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104-431: They are less common than Charcot-Marie-Tooth disease . Eight different clinical entities have been described under hereditary sensory and autonomic neuropathies – all characterized by progressive loss of function that predominantly affects the peripheral sensory nerves . Their incidence has been estimated to be about 1 in 250,000. Hereditary sensory neuropathy type 1 is a condition characterized by nerve abnormalities in

208-451: A bluish appearance of the skin or lips (cyanosis) or fainting. This breath-holding behavior usually stops by age 6. Developmental milestones, such as walking and speech, are usually delayed, although some affected individuals show no signs of developmental delay. Additional signs and symptoms in school-age children include bed wetting, episodes of vomiting, reduced sensitivity to temperature changes and pain, poor balance, abnormal curvature of

312-417: A child's activities to prevent injuries. Inability to provide proper immobilization as a treatment for orthopedic injuries often delays healing; additionally, bracing and invasive orthopedic procedures increase the risk for infection. Methods used to prevent injuries to the lips, buccal mucosa, tongue, and teeth include tooth extraction, and/or filing (smoothing) of the sharp incisal edges of teeth, and/or use of

416-449: A deficient amount of glycyl-tRNA in cells, preventing the elongation phase of protein synthesis . Elongation is a key step in protein production, so when there is a deficiency of glycyl-tRNA, protein synthesis is unable to continue at glycine sites. GARS1 mutations also stall initiation of translation due to a stress response that is induced by glycine addition failure. By stalling elongation and initiation of translation, CMT2D mutations in

520-533: A definitive diagnosis, but not all the genetic markers for CMT are known. CMT is first most noticed when someone develops lower leg weakness, such as foot drop, or foot deformities, including hammertoes and high arches, but signs alone do not lead to diagnosis. Patients must be referred to a physician specialising in neurology or rehabilitation medicine. To see signs of muscle weakness, the neurologist may ask patients to walk on their heels or to move part of their leg against an opposing force. To identify sensory loss,

624-497: A different gene. HSAN2A is caused by mutations in the WNK1 gene, and HSAN2B is caused by mutations in the RETREG1 gene (FAM134B). Although two different genes are involved, the signs and symptoms of HSAN2A and HSAN2B are the same. The WNK1 gene provides instructions for making multiple versions (isoforms) of the WNK1 protein. HSAN2A is caused by mutations that affect a particular isoform called

728-424: A loss of ability to sleep, intermingled with confusional oneiric status, and the emergence of atypical REM sleep from wakefulness. The polysomnogram (PSG) picture of this disease is characterized by an inability to generate physiological sleep (key features are the suppression of the hallmarks of stage 2 non-REM sleep: spindles and K complexes) and by the emergence of REM sleep without atonia . The involvement of

832-598: A loss of muscle atonia. The “subwakefulness” state was characterized by 4–6 Hz theta activity intermingled with fast activity and desynchronized lower voltage theta activity, behaviourally associated with sleep-like somatic and autonomic behavior. The subject was said to have “agrypnia excitata”, which consists of severe total insomnia of long duration associated with decreased vigilance, mental confusion, hallucinations, motor agitation, and complex motor behavior mimicking dreams, and autonomic activation. CNS and autonomic symptoms were caused by impaired corticolimbic control of

936-687: A mouth guard. Skin care with moisturizers can help prevent palmar and plantar hyperkeratosis and cracking and secondary risk of infection; neurotrophic keratitis is best treated with routine care for dry eyes, prevention of corneal infection, and daily observation of the ocular surface. Interventions for behavioral, developmental and motor delays, as well as educational and social support for school-age children and adolescents, are recommended. Prevention of secondary complications: Preventative care includes regular dental examinations and restriction of sweets to prevent dental caries, and early treatment of dental caries and periodontal disease to prevent osteomyelitis of

1040-433: A normal lifespan, albeit with symptoms of HSAN6. DST is involved in maintaining cytoskeleton integrity and intracellular transport systems, each of which are critical to the normal function of the particularly long neurons found in the peripheral nervous system. It's believed that this disrupts the cell's internal autophagy process, in which toxic proteins and other normally-occurring debris are captured and transported to

1144-484: A patient with myokymia (muscle twitching) associated with muscle pain, excessive sweating, and disordered sleep. This rare disorder is characterized by severe insomnia, amounting to no less than complete lack of sleep (agrypnia) for weeks or months in a row, and associated with autonomic alterations consisting of profuse perspiration with characteristic skin miliaria (also known as sweat rash), tachycardia , increased body temperature, and hypertension . Patients display

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1248-530: A patient with Morvan's Syndrome to the hippocampus in a similar pattern of antibodies to known VGKC suggest that these antibodies can also cause CNS dysfunction. Additional antibodies against neuromuscular junction channels and receptors have also been described. Experimental evidence exists that these anti-VGKC antibodies cause nerve hyperexcitability by suppression of voltage gated K+ outward currents, whereas other, yet undefined humoral factors have been implicated in anti-VGKC antibody negative neuromyotonia. It

1352-484: A person's teens or twenties. While the features of this disorder tend to worsen over time, affected individuals have a normal life expectancy if signs and symptoms are properly treated. Type 1 is the most common form among the 5 types of HSAN. Its historical names include mal perforant du pied , ulcero-mutilating neuropathy, hereditary perforating ulcers, familial trophoneurosis, familial syringomyelia, hereditary sensory radicular neuropathy, among others. This type includes

1456-401: A popular disease called Charcot-Marie-Tooth type 2B syndrome (HMSN 2B), which is also referred to as HSAN sub-type 1C. Type 1 is inherited as an autosomal dominant trait. The disease usually starts during early adolescence or adulthood. The disease is characterized by the loss of pain sensation mainly in the distal parts of the lower limbs; that is, in the parts of the legs farther away from

1560-597: A progressive worsening of insomnia and diurnal drowsiness, which promptly disappeared after another two PE sessions. In one case, high dose steroid treatment resulted in a transient improvement, but aggressive immuno-suppressive therapy with cyclophosphamide was necessary to control the disease and result in a dramatic clinical improvement. In another case, the subject was treated with prednisolone (1 mg/kg body weight) with carbamazepine, propranolol , and amitriptyline . After two weeks, improvement with decreased stiffness and spontaneous muscle activity and improved sleep

1664-442: A reduction in the number of sensory neurons; however, the role that WNK1/HSN2 mutations play in that loss is unclear. HSAN2B is caused by mutations in the RETREG1 gene. These mutations may lead to an abnormally short and nonfunctional protein. The RETREG1 protein is found in sensory and autonomic neurons. It is involved in the survival of neurons, particularly those that transmit pain signals, which are called nociceptive neurons. When

1768-481: A remarkable hallucinatory behavior, and peculiar motor disturbances, which Morvan reported under the term “fibrillary chorea” but which are best described in modern terms as neuromyotonic discharges. The association of the disease with thymoma, tumour, autoimmune diseases, and autoantibodies suggests an autoimmune or paraneoplastic aetiology. Besides an immune-mediated etiology , it is also believed to occur in gold , mercury , or manganese poisoning . In one of

1872-444: A secondary injury, as prolonged periods of limited mobility can drastically accelerate symptoms of CMT. Pain due to postural changes, skeletal deformations, muscle fatigue, and cramping is fairly common in people with CMT. It can be mitigated or treated by physical therapies, surgeries, and corrective or assistive devices. Analgesic medications may also be needed if other therapies do not provide relief from pain. Neuropathic pain

1976-409: A short attention span, that require special education classes. By adulthood, affected individuals often have increasing difficulties with balance and walking unaided. Other problems that may appear in adolescence or early adulthood include lung damage due to repeated infections, impaired kidney function, and worsening vision due to the shrinking size (atrophy) of optic nerves, which carry information from

2080-444: A similarly nonspecific finding that indicates a cycle of denervation / reinnervation . Normally, type I and type II muscle fibers show a checkerboard-like random distribution. However, when reinnervation occurs, the group of fibers associated with one nerve are of the same type. The standard for indicating fiber type is histoenzymatic adenosine triphosphatase (ATPase at pH 9.4). Often, the most important goal for patients with CMT

2184-532: A spectrum of neurological disease presenting with symptoms arising peripherally, centrally, or both. Yet, in two cases, oligoclonal bands were absent in the CSF and serum, and CSF immunoglobulin profiles were unremarkable. In one case, a patient was diagnosed with both Morvan's syndrome and pulmonary hyalinizing granulomas (PHG). PHG are rare fibrosing lesions of the lung, which have central whorled deposits of lamellar collagen . How these two diseases relate to one another

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2288-491: A striking similarity to limbic encephalitis (LE). These include the CNS symptoms consisting of insomnia, hallucinations, and disorientation, as well as dementia and psychosis. Both entities can be paraneoplastic and associated with thymoma . Recently, VGKC antibodies were found in patients with LE, strengthening the hypothesis that LE and Morvan's Syndrome may be closely connected. Varying symptoms may be used to determine which of

2392-566: A sweating abnormality. Examinations of the nerve structure and function showed signs of neuronal degeneration such as a marked reduction in the number of myelinated fibers and axonal loss. Sensory neurons lose the ability to transmit signals, while motor neurons has reduced ability to transmit signals. Mutations in the SPTLC1 gene cause hereditary sensory neuropathy type 1. The SPTLC1 gene provides instructions for making one part (subunit) of an enzyme called serine palmitoyltransferase (SPT). The SPT enzyme

2496-514: 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

2600-512: Is a condition that primarily affects the sensory nerve cells (sensory neurons) which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN2. In some affected people, the condition may also cause mild abnormalities of the autonomic nervous system, which controls involuntary body functions such as heart rate, digestion, and breathing. The signs and symptoms of HSAN2 typically begin in infancy or early childhood. The first sign of HSAN2

2704-529: Is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection. Mutations in the DST ( Dystosin ) gene are associated HSAN6. In two separate studies of families with presentations of HSAN6,

2808-433: Is absent, resulting in repeated injuries including: oral self-mutilation (biting of tongue, lips, and buccal mucosa); biting of fingertips; bruising, scarring, and infection of the skin; multiple bone fractures (many of which fail to heal properly); and recurrent joint dislocations resulting in joint deformity. Sense of touch, vibration, and position are normal. Anhidrosis predisposes to recurrent febrile episodes that are often

2912-460: Is affected predominantly and deep tendon reflexes are reduced. Autoamputation of the distal phalanges is common and so is neuropathic joint degeneration. The NCV shows reduced or absent sensory nerve action potentials and nerve biopsy shows total loss of myelinated fibers and reduced numbers of unmyelinated fibers. It is inherited as an autosomal recessive condition. There are two types of HSAN2, called HSAN2A and HSAN2B, each caused by mutations in

3016-621: Is also present in oligodendrocytes , demyelination can appear in the CNS as well. Schwann cells create the myelin sheath by wrapping their plasma membranes around the axon. These Schwann cells work together with neurons and fibroblasts to create a functional nerve. Schwann cells and neurons exchange molecular signals by way of gap junctions that regulate survival and differentiation Demyelinating Schwann cells cause abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction. The myelin sheath allows nerve cells to conduct signals faster. When

3120-742: Is believed that antibodies to the Shaker-type K+ channels (the Kv1 family) are the type of potassium channel most strongly associated with acquired neuromyotonia and Morvan's Syndrome. Whether VGKC antibodies play a pathogenic role in the encephalopathy as they do in the peripheral nervous system is as yet unclear. It has been suggested that the VGKC antibodies may cross the blood–brain barrier and act centrally, binding predominantly to thalamic and striatal neurons causing encephalopathic and autonomic features. The symptoms of Morvan's Syndrome have been noted to bear

3224-459: Is common in people with HSAN2, typically by biting the tongue, lips, or fingers. These injuries may lead to spontaneous amputation of the affected areas. Affected individuals often have injuries and fractures in their hands, feet, limbs, and joints that go untreated because of the inability to feel pain. Repeated injury can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed. The effects of HSAN2 on

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3328-525: Is considered to be targetable for CMT2D treatment. CMT can also be produced by X-linked mutations, in which case it is called X-linked CMT (CMTX). In CMTX, mutated connexons create nonfunctional gap junctions that interrupt molecular exchange and signal transport. The mutation can appear in the GJB1 gene coding for the connexin 32 protein, a gap junction protein expressed in Schwann cells. Because this protein

3432-556: Is due to abnormal functioning of small, unmyelinated nerve fibers and portions of the spinal cord that control responses to pain and temperature as well as other involuntary or automatic body processes. Sweating is almost completely absent with this disorder. Intellectual disability is usually present. Type 4, congenital insensitivity to pain with anhidrosis (CIPA), is an autosomal recessive condition and affected infants present with episodes of hyperthermia unrelated to environmental temperature, anhidrosis and insensitivity to pain. Palmar skin

3536-543: Is found in a variety of cells throughout the body, including brain cells. Nearly all individuals with familial dysautonomia have two copies of the same IKBKAP gene mutation in each cell. This mutation can disrupt how information in the IKBKAP gene is pieced together to make a blueprint for the production of IKAP protein. As a result of this error, a reduced amount of normal IKAP protein is produced. This mutation behaves inconsistently, however. Some cells produce near normal amounts of

3640-447: Is frequent. Intelligence remains normal. Many patients die in infancy and childhood. Lack of flare with intradermal histamine is seen. Histopathology of peripheral nerve shows reduced number of myelinated and non-myelinated axons. The catecholamine endings are absent. Mutations in the IKBKAP gene cause familial dysautonomia. The IKBKAP gene provides instructions for making a protein called IKK complex-associated protein (IKAP). This protein

3744-460: Is important in the development and survival of nerve cells (neurons), including sensory neurons. The NGFβ protein functions by attaching (binding) to its receptors, which are found on the surface of neurons. Binding of the NGFβ protein to its receptor transmits signals to the cell to grow and to mature and take on specialized functions (differentiate). This binding also blocks signals in the cell that initiate

3848-600: Is integral to protein translation and attaches glycine to its cognate tRNA. Many different mutations have been found in CMT2D patients, and it remains unclear how mutations in GARS1 cause CMT2D. However, it is thought that mutant glycyl-tRNA synthetase (GlyRS) interferes with transmembrane receptors, causing motor disease, and that mutations in the gene could disrupt the ability of GlyRS to interact with its cognate RNA, disrupting protein production. The GARS1 mutations present in CMT2D cause

3952-448: Is involved in making certain fats called sphingolipids. Sphingolipids are important components of cell membranes and play a role in many cell functions. SPTLC1 gene mutations reduce the amount of SPTLC1 subunit that is produced and result in an SPT enzyme with decreased function. A lack of functional SPT enzyme leads to a decrease in sphingolipid production and a harmful buildup of certain byproducts. Sphingolipids are found in myelin, which

4056-544: 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). Ankyrin : Long QT syndrome 4 Morvan%27s disease Morvan's syndrome is a rare, life-threatening autoimmune disease named after the nineteenth century French physician Augustin Marie Morvan . "La chorée fibrillaire"

4160-554: Is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity vary from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When neuropathic pain is present as a symptom of CMT, it is comparable to that seen in other peripheral neuropathies , as well as postherpetic neuralgia and complex regional pain syndrome , among other diseases. Atypical presentations of CMT can also lead to leg muscles, specifically

4264-523: Is still unclear. Thymoma, prostate adenoma, and in situ carcinoma of the sigmoid colon have also been found in patients with Morvan's Syndrome. Antibodies against voltage-gated potassium channels (VGKC), which are detectable in about 40% of patients with acquired neuromytonia, have been implicated in Morvan's pathophysiology . Raised serum levels of antibodies to VGKCs have been reported in three patients with Morvan's Syndrome. Binding of serum from

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4368-530: Is the covering that protects nerves and promotes the efficient transmission of nerve impulses. A decrease in sphingolipids disrupts the formation of myelin, causing nerve cells to become less efficient and eventually die. When sphingolipids are not made, an accumulation of toxic byproducts can also lead to nerve cell death. This gradual destruction of nerve cells results in loss of sensation and muscle weakness in people with hereditary sensory neuropathy type 1. Hereditary sensory and autonomic neuropathy type II (HSAN2)

4472-594: Is thickened and charcot joints are commonly present. NCV shows motor and sensory nerve action potentials to be normal. The histopathology of peripheral nerve biopsy reveals absent small unmyelinated fibers and mitochondria are abnormally enlarged. Treatment of manifestations: Treatment is supportive and is best provided by specialists in pediatrics, orthopedics, dentistry, ophthalmology, and dermatology. For anhidrosis: Monitoring body temperature helps to institute timely measures to prevent/manage hyperthermia or hypothermia. For insensitivity to pain: Modify as much as reasonable

4576-425: Is thought to be caused by aberrant gain-of-function missense mutations . The GARS1 gene is a protein-coding gene responsible for the encoding of glycyl-tRNA synthetase (GlyRS). Glycyl-tRNA synthetase is a class II aminoacyl-tRNA synthetase and acts as the catalyst for the synthesis of glycyl-tRNA by covalently bonding amino acids with their corresponding cognate tRNAs for protein translation . Glycyl-tRNA synthetase

4680-407: Is to maintain movement, muscle strength, and flexibility. Therefore, an interprofessional team approach with occupational therapy (OT), physical therapy (PT), orthotist, podiatrist, and or orthopedic surgeon is recommended. Appropriate footwear is also very important for people with CMT, but they often have difficulty finding well-fitting shoes because of their high-arched feet and hammertoes. Due to

4784-436: Is usually numbness in the hands and feet. Soon after, affected individuals lose the ability to feel pain or sense hot and cold. People with HSAN2 often develop open sores (ulcers) on their hands and feet. Because affected individuals cannot feel the pain of these sores, they may not seek treatment right away. Without treatment, the ulcers can become infected and may lead to amputation of the affected area. Unintentional self-injury

4888-407: The blood serum . Marked changes in circadian serum levels of neurohormones and increased levels of peripheral neurotransmitters were also observed. The absence of morphological alterations of the brain pathology, the suggestion of diffusion of IgG into the thalamus and striatum, more marked than in the cortex (consistent with effects on the thalamolimbic system) the oligoclonal bands in the CSF and

4992-399: The laryngeal muscles . Laryngeal spasm possibly resulting from neuromyotonia has been described previously, and this highlights that, in patients with unexplained laryngospasm , neuromytonia should be added to the list of differential diagnoses. Studies have shown subtly decreased metabolism on positron emission tomography (PET) and single photon emission computed tomography (SPECT) in

5096-484: The neuromuscular junction (NMJ). The neuromuscular junction is abnormal in CMT2D mice, with subjects showing neuromuscular junction degeneration in hind muscles. The dorsal root ganglia (DRG) are also affected via aberrant sensory neuron fate, meaning that sensory neuron cell fates are abnormally determined. CMT2D mice have fewer proprioceptive and mechanosensitive neurons, but have more nociceptive neurons, possibly due to mutant GlyRS aberrantly interacting with

5200-435: The soleus muscle , forms the triceps surae muscles (distal calf muscles), occurs causing the known "stork leg deformity". In most cases, ankle-foot orthoses that have functional elements for the foot lifting and adjustable control of the lowering of the forefoot make sense. Weak calf muscles lead to insufficient activation of the forefoot lever. This leads to an additional increasing uncertainty when standing and walking. If

5304-489: The thalamus and connected limbic structures in the pathology indicate the prominent role that the limbic thalamus plays in the pathophysiology of sleep. In a case documented in 1974, PSG findings documented the sustained absence of all sleep rhythms for up to a period of 4 months. Electroencephalography (EEG) in one case was dominated by " wakefulness " and “subwakefulness” states alternating or intermingled with short (< 1 min) atypical REM sleep phases, characterized by

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5408-407: The Briton Howard Henry Tooth (1856–1925). There is no known cure. Care focuses on maintaining function. CMT was previously classified as a subtype of muscular dystrophy . Symptoms of CMT usually begin in early childhood or early adulthood but can begin later. Some people do not experience symptoms until their early 30s or 40s. Usually, the initial symptom is foot drop or high arches early in

5512-403: The DST gene was found to be mutated, in one case with a truncating mutation, and in the other a non-sense or missense mutation. In the latter case, the authors proposed that homozygous truncating mutations result in a severe form of HSAN6, with congenital defects and early lethality, while heterozygosity for a truncating or missense mutation maintains enough dystosin expression and function to allow

5616-453: The English literature. With only a limited number of reported cases, the complete spectrum of the central nervous system (CNS) symptomatology has not been well established. The natural history of Morvan's is highly variable. Two cases have been reported to remit spontaneously. Others have required a combination of plasmapheresis and long term immunosuppression, although in one of these cases

5720-587: The GARS1 gene cause translational repression, meaning that overall translation is inhibited. GARS1-associated axonal neuropathy is progressive , meaning that it worsens over time. Unknown mechanisms are thought to cause the chronic neurodegeneration resulting from the aberrant GlyRS; however, one theory on the mechanism for the disease is VEGF deficiency. Mutant GlysRS interferes with neuronal transmembrane receptors, including neuropilin 1 (Nrp1) and vascular endothelial growth factor (VEGF) , causing neuropathy. GARS-CMT2D mutations alter GlyRS and allow it to bind to

5824-500: The Nrp1 receptor, interfering with the normal binding of Nrp1 to VEGF. While enhanced expression of VEGF improves motor function, reduced expression of Nrp1 worsens CMT2D; because Nrp1 binds to mutant GlyRS in mutant GARS1-CMT2D individuals, Nrp1 expression is reduced, in turn worsening motor function. Mice with deficient VEGF demonstrate motor neuron disease over time. Thus, the VEGF/Nrp1 pathway

5928-417: The RETREG1 protein is nonfunctional, neurons die by a process of self-destruction called apoptosis. The loss of neurons leads to the inability to feel pain, temperature, and touch sensations and to the impairment of the autonomic nervous system seen in people with HSAN2. Familial dysautonomia is a genetic disorder that affects the development and survival of certain nerve cells. The disorder disturbs cells in

6032-512: The WNK1/HSN2 protein. This protein is found in the cells of the nervous system, including nerve cells that transmit the sensations of pain, temperature, and touch (sensory neurons). The mutations involved in HSAN2A result in an abnormally short WNK1/HSN2 protein. Although the function of this protein is unknown, it is likely that the abnormally short version cannot function properly. People with HSAN2A have

6136-405: The ability to feel pain, heat, and cold. Deep pain perception, the feeling of pain from injuries to bones, ligaments, or muscles, is especially affected in people with HSAN5. Because of the inability to feel deep pain, affected individuals suffer repeated severe injuries such as bone fractures and joint injuries that go unnoticed. Repeated trauma can lead to a condition called Charcot joints, in which

6240-514: The amelioration after PE all strongly support an antibody-mediated basis for the condition. Raised CSF IgG concentrations and oligoclonal bands have been reported in patients with psychosis. Anti- acetylcholine receptors (anti-AChR) antibodies have also been detected in patients with thymoma, but without clinical manifestations of myasthenia gravis . There have also been reports of non-paraneoplastic limbic encephalitis associated with raised serum VGKC suggesting that these antibodies may give rise to

6344-446: The autonomic nervous system are more variable. Some infants with HSAN2 have trouble sucking, which makes it difficult for them to eat. People with HSAN2 may experience episodes in which breathing slows or stops for short periods (apnea); digestive problems such as the backflow of stomach acids into the esophagus (gastroesophageal reflux); or slow eye blink or gag reflexes. Affected individuals may also have weak deep tendon reflexes, such as

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6448-795: The autonomic nervous system, which controls involuntary actions such as digestion, breathing, production of tears, and the regulation of blood pressure and body temperature. It also affects the sensory nervous system, which controls activities related to the senses, such as taste and the perception of pain, heat, and cold. Familial dysautonomia is also called hereditary sensory and autonomic neuropathy, type III. Problems related to this disorder first appear during infancy. Early signs and symptoms include poor muscle tone (hypotonia), feeding difficulties, poor growth, lack of tears, frequent lung infections, and difficulty maintaining body temperature. Older infants and young children with familial dysautonomia may hold their breath for prolonged periods of time, which may cause

6552-407: The axon towards the synapses . This prevents the synapses from functioning. CMT is a heterogeneous disease and the mutations linked to it may occur in many different genes. Based on the affected gene, CMT is categorized into several types and subtypes. CMT2 variants are typically referred to as axonal neuropathies due to the axonal degeneration observed. CMT2 variants are a result of damage to

6656-476: The bones and tissue surrounding joints are destroyed. Type 5, congenital insensitivity to pain with partial anhidrosis, also manifests with congenital insensitivity to pain & anhidrosis. There is a selective absence of small myelinated fibers differentiating it from Type IV (CIPA). Mutations in the NGF gene cause HSAN5. The NGF gene provides instructions for making a protein called nerve growth factor beta (NGFβ) that

6760-478: The calf muscles are weak, an orthosis should therefore be equipped with functional elements to activate the forefoot lever. An orthotic joint with an adjustable dynamic dorsiflexion stop with a strong spring in combination with a lower leg shell in front of the shin is recommended for this. Such orthoses help to control foot drop, and instability of the foot and ankle and offer the patient a better sense of balance when standing and walking without restricting mobility and

6864-448: The calves, enlarging. This hypertrophic type of CMT is not caused by the muscles enlarging directly, but by pseudohypertrophy of the legs as fatty tissue enters the leg muscles. Charcot–Marie–Tooth disease is caused by genetic mutations that cause defects in neuronal proteins. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. Most mutations in CMT affect

6968-565: The cell center for recycling or destruction. In neurons, autophagosomes , are generated at the ends of the neuron to carry the discardable material, and they are then transported toward center. With the intracellular transport system disrupted by a mutation in DST, the autophagosomes are unable to carry away the debris, which builds up at the ends of the neuron, leading to damage. https://www.jsaapd.com/abstractArticleContentBrowse/JSAAPD/1/4/3/26394/abstractArticle/Article Charcot-Marie-Tooth disease Charcot–Marie–Tooth disease ( CMT )

7072-460: The center of the body. Since the affected individuals cannot feel pain, minor injuries in this area may not be immediately recognized and may develop into extensive ulcerations. Once infection occurs, further complications such as progressive destruction of underlying bones may follow and may necessitate amputation. In rare cases, the disease is accompanied with nerve deafness and muscle wasting. Autonomic disturbance, if present, appears as anhidrosis ,

7176-425: The course of the disease. This can be accompanied by hammertoe , where the toes are always curled. Wasting atrophy of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted champagne bottle" appearance. Weakness in the hands and forearms occurs in many people as the disease progresses. High-arched feet ( pes cavus ) or flat-arched feet ( pes planus ) are classically associated with

7280-578: The degradation of sensory axons) are observed along with motor deficits; otherwise, distal hereditary motor neuropathy type V is diagnosed. It is unknown why sensory involvement is so varied between GARS1 neuropathy patients. Symptoms of CMT2D include foot deformity, muscle weakness and cramping, compromised reflexes, loss of sensation, and muscle atrophy, and are similar to the symptoms of both CMT1 and CMT2 variants. Symptoms and severity vary from patient to patient. Mice are often used to model CMT2D, and typically demonstrate aberrant neuromuscular function at

7384-659: The disease can vary. Involuntary grinding of teeth and squinting are prevalent and often go unnoticed by the person affected. Breathing can be affected in some, as can hearing, vision, and neck and shoulder muscles. Scoliosis is common, causing hunching and loss of height. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT, as can difficulty chewing, swallowing, and speaking (due to atrophy of vocal cords ). A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as severe emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from

7488-483: The disease. The mother and father each had one normal and one mutant copy of this gene and had mild or no symptoms. The offspring who inherited two mutant genes presented fully with the disease. The constant cycle of demyelination and remyelination , which occurs in CMT, can lead to the formation of layers of myelin around some nerves, termed an "onion bulb". These are also seen in chronic inflammatory demyelinating polyneuropathy . Muscles show fiber type grouping,

7592-556: The disorder. Loss of touch sensation in the feet, ankles, and legs as well as in the hands, wrists, and arms occurs with various types of the disease. Early- and late-onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates. Sensory and proprioceptive nerves in the hands and feet are often damaged, while unmyelinated pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping. Symptoms and progression of

7696-409: The dynamics of the ankle joint. Studies confirm the positive effect of orthoses with adjustable functional elements in patients with paralysis of these muscle groups. It is of great advantage if the resistances of the two functional elements can be set separately from one another in the two directions of movement, dorsiflexion and plantar flexion . The severity of symptoms varies widely even for

7800-403: The extracellular region of tropomyosin receptor kinase, or Trk, receptors. Trk receptors are crucial to the survival and development of sensory neurons; when disrupted, nerve development and survival is disrupted as well, possibly leading to the abnormal sensory neuron counts observed in CMT2D mice. CMT2D is a result of autosomal dominant mutations in the human GARS1 gene located at 7p14.3 and

7904-617: The eyes to the brain. Type 3, familial dysautonomia (FD) or Riley-Day syndrome, is an autosomal recessive disorder seen predominantly in Jews of eastern European descent. Patients present with sensory and autonomic disturbances. Newborns have absent or weak suck reflex, hypotonia and hypothermia. Delayed physical development, poor temperature and motor incoordination are seen in early childhood. Other features include reduced or absent tears, depressed deep tendon reflexes, absent corneal reflex, postural hypotension and relative indifference to pain. Scoliosis

8008-410: The few reported cases, the subject presented with muscle weakness and fatigue, muscle twitching, excessive sweating and salivation, small joint pain, itching and weight loss. The subject also developed confusional episodes with spatial and temporal disorientation, visual and auditory hallucinations, complex behavior during sleep and progressive nocturnal insomnia associated with diurnal drowsiness. There

8112-514: The genetic cause of a particular patient's disease was precisely determined by sequencing the whole genome of an affected individual. This was done by the scientists employed by the Charcot Marie Tooth Association (CMTA). Two mutations were identified in a gene, SH3TC2 , known to cause CMT. Researchers then compared the affected patient's genome to the genomes of the patient's mother, father, and seven siblings with and without

8216-438: The initial manifestation of CIPA. Hypothermia in cold environments also occurs. Intellectual disability of varying degree is observed in most affected individuals; hyperactivity and emotional lability are common. Hereditary sensory neuropathy type IV (HSN4) is a rare genetic disorder characterized by the loss of sensation (sensory loss), especially in the feet and legs and, less severely, in the hands and forearms. The sensory loss

8320-420: The lack of good sensory reception in the feet, CMT patients may also need to see a podiatrist for assistance in trimming nails or removing calluses that develop on the pads of the feet. Lastly, patients can also decide to have surgery performed by a podiatrist or an orthopedic surgeon. Surgery may help to stabilize the patients' feet or correct progressive problems. These procedures include straightening and pinning

8424-435: The left inferior frontal and left temporal lobes . and or basal ganglia hypermetabolism. Ancillary laboratory tests including MRI and brain biopsy have confirmed temporal lobe involvement. Cranial MRI shows increased signal in the hippocampus . Cerebral spinal fluid (CSF) shows normal protein, glucose , white blood cell , and immunoglobulin G (IgG) levels, but there are weak oligoclonal bands , which are absent in

8528-594: The legs and feet (peripheral neuropathy). Many people with this condition have tingling, weakness, and a reduced ability to feel pain and sense hot and cold. Some affected individuals do not lose sensation, but instead feel shooting pains in their legs and feet. As the disorder progresses, the sensory abnormalities can affect the hands, arms, shoulders, and abdomen. Affected individuals may also experience muscle wasting and weakness as they get older, but this varies widely within families. Affected individuals typically get open sores (ulcers) on their feet or hands or infections of

8632-518: The limbs, absence of tendon reflexes in the lower limbs and diffuse erythema especially on the trunk with scratching lesions of the skin. Compulsive behaviours, stereotypies and reduplicative paramnesias can be part of the CNS spectrum. In all of the reported cases, the need for sleep was severely reduced and in some cases not necessary. The duration of sleep in one case decreased to about 2–4 hours per 24-hour period. Clinical features pertaining to insomnia include daytime drowsiness associated with

8736-621: The mandible. During and following surgical procedures, potential complications to identify and manage promptly include hyper- or hypothermia and inadequate sedation, which may trigger unexpected movement and result in secondary injuries. Hereditary sensory and autonomic neuropathy type V (HSAN5) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN5. The signs and symptoms of HSAN5 appear early, usually at birth or during infancy. People with HSAN5 lose

8840-456: The muscles exhibiting twitching include the bilateral gastrocnemii , quadriceps femoris , biceps brachii , and right masseter . In vivo electrophysiological studies suggest at least some dysfunction of the muscle cell membrane . In the examined muscles, no abnormal insertional activity or fibrillation potentials were noted. Nerve conduction studies were normal. Breathing difficulties can occur, resulting from neuromyotonic activity of

8944-422: The myelin sheath is damaged, however, nerve signals are slower. This can be measured by a common neurological test, electromyography . When the axon is damaged, the result is a reduced compound muscle action potential . CMT can be diagnosed through three different forms of tests: measurement of the speed of nerve impulses ( nerve conduction studies ), a biopsy of the nerve, and DNA testing. DNA testing can give

9048-449: The myelin sheath, but some affect the axon. Chromosome 17 The most common cause of CMT (70–80% of the cases) is the duplication of a large region on the short arm of chromosome 17 that includes the gene PMP22 . Chromosome 1 Some mutations affect the gene MFN2 , on chromosome 1 , which codes for a mitochondrial protein. Mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down

9152-445: The nerve axons , rather than damage to the myelin sheath (as is the case with CMT1). Damaged axons cause slowed transmission of signals to the muscles and brain, causing symptoms including muscle atrophy, weakness, decreased sensitivity, and foot deformity. Symptoms of CMT2 variants typically appear between the ages of 5 and 25. CMT2D is one of 31 CMT2 variants, and is only diagnosed if sensory deficits (such as loss of sensation due to

9256-407: The neurologist tests for deep-tendon reflexes, such as the knee jerk, which are reduced or absent in CMT. The doctor may also ask about the patient's family history since CMT is hereditary. The lack of family history does not rule out CMT but is helpful to rule out other causes of neuropathy, such as diabetes or exposure to certain chemicals or drugs. In 2010, CMT was one of the first diseases where

9360-446: The physical condition of the affected individuals. If the muscles of the lower extremities are weak, it makes sense to prescribe custom-fabricated orthotics . Depending on which muscle groups are affected, the correct orthoses with appropriate functional elements should be prescribed. A weakness of the tibialis anterior muscle , which lifts the feet, is usually accompanied by an atrophy of the gastrocnemius muscle which, together with

9464-500: The process of self-destruction (apoptosis). Additionally, NGFβ signaling plays a role in pain sensation. Mutation of the NGF gene leads to the production of a protein that cannot bind to the receptor and does not transmit signals properly. Without the proper signaling, sensory neurons die and pain sensation is altered, resulting in the inability of people with HSAN5 to feel pain. Hereditary sensory and autonomic neuropathy type 6 (HSAN6), also known as familial dysautonomia with contractures,

9568-556: The protein, and other cells—particularly brain cells—have very little of the protein. Critical activities in brain cells are probably disrupted by reduced amounts or the absence of IKAP protein, leading to the signs and symptoms of familial dysautonomia. Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN IV), is characterized by insensitivity to pain, anhidrosis (the inability to sweat), and intellectual disability. The ability to sense all pain (including visceral pain)

9672-513: The reflex being tested when a doctor taps the knee with a hammer. Some people with HSAN2 experience a diminished sense of taste due to the loss of a type of taste bud on the tip of the tongue called lingual fungiform papillae. Type 2, congenital sensory neuropathy (also historically known as Morvan's disease ), is characterized by onset of symptoms in early infancy or childhood. Upper & lower extremities are affected with chronic ulcerations and multiple injuries to fingers and feet. Pain sensation

9776-405: The same type of CMT. Cases of monozygotic twins with varying levels of disease severity have been reported, showing that identical genotypes are associated with different levels of severity (see penetrance ). Some patients can live a normal life and are almost or entirely asymptomatic. A 2007 review stated that "life expectancy is not known to be altered in the majority of cases." The disease

9880-526: The soft tissue of the fingertips (whitlows) that are slow to heal. Because affected individuals cannot feel the pain of these sores, they may not seek treatment right away. Without treatment, the ulcers can become infected and may require amputation of the surrounding area. Albeit rarely, people with hereditary sensory neuropathy type 1 may develop hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). The signs and symptoms of hereditary sensory neuropathy type 1 typically appear during

9984-520: The spine (scoliosis), poor bone quality and increased risk of bone fractures, and kidney and heart problems. Affected individuals also have poor regulation of blood pressure. They may experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting. They can also have episodes of high blood pressure when nervous or excited, or during vomiting incidents. About one-third of children with familial dysautonomia have learning disabilities, such as

10088-563: The subcortical structures regulating the sleep-wake and autonomic functions. Neuromyotonia refers to muscle twitching and cramping at rest that is exacerbated with exercise. It is caused by sustained or repetitive spontaneous muscle activity of peripheral nerve origin. Myokymia, or spontaneous rippling and twitching movements of muscles, is a visible component of neuromyotonia. Electromyography (EMG) discloses spontaneous, repetitive motor unit or single fiber discharges firing in irregular rhythmic bursts at high intraburst frequencies. Some of

10192-401: The subject failed to improve the spontaneous muscle activity. Plasma Exchange (PE) was initiated, and after the third such session, the itching, sweating, mental disturbances, and complex nocturnal behavior improved and these symptoms completely disappeared after the sixth session, with improvement in insomnia and reduced muscle twitching. However, one month after the sixth PE session, there was

10296-593: The toes, lowering the arch, and sometimes, fusing the ankle joint to provide stability. CMT patients must take extra care to avoid falling as fractures take longer to heal in someone with an underlying disease process. Additionally, the resulting inactivity may cause the CMT to worsen. The Charcot–Marie–Tooth Association classifies the chemotherapy drug vincristine as a "definite high risk" and states, "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms." Several corrective surgical procedures can be done to improve

10400-624: The two diseases the subject has. Amnesia, seizures, and mesial temporal lobe structural abnormalities are features of LE, whereas myokymia, hyperhydrosis, and insomnia favor Morvan's Syndrome. In most of the reported cases, the treatment options were very similar. Plasmapheresis alone or in combination with steroids, sometimes also with thymectomy and azathioprine , have been the most frequently used therapeutic approach in treating Morvan's Syndrome. However, this does not always work, as failed response to steroids and to subsequently added plasmapheresis have been reported. Intravenous immunoglobulin

10504-452: Was also severe constipation, urinary incontinence, and excessive lacrimation . When left alone, the subject would slowly lapse into a stuporous state with dreamlike episodes characterized by complex and quasi-purposeful gestures and movements (enacted dreams). Marked hyperhidrosis and excessive salivation were evident. Neurological examination disclosed diffuse muscle twitching and spontaneous and reflex myoclonus , slight muscle atrophy in

10608-457: Was effective in one case. In one case, the dramatic response to high-dose oral prednisolone together with pulse methylprednisolone with almost complete disappearance of the symptoms within a short period should induce consideration of corticosteroids. In another case, the subject was treated with haloperidol (6 mg/day) with some improvement in the psychomotor agitation and hallucinations, but even high doses of carbamazepine given to

10712-404: Was first coined by Morvan in 1890 when describing patients with multiple, irregular contractions of the long muscles , cramping , weakness, pruritus , hyperhidrosis , insomnia and delirium . It normally presents with a slow insidious onset over months to years. Approximately 90% of cases spontaneously go into remission, while the other 10% of cases lead to death. In 1890, Morvan described

10816-494: Was observed. After another 7–10 days, the abnormal sleep behavior disappeared completely. In another case, symptomatic improvement with plasmapheresis, thymectomy, and chronic immunosuppression provide further support for an autoimmune or paraneoplastic basis. Although thymectomy is believed to be a key element in the proposed treatment, there is a reported case of Morvan's Syndrome presenting itself post-thymectomy. There are only about 14 reported cases of Morvan's syndrome in

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