Myotonic dystrophy

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Myotonic dystrophy
ICD-10 G71.1
OMIM 160900 602668
DiseasesDB 8739
MeSH D009223

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Myotonic dystrophy (DM) is a chronic, slowly progressing, highly variable inherited multisystemic disease that can manifest at any age from birth to old age. It is characterized by wasting of the muscles (muscular dystrophy), posterior subcapsular iridescent cataracts (opacity of the lens of the eyes), heart conduction defects, endocrine changes and myotonia (difficulty relaxing a muscle). Most notably, the highly variable age of onset decreases with successive generations. Thus the disease shows at an earlier age in successive generations, a phenomenon termed anticipation. There are three classifications of DM, each having different associated symptoms.

Epidemiology, Prevalance and Demographics

  • Muscular dystrophies are a group of progressive, hereditary myopathic disorders stemming from defects in genes required for normal function.
  • Myotonic dystrophy is the most common form of muscular dystrophy among Caucasians with incidence of 8-14/100,000 and prevalence of 35/100000.
  • It is autosomal dominant with variable penetrance.
  • An unstable expansion of a trinucleotide (CTG) repeat occurs in a gene at 19q13.
  • An increase in severity of the phenotype occurs with progressive generations accompanied by an increase in the number of CTG repeats (genetic anticipation).

Classification

Myotonic dystrophy is the most common form of adult onset muscular dystrophy and the second most common form of any skeletal muscle disease after Duchenne muscular dystrophy. There are currently two known types of adult onset DM: Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, and Myotonic dystrophy type 2 (DM2), commonly referred to as PROMM or proximal myotonic myopathy. Both are identifiable by DNA analysis. DM1 also has a congenital form that can severely affect babies and a childhood onset form. Further forms of myotonic dystrophy (DM3, DM4, DMX) are currently suspected by researchers to exist.

Differences between DM1 and DM2

While both diseases are considered slow degenerative conditions, DM2 is considered to be generally milder than DM1. The severe congenital form that affects babies in DM1 has not been found in DM2 and the early onset of symptoms is rarely noted to appear in younger patients in the medical literature. The repeat expansion for DM2 is considerably larger than for DM1, ranging from 75 to over 11,000. Unlike DM1, the size of the repeated DNA expansion does not appear to make a difference in the age of onset or disease severity in DM2. Anticipation is a common feature of DM1. It appears to be less significant in type 2 and most current reviews only report mild anticipation as a feature of DM2. [1] [2] [3]

Genetics

Myotonic dystrophy is inherited in an autosomal dominant pattern.

DM is a genetic condition which is inherited in an autosomal dominant pattern, meaning that inheriting a mutant gene from one parent will result in the condition. There is a 50% chance of inheriting DM from an affected parent. In DM1, the affected gene is called DMPK (myotonic dystrophy protein kinase) which codes for a myosin kinase expressed in skeletal muscle. The gene is located on the long arm of chromosome 19. DM2 is similarly caused by a defect of the ZNF9 gene on chromosome 3q21.

DM is one of several known trinucleotide repeat disorders. Certain areas of DNA have repeated sequences of two or three nucleotides. In DM1, there is a triplet repeat of Cytosine - Thymine - Guanine (CTG) in the DMPK gene. The number of repeats varies greatly from person to person, but the average number in a healthy person is between 5 and 37. Sometimes when repetitive sequences of DNA are replicated during cell division the cellular machinery slips and an extra copy of the triplet repeat is added to the sequence. Once there are more than 37 triplet repeats in the DMPK gene the sequence becomes unstable and slippage becomes a lot more likely to happen. People affected with DM1 have over 50 and can have as many as 2000 repeats.

The result of this is that the repeat size of an individual with DM1 will become larger the older they are. This explains the phenomenon of anticipation, as each child of an affected adult will have a larger expansion than their parent due to slippage during gametogenesis. Individuals with larger expansions have an earlier onset of the disorder and a more severe phenotype. The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11000 repeats. Unlike DM1, the size of the repeated DNA expansion does not appear to make a difference in the age of onset or disease severity in DM2. Anticipation appears to be less significant in DM2 and most current reviews only report mild anticipation as a feature of DM2.

Diagnosis

The diagnosis of DM1 and DM2 are most likely to occur by doctors with specialized training in both neurology and adult neuromuscular disorders. Without appropriately trained and experienced medical resources, it is common for patients to be undiagnosed or misdiagnosed.

Family doctors are generalists who are more likely to follow advances in conditions they commonly see in their practice. They may not always recognize symptoms that appear unrelated which could alert them to the presence of a complex underlying multisystemic disorder such as DM1 or DM2 and fail to refer patients to a specialist familiar with these disorders. Depending on the presentation of symptoms, patients may be referred to a number of medical specialists including cardiologists, ophthalmologists, endocrinologists, rheumatologists.

Neuromuscular disorders can cover more than 40 different diseases and additional forms of these bring the number of distinct disorders closer to 100. Many diseases have seen dramatic advances in the research literature like DM1 and DM2 and it is not humanly possible for all doctors to closely follow all research. In general, the diagnostic criteria for DM2 is less known because the research in the area is relatively new and takes a long time to filter down effectively to all clinicians.

Some neuromuscular specialists focus primarily on many of the childhood onset neuromuscular diseases, while others may have research and clinical interests focused on specific diseases such as ALS and may be unaware of the potential relationship of specific symptoms to DM. It is common that the clinical presentation for both DM1 and DM2 patients does not conform to the perceptions of these diseases held by many neurologists. Clinicians who are less familiar with the myotonic dystrophies in their day to day practice may expect patients with both forms to present with the more severe classic symptoms of DM1. As a result, patients may remain undiagnosed or be misdiagnosed.

In addition, the clinical presentation for patients can vary considerably depending on the degree of severity or the presence of unusual phenotypes. This can legitimately make diagnosis more difficult for these patients.

Since there is presently no cure for DM and management is currently symptom based, many clinicians also do not recognize the importance of a precise diagnosis. They are unaware of significant health risks, including potentially fatal ones which even mildly affected DM1 & DM2 patients should be routinely monitored for (i.e. cardiac conduction issues, insulin resistance, cataracts). An accurate diagnosis is important to assist with appropriate medical monitoring and medical management of symptoms. In addition, genetic counseling should be made available to all patients because of the high risk of transmission. Potentially serious anesthetic risks are important to note, so the presence of this disorder should be brought to the attention of all medical providers.

History and Symptoms

  • Affected persons have “hatchet faces” from temporalis, masseter and facial muscle atrophy.
  • Necks appear thin from sternocleidomastoid involvement.
  • Typically, distal extensors are prominently involved.
  • Myotonia, a slow relaxation following voluntary contraction, is often elicited in the thenar eminence.
  • Palatal, pharyngeal and tongue involvement produces dysarthria and nasal speech.
  • Footdrop occurs, but proximal flexors remain intact until late.
  • Respiratory muscles can be involved.
  • Other findings include:

Physical Examination

Presentation of symptoms varies considerably by form (DM1/DM2), severity and even unusual DM2 phenotypes. DM1 patients often present with myotonia, disabling distal weakness and severe cognitive problems. DM2 patients commonly present with muscle pain, stiffness, fatigue, or the development of proximal lower extremity weakness (Day & al, 2003). The characteristic pattern of weakness is different for DM1 and DM2: In DM1, it is noted in face and jaw muscles, the drooping of the eyelids (ptosis), weakness of the neck muscles, hands and lower legs. In DM2, the weakness is more evident in proximal muscles, those closer to the trunk of the body: neck, shoulders, hip flexors and upper legs.

Noted DM1 symptoms which are considered less severe or common for DM2 are problems with smooth muscle (including G.I. symptoms), hypersomnia (daytime sleepiness), muscle wasting, dysphagia and respiratory insufficiency. DM1 patients may experience a more diverse range of cognitive problems than DM2. Depending on what form they have and the degree of severity, DM1 cognitive problems may range from developmental delays, learning problems, language, speech, behaviour, apathy or hypersomnia. Cognitive manifestations for DM2 include problems with executive function (i.e. organization, concentration, word-finding etc) and hypersomnia. Conduction abnormalities are more common in DM1 than DM2, but all patients are advised to have an annual ECG. Insulin resistance is a significant risk factor in both forms of the disease for diabetes, cholesterol, heart, stroke, lipids, fatty liver, etc.

Testing for insulin resistance must be at least 3 hours and include serial monitoring of the lipid profile and intermittent assessment of oral glucose tolerance testing as per the report from the 140th ENMC International Workshop: Myotonic Dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management (2006) Diabetes type 2 is suspected of being more common in DM2 than in DM1. Generally far fewer DM2 patients require assistive devices (canes, walkers, wheelchairs, scooters) than in DM1, though they experience increasing difficulties climbing stairs as the disease progresses, and falling or stumbling may sometimes be reported.

Heart

  • Cardiomyopathy develops in a small percentage.
  • More common are conduction defects that may necessitate pacemaker placement to mitigate the risk of sudden cardiac death.
  • Congestive heart failure (CHF) may occur as a primary muscle disorder or from cor pulmonale secondary to respiratory failure from repeated infections.

Laboratory Findings

Electrolyte and Biomarker Studies

  • Creatinine kinase (CKs) are normal or mildly elevated.

Other Diagnostic Studies

  • Unlike biopsy findings in other myopathies, necrosis of muscle fibers and connective tissue replacement is not usually seen.
  • Selective atrophy of Type I fibers and increased numbers of central nuclei are seen.
  • A congenital variant occurs exclusively in infants born to affected mothers and is more severe.

AHA Scientific Statement: Management of Cardiac Involvement Associated With Neuromuscular Diseases

Cardiac Evaluation in Myotonic Dystrophy (DM)

Class I
"1. Cardiology evaluation with examination, ECG, echocardiogram, and ambulatory electrocardiographic monitoring should occur at the time of DM diagnosis, regardless of symptoms. (Level of Evidence: C) "
"2. DM patients with palpitations, dizziness, syncope, non–sinus rhythm, PR interval >240 ms, QRS duration >120 ms, or second- or third-degree atrioventricular block should be evaluated at least annually and also considered for invasive electrophysiology study for possible pacemaker or ICD placement. (Level of Evidence: C) "
Class IIa
"1. For DM patients with normal LVEF who lack the features listed in recommendation 2, it is reasonable to reassess by examination, ECG, and ambulatory electrocardiographic monitoring annually and by echocardiogram every 2 to 4 years. (Level of Evidence: B) "
Class IIb
"1. For young DM1 patients, serial exercise stress testing and signal-averaged ECGs may be considered. (Level of Evidence: B) "

Management

There is currently no cure for or treatment specific to myotonic dystrophy.

Heart problems, cataracts, and other abnormalities associated with the condition can be treated but not cured. However there are medical interventions and medications that may relieve some of the symptoms such as myotonia, pain and excessive sleepiness. Some treatments have been subject to systematic review for safety and efficacy through the Cochrane Reviews for symptoms such as hypersomnia (excessive daytime sleepiness), myotonia, strength training and aerobic exercise training and foot drop.

Myotonia can be treated with quinidine and procainamide, but phenytoin is the drug of choice.

Recent research has provided more information on the underlying molecular pathomechanisms involved in myotonic dystrophy and has fueled interest and research into new approaches for more specific and effective treatment. Research in areas such as high throughput screening and antisense therapy hold hope for more effective targeted treatments for the future.

Progress in this area is being fueled by the sharing of research by scientists and clinicians at biannual meetings by the International Myotonic Dystrophy Consortium (IDMC). The 6th meeting (IDMC-6) took place in Milan Italy in September 2007.

Screening

Screening for the DMPK gene for DM1 is targeted at chromosome 19 while the ZNF9 gene for DM2 is found on chromosome 3. Genetic tests are available for both confirmed forms. Molecular testing is considered the gold standard of diagnosis. Further forms of myotonic dystrophy (DM3, DM4, DMX) are suspected by researchers with possible defects on chromosome 16 and chromosome 21.

References

  1. Le Ber I, Martinez M, Campion D, et al (2004). "A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24". Brain 127 (Pt 9): 1979–92. doi:10.1093/brain/awh216. PMID 15215218.
  2. Udd B, Meola G, Krahe R, et al (2006). "140th ENMC International Workshop: Myotonic Dystrophy DM2/PROMM and other myotonic dystrophies with guidelines on management". Neuromuscul. Disord. 16 (6): 403–13. doi:10.1016/j.nmd.2006.03.010. PMID 16684600.
  3. Wheeler, TM; Lueck JD, Swanson MS, Dirkson RT, Thornton CA (2007). "Correction of CIC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy" (Pubmed). JCI. doi:doi:10.1172/JCI33355.

Recommended Reading

  • Sir Peter S. Harper,. Myotonic Dystrophy: The Facts : A Book for Patients and Families (Oxford Medical Publications). Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-852586-9.
  • Peter S. Harper... [et al.] (2004). Myotonic dystrophy: present management, future therapy. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-852782-9.
  • Robert D. Wells (Editor), Tetsuo Ashizawa (Editor). Genetic Instabilities and Neurological Diseases, Second Edition, 2006. Boston: Academic Press. ISBN 0-12-369462-0. This book has chapters on multiple disorders including both Steinhart’s (DM1) and PROMM (DM2). The revised 2006 edition is the first print resource to have a full chapter on DM2: Myotonic Dystrophy Type 2: Clinical and Genetic Aspects by Krahe, Bachinski, and Udd This book is intended to be a reference for medical professionals such as neurologists, neuroscientists, biochemists, geneticists, molecular biologists & human geneticists.

Research and Reviews

The research on DM1/DM2/DM3 has rapidly evolved over the last decade. Always note dates of research or the update period for websites to provide context for how current and accurate the information may be. Although the newest research is rarely available without journal subscription, there are many free online reports and reviews which discuss the clinical spectrum of symptoms, therapies, etc for both DM1 and DM2. These papers are a collaborative effort by those on the front lines to document the current state of research and should be used as a resource by doctors for guidance on diagnosis and management.

External links

NOTE: The research on DM1/DM2/DM3 has rapidly evolved over the last decade. Always note update period for websites to provide context for how current and accurate the information may be. The better websites tend to have updated information on both DM1 and DM2, and provide some differentiation between them.

DM1 Websites

DM2 Websites

DM3 Websites

Patient Education and Support

Web-based discussion group for patients diagnosed with DM

Regional Support Groups

Muscular Dystrophy

Cost Effectiveness of Myotonic dystrophy

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| group16 = Business Resources on Myotonic dystrophy | list16 = Myotonic dystrophy in the MarketplacePatents on Myotonic dystrophy

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de:Myotone Dystrophie nl:Ziekte van Steinert



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