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Bethlem Myopathy What is Bethlem myopathy? Bethlem myopathy is a hereditary muscle disorder, which is named after the Dutch doctor who first described the condition in 1976. People with this condition experience slowly progressing muscle weakness and develop joint stiffness (contractures) in their fingers, wrists, elbows, and ankles that can restrict movement. There is a wide range of severity and symptoms can appear at any age. Bethlem myopathy falls under the category of congenital muscular dystrophies (CMD). It is caused by a change in one of the collagen VI genes. Another more severe muscle condition called Ullrich CMD is caused by different changes to the same genes and collectively they are known as the collagen VI-related myopathies. In this factsheet: • What are the symptoms of Bethlem myopathy? • What causes Bethlem myopathy? • How is Bethlem myopathy diagnosed? • Is Bethlem myopathy inherited? • Does the condition get worse? • Is there a treatment or cure? • What can be done to manage the condition? • What research is being done? • Further information What are the symptoms of Bethlem myopathy? The first symptoms of Bethlem myopathy can present at any time from birth through to adulthood and are very variable. In childhood these symptoms can be hypotonia (floppiness), joint laxity (double-jointedness), 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, hips, knees and elbows. The contractures are often quite variable and can come and go over time. Some stiffness of the spine can also develop over the years. Adults with Bethlem myopathy 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. The muscles used for breathing are only mildly affected, and breathing problems are very rare and limited to the late adult years. The heart, although a muscle, is usually not affected by Bethlem myopathy. Collagen VI is also found in the skin and consequently the skin of some people with Bethlem myopathy has an unusual appearance. Especially over the outer surfaces of the arms and legs it can feel rough or dry to touch which is called ‘keratosis pilaris’. Others might find that they scar in an unusual way, either by forming keloids (raised, rather angry looking scars) or thin silvery “cigarette paper scars”. What causes Bethlem myopathy? Bethlem myopathy is caused by a change in one of the collagen VI genes (which are called COL6A1, COL6A2 and COL6A3). This results in either the production of abnormal collagen VI protein or reduced levels of collagen VI protein in the body. Collagen is the main protein of connective (supporting) tissue in the body and provides support for the muscle cells. The exact mechanisms how these genetic changes lead to the disease are not fully understood but the muscle cells of people with Bethlem myopathy are more sensitive to cell death and there might be a change in the energy supplying parts of the cells called mitochondria. How is Bethlem myopathy diagnosed? The diagnosis of Bethlem myopathy is usually suspected from the medical history and examination. The specific diagnosis however is generally made by looking at a piece of muscle or skin (muscle and skin biopsy). Before doing a muscle biopsy (which involves taking a small piece of muscle, usually from the thigh) a few other tests may be done. One of these tests is a blood test, which measures the level of a muscle protein (creatine kinase or CK). The levels of this protein in the blood are only slightly raised in Bethlem myopathy. Muscle ultrasound may also help to detect changes in the muscle. The technique is very simple, similar to the ultrasound studies carried out in pregnancy and may provide further evidence of the involvement of the muscle. These tests provide a broad indication that there is a muscle condition but cannot pin-point the precise diagnosis. Muscle biopsy can provide a precise diagnosis in two ways: 1. Signs which might indicate a muscle condition can be observed through the microscope. The muscle fibres of people with muscular dystrophy are not evenly sized and some of the fibres are replaced by fat and fibrous tissue. 2. It is also possible to assess the amount of collagen VI protein present in the muscle under the microscope using specific stains that highlight the presence of this protein. As collagen VI is normally present both in muscle and skin, taking a small piece of skin (skin biopsy) can also help to confirm the diagnosis. In some cases it is easier to detect a reduction of collagen VI on skin cells than on muscle cells. Taking a piece of skin however cannot provide some of the information that a muscle biopsy can and it is therefore important to have both muscle and skin biopsies to obtain all the information needed. Genetic tests looking for abnormalities in one of the three genes responsible for Bethlem myopathy are now available and provide the ultimate diagnosis. Other tests may also be performed because Bethlem myopathy can initially appear like other neuromuscular conditions. These tests may include electromyography (EMG) and nerve conduction velocity (NCV) which determines if it is the nerves or the muscles that are the cause of the weakness. Is Bethlem myopathy inherited? Bethlem myopathy is usually inherited in what is known as an “autosomal dominant” way. This means that one copy of the altered gene, inherited from either parent, is sufficient to cause the disorder. There is a 50 percent (one in two) chance of the children of a person affected by Bethlem myopathy inheriting the condition. Some people are diagnosed as having Bethlem myopathy and neither of their parents seems to be affected. In this case, the parents may be so mildly affected that they don’t realise they have the condition. Alternatively, the fault in the gene may have arisen for the first time in the affected person. These people may still pass the altered gene onto their children. Occasionally Bethlem myopathy is inherited in an “autosomal recessive” way which means that two copies of the altered gene are inherited – one from each parent. All families affected by Bethlem myopathy should be referred for genetic counseling. Genetic counseling provides information on the inheritance pattern, risks to other family members, and the ‘prognosis’ (likely outcome of the disorder). Does the condition get worse? For most patients with Bethlem myopathy 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 mobility problems, others need to make use of equipment to remain mobile. About two thirds of adults with Bethlem myopathy over the age of 50 need aids to help movement (i.e. cane, crutches or wheelchair) outside the house and some 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 can be done to manage the condition? The muscle clinic will keep a close eye on mobility and joints and work with the local physiotherapy team. Physiotherapy will involve a programme of exercises to stretch tight joints, help to maintain suppleness and keep the muscles flexible. Occasionally surgery to release the Achilles tendon can help a person with Bethlem myopathy to stand and walk more easily. Children and adults with Bethlem myopathy 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. Although breathing is rarely affected in Bethlem myopathy, the muscle clinic may recommend breathing tests to monitor the strength of the breathing muscles. In some cases overnight sleep studies may be required. It is also worth being aware of the early signs of breathing difficulty which might only occur at night. These signs include frequent chest infections, daytime sleepiness and morning headaches. If a breathing problem is detected a non-invasive ventilator device can be used, which is usually only needed at night. People with Bethlem myopathy can be prone to chest infections if their cough is not strong due to weakness of their breathing muscles. It is therefore recommended that the flu and pneumococcal vaccines are given to people with respiratory weakness and that any respiratory infections are promptly treated. Constipation, possibly due to the fact that a person is not very active, can be a problem. This can be treated by a high fibre diet, drinking plenty of fluids and very occasionally by laxatives. The MDA can give support and information to schools and other professionals where this is needed to be sure that a person with Bethlem myopathy is getting the help he or she needs. What research is being done? In recent years researchers have discovered a lot about what is happening inside the cells of people with Bethlem myopathy (and the related condition Ullrich CMD). One of the findings is that structures in the cells called mitochondria - which are the ‘batteries’ supplying energy - are not functioning correctly. This has led to several drugs that work on the mitochondria being tested in animal models of the conditions. Two drugs have shown promise - omigapil and Debio 025. A company called Santhera is planning a clinical trial of omigapil to be conducted in the USA. This trial will involve children with CMD, including Ullrich CMD. If the drug proves to be beneficial in this patient group it may be tested for other muscle conditions such as Bethlem myopathy. Debio 025 has been shown to restore mitochondrial function in muscle cells of patients grown in the laboratory and in a mouse model. Plans for a clinical trial in people with Bethlem myopathy or Ullrich CMD have not been announced. Another possible avenue being considered for the development of therapies includes drugs that reduce 'fibrosis' or scarring in the muscles which is thought to be a major contributor to the muscle weakness in CMD. Losartan, a commonly prescribed medication for high blood pressure, is one possible candidate for testing in clinical trial as it has been shown to reduce fibrosis in mouse models of CMD. These approaches that target the mitochondria and fibrosis do not address the root cause of the condition so would only be able to treat some of the symptoms of the condition. Ideally a treatment would result in the production of properly functioning collagen in the body. Gene therapy to correct genetic mutations is being researched for other genetic conditions including muscular dystrophy and if these prove to be successful it may be possible to apply this technology to the development of treatments for Bethlem myopathy and Ullrich CMD. You may be interested in registering with the Congenital Muscle Disease International Registry (CMDIR). This is a patient registry: a database that contains information about patients with a particular condition. Clinical trial organisers and other researchers use this (anonymous) information to learn more about the conditions and plan clinical trials. If a clinical trial were to start the registry would be used to contact suitable potential participants and invite them to take part. Patient registries are also a useful source of information for patients and their families as regular newsletters are sent out. You can find out more about patient registries on our website. NOTE: Research is moving forward at a fast pace, so this research summary may not be up-to-date at the time of reading. Feel free to contact MDA’s Scientific Communications Officer for an update on the latest developments - kristina.elvidge@mda.org.au. Further information • Clinical trials – your questions answered • Read about the research MDA funds which aims to reduce inflammation in the muscles and improve muscle regeneration • For definitions of any terms that you are not familiar with please take a look at our glossary • You can get regular updates by becoming a friend of the MDA Facebook page or follow our Scientific Communications Officer on Twitter (@kelvidge) For further information on any of the areas discussed above, please contact MDA: Phone: (03) 9320 9555 Email: info@mda.org.au Click here for PDF version Revised and uploaded 20 May 2014.

corne
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10 reacties

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Ik kan niet nachecken de volledigheid van dit onderzoek, maar het geeft in ieder geval meer info over de spierziekte en ook over het huidig onderzoek. Dit artikel is van eind 2014, dus vrij recent

corne
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op dit moment lopen er in de usa trails met medicatie, ik ben aan het proberen wat eea inhoudt.

ook wat betreft het feit dat in de usa ulrich en bethlem als de zelfde aandoening wordt gezien, alleen de ernst verschilt

corne
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Hallo,

Bij mijn dochtertje van 11 hebben ze zojuist na 9 lange jaren onderzoek de ziekte van Bethlem vastgesteld. Zij heeft vooral problemen met contracturen aan de ellebogen (kan haar armen niet strekken), knieen en enkels. De spierzwakte zit vooral in de bekken en schoudergordel alsook de bovenbenen, zij kan sinds een goed jaar niet meer stappen of rechtstaan en zit dus in een rolstoel. Zij gaat 2 x per week naar een revalidatiecentrum en daar krijgt zij kine, ergo, alsook psychologische begeleiding. Aangezien wij in Belgie wonen kan ik weinig bijbrengen aangaande tussenkomsten van overheid of ziekteverzekering. Om een vergelijk te kunnen maken kan ik wel vertellen dat wij verhoogd kindergeld krijgen, en wij ook steeds terrecht kunnen bij het VAPH (Vlaams agentschap voor  personen met een handicap) voor aanpassingen aan het huis, rolstoel, aanpassingen aan de auto enzoverder. Wij hebben ook een PAB (persoonlijk assistentie budget), waarmee wij dus een persoonlijke assistent kunnen aanwerven die dagelijks onze dochter Emma begeleid op school, zodat zij niet naar het bijzonder onderwijs hoeft te gaan. Nu er uiteindelijk een diagnose is zijn wij uiteraard ook heel benieuwd naar de ontwikkelingen op medisch vlak. Ik vind het zeer interresant om de bevindingen van andere mensen hier te kunnen lezen, en zal ook mijn ervaringen hier delen.

Grtn,

Jim 

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Hoi Jim,

Ik heb zelf een dochter van 13 maanden met Ullrich en sta dus nog helemaal aan het begin van de rit.

Op facebook is sinds kort een groep voor mensen met de ziekte van Ullrich (en ouders natuurlijk). Heel fijn om vragen te kunnen stellen en verhalen te kunnen lezen en foto's te kunnen zien.

In de groep zitten ook mensen die werken bij de amerikaanse Spierziekten club, dus er is daar erg veel kennis beschikbaar, ook over het medicijnonderzoek dat nu loopt.


Je kan de groep vinden via https://www.facebook.com/groups/col6cmd/?fref=ts? 

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een lezing over mogelijke behandelingen

https://www.youtube.com/watch?v=Xhhpy-SEwaE??

dit bericht is gewijzigd door Corne op 4 december 2015 om 20:37

corne
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Nieuwe DNA-techniek helpt bij spierziekte muis

Geneeskunde Het kapotte gen dat de spierziekte van Duchenne veroorzaakt, kan met de precisietechniek CRISPR-Cas gerepareerd worden.

4 januari 2016

Volwassen muizen met de spierziekte van Duchenne hebben de kracht in hun spieren deels weer teruggekregen door de reparatie van een gen. Niet alleen hun skeletspieren werden sterker, ook hun hartspier en middenrifspier werden krachtiger. Drie teams van verschillende Amerikaanse universiteiten publiceerden op nieuwjaarsdag tegelijk hun resultaten in Science

Alle drie maakten ze gebruik van CRISPR-Cas, een nieuwe techniek die het mogelijk maakt heel nauwkeurig in het DNA te knippen. Dat dit nu in drievoud bij muizen is gelukt, laat zien dat met deze techniek in principe ook voor mensen met de spierziekte van Duchenne een nieuwe geneeswijze ontwikkeld kan worden, al zal dat nog wel even duren.

„Een mooie aanpak”, reageert de Leidse geneticus Gert-Jan van Ommen, „omdat het fouten in het gen in principe permanent kan herstellen”. Van Ommen ontwikkelde eerder de zogeheten exon-skipping-techniek om Duchenne te behandelen. Die beoogt hetzelfde effect, maar dan door een gedeelte van het gen af te dekken met een passend molecuul, waardoor het stukje met de mutatie overgeslagen wordt bij het maken van het eiwit.

De behandelde muizen kregen weer iets van hun eigen spierkracht terug

De ziekte van Duchenne is een ernstige erfelijke aandoening die vooral bij jongens voorkomt (in Nederland wordt 1 op de 4.000 jongens ermee geboren). De ziekte wordt veroorzaakt door een fout in het dystrofine-gen, waardoor er geen of een te kort dystrofine-eiwit wordt geproduceerd in spiercellen. Dat leidt ertoe dat spiercellen op den duur afsterven. Patiënten hebben last van toenemende spierzwakte, hartproblemen en problemen met de ademhaling. De meeste patiënten overlijden tussen hun twintigste en dertigste.

Met de CRISPR-Cas-techniek zijn de Amerikaanse teams erin geslaagd een stuk uit het dystrofine-gen te knippen dat de gewraakte mutatie bevatte. Na de ingreep produceerden sommige spiercellen een verkorte, maar functionele versie van het dystrofine-eiwit. Dat was voldoende om Duchenne-muizen weer iets van hun normale spierkracht terug te geven. Volgens de onderzoekers kwam dystrofine in behandelde spieren weer terug op 8 procent van het normale niveau. De helft daarvan is al genoeg om de spierfunctie gedeeltelijk te herstellen.

De CRISPR-Cas is ontleend aan de manier waarop bacteriën binnenkomende virussen onschadelijk maken. Het systeem herkent bepaalde genetische sequenties en knipt die door. Onderzoekers hebben dit systeem aangepast zodat het gebruikt kan worden als precisie-instrument om in zoogdiercellen genen uit te schakelen of deels weg te knippen.

Mail de redactie?

corne
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het gaat wel over duchenne, maar geeft aan wat er steeds meer ontwikkeld zou kunnen worden

corne
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Beste Corne,

Ik heb een mail van jou gekregen met een vraag erin. Ik heb het beantwoord maar kreeg het helaas terug.

De post mag verwijderd worden.

alvast bedankt.

Mvg Marlinda

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ok zal ik doen

corne
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Developing molecular patches for the treatment of collagen VI-related conditionsDonate now 

Professor Francesco Muntoni and his team at University College London will develop molecular patches that could be a potential treatment for people with Ullrich congenital muscular dystrophy. This research will also help to further enhance molecular patch technology, which will be beneficial for the neuromuscular field in the long-term.

Background

Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are known as collagen VI-related myopathies, as they are caused by mutations in genes that produce collagen VI protein. This protein forms networks around our muscle cells and acts as a scaffold to hold and support them. In someone with UCMD or BM, collagen VI is faulty or absent, which means that their muscle cells are not supported properly and become damaged over time.

Most of our genes are inherited in pairs; one from our mother and one from our father. Everyone with BM and most people with UCMD have one healthy copy and one faulty copy of a particular collagen VI gene. This is known as ‘dominant’ inheritance, as the faulty copy overrides the healthy one and disrupts collagen VI production.

What are the aims of the project?

The primary aim of this project is to develop molecular patches that switch off or ‘silence’, or correct the faulty copy of the collagen VI gene. This aims to restore the production of collagen VI protein in people with UCMD or BM and stabilise or at least slow down the progression of the condition.

Some of the molecular patches will be linked to short protein fragments called peptides. These peptides help the molecular patches to get inside cells, thus improving their delivery into muscle and other tissues.

Professor Muntoni and his team will design molecular patches targeting four of the most common UCMD mutations. They will test them in cells originating from people with UCMD and evaluate their effect on collagen VI production.

The researchers will also test some of the molecular patches in a new mouse model of UCMD. This will be done in collaboration with Professor Bonnemann and his team at the NIH, USA (read more about Prof Bonnemann’s project).

Why is this research important?

Currently there is no effective treatment for UCMD or BM. This research could be an important step towards a treatment that addresses the genetic cause of these conditions.

Although molecular patches are now in clinical use for some muscle-wasting conditions, there are problems associated with their delivery to muscles and other target organs. This project will help to address this by linking the molecular patches to peptides and other novel advanced technology in this field. Enhancing the technology in this way could lead to better therapeutic outcomes.

How will the outcomes of this research benefit people with UCMD?

This project will test the effectiveness of molecular patches in cell and mouse models of UCMD. This pre-clinical research is essential for new drugs or treatments to be able to advance to human clinical trials.

How might this research impact on other neuromuscular conditions?

The knowledge gained from this project could help to enhance molecular patch technology generally. This could be beneficial for several muscle-wasting conditions for which molecular patches are being developed, including Duchenne muscular dystrophy, spinal muscular atrophy, facioscapulohumeral muscular dystrophy and myotonic dystrophy.

Grant information

Project leader: Professor Francesco Muntoni
Institute: University College London
Condition: Ullrich congenital muscular dystrophy, Bethlem myopathy
Duration: Three years
Total cost (£): 224,040
Official title: Developing antisense oligonucleotide therapy for collagen VI-related congenital muscular dystrophy

This research would not have been possible without individual donations, family fundraising activities, trusts and corporate support for our Ullrich CMD Appeal.

Donate now and help us ensure that effective treatments and expert care are available to all those living with collagen VI-related conditions, including UCMD. Thank you.?

corne
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