Duchenne muscular dystrophy

from Wikipedia, the free encyclopedia
Classification according to ICD-10
G71.0 Muscular dystrophy
ICD-10 online (WHO version 2019)

The muscular dystrophy of the type Duchenne (including Duchenne muscular dystrophy and / or DMD called) is the most common muscular hereditary disease in childhood. It occurs approximately at a frequency of 1: 3600 to 1: 6000. Due to the X-linked recessive inheritance , almost only boys are affected. However, female carriers of this gene can also show symptoms, e.g. B. in the cardiac area and occasional monitoring for cardiomyopathy by means of cardiac ultrasound examination or cardiac MRI and ECG is recommended for these women from the age of 25–30 years.

Duchenne muscular dystrophy begins in infancy with weakness in the pelvic and thigh muscles and progresses rapidly. Thanks to optimized therapy with home ventilation and the use of cortisone preparations in early childhood, the prognosis has improved in recent years, and life expectancy has also increased due to improved medical care in recent years. Just a few years ago, most patients died in adolescence. Today the third decade of life is often reached. Duchenne muscular dystrophy was described by Guillaume-Benjamin Duchenne in Paris as early as the 19th century .

causes

Histopathological image of a cross-section through the calf muscle of a patient with Duchenne muscular dystrophy. The muscle fibers (red) are extensively replaced by fat cells (optically empty = white).

The Muscular Dystrophy Duchenne is a genetically determined abnormal synthesis of muscle structural protein dystrophin . It is not produced in this form of the disease. In contrast, in the milder muscular dystrophy, Becker-Kiener dystrophin is formed in a shortened but partially functional variant. The dystrophin deficiency leads over time to the breakdown of muscle fibers and replacement by fatty or connective tissue.

In the Duchenne muscular dystrophy, a mutation in the dystrophin gene on the X chromosome (locus Xp21.2) can be detected. In 60 to 70% this is a deletion , in approx. 5% a duplication and in approx. 35% a point mutation . A point mutation can also occur as a nonsense mutation, which results in an early stop codon in the reading frame. This occurs in around 10-15% of patients. More than 80% of the mutations here cause a shift ( frameshift ) of the reading frame and thus lead to a complete loss of Dystrophinproteins. About 1/3 of the cases are new mutations and only 2/3 are inherited from the mother ( carrier ) who is not manifestly ill .

Symptoms and course

The course varies, but early childhood development is usually normal at first. Depending on the severity of the disease, a slight muscle weakness of the legs can be noticed from the 3rd to 5th year of life, which leads to frequent stumbling and falling. In the further course, climbing stairs can only be possible with the help of a handrail. The muscle weakness of the pelvic and thigh muscles can lead to a waddling gait ( Trendelenburg sign ) and make it difficult to straighten up from a sitting or lying position. The children prop themselves on their thighs when standing up ( Gowers maneuver ) or use walls and furniture for support. In severe forms, from the age of 5 to 7, climbing stairs and getting up from sitting or lying down are only possible with the help of others, as the disease also affects the muscles of the shoulders and arms. Between the ages of 7 and 12, it is hardly possible to raise your arms horizontally. Many children at this age are already dependent on a wheelchair, but can still look after themselves to a limited extent. In severe cases, there is often a complete need for care from the age of 18.

As a result of muscle wasting, painful misalignments of joints and bone deformations occur. The so-called “gnome” or “ball calves” are characteristic of the Duchenne type. They arise from fat deposits in the connective tissue of the lower leg muscles ( pseudohypertrophy ). When the shoulder girdle muscles break down, the shoulder blades protrude (" Scapulae alatae "), also called angel wings. Weakness of the respiratory muscles makes coughing up significantly more difficult in the case of infections of the airways and this can considerably reduce life expectancy. The heart muscle is usually affected by the disease process, but increased heart rate and other changes in the rhythm or impairment of the heart's strength rarely lead to subjective complaints. The life expectancy of the patients is about 40 years, depending on the course, but some patients die before the onset of puberty.

In 50–95% of cases, a lateral curvature of the spine ( scoliosis ) also forms, which begins when the ability to walk is lost, usually between 10 and 14 years. In around 85% of the affected children, the scoliosis progresses initially with a mean increase in the Cobb angle , which describes the extent of the deformity, by 2.1 ° per month. This also affects the lung function and the forced vital capacity (FVC) decreases in the sense of a restrictive lung dysfunction by about 4% for every 10 ° increase in scoliosis. It is possible to stop the progression and decrease in lung volume by stiffening the spine for a long time ( spondylodesis ). However, the intervention is associated with risks and its significance is not clear. A Scottish retrospective study examined the complication rate in 26 posterior spinal fusion surgeries. The boys were on average 14.2 years old, the operation lasted an average of 260 minutes, the average postoperative stay in the intensive care unit was five days, and the average hospital stay was fifteen days. Complications were found significantly more frequently than with comparable operations for other underlying diseases and existed in 10 children (39%), four of which were acute liver damage ( hepatotoxicity , with complete improvement in all children in the further course) and five deep wound infections.

Diagnosis

Muscular dystrophy is suspected when an unusual, symmetrically developed muscle weakness is observed in childhood. When taking the anamnesis , the onset of the functional disorders, the course and occurrence of similar disorders in the family, especially in the mother's male relatives, are of particular interest. As part of the physical examination, general abnormalities such as posture, mobility and breathing are checked. The neurological examination checks the function of the nerves and muscles.

Laboratory values ​​provide important information - the concentration of transaminases is often increased, but above all the concentration of creatine kinase , a muscle enzyme, is greatly increased, often to values ​​above 10-100 times the normal range. However, an increased creatine kinase value is no substitute for further diagnostics, since there can also be other causes.

The usual additional examinations include electroneurography , in which the nerve conduction velocity is determined, and electromyography , which helps differentiate whether a primary muscle disease or a disease of the motor nerves is the cause of the weakness. MRI and ultrasound are used as imaging methods . Structural changes in the muscles can be assessed here without stressing the patient. The muscle biopsy allows the muscle to be examined under a light or electron microscope . The metabolic processes in the muscle can thus be examined in detail. The genetic diagnosis confirms the diagnosis and enables an exact classification according to type. This genetic diagnosis is important, among other things, because it provides information about which therapy is possible. Not all therapies are suitable for all patients with Duchenne

Importance of respiratory function

Many of the deaths in DMD patients are due to decreased respiratory function. The early detection of the loss of respiratory function in DMD is therefore very important. In the early stages, the decreasing respiratory function is asymptomatic. If the respiratory function is restricted (FVC and PEF), the measured values ​​usually drop by around 5% per year. DMD patients with impaired respiratory function are at an increased risk of - sometimes serious and life-threatening - respiratory infections. To avoid respiratory infections caused by accumulated mucus (not only in the context of colds), systems can be used that lead to cough support. Air is fed into the lungs by an automatic air flow and quickly sucked out again, which makes coughing easier. Current therapeutic options cannot sufficiently influence the progressive decline in respiratory function in DMD. Regular monitoring of respiratory function increases the chances of slowing progression through early interventions. The increasing loss of muscle strength irreversibly reduces the respiratory function and is responsible for many deaths in DMD.

In most centers, lung function measurements are first performed on patients at around six years of age and then repeated annually. The values ​​are usually not noticeable at this age. In its guideline, the German Society for Pneumology recommends lung function screening at regular intervals (every 3-12 months depending on the clinical course) in order to monitor the risk of developing a weakness of the breathing pump and to diagnose a weakness of the breathing pump in good time and not only in the case of respiratory decompensation and existing neuromuscular disease). From the age of twelve, the FVC measurement is recommended twice a year - however, only about 50% of patients of this age receive this lung function monitoring. It is important to regularly check the lung function values ​​of patients in wheelchairs as they support important decisions that have a very positive effect on the disease.

The earlier interventions are made and the attempt is made to halt the decline in respiratory function, the higher the chance that the previously inevitable progression will progress more slowly. This could - even if not yet proven by clinical data - possibly also mean the extension of a higher quality of life for the patients. Because patients sitting in wheelchairs describe the decrease in respiratory function as their greatest concern.

therapy

A cure is not yet possible. A first attempt to treat Duchenne muscular dystrophy by gene therapy failed. The reason for this was probably an autoimmune reaction after an attempt to insert the corresponding genes into a muscle protein. Further studies with adjuvant immunomodulation were carried out in October 2010.

Therapy is therefore symptomatic and aims to alleviate the consequences of muscular dystrophy, to halt progress and to treat complications. Effective treatment is multidisciplinary and requires cooperation between the doctor , physiotherapy , occupational therapy and nursing staff , often with psychological support for those affected and their relatives.

The aim of all physiotherapeutic measures is to keep the consequences of muscle weakness as low as possible or to correct them to a certain extent. Exercise should be done, but in a way that would never cause sore muscles in healthy people. In a sense, the ability of Duchenne patients to recover from sore muscles is extremely limited. However, moderate training makes sense and delays z. B. scoliosis. Through economical training with light to moderate stress such as walking, swimming and riding on the ergometer , an improvement in endurance and thus a reduction in weakness can be achieved. Cortisone administration and surgical resolution of contractures increase the ability to walk, creatine can cause a discreet improvement in muscle energy metabolism (regular breaks in therapy are necessary). A developing scoliosis (curvature of the spine) can be surgically straightened by the implantation of metal rods ( Harrington rod ); this mainly improves the respiratory function. Telescopic rods that grow with the child have been used since 1989. Auxiliaries used orthoses , wheelchair , shower chair, bath lifts , toilet seats and wheelchair ramps used. As the breathing muscles continue to decrease due to the increasing weakness of the respiratory muscles, breathing problems occur at night. This manifests itself, for example, in daytime sleepiness, lack of appetite in the morning, difficulty concentrating, listlessness. Mechanical ventilation may be necessary between the average age of 18 and 20 years. This is mostly done non-invasively, using a nose or nose and mouth mask . Performing a tracheotomy is usually not necessary at the beginning and is usually not performed until late when the patient is also dependent on ventilation during the day. A general tracheostomy has now largely been abandoned. At the same time, however, a tracheotomy also enables speaking, as it is not hindered by the breathing mask. Particular attention should also be paid to whether a cough weakness develops, which should be consistently treated with cough support systems to avoid developing infections. A lot of support is currently possible in the area of ​​breathing through physiotherapeutic techniques (breathing training and / or technical measures).

Another approach is based on reading out the defective gene completely despite the mutation. This should z. B. be possible with the help of Ataluren . This is an option for around 10-15% of patients. Accurate mutation determination is therefore very important when considering therapy with ataluren. As soon as the disease spreads to the respiratory muscles, regular lung function tests must be carried out. In recent years there has been good progress in the possibility of home ventilation. When creating a training program, cardiac resilience must be checked. Sometimes it may be necessary to use a pacemaker.

A genetic counseling of the parents is part of the therapy. If the mother is a carrier, brothers of affected children have a 50% probability of falling ill, while sisters are asymptomatic carriers of the defective gene with the same 50% probability.

Glucocorticoids

Glucocorticoids have a very positive effect and lead to a delay in the course of the disease and the loss of the ability to walk for about 3 years, as was shown in an analysis of the currently largest patient database. It often begins at around the age of 4. The starting dose is 0.75 mg / kg body weight (per kilogram body weight) of prednisone or prednisolone.

Deflazacort

In a Canadian, but not randomized, comparative clinical study with 54 boys who were on average 8.7 years old at the start of the study and of whom 30 received 0.9 mg / kg body weight deflazacort daily and 24 no therapy, the average was after 15.2 Years one boy with therapy (3%) and five boys without therapy (21%) died. Significantly more boys without therapy had developed severe scoliosis and had been operated on (six (20%) and twenty-two (92%) boys with or without cortisone therapy). Lung function was significantly better during therapy, the children walked independently for longer and were able to climb stairs without assistance for an average of one and a half years longer. However, twenty-one boys (70%) developed a cataract on cortisone (and no child without therapy), but only two children were operated on for the cataract. With cortisone, the size was on average 17 cm smaller, the average weight 4 kg higher.

Atalures

The active ingredient Ataluren is used for the treatment of Duchenne muscular dystrophy due to a nonsense mutation in the dystrophin gene in ambulatory patients aged 2 years and over. The interaction of ataluren and the ribosome causes an amino acid to be inserted instead of the stop codon. This enables the ribosome to continue the translation process (the synthesis of dystrophin mRNA). In this way, the genetic information can still be read despite the nonsense mutation and the target protein can be produced in small quantities. Studies have shown that patients treated with Ataluren can walk up to five years longer (on average up to the age of 16.5 years) than in untreated Duchenne patients as part of the natural course of the disease. If the therapeutic measures begin at a point in time at which the muscles still have sufficient regenerative capacity, muscle function and the ability to walk can be maintained for as long as possible and the progression of the disease slowed down. The longer the affected boys are able to walk, the further the decline in pulmonary capacity can be delayed. In the advanced stage of the disease, this requires ventilation of the patient.

Clinical development

Various companies are developing novel substances for the treatment of DMD, including a .:

  • The company Sarepta Therapeutics is investigating Eteplirsen / EXONDYS 51 ( Phase IV ): it is already approved in the USA for the treatment of DMD. This is a drug for so-called exon skipping, with which it is achieved that there is a milder form of Duchenne muscular dystrophy, this in patients who are suitable after genetic testing. Approval is still pending in Europe.
  • The drug Idebenone / Raxone , already approved in Leber's optic atrophy (LHON) and acting on the mitochondria, was examined by the manufacturer Santhera in several study programs on DMD. Approval from the European Medicines Agency (EMA) was applied for in May 2019. As part of the study program, a reduced decrease in respiratory function over a longer period of time was demonstrated for patients aged 10 and over.
  • Bristol-Myers Squibb is partnering with Biogen and Roche to develop BMS-986089 for the treatment of DMD.
  • The Reveragen company has a drug in clinical testing ( phase III ) that acts as a novel glucocorticoid with an improved side effect profile.
  • Catabasis Pharmaceuticals Inc. is investigating the effectiveness of the specially developed active ingredient Edasalonexent (Phase III) as part of the " PolarisDMD " clinical study .

Web links

Individual evidence

  1. ↑ Flotats-Bastardas M, Ebrahimi-Fakhari D, Bernert G, Ziegler A, Schlachter K, Poryo M, Hahn A, Meyer S .: Non-walking patients with Duchenne muscular dystrophy . In: The neurologist . 90, No. 8, August 2019, pp. 817–823. doi : 10.1007 / s00115-019-0754-y .
  2. ↑ 23. Mah JK, Korngut L, Dykeman J et al: A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy . In: NeuromusculDisord . 24, No. 6, June 2014, pp. 482–491. doi : 10.1016 / y.nmd.2014.03.008 .
  3. ↑ a b Birnkrant DJ, Bushby K, Bann CM et al: Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management . In: The Lancet Neurology . 17, No. 3, March 2018, pp. 251–267. doi : 10.1016 / S1474-4422 (18) 30024-3 .
  4. ↑ a b c Birnkrant DJ, Bushby K, Bann CM et al: Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopedic management . In: The Lancet Neurology . 17, No. 4, April 2018, pp. 347-361. doi : 10.1016 / S1474-4422 (18) 30025-5 .
  5. ↑ Birnkrant DJ, Bushby K, Bann CM et al: Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan . In: The Lancet Neurology . 17, No. 5, March 2018, pp. 445–455. doi : 10.1016 / S1474-4422 (18) 30026-7 .
  6. ↑ German Society for Muscular Diseases eV DGM: Explanatory video for muscular dystrophies Duchenne and Becker. April 18, 2018. Retrieved November 19, 2018 .
  7. ↑ Rosenberg AS et al. Sci Transl Med. 2015; 7: 299rv4.
  8. ↑ a b Muntoni F, Desguerre I, Guglieri M, Osorio AN, Kirschner J, Tulinius M, Buccella F, Elfring G, Werner C, Schilling T, Trifillis P, Zhang O, Delage A, Santos CL, Mercuri E .: Ataluren use in patients with nonsense mutation Duchenne muscular dystrophy: patient demographics and characteristics from the STRIDE Registry . In: J Comp Eff Res . 8, No. 14, August 2019, pp. 445–455. doi : 10.2217 / cer-2019-0086 .
  9. ↑ AD Duckworth, MJ Mitchell, AI Tsirikos: Incidence and risk factors for post-operative complications after scolioses surgery in patients with Duchenne muscular dystrophy . The Bone & Joint Journal 2014, Volume 96-B, Issue 6, July 2014, pages 943-949; doi: 10.1302 / 0301-620X.96B7.33423
  10. ↑ Henricson EK, et al .: The cooperative international neuromuscular research group Duchenne natural history study; Muscle Nerve 2013; Volume 48, pages 55-67; doi: 10.1002 / mus.23808
  11. ↑ Mayer OH, et al .: Characterization of pulmonary function in Duchenne Muscular Dystrophy; Pediatr Pulmonol 2015; Volume 50, pages 487-94; doi: 10.1002 / ppul.23172
  12. ^ S2k guideline: Non-invasive and invasive ventilation as a therapy for chronic respiratory failure - Revision 2017 , accessed on December 2, 2019
  13. ↑ Andrews JG, et al .: Respiratory Care Received by Individuals With Duchenne Muscular Dystrophy From 2000 to 2011 , Respir Care 2016; Volume 61, pages 1349-59
  14. ^ A b Daniel W. Sheehan, David J. Birnkrant, Joshua O. Benditt, Michelle Eagle, Jonathan D. Finder, John Kissel, Richard M. Kravitz, Hemant Sawnani, Richard Shell, Michael D. Sussman and Lisa F. Wolfe: Respiratory Management of the Patient With Duchenne Muscular Dystrophy . In: Pediatrics . 142, No. 2, October 2018, pp. 62-71. doi : 10.1542 / peds.2018-0333H .
  15. ↑ a b www.aktionbenniundco.de , website aktion Benni & Co eV, accessed on December 2, 2019
  16. ^ New England Journal of Medicine , Volume 363, 2010, pp. 1429-1437
  17. ↑ Anita K. Simonds: Recent advances in respiratory care for neuromuscular disease. In: Chest. Volume 130, December 2006, p. 1881, section DMD , doi: 10.1378 / chest.130.6.1879 .
  18. ↑ Prof Craig M McDonald, Erik K Henricson, Richard T Abresch, Tina Duong, Nanette C Joyce, Fengming Hu et al .: Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study . In: The Lancet . 391, No. 10119, November 2017, pp. 51-461. doi : 10.1016 / S0140-6736 (17) 32160-8 .
  19. ↑ David E. Lebel, John A. Corston, Laura C. McAdam, W. Douglas Biggar, Benjamin A. Alman: Glucocorticoid treatment for the prevention of scoliosis in children with Duchenne Muscular Dystrophy: Long-term follow-up. In: Journal of Bone and Joint Surgery , Volume 95, No. 12, June 19, 2013, pp. 1057-1061, doi: 10.2106 / JBJS.L.01577 .
  20. ↑ European Medicines Agency: Translarna (ataluren). In: European Medicines Agency . September 17, 2018, accessed October 24, 2019 .
  21. ↑ Bushby K et al. Muscle Nerve 2014; 50: 477-487.
  22. ↑ Haas M et al. Neuromuscul Disord. 2015; 25: 5-13.
  23. ↑ Delage et al. Effect of atalures on age at loss of ambulation in nonsense mutation Duchenne muscular dystrophy: observational data from the STRIDE Registry. Poster presented at The 23RD International Annual Congress of the World Muscle Society Congress, 2. – 6. October 2018, Mendoza, Argentina
  24. ↑ Bello L et al. Neurology 2016; 87 (4): 401-09
  25. ↑ Delage et al. Long-term efficacy of atals for the treatment of nonsense mutation Duchenne muscular dystrophy: observational data from the STRIDE Registry. Poster presented at The 23RD International Annual Congress of the World Muscle Society Congress, 2. – 6. October 2018, Mendoza, Argentina
  26. ↑ Merlini L and Sabatelli P. BMC Neurol. 2015; 15: 153
  27. ↑ Rosenberg AS et al. Sci Transl Med. 2015; 7: 299rv4
  28. ↑ Humbertclaude V et al. Eur J Pediatr Neurol. 2012; 16: 149-60
  29. ↑ FDA grants accelerated approval to first drug for Duchenne muscular dystrophy , PM FDA, September 19, 2016, accessed June 29, 2018
  30. ↑ Idebenon at DMD , manufacturer's website, accessed June 29, 2018
  31. ↑ Santhera submits approval application to the European Medicines Agency for Puldysa® (idebenone) in Duchenne muscular dystrophy , PM Santhera of May 27, 2019, accessed on December 3, 2019
  32. ↑ Servais L, Straathof C, Schara U, Klein A, Leinonen M, Hasham S, Meier T, de Waele L, Gordish-Dressman H, McDonald C, Mayer O, Voit T, Mercuri E, Buyse G for the SYROS and CINRG DNHS Investigators: Long-term data with idebenone on respiratory function outcomes in patients with Duchenne muscular dystrophy . In: Neuromusc Disorder . 29, No. 10, October 2019. doi : 10.1016 / j.nmd.2019.10.008 .
  33. ↑ Bristol-Myers Squibb Enters into Separate Agreements with Biogen and Roche to License Anti-eTau and Anti-Myostatin Compounds, Respectively , PM BMS, April 13, 2017, accessed June 29, 2018
  34. ↑ Eric P. Hoffman, Benjamin D. Schwartz, Laurel J. Mengle-Gaw, Edward C. Smith, Diana Castro, Jean K. Mah, Craig M. McDonald, Nancy L. Kuntz, Richard S. Finkel, Michela Guglieri, Katharine Bushby, Mar Tulinius, Yoram Nevo, Monique M. Ryan, Richard Webster, Andrea L. Smith, Lauren P. Morgenroth, Adrienne Arrieta, Maya Shimony, Catherine Siener, Mark Jaros, Phil Shale, John M. McCall, Kanneboyina Nagaraju, John van den Anker, Laurie S. Conklin, Avital Cnaan, Heather Gordish-Dressman, Jesse M. Damsker, Paula R. Clemens, the Cooperative International Neuromuscular Research Group: Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function . In: Neurology . 93, No. 13, September 2019, pp. E1312-e1323. doi : 10.1212 / WNL.0000000000008168 .