Myotonia Congenita (MC)
| Congenital myotonia (also myotonia congenita) is a genetic, neuromuscular channelopathy that affects muscles used for movement (skeletal muscles). It is congenital, meaning that it is present from birth. Amongst other problems, it causes delayed relaxation of the muscles (myotonia) and rigidity. The disorder is caused by mutations in the part of an ion channel gene responsible for shutting off electrical excitation in the muscles, causing muscle fiber membranes to have an unusually exaggerated response to stimulation (hyperexcitability). Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), sluggishness of the muscles, transient weakness in some mutations, pain, and cramping. The disorder is caused by a genetic mutation involving the chloride channel of the muscles. The prolonged muscle contractions, which occurs most commonly in the leg muscles (more often in dominate mutations) as well as the eyelids and hands, is often enhanced by cold and inactivity, and in some forms is relieved by repetitive movement. This phenomena is known as the warm-up effect, and often diminishes quickly with rest. The two major types of myotonia congenita are known as Thomsen disease and Becker type myotonia congenita. These diseases are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease and causes more severe myotonia, muscle stiffness and pain. People with Becker disease often experience temporary attacks of muscle weakness, particularly in the arms and hands, brought on by movement after periods of rest. They may also develop mild, permanent muscle weakness over time. This muscle weakness is not seen in people with Thomsen disease. However, in recent times, as more and more of the individual mutations that cause myotonia congenita are identified, these limited disease classifications are becoming less widely used. This disorder has high phenotype variability. Severity of symptoms can vary greatly between individuals and throughout the life of the individuals themselves. Part of this may be due to the fact that there are over 80 different mutations that can cause the disorder, each with their own specifics, and also due to the fact that myotonia congenita is an ion channel disorder, and ion channels are sensitive to internal and external environmental factors. Adrenaline/epinephrine is well known to make myotonia worse in most individuals with the disorder, and a person with myotonia congenita may experience a sudden increase in difficulty with mobility in a particularly stressful situation during which adrenaline is released. Do to the invisible nature of the disorder, the fact that those with myotonia congenita often appear very fit and able bodied, general lack of knowledge about the disorder by the general and medical community, and oftentimes by the individual themselves, and the potential for inconsistency with the symptoms, many people with myotonia congenita have experienced a degree of social persecution at one time or another because of the effects of their disorder. Some form of myotonia congenita is estimated to affect 1 in 100,000 people worldwide. Early symptoms in a child may include: Difficulty swallowing Gagging Stiff movements that improve when they are repeated Possible complications may include: Aspiration pneumonia (caused by swallowing difficulties) Frequent choking or gagging in infants (also caused by swallowing difficulties) Abdominal muscle weakness Chronic joint problems |
| Cause |
| Myotonia congenita is caused by mutations in the gene CLCN1. CLCN1 is the genetic code for the protein CLCN1, that is critical for the normal function of skeletal muscle cells. This protein is used to make skeletal muscle chloride ion channels. In normal individuals, cessation of muscle contraction is initiated when the chloride channels open and shunt chloride ions into the muscle to halt the processes inducing the contraction. In people with myotonia congenita, the chloride channel is defective and the open gate probability potentials are shifted by a number of millivolts either in the positive or negative direction. In some mutations, the mutated proteins/channels are unstable and deteriorate quickly, or a defective endoplasmic reticulum exists, meaning the protein/channel cannot be transported efficiently to the cell surface. The result is prolonged muscle contractions, which are the hallmark of myotonia. The two forms of myotonia congenita have different patterns of inheritance. Thomsen disease is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases of Thomsen Myotonia Congenita, an affected person has one parent with the condition. However some individuals may be so mildy affected that they do not notice the symptoms, while others may be very severely affected. Becker disease is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder each carry one copy of the altered gene, but do not show signs and symptoms of the disorder. With the advent of genetic testing, it has recently been found that some recessive mutations may occur in a dominant fashion in some individuals. The reason for this is not known. Because several CLCN1 mutations can cause either Becker disease or Thomsen disease, doctors usually rely on characteristic signs and symptoms to distinguish the two forms of myotonia congenita. However, myotonia caused by CLCN1 mutations can occasionally be clinically indistinguishable from myotonia caused by sodium channel SCN4A mutations. A so-called Finnish heritage disease, congenital myotonia is more common in Finland and among ethnic Finns. A molecular study of the CLCN1 gene in 24 families in northern Finland, including 46 affected individuals, showed that although the inheritance appeared to be dominant (Thomsen type), in fact it is recessive (Becker type).[1] |
| Treatment |
| Some cases of myotonia congenita do not require treatment, or it is determined that the risks of the medication outweigh the benefits. If necessary, however, symptoms of the disorder may be relieved with quinine, phenytoin, and mexiletine and other anticonvulsant drugs. Physical therapy and other rehabilitative measures may also be used to help muscle function. ManyGenetic counseling is available. The disease is not fatal but when the muscles tighten up, the person with MC can fall. Depending what they fall on will determine the outcome of the injury. If a person with MC were to fall into water they may be unable to keep their head above water due to being unable to move hands & feet adequately. |
| External links |
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| References |
| 1 - Papponen H, Toppinen T, Baumann P, Myllylä V, Leisti J, Kuivaniemi H, Tromp G, Myllylä R (July 1999). "Founder mutations and the high prevalence of myotonia congenita in northern Finland". Neurology 53 (2): 297–302. PMID 10430417. |
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Paramyotonia Congenita (PC)
| Paramyotonia Congenita (PC), also known as Paramyotonia congenita of von Eulenburg or Eulenburg disease, is a rare congenital autosomal dominant neuromuscular disorder characterized by “paradoxical” myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct. |
| Symptoms and signs |
| Patients typically complain of muscle stiffness that can continue to focal weakness. This muscle stiffness cannot be walked-off, in contrast to myotonia congenita. These symptoms are increased (and sometimes induced) in cold environments. For example, some patients have reported that |
| Diagnosis |
| Diagnosis of paramyotonia congenita is made upon evaluation of patient symptoms and case history. Myotonia must increase with exercise/movement and usually must worsen in cold temperatures. Patients that present with permanent weakness are normally not characterized as having PC. Electromyography may be used to distinguish between paramyotonia congenita and myotonia congenita. Clinicians may also attempt to provoke episodes or myotonia and weakness/paralysis in patients in order to determine whether the patient has PC, hyperkalemic periodic paralysis, or one of the potassium-aggravated myotonias. Genomic sequencing of the SCN4A gene is the definitive diagnostic determinant. |
| Pathophysiology |
| Paramyotonia congenita (as well as hyperkalemic periodic paralysis and the potassium-aggravated myotonias) is caused by mutations in a sodium channel, SCN4A. The phenotype of patients with these mutations is indicated in Table 1. These mutations affect fast inactivation of the encoded sodium channel. There are also indications that some mutations lead to altered activation and deactivation. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a “window current” due to changes in the voltage sensitivity of the channel’s kinetics. These lead to a general increase in cellular excitability, as shown in figure 1. Figure 1. Theoretical simulation of a muscle membrane potential in response to 150ms depolarizing pulse of -45pA. (A) Normal muscle produces only a single action potential due to such stimulus. This is due to inactivation of sodium channels, preventing their further activation even during depolarization. (B) Myotonic muscle, however, is hyperexcitable and able to produce action potentials for the duration of the stimulus pulse. This model adapted from Cannon, 1993 .There has been one study of a large number of patients with paramyotonia congenita. Of 26 kindreds, it found that 17 (71%) had a mutation in SCN4A while 6 (29%) had no known mutation. There is no large difference between these two groups except that patients with no known mutation have attacks precipitated less by cold but more by hunger, are much more likely to have normal muscle biopsies, and show less decreased compound muscle action potentials when compared to patients with known mutations. |
| Treatment/Management |
| Some patients do not require treatment to manage the symptoms of paramyotonia congenita. Others, however, require treatment for their muscle stiffness and often find mexiletine to be helpful. Others have found acetazolamide to be helpful as well. Avoidance of myotonia triggering events is also an effective method of mytonia prevention. |
| Epidemiology |
| Paramyotonia congenita is considered an extremely rare disorder, though little epidemiological work has been done. Prevalence is generally higher in European derived populations and lower among Asians. Epidemiological estimates have been provided for the German population. Here, it was estimated that the prevalence of PC is between 1:350,000 (0.00028%) and 1:180,000 (0.00056%). It should be noted, however, that the German population of patients with PC is not uniformly distributed across the country. Many individuals with PC herald from the Ravensberg area in North-West Germany, where a founder effect is seems to be responsible for most cases. The prevalence here is estimated at 1:6000 or 0.017%. |
| History |
| Originally thought to be separate from hyperkalemic periodic paralysis and the sodium channel myotonias, there is now considerable disagreement as to whether these disorders represent separate entities or overlapping phenotypes of a complex disorder spectrum. |
| External links |
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| Notes |
| Lehmann-Horn F, Rüdel R, Ricker K (1993). "Non-dystrophic myotonias and periodic paralyses. A European Neuromuscular Center Workshop held 4-6 October 1992, Ulm, Germany.". Neuromuscul Disord 3 (2): 161–8. doi:10.1016/0960-8966(93)90009-9. PMID 7689382. Cannon S (2006). "Pathomechanisms in channelopathies of skeletal muscle and brain.". Annu Rev Neurosci 29: 387–415. doi:10.1146/annurev.neuro.29.051605.112815. PMID 16776591. |
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Central Core Disease (CCD)
| What is central core disease? |
| Central core disease falls under the category of congenital myopathies which are a group of conditions characterised by muscle weakness and wasting. Central core disease is a rare condition and symptoms usually become apparent at birth or early infancy, although cases have been reported where symptoms are present in the foetus. The condition is generally non- or slowly progressive and people affected usually have a normal life span. |
| What causes it? |
| In some families, central core disease is caused by an error in the ryanodine receptor (RYR1) gene, located on chromosome 19q13. This gene produces a protein which is involved in calcium release in muscle. It is not known exactly how errors in this gene cause the condition. In many other families, the genetic cause has not been determined. Central core disease is inherited in an autosomal dominant pattern, although many cases occur sporadically, sometimes caused by recessive inheritance with no previous family history. Autosomal dominant inheritance means if a parent has the condition, there is a 50% chance that each child will have the condition also. Either parent can pass on the error, and both male and female children can be affected. More information on genetic inheritance is available in our factsheet ‘Inheritance and the Muscular Dystrophies’. |
| What are the common features? |
| In most cases symptoms become apparent at birth or shortly after, and include hypotonia (floppiness) and weakness of the muscles closest to the trunk of the body. There is often a delay in achieving motor milestones, but the majority of people affected should eventually be able to walk. Muscle cramps are common and mild facial weakness has been seen in some cases, specifically involving the eyes. Weakness round the hips can lead to hip dislocations or tightening of the joints (contractures), particularly the knees and hips. Curvature of the spine (scoliosis) may also occur. Generally the heart and respiratory function are not affected.Malignant hyperthermia (MH) is an acute reaction triggered by certain general anaesthetics or muscle relaxants (which are used for general anaesthesia). Symptoms of MH include high fever, muscle rigidity, dark brown colouration of urine and acute kidney failure. MH is potentially fatal if not treated immediately with a drug called dantrolene. MH can be prevented by avoiding the triggering anaesthetic agents with alternative drugs. Local anaesthetics are quite safe. Both MH and central core disease are associated with abnormalities in the RYR1 gene thus it is important to inform the consultant surgeon or anaesthetist if surgery is being considered. |
| How is it diagnosed? |
| Muscle biopsy. Generally, diagnosis is made through a muscle biopsy. A sample of muscle is taken, and examined under a microscope. This is done in one of two ways: either a small piece of muscle is taken under general anaesthetic (avoiding the drugs which precipitate MH) or a needle biopsy is performed to remove a small sample. Muscle from people affected by central core disease has a distinctive pattern with core structures centrally located within the muscle cells. It is important to note that these structures are also seen in other, unrelated conditions. For this reason, the muscle sample must be considered along with the physical signs and/or molecular tests, in order for a diagnosis of central core disease to be made. A fact sheet on Muscle biopsies is available from the Information and Support Line. Molecular testing. In families where the mutation is known to occur in the RYR1 gene, molecular testing is available. This involves taking a blood sample and analysing the DNA for the presence of a mutation. This process can take up to several months to complete. |
| What other tests are available? |
Prenatal diagnosis is available for families where the mutation has been identified as being in the RYR1 gene. The technique is described in the section Molecular testing, but there are two ways to obtain samples for testing:
Chorionic villus sampling (CVS) is carried out at 10 to 11 weeks. This involves taking a sample of tissue from the placenta. Results are available earlier using this technique than amniocentesis, but the rate of spontaneous abortion is slightly higher. |
| How will it progress? |
| Central core disease is generally thought to be non- or very slowly progressive. Sometimes progression is seen in adulthood, but some people actually show an improvement over time, with reduced weakness and increased mobility. |
| Is there a treatment? |
| Currently there is no treatment for central core disease, but management of the condition is very important. |
| Physiotherapy |
| The primary aim of an individual with a neuromuscular disorder is to increase or at least maintain function and mobility. Physiotherapy can assist in doing this, and it can also maintain breathing capacity, delay the onset of curvature of the spine (scoliosis), and help prevent the development of contractures. It is important that the physiotherapist involved is familiar with the treatment of people with neuromuscular disorders. |
| Exercise |
| There is debate over whether people with neuromuscular disorders should undertake strenuous physical exercise. Some say that putting additional strain on already weakened muscles will cause additional harm, whilst others believe that the exercise may increase muscle strength. Insufficient evidence exists to support either, but it is believed that moderate non-weight bearing exercise such as swimming, walking or peddling may be the best solution. This sort of aerobic exercise helps to maintain a healthy cardiovascular system and a steady weight. It is however, important that this is discussed fully with a clinician. |
| Corrective surgery |
| Scoliosis, or curvature of the spine, is common with central core disease. Spinal surgery aims to correct the posture by realigning the spinal column, and involves the insertion of rods, screws or wires. There are benefits and risks associated with this surgery, and more information is available from the Information and Support Line. As with other treatments, it is very important that the options are discussed fully with a consultant or specialist, before a decision is made. In young children a spinal brace may be used and in children who do not walk moulded seating is used. |
| Is there a cure? |
| Currently there is no cure for central core disease although much research is being conducted into all of the neuromuscular disorders. Although there is no effective treatment, there are a number of different ways in which to manage the symptoms of central core disease and these are outlined above. |
| What research is currently being done? |
| Researchers world-wide are exploring many avenues in an attempt to develop more effective treatments and hopefully a cure. The research department at the Muscular Dystrophy Campaign regularly monitors research advances in congenital myopathies, and produces releases, which are sent to members when significant scientific advances occur. |
| Planning for the future? |
Since central core disease is generally non- or slowly progressive, the needs of a person affected will not vary greatly over time. Depending on the severity of the condition there are things which may have to be considered, such as:
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| Other things to consider |
| Anaesthetics and muscle relaxants |
| As mentioned, there is an association between central core disease and a condition called malignant hyperthermia, which is triggered by the administration of certain general anaesthetics and muscle relaxants. It is important that this is brought to the attention of the consultant and the anaesthetist if surgery is being considered. |
| Medical alert card |
| It is very important that health professionals are aware of your condition should you require treatment. There are often issues they will have to consider. Many companies are able to provide a Medic Alert Card, which can be carried to advise of any medical condition. These come in the form of bracelets, pendants etc and carry essential information. In the case of central core disease, the risk of malignant hyperthermia should be clearly displayed. |
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Nemaline Myopathy (NM)
| What is nemaline myopathy? |
| Nemaline myopathies, or rod body myopathies, are a group of conditions which fall under the category of congenital myopathies. There are a number of different types of rod myopathies and they affect both males and females. In the majority of cases (90%) the condition becomes apparent at birth or early childhood, although in very rare cases, it does not become apparent until adulthood. Rod myopathies are estimated to affect 1 in 50,000 individuals. |
| What causes it? |
| In the majority of cases, a rod myopathy is inherited, although there are sometimes sporadic cases where there are no other family members affected. There have been mutations identified in 5 different genes, which cause a rod myopathies. The protein products of all of these genes are involved in muscle tone and contraction. ACTA1 - This gene produces a protein called α- actin. Mutations in this gene account for around 15-25% of cases. Errors in this gene are inherited in an autosomal dominant or autosomal recessive pattern. NEM2 - The product of this gene is a protein called nebulin. It is thought that mutations in this gene are a common cause of nemaline myopathy but definite statistics are unavailable. Mutations in this gene are inherited in an autosomal recessive pattern. TPM3 - The product of this gene is a protein called α- Tropomyosin 3. Mutations in this gene account for only 2-3% of affected individuals, and are inherited in an autosomal dominant or autosomal recessive pattern. TPM2 - This gene encodes a protein called β-Tropomyosin. Only very few individuals have been identified with errors in this gene. Inheritance is in a autosomal dominant pattern.TNNT1 - This gene produces a protein called Troponin 1. Errors in this gene have only been identified in a population of Old Order Amish individuals. Inheritance is in an autosomal recessive pattern. |
| What are the common features? |
| There are six sub-groups of nemaline myopathy which are defined based on age of onset and severity of condition, although there is a high degree of overlap between the conditions. There does not seem to be a correlation between severity of the condition and the gene which has the mutation. Although heart problems are not common in people with a rod myopathy, it is important that cardiac function is regularly monitored. |
| How is it diagnosed? |
| Muscle biopsy - Generally, diagnosis is made through a muscle biopsy. A sample of muscle is taken, and examined under a microscope. This is done in one of two ways: either a small piece of muscle is taken under general anaesthetic or a needle biopsy is performed to remove a small sample. Muscle from people affected by nemaline myopathy has a distinctive pattern with thin thread- or rod-like structures in the muscle cells. It is important to note that these structures are also seen in other, unrelated conditions. For this reason, the muscle sample must be considered along with the physical signs and/or molecular tests, in order for a diagnosis of nemaline myopathy to be made. A factsheet on Muscle biopsies is available from the Information and Support Line, or from the website at www.muscular-dystrophy.org Molecular testing - In families where the mutation is known to occur in the gene for α- actin, molecular testing is available. This involves taking a blood sample and analysing the DNA for the presence of a mutation. The gene is “read” from end to end, and this sequence is compared to a normal α- actin sequence. This process can take up to several weeks to complete. Once this error has been identified in one family member, it is possible to use this sequence to diagnose other family members |
| What other tests are available? |
Prenatal diagnosis - Prenatal diagnosis is available for families where the mutation has been identified as being in the gene for α- actin, and the precise nature of the mutation established. The technique is described in the section Molecular testing, but there are two ways to obtain samples for testing:
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| How will it progress? |
| The progression of these conditions is variable, and some may progress more quickly then others. Generally it is accepted that the earlier the onset, the more severe the condition. For children who live beyond the early years, only some will lose the ability to walk. Respiratory function is thought to improve over time, with the most severe problems occurring earlier in life. |
| Is there a treatment? |
There is currently no effective treatment to halt the progression of the nemaline myopathies, but management of the condition is very important for prolonging life.
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| Is there a cure? |
| Currently there is no cure for the nemaline myopathies although much research is being currently being conducted into the myopathies, including the rod body myopathies. Although there is no effective treatment to halt the progression, there are a couple of different ways in which to manage the symptoms of the nemaline myopathies and these are outlined above. |
| What research is currently being done? |
| Researchers world-wide are exploring many avenues in an attempt to develop more effective treatments and hopefully a cure. The research department at the Muscular Dystrophy Campaign, regularly monitors research advances in the congenital myopathies, and produces releases which are sent to members when significant scientific advances occur. |
| Planning for the future? |
Nemaline myopathies are progressive conditions which means that the needs of individuals with the condition will change with time.There are a number of things which should be considered:
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| Other things to consider: |
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| ---------------------------------- |
| Support Group |
| Nemaline Myopathy Foundation (USA) |
| P.O. Box 5937 |
| Round Rock, Tx 78683-5937 |
| Tel: 00 1 (512) 388-7985 |
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Myotubular Myopathy/Centronuclear Myopathy (MTM or CNM)
| What is myotubular myopathy? |
| Myotubular, or centronuclear, myopathy belongs to the family of congenital myopathies which are characterised by muscle weakness. Congenital means “from birth” and myotubular myopathy is generally apparent very early in life. Myotubular myopathy is so named because of the presence of structures that look like myotubes, immature muscle cells. |
| What causes it? |
| There are three different types of myotubular myopathy each defined by the pattern of inheritance seen. There are also sporadic cases where there is no previous family history, but the prevalence of these has not yet been determined. X-linked myotubular myopathy (or XMTM) -This is the most common form of myotubular myopathy, and is caused by an error in the myotubularin (MTM1) gene which produces a protein called myotubularin. This protein is known to be required in muscle development, for the formation of adult muscle.The MTM1 gene is located on the X chromosome. Individuals have 46 chromosomes, two of which are called the sex chromosomes. Females have two copies of the X chromosome whilst males have one copy of X and one copy of the Y chromosome. If a female has an error on one copy of her X chromosomes, usually she will have enough protein from the “good” chromosome to compensate for the error, and will not have the condition. Manifesting carriers are the exception to this rule (see later section). If males have the error on their X chromosome, they have no “good” gene to compensate and they will have the condition. Autosomal dominant myotubular myopathy - This pattern of inheritance is very rare and only a few families have been described with this condition. The gene abnormality causing the condition was very recently identified by researchers in Paris; it is called the Dynamin 2 gene (DNM2). Autosomal dominant inheritance means that only one copy of the genetic error is needed to cause the condition, and one good copy cannot compensate. This form of the condition affects both males and females. Autosomal recessive myotubular myopathy -This pattern of inheritance is also very rare. As with the autosomal dominant form, the gene involved has not been identified, but is expected to have a similar function to the myotubularin gene. Autosomal recessive means that, in order for a person to be affected, he or she must have two copies of the genetic error. Each parent must carry a copy of the error, but usually they do not show any signs of the condition. This form of the condition also affects males and females. More information on genetic inheritance is available from the Information and Support Line (contact details shown below). |
| What are the common features? |
| X-linked myotubular myopathy (or XMTM) - This is the most severe form of myotubular myopathy. It generally affects only males, and has the earliest onset. Commonly there are signs of the condition before the baby is born, and often an excessive accumulation of amniotic fluid around the baby is seen. Most individuals are born with severe floppiness (hypotonia), muscle weakness, and infants may fail to breathe spontaneously at birth, most will require breathing support. There are usually problems with feeding, in particular swallowing, and breathing problems can persist. Chest infections may occur frequently. The child may have a long face, which could seem expressionless. The eyelids may be puffy, and some of the muscles in the eyes may not function correctly. There may be tightening of the knee and ankle joints (contractures). The severity of the condition varies considerably. In many cases death occurs in the first few months. Some children who survive infancy may show improvement in the first few years, although many will be severely disabled. Many of these children will require ventilatory support to assist their breathing. Occasionally, some children improve significantly and are left with only mild residual weakness even into adulthood. Female manifesting carriers of XMTM - Manifesting carriers of myotubular myopathy are very rare. As mentioned earlier, every female has two copies of the X chromosome. In every cell, one copy is “switched off”. Usually this is random, but in some exceptional cases, more copies of the “good” chromosome are inactivated. In such cases a female may show signs of the condition, but this is likely to be only mild weakness. Autosomal recessive myotubular myopathy - This is the intermediate form, with onset occurring in infancy or early childhood. Weakness of the muscles in the face may occur, as may droopiness of the eyelids. Some people may have problems with feeding. There is usually weakness of the proximal muscles (those closest to the trunk of the body).Autosomal dominant myotubular myopathy - Onset of this form is very variable, ranging from birth to 30 years. It is not as severe as X-linked, and the condition generally follows a mild course. There is weakness of the muscles closest to the trunk of the body, although some people may show weakness of the more distal muscles. A problem with the heart has been seen in one person previously, and so is rare. It is, however, important to regularly monitor heart and lung function. |
| How is it diagnosed? |
The clinical signs are usually the first indication that there is a problem with the muscles. In order to confirm the diagnosis a muscle biopsy is required.
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| What other tests are available? |
Prenatal diagnosis is available for families that are known to have a history of X-linked myotubular myopathy. The technique is described in the section Molecular testing, but there are two ways to obtain samples for testing:
|
| How will it progress? |
| Myotubular myopathy is a non-progressive or slowly progressive condition. However, infants with X-linked myotubular myopathy may progress into respiratory failure rapidly and the majority of those who survive beyond infancy are dependent on artificial respiration. The autosomal forms are usually less severe. |
| Is there a treatment? |
There is currently no effective treatment for myotubular myopathy, but management of the condition is very important for prolonging life.
|
| Is there a cure? |
| Currently there is no cure for myotubular myopathy although much research is being conducted into the congenital myopathies, including myotubular. Although there is no effective treatment for the condition, there are a couple of different ways in which to manage the symptoms of myotubular myopathy and these are outlined above. |
| What research is currently being done? |
| Researchers world-wide are exploring many avenues in an attempt to develop more effective treatments and hopefully a cure. The research department at the Muscular Dystrophy Campaign, regularly monitors research advances in the congenital myopathies, and produces research updates, which are sent to members when significant scientific advances occur. |
| Planning for the future? |
Myotubular myopathy, although thought to be non-progressive, may change with time, especially as the child grows. This means that the needs of individuals with the condition may change over time.There are a number of things which should be considered:
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| Other things to consider |
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| ---------------------------------- |
| Support Group |
| Myotubular Trust |
| 15 Barnard Road |
| London, SW11 1QTTel: 07518 113692 Email: contact@myotubulartrust.org |
| Web: www.myotubulartrust.com |
| Centronuclear and myotubular myopathy information point (UK) |
| Email: toni.abram1@btopenworld.com |
| Website: http://www.centronuclear.org.uk/ |
| Myotubular Myopathy Resource Group (USA) |
| 2602 Quaker Drive |
| Texas City, TX 77590 |
| Tel: 001 409 945-8569 |
| Email: info@mtmrg.org |
| Contact a Family |
| 209-211 City Road, |
| London EC1V 1JN |
| Tel: 020 7608 8700 |
| Helpline: 0808 808 3555 or textphone: 0808 808 3556 |
| Email: info@cafamily.org.uk |
| Website: www.cafamily.org.uk |
| Provides information and support for families affected by rare disorders. |
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Bethlem myopathythy (MB)
| What is Bethlem myopathy? |
| Bethlem myopathy (BM) is a little known muscle disorder, which is named after the Dutch doctor who first described the condition in 1976. Diagnosis and recognition of it has improved over the past few years following work done by a number of researchers around the world on the identification of the protein involved. The protein is called |
| How does the disease present? |
| First symptoms of BM can present at any time from birth through to adulthood and are very variable. In childhood these symptoms can be hypotonia (floppiness), muscle weakness, delayed motor milestones (for example when a baby first sits up unaided or learns to walk), talipes (clubfoot), torticollis (stiff neck) and contractures (tightness) in the ankles, hip, knees and elbows. The contractures are often quite variable and can come and go over time.Adults with BM can have tight tendons at the back of their ankles, as well as tightness of various other joints (elbows, knees, joints in the back) and especially some of the muscles in the hands. Other symptoms such as poor stamina/poor exercise tolerance and difficulties walking upstairs or doing tasks which require lifting the arms above the head are related to the subtle muscle weakness that tends to go with Bethlem myopathy. In addition, the skin of some people with BM can be unusual. Over the outer surfaces of the arms and legs especially it can feel rough or dry to touch and has been described as looking like "plucked chicken skin". Other patients might find that they scar in an unusual way, either by forming keloids (raised, rather angry looking scars) or thin silvery "cigarette paper scars". |
| How is Bethlem myopathy diagnosed? |
| The diagnosis of BM is usually suspected from the symptoms and examination, paying special attention to the features described above. Because it is a rare disorder not very many doctors have experience of these features and people with Bethlem myopathy may often have had other diagnoses suggested in the past. It is often necessary to do a blood test and a muscle biopsy to exclude other conditions that can present in a similar fashion. The muscle biopsy is studied through a microscope to check how the muscle is put together and whether there is any evidence of it being damaged. In BM the muscle fibres, instead of being evenly sized, show some variation but no significant damage or scarring. With special stains we can also check for a special protein called laminin beta 1, which can sometimes be reduced. However this only provides additional evidence, as these findings are not entirely specific to BM. At present the diagnosis of BM is usually made by collating the information gathered from history and clinical examination with laboratory findings. In some cases it is possible to prove the specific diagnosis by demonstrating a fault in one of the genes encoding for collagen VI. This can be done using a skin biopsy or blood sample. At present it is available on a research basis only and results take months to years to come through. However, we are hoping this will change over the coming year. |
| Is Bethlem inherited? |
| BM is inherited in what we call an autosomal dominant way. This means that there is a 50% (one in two) chance for the children of a person affected by BM to inherit the faulty gene and be affected by BM themselves. This is independent of how mildly the parent might be affected. Sometimes when people are diagnosed as having BM, neither of their parents seems to be affected. In some cases the fault in the gene may have arisen for the first time in the affected person, which is quite a common situation. |
| Are there any risks of developing any complications? |
| The main complications to look out for at the regular check ups in the muscle clinic are contractures (muscle tightness causing restrictions in the range of joint movement) and chest problems. People with BM can be prone to chest infections if their cough is not strong due to weakness of their breathing muscles and in some cases overnight sleep studies may be required to assess breathing. From what we know so far the heart, although a muscle, is usually not affected by BM.It is important to note that collagen VI mutations cause a more severe condition as well called Ullrich congenital muscular dystrophy. |
| Does the condition get worse? |
| For most patients with BM the weakness and contractures are known to get worse over the years, however, this usually only happens very slowly. Whereas some adults remain unaware of any muscle weakness and only have very slight contractures which do not pose them any functional problems others need to make use of practical home aids to work around their muscle weakness and contractures. A proportion of adults over the years might need aids to help movements (for example, cane, crutches or wheelchair) outside the house and might also experience breathing problems for which they require treatment. |
| Is there a treatment or cure? |
| At the moment, there is no cure, nor any specific drug treatment for Bethlem myopathy. However, there are ways, described below, of helping to alleviate the effects of the condition and to prevent complications from occurring. |
| What help can be offered? |
| Physiotherapy is one of the main forms of help. A programme of exercises is usually worked out with a physiotherapist at the time of the diagnosis to stretch tight joints and help to maintain suppleness and keep muscles flexible. It is important to keep a close eye on mobility and joints and this can be done in conjunction with the local physiotherapy team as well as through regular check-ups with your consultant or muscle clinic. Occasionally surgery to release the Achilles tendon can help a person with BM to stand and walk more easily. Children and adults with BM are encouraged to remain as active as possible and ensure that they do not become overweight, so that the strain imposed on their muscles is kept to a minimum.People with BM can have chest problems if their cough is not strong. It is helpful to keep a close eye on things by doing specific breathing tests at regular intervals. Where there may be a problem, flu and pneumovax immunisations are advisable. It also important, that every chest infection is treated promptly with antibiotics. Constipation, possibly due to the fact that a person is not very active, can be a problem. This can be treated by high fibre diet, drinking plenty of fluids and very occasionally by laxatives. Your consultant or muscle clinic may be able to give support and information to schools and other professionals where this is needed to be sure a person with BM is getting the help he or she needs. The specialised Muscular Dystrophy Campaign Care Advisors can sometimes help to liaise between the various professionals such as physiotherapists, occupational therapists, social workers and teachers and may also be able to put you in touch with like-minded people in similar positions. |
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Periodic Paralysis (PP)
| Periodic paralysis is a group of rare genetic diseases that lead to weakness or paralysis (rarely death) from common triggers such as cold, heat, high carbohydrate meals, not The symptoms of periodic paralysis can also be caused by hyperthyroidism; however, if this is the underlying condition there are likely to be other characteristic manifestations, enabling a correct diagnosis. |
| Types |
| Periodic paralysis is an autosomal dominant myopathy with considerable variation in penetrance, leading to a spectrum of familial phenotypes (only one parent needs to carry the gene mutation to affect the children, but not all family members who share the gene are affected to the same degree). Specific diseases include: |
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| Diagnosis |
| This disease is unusually difficult to diagnose. Patients often report years of wrong diagnosis and treatments that made them worse instead of better. Part of this may be that migraines are present in up to 50% of patients and can cause a confusing array of symptoms including headaches, speech difficulties and visual, auditory or sensory auras. DNA testing is available for only a half dozen common gene mutations, while dozens of known mutations are possible but are not routinely tested. EMG results will be normal except during attacks. A properly performed Exercise EMG (Compound Muscle Amplitude Potential Test) can provide an accurate diagnosis in better than 80% of cases. The old glucose/insulin provocative testing can cause life-threatening symptoms and should not be used. Also of note is that potassium levels do not have to range outside of normal limits to cause serious, even life-threatening paralysis. These diseases are not the same as having a very low level of potassium (hypokalemia) or high potassium (hyperkalemia) and must not be treated as such. The total body store of potassium is usually normal; it is just in the wrong place. |
| Treatment |
| Treatment of the periodic paralyses usually includes carbonic anhydrase inhibitors (such as acetazolamide or dichlorphenamide), taking supplemental oral potassium chloride and a potassium-sparing diuretic (for hypos) or avoiding potassium (for hypers), thiazide diuretics to increase the amount of potassium excreted by the kidneys (for Hypers), and significant lifestyle changes including tightly controlled levels of exercise or activity. However, the exact gene mutation, the ion channel affected, and the amount of genetic change or expression can have significant impact on disability and treatment. Treatment of Andersen-Tawil syndrome is similar to that for other types of periodic paralysis, with dichlorphenamide the drug of first choice. However, Pacemaker insertion or an implantable cardioverter-defibrillator may be required to control cardiac symptoms. Also having potassium ions administered intravenously. Which will speed up recovery. |
| Prognosis |
| While the disability can range from minor, occasional weakness to permanent muscle damage, inability to hold a normal job and use of a powerchair, most people function fairly well with drugs and lifestyle changes. |
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