battle this disease; though many have proven ineffective.[ citation needed ]

Immunotherapy and chemotherapy

While immunotherapy works for some patients in relieving minor symptoms, overall most conventional therapies using steroids, immunosuppressants, chemotherapy, and intravenous immunoglobulin therapies have not helped most patients. This has created a need for newer and more novel therapies to be developed. [1] [9]

Chlorambucil and prednisone

Chlorambucil is a chemotherapy drug normally used to treat leukemia as it is often used as an immunosuppressant drug, and prednisone is a steroid that has also been found to be particularly effective as an immunosuppressant. This combination of drugs has minimal to no benefits in most patients, but a small number do see small improvements such as decreased tremors. This combination has not been very effective in more severe cases, though, and is not considered a long term therapy. [1]

Cyclophosphamide

Cyclophosphamide is a drug often used in the treatment of lymphomas and works by slowing or stopping cell growth. It also works as an immunosuppressant by decreasing the body's immune response to various diseases and conditions. This drug has been found to make significant improvements in people with anti-MAG neuropathy by relieving sensory loss and helping to improve quality of life in a few short months. There is, however, a risk of cancer because of this treatment and is therefore not used on a regular basis. [1]

Fludarabine

Fludarabine is a drug normally used to treat hematological malignancies and acts as an immunosuppressant. It has been shown to significantly improve conditions in neuropathy patients, but because of the lack of studies it is not used regularly. There is also a danger of potential toxicity as the treatment takes a year to stabilize the patient. [1]

Intravenous immunoglobulin

Intravenous immunoglobulin is a blood product administered by IV. It is used to treat various immune deficiencies and autoimmune diseases. While this has been shown to be effective on various types of disorders, there have been no studies that show promise in this technique treating anti-MAG neuropathies.[ citation needed ]

Most promising drug: Rituximab

Rituximab is considered to be one of the most promising drugs in the treatment of anti-MAG peripheral neuropathy. This drug is an antibody against a protein which is primarily found on the surface of B cells which, when attached, destroys the B cells. This drug has been used as a treatment in many autoimmune diseases as well as lymphomas and transplant rejection. Because of its ability to suppress the immune system, it has been used to treat anti-MAG neuropathy in the hopes that it will destroy cells that would target necessary glycoproteins on the Schwann cells. Studies in patients has shown that most patients experience marked increase in sensory and motor abilities within the first few months of therapy. [1] There are, however, long term studies that have shown that treatment with rituximab can create many immune problems. As with most immunosuppressant drugs, there is a risk of other infections and diseases that are normally easily fought off by the immune system will be allowed take a foothold. Studies have shown that after long term treatment, patients experience many of these problems as well as a decline in their neuropathy. This has led to further studies being conducted on the drug's safety profile and overall effectiveness as a treatment. [10] [11]

Unfortunately, more recent studies have concluded that "rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy." [12]

Current research

Current research has focused mostly on determining treatment options. This has been studied through clinical trials with drugs listed previously or through new therapy techniques that delay loss in function. Most drugs being studied are immunosuppressants that can attack the antibodies or other aspects in the hope of preventing damage to the Schwann cells. This will, ideally, prevent the loss of myelination on peripheral nerve fibers. [13]

Related Research Articles

<span class="mw-page-title-main">Charcot–Marie–Tooth disease</span> Neuromuscular disease

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).

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

In vertebrates, most neuronal cell axons are encased in myelin. Simply put, myelin insulates axons and increases the rate at which electrical impulses are passed along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon in segments: in general, each axon is encased in multiple long myelin sheaths separated by short gaps called nodes of Ranvier.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Peripheral neuropathy</span> Nervous system disease affecting nerves beyond the brain and spinal cord

Peripheral neuropathy, often shortened to neuropathy, is a general term describing damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerves are affected. Neuropathy affecting motor, sensory, or autonomic nerves result in different symptoms. More than one type of nerve may be affected simultaneously. Peripheral neuropathy may be acute or chronic, and may be reversible or permanent.

<span class="mw-page-title-main">Demyelinating disease</span> Any neurological disease in which the myelin sheath of neurons is damaged

A demyelinating disease refers to any disease affecting the nervous system where the myelin sheath surrounding neurons is damaged. This damage disrupts the transmission of signals through the affected nerves, resulting in a decrease in their conduction ability. Consequently, this reduction in conduction can lead to deficiencies in sensation, movement, cognition, or other functions depending on the nerves affected.

<span class="mw-page-title-main">Polyneuropathy</span> Medical condition

Polyneuropathy is damage or disease affecting peripheral nerves in roughly the same areas on both sides of the body, featuring weakness, numbness, and burning pain. It usually begins in the hands and feet and may progress to the arms and legs and sometimes to other parts of the body where it may affect the autonomic nervous system. It may be acute or chronic. A number of different disorders may cause polyneuropathy, including diabetes and some types of Guillain–Barré syndrome.

<span class="mw-page-title-main">Alcoholic polyneuropathy</span> Medical condition

Alcoholic polyneuropathy is a neurological disorder in which peripheral nerves throughout the body malfunction simultaneously. It is defined by axonal degeneration in neurons of both the sensory and motor systems and initially occurs at the distal ends of the longest axons in the body. This nerve damage causes an individual to experience pain and motor weakness, first in the feet and hands and then progressing centrally. Alcoholic polyneuropathy is caused primarily by chronic alcoholism; however, vitamin deficiencies are also known to contribute to its development. This disease typically occurs in chronic alcoholics who have some sort of nutritional deficiency. Treatment may involve nutritional supplementation, pain management, and abstaining from alcohol.

<span class="mw-page-title-main">Neuritis</span> Inflammation of a nerve or generally any part of the nervous system

Neuritis is inflammation of a nerve or the general inflammation of the peripheral nervous system. Inflammation, and frequently concomitant demyelination, cause impaired transmission of neural signals and leads to aberrant nerve function. Neuritis is often conflated with neuropathy, a broad term describing any disease process which affects the peripheral nervous system. However, neuropathies may be due to either inflammatory or non-inflammatory causes, and the term encompasses any form of damage, degeneration, or dysfunction, while neuritis refers specifically to the inflammatory process.

<span class="mw-page-title-main">Chronic inflammatory demyelinating polyneuropathy</span> Medical condition

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired autoimmune disease of the peripheral nervous system characterized by progressive weakness and impaired sensory function in the legs and arms. The disorder is sometimes called chronic relapsing polyneuropathy (CRP) or chronic inflammatory demyelinating polyradiculoneuropathy. CIDP is closely related to Guillain–Barré syndrome and it is considered the chronic counterpart of that acute disease. Its symptoms are also similar to progressive inflammatory neuropathy. It is one of several types of neuropathy.

Sulfatide, also known as 3-O-sulfogalactosylceramide, SM4, or sulfated galactocerebroside, is a class of sulfolipids, specifically a class of sulfoglycolipids, which are glycolipids that contain a sulfate group. Sulfatide is synthesized primarily starting in the endoplasmic reticulum and ending in the Golgi apparatus where ceramide is converted to galactocerebroside and later sulfated to make sulfatide. Of all of the galactolipids that are found in the myelin sheath, one fifth of them are sulfatide. Sulfatide is primarily found on the extracellular leaflet of the myelin plasma membrane produced by the oligodendrocytes in the central nervous system and in the Schwann cells in the peripheral nervous system. However, sulfatide is also present on the extracellular leaflet of the plasma membrane of many cells in eukaryotic organisms.

<span class="mw-page-title-main">Myelin-associated glycoprotein</span> Protein-coding gene in the species Homo sapiens

Myelin-associated glycoprotein is a type 1 transmembrane protein glycoprotein localized in periaxonal Schwann cell and oligodendrocyte membranes, where it plays a role in glial-axonal interactions. MAG is a member of the SIGLEC family of proteins and is a functional ligand of the NOGO-66 receptor, NgR. MAG is believed to be involved in myelination during nerve regeneration in the PNS and is vital for the long-term survival of the myelinated axons following myelinogenesis. In the CNS MAG is one of three main myelin-associated inhibitors of axonal regeneration after injury, making it an important protein for future research on neurogenesis in the CNS.

<span class="mw-page-title-main">Nerve injury</span> Damage to nervous tissue

Nerve injury is an injury to nervous tissue. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, peripheral nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.

Neuroregeneration involves the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

<span class="mw-page-title-main">Myelin protein zero</span> Protein-coding gene in the species Homo sapiens

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.

Nerve tissue is a biological molecule related to the function and maintenance of normal nervous tissue. An example would include, for example, the generation of myelin which insulates and protects nerves. These are typically calcium-binding proteins.

Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system. Typically, both sides of the body are involved, and the initial symptoms are changes in sensation or pain often in the back along with muscle weakness, beginning in the feet and hands, often spreading to the arms and upper body. The symptoms may develop over hours to a few weeks. During the acute phase, the disorder can be life-threatening, with about 15% of people developing weakness of the breathing muscles and, therefore, requiring mechanical ventilation. Some are affected by changes in the function of the autonomic nervous system, which can lead to dangerous abnormalities in heart rate and blood pressure.

Antiganglioside antibodies that react to self-gangliosides are found in autoimmune neuropathies. These antibodies were first found to react with cerebellar cells. These antibodies show highest association with certain forms of Guillain–Barré syndrome.

<span class="mw-page-title-main">GJB1</span> Protein-coding gene in humans

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.

Progressive inflammatory neuropathy is a disease that was identified in a report, released on January 31, 2008, by the Centers for Disease Control and Prevention. The first known outbreak of this neuropathy occurred in southeastern Minnesota in the United States. The disease was reported among pig slaughterhouse workers who appeared at various care facilities in the area reporting similar neurological symptoms. The disease was later identified at pork processing plants in Indiana and Nebraska as well. The condition is characterized by acute paralysis, pain, fatigue, numbness, and weakness, especially in extremities. It was initially believed that workers might have contracted the disease through inhaling aerosols from pig brains blown through a compressed-air hose and that this exposure to pig neural tissue induced an autoimmune response that might have produced their mysterious peripheral neuropathy. These suspicions were confirmed in reports and investigations conducted at the Mayo Clinic in Rochester, Minnesota.

Peripheral mononeuropathy is a nerve related disease where a single nerve, that is used to transport messages from the brain to the peripheral body, is diseased or damaged. Peripheral neuropathy is a general term that indicates any disorder of the peripheral nervous system. The name of the disorder itself can be broken down in order to understand this better; peripheral: in regard to peripheral neuropathy, refers to outside of the brain and spinal cord; neuro: means nerve related; -pathy; means disease. Peripheral mononeuropathy is a disorder that links to Peripheral Neuropathy, as it only effects a single peripheral nerve rather than several damaged or diseased nerves throughout the body. Healthy peripheral nerves are able to “carry messages from the brain and spinal cord to muscles, organs, and other body tissues”.

References

  1. 1 2 3 4 5 6 7 8 9 10 Dalakas, M. C. (2010). "Pathogenesis and Treatment of Anti-MAG Neuropathy". Current Treatment Options in Neurology. 12 (2): 71–83. doi:10.1007/s11940-010-0065-x. PMID   20842571. S2CID   22100604.
  2. ↑ Launay, M.; Delmont, E.; Benaim, C.; Sacconi, S.; Butori, C.; Desnuelle, C. (2009). "Anti-MAG paraproteinemic demyelinating polyneuropathy: A clinical, biological, electrophysiological and anatomopathological descriptive study of a 13-patients' cohort". Revue Neurologique. 165 (12): 1071–1079. doi:10.1016/j.neurol.2009.04.008. PMID   19487003.
  3. ↑ Gajos, A.; Kielis, W.; Szadkowska, I.; Chmielowska, E.; Niewodniczy, A.; Bogucki, A. (2007). "Acquired peripheral neuropathies associated with monoclonal gammopathy". Neurologia I Neurochirurgia Polska. 41 (2): 169–175. PMID   17530580.
  4. 1 2 Neuroscience. (2008). Sunderland (Mass.): Sinauer.
  5. 1 2 3 4 Quarles, R. H. (2007). "Myelin-associated glycoprotein (MAG): past, present and beyond". Journal of Neurochemistry. 100 (6): 1431–1448. doi:10.1111/j.1471-4159.2006.04319.x. PMID   17241126. S2CID   1544418.
  6. ↑ Garces-Sanchez, M.; Dyck, P. J.; Kyle, R. A.; Zeldenrust, S.; Wu, Y.; Ladha, S. S.; et al. (2008). "Antibodies to myelin-associated glycoprotein (anti-MAG) in IgM amyloidosis may influence expression of neuropathy in rare patients". Muscle & Nerve. 37 (4): 490–495. doi:10.1002/mus.20955. PMID   18236455. S2CID   606665.
  7. ↑ Kawagashira, Y.; Kondo, N.; Atsuta, N.; Iijima, M.; Koike, H.; Katsuno, M.; et al. (2010). "IgM MGUS Anti-MAG Neuropathy With Predominant Muscle Weakness and Extensive Muscle Atrophy". Muscle & Nerve. 42 (3): 433–435. doi:10.1002/mus.21741. PMID   20665518. S2CID   8611510.
  8. ↑ Kuijf, M. L.; Eurelings, M.; Tio-Gillen, A. P.; van Doorn, P. A.; den Berg, L. H.; Hooijkaas, H.; et al. (2009). "Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy". Neurology. 73 (9): 688–695. doi:10.1212/wnl.0b013e3181b59a80. PMID   19720975. S2CID   22996467.
  9. ↑ Leger, J. M., Chassande, B., Bombelli, F., Viala, K., Musset, L., & Neil, J. (2009). Polyneuropathy associated with monoclonal gammapathy: treatment perspectives. Bulletin De L Academie Nationale De Médecine, 193(5), 1099-1110.
  10. ↑ Benedetti, L.; Briani, C.; Franciotta, D.; Carpo, M.; Padua, L.; Zara, G.; et al. (2008). "Long-Term Effect of Rituximab in Anti-MAG Polyneuropathy. [Editorial Material]". Neurology. 71 (21): 1742–1744. doi:10.1212/01.wnl.0000335268.70325.33. PMID   19015493. S2CID   28723175.
  11. ↑ Broglio, L.; Lauria, G. (2005). "Worsening after rituximab treatment in anti-MAG neuropathy. [Letter]". Muscle & Nerve. 32 (3): 378–379. doi:10.1002/mus.20386. PMID   15986418. S2CID   30592290.
  12. ↑ Léger, JM; Viala, K; Nicolas, G; Créange, A; Vallat, JM; Pouget, J; Clavelou, P; Vial, C; Steck, A; Musset, L; Marin, B (2013). "Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy". Neurology. 80 (24): 2217–25. doi:10.1212/WNL.0b013e318296e92b. PMC   3721095 . PMID   23667063.
  13. ↑ Lunn, M (2008). "What's new in paraproteinemic demyelinating neuropathy in 2007-2008?". Journal of the Peripheral Nervous System. 13 (4): 264–266. doi:10.1111/j.1529-8027.2008.00191.x. PMID   19192065. S2CID   34972889.
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