|Other names||Dystrophia myotonica, myotonia atrophica, myotonia dystrophica|
|Areas of body affected in myotonic dystrophy, types 1 and 2, colored in red|
|Specialty||Neurology, neuromuscular medicine, physical medicine and rehabilitation, medical genetics, pediatrics|
|Symptoms||Muscle loss, weakness, muscles which contract and are unable to relax|
|Complications||Cataracts, intellectual disability, heart conduction problems|
|Usual onset||20s to 30s|
|Types||Type 1, type 2|
|Causes||Genetic disorder (autosomal-dominant)|
|Diagnostic method||Genetic testing.|
|Treatment||Braces, wheelchair, pacemakers, non invasive positive pressure ventilation|
|Medication||Mexiletine, carbamazepine, tricyclic antidepressants, nonsteroidal anti inflammatory drugs|
|Frequency||>1 in 8,000 people|
Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness.In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intellectual disability and heart conduction problems. In men, there may be early balding and an inability to have children. While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s.
Myotonic dystrophy is caused by a genetic mutation in one of two genes. Mutation of the DMPK gene causes myotonic dystrophy type 1 (DM1). Mutation of CNBP gene causes type 2 (DM2).DM is typically inherited from a person's parents, following an autosomal dominant inheritance pattern, and it generally worsens with each generation. A type of DM1 may be apparent at birth. DM2 is generally milder. Diagnosis is confirmed by genetic testing.
There is no cure.Treatments may include braces or wheelchairs, pacemakers and non-invasive positive pressure ventilation. The medications mexiletine or carbamazepine can help relax muscles. Pain, if it occurs, may be treated with tricyclic antidepressants and nonsteroidal anti-inflammatory drugs (NSAIDs).
Myotonic dystrophy affects more than 1 in 8,000 people worldwide.It is the most common form of muscular dystrophy that begins in adulthood. It was first described in 1909, with the underlying cause of type 1 determined in 1992.
DM causes muscle weakness, early onset of cataracts, and myotonia, which is delayed relaxation of muscles after contraction. [ citation needed ] DM1 and DM2 differ in regards to the muscles they affect, age of onset, severity of disease, and extramuscular manifestations.Cataracts can be either a cortical cataract with a blue dot appearance, or a posterior subcapsular cataract. Other organs affected include the heart, lungs, gastrointestinal tract, skin, and brain. Insulin resistance can also occur. Signs and symptoms vary considerably by severity, unusual phenotype, and form (DM1/DM2).
DM1 usually begins in the muscles of the hands, feet, neck, or face. [ citation needed ] It slowly progresses to involve other muscle groups, including the heart. Myotonia tends to be more prominent in DM1 compared to DM2. Other DM1 manifestations include problems with executive function (e.g., organization, concentration, word-finding) and hypersomnia. Abnormalities in the electrical activity of the heart are common in DM1, manifesting as arrhythmias or conduction blocks. Sometimes, dilated cardiomyopathy occurs. Symptoms onset any time from birth to adulthood. The earlier the disease onset, the greater the variety of possible signs and symptoms. [ citation needed ] Thus, various diagnostic classifications based on the age of onset/severity of the disease have been proposed, although DM1 manifestations likely lie on a continuum.One manifestation of facial weakness is drooping of the eyelid (ptosis).
When DM1 onsets at birth, it is called congenital DM1. [ citation needed ]Manifestations that can be present at birth include hypotonia, respiratory failure, feeding difficulty, and club foot (talipes equinovarus), any of which tend to resolve over several years. During childhood, intellectual impairment, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASD) can result. Gastrointestinal issues can result, which can be severe, manifestations including diarrhea, constipation, and fecal incontinence. The symptoms of adult DM often manifest during adolescence. Infantile DM1 can be distinguished as another disease category, or it can be grouped with congenital DM1 or childhood-onset DM1.
Childhood-onset DM1 is defined as onset of symptoms between ages 1 and 10 years.Manifestations include the same intellectual and gastrointestinal symptoms seen in congenital DM1.
DM2 is generally milder than DM1, with generally fewer DM2 people requiring assistive devices than DM1 people.DM2 preferentially affects muscles closer to or on the torso, including the neck flexors, hip flexors, and hip extensors. Muscle pain is prominent in DM2. Heart issues, while still potentially fatal, are less common and severe in DM2 than DM1. Symptoms onset in early to late adulthood. Severe congenital onset, which can occur in DM1, has not been observed in DM2.
Myotonic dystrophy (DM) is a genetic condition that is inherited in an autosomal dominant pattern, meaning each child of an affected individual has a 50% chance of inheriting the disease. The mutation involves satellite DNA, which is tandemly repeated sequences of DNA that do not code for a protein. The repeats implicated in myotonic dystrophy are either 3 or 4 nucleotides in length, classified as microsatellites. Disease results from an abnormally increased number of these microsatellites, termed microsatellite expansion.
The microsatellite expansion responsible for DM1 is of cytosine-thymine-guanine (CTG) triplet repeats, termed trinucleotide repeat expansion and classifying DM1 as a one of several trinucleotide repeat disorders. This expansion occurs at the end of the DMPK gene, in the 3' untranslated region. DMPK is located on the long arm of chromosome 19.DMPK codes for myotonic dystrophy protein kinase, a protein expressed predominantly in skeletal muscle.
Between 5 and 37 repeats is considered normal; between 38 and 49 repeats is considered pre-mutation, and although not producing symptoms, children can have further repeat expansion and symptomatic disease; [ citation needed ]greater than 50 repeats almost invariably is symptomatic, with some noted exceptions. Longer repeats are usually associated with earlier onset and more severe disease.
DMPK alleles with greater than 37 repeats are unstable and additional trinucleotide repeats may be inserted during cell division in mitosis and meiosis. Consequently, the children of individuals with premutations or mutations inherit DMPK alleles which are longer than their parents and therefore are more likely to be affected or display an earlier onset and greater severity of the condition, a phenomenon known as anticipation. Repeat expansion is generally considered to be a consequence of the incorporation of additional bases as a result of strand slippage during either DNA replication or DNA repair synthesis. [ citation needed ]Misalignments occurring during homologous recombinational repair, double-strand break repair or during other DNA repair processes likely contribute to trinucleotide repeat expansions in DM1. Paternal transmission of the congenital form is uncommon (13%), possibly due to selection pressures against sperm with expanded repeats, but juvenile or adult-onset is equally transmitted from either parent. Anticipation tends to be less severe than in cases of maternal inheritance.
The RNA from the expanded trinucleotide repeat region forms intranucleoplasmic hairpin loops due to the extensive hydrogen bonding between C-G base pairs, and it has been demonstrated that these sequester the splicing regulator MBNL1 to form distinctive foci.
A severe form of DM1, congenital myotonic dystrophy, may appear in newborns of mothers who have DM. Congenital myotonic dystrophy can also be inherited via the paternal gene, although it is said to be relatively rare. Congenital means that the condition is present from birth.
The microsatellite expansion responsible for DM2 is of cytosine-cytosine-thymine-guanine (CCTG) repeats, classifying it as a tetranucleotide repeat disorder. This expansion occurs in the first intron CNBP gene on chromosome 3.
The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats.Like DM1, the size of the microsatellite repeat array lengthens from generation to generation. Unlike DM1, anticipation does not result, as the degree of repeat expansion beyond 75 repeats does not affect the age of onset or disease severity.
The repeat expansion produces an RNA transcript that binds to RNA-binding proteins such as MBNL1, as in DM1.Also, repeat expansion likely reduces expression of CNBP, loss of which causes muscle toxicity.
Mutations of DM1 and DM2 cause production of RNA that sequesters RNA-binding proteins, causing dysregulated RNA splicing. [ citation needed ] One example in DM1 involves the chloride channel ClC-1. Mutated DMPK RNA binds to MBNL1, causing ClC-1 pre-mRNA to be spliced into the fetal form instead of the adult form. Functional loss of the chloride channel causes myotonia.This dysregulated RNA splicing is particularly toxic to skeletal, cardiac, and smooth muscle.
In DM1, there can be increased central nuclei, angular fibers, fiber atrophy, and pyknotic clumps.There can be selective atrophy of type 1 muscle fibers. Muscle fibers show signs of degeneration and regeneration. There is modest fibrosis of the endomysium.
In DM2, there can be variation in the sizes of muscle fibers, although often there are no abnormalities.There is selective atrophy of type 2 muscle fibers. Again, there are central nuclei and nuclear clumps.
The diagnosis of DM1 and DM2 can be difficult due to the large number of neuromuscular disorders, most of which are very rare. One study found that diagnosis is made an average of seven years after symptom onset for DM1, and fourteen years for DM2.
As a result, people with multiple symptoms that may be explained by a complex disorder such as DM1 or DM2 will generally be referred by their primary care physician to a neurologist for diagnosis. Depending on the presentation of symptoms, people may be referred to a number of medical specialists including cardiologists, ophthalmologists, endocrinologists, and rheumatologists. In addition, the clinical presentation is obscured by the degree of severity or the presence of unusual phenotypes.
Though there is presently no cure for DM and management is currently symptom-based, a precise diagnosis is still necessary to anticipate multiple other problems that may develop over time (e.g. cataracts). An accurate diagnosis is important to assist with appropriate medical monitoring and management of symptoms. In addition, genetic counseling should be made available to all people 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.
There are two main types of myotonic dystrophy. Type 1 (DM1), also known as Steinert disease, has a severe congenital form and a milder childhood-onset form as well as an adult-onset form.This disease is most often in the facial muscles, levator palpebrae superioris, temporalis, sternocleidomastoids, distal muscles of the forearm, hand intrinsic muscles, and ankle dorsiflexors. Type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is rarer and generally manifests with milder signs and symptoms than DM1.
Other forms of myotonic dystrophy not associated with DM1 or DM2 genetic mutations have been described.One case which was proposed as a candidate for the "DM3" label, was later characterized as an unusual form of inclusion body myopathy associated with Paget's disease and frontotemporal dementia.
Genetic tests, including prenatal testing, are available for both confirmed forms. Molecular testing is considered the gold standard of diagnosis.
Testing at pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a DMPK mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS) that involves removing a tiny piece of the placenta and analyzing DNA from its cells. It can also be done by amniocentesis after 14 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with it and those who are interested in learning more should check with their doctor or genetic counselor. There is also another procedure called preimplantation diagnosis that allows a couple to have a child that is unaffected by the genetic condition in their family. This procedure is experimental and not widely available. Those interested in learning more about this procedure should check with their doctor or genetic counselor.
It is possible to test someone who is at risk for developing DM1 before they are showing symptoms to see whether they inherited an expanded trinucleotide repeat. This is called predictive testing. Predictive testing cannot determine the age of onset that someone will begin to have symptoms or the course of the disease. If the child is not having symptoms, the testing is not possible with an exception of emancipated minors as a policy.
Electrodiagnostic testing (EMG and NCS) can detect the electrical signs of myotonia before myotonia becomes noticeable to the affected individual.
Muscle biopsy can reveal damage of the muscle, but findings are generally nonspecific and do not greatly aid in diagnosis.
There is currently no cure for or treatment specific to myotonic dystrophy. Management is focused on the complications of the disease, particularly those related to the lungs and heart, which are life-threatening.Complications relating to the cardiopulmonary system account for 70% of deaths due to DM1. Compromised lung function can, in turn, contribute to life-threatening complications during anesthesia and pregnancy.
Lung complications are the leading cause of death in DM1, warranting lung function monitoring with pulmonary function tests every 6 months. [ citation needed ]Central sleep apnea or obstructive sleep apnea may cause excessive daytime sleepiness, and these individuals should undergo a sleep study. Non-invasive ventilation may be offered if there is an abnormality. Otherwise, there is evidence for the use of modafinil as a central nervous system stimulant, although a Cochrane review has described the evidence thus far as inconclusive.
Cardiac complications are the second leading cause of death in DM1, and commonly no symptoms are present prior to adverse events.All affected individuals are advised to have an annual or biennial ECG. Pacemaker insertion may be required for individuals with cardiac conduction abnormalities. Improving the quality of life which can be measured using specific questionnaires is also a main objective of the medical care.
There is a lack of high-quality evidence to determine the effectiveness and the safety of physical activities for people who have myotonic dystrophy.Further research is required to determine if combined strength and aerobic training at moderate intensity is safe for people who have neuromuscular diseases, however the combination of aerobic and strength exercises may increase muscle strength. Aerobic exercise via stationary bicycle with an ergometer may be safe and effective in improving fitness in people with DM1. Cardiovascular impairments and myotonic sensitivities to exercise and temperature necessitate close monitoring of people and educating people in self-monitoring during exercise via the Borg scale, heart rate monitors, and other physical exertion measurements.
Muscular weakness of dorsiflexors (dorsiflexion) hinders the ability to clear the floor during the swing phase of gait and people may adopt a steppage gait patternor ankle-foot-orthotics may be indicated. Factors such as hand function, skin integrity, and comfort must be assessed prior to prescription. Neck braces can also be prescribed for neck muscle weakness.
Upper and lower limb weakness, visual impairments and myotonia may lead to the need for mobility aids and functional adaptive equipment such as buttonhooks and handled sponges for optimal hand function. If assistive devices and home adaptations are needed, physical therapists may refer on to occupational therapist(s) for further assessment.
Life expectancy in non-congenital late-onset or adult onset DM1 is in the early 50s,with pulmonary complications being the leading cause of death, followed by cardiac complications. DM2 life expectancy has yet to be studied.
The prevalence of DM1 ranges from 5 to 20 per 100,000 (1:20,000–1:5000). [ citation needed ] About 30,000 people in the United States are affected.[ citation needed ] In most populations, DM1 appears to be more common than DM2. However, recent studies suggest that type 2 may be as common as type 1 among people in Germany and Finland.Up to 48 per 100,000 (1:2100) of individuals tested positive for the mutation of DM1 in New York, although not all of these individuals would have become symptomatic. Again in New York, premutations for DM1 were found in 191 per 100,000 (1:525). DM2 prevalence is not known, but genetic studies estimate it to be as high as 1:1830. DM affects males and females approximately equally.
DM1 is the most common form of myotonic muscular dystrophy diagnosed in children, with a prevalence ranging from 1 per 100,000 in Japan to 3–15 per 100,000 in Europe.The prevalence may be as high as 1 in 500 in regions such as Quebec, possibly due to the founder effect. The incidence of congenital myotonic dystrophy is thought to be about 1:20,000.
Myotonic dystrophy was first described by a German physician, Hans Gustav Wilhelm Steinert, who first published a series of 6 cases of the condition in 1909.Isolated case reports of myotonia had been published previously, including reports by Frederick Eustace Batten and Hans Curschmann, and type 1 myotonic dystrophy is therefore sometimes known as Curschmann-Batten-Steinert syndrome. The underlying cause of type 1 myotonic dystrophy was determined in 1992.
Altered splicing of the muscle-specific chloride channel 1 (ClC-1) has been shown to cause the myotonic phenotype of DM1 and is reversible in mouse models using Morpholino antisense to modify splicing of ClC-1 mRNA.
Some small studies have suggested that imipramine, clomipramine and taurine may be useful in the treatment of myotonia.However, due to the weak evidence and potential side effects such as cardiac arrhythmias, these treatments are rarely used. A recent study in December 2015 showed that a common FDA approved antibiotic, Erythromycin reduced myotonia in mice. Human studies are planned for erythromycin. Erythromycin has been used successfully in patients with gastric issues.
Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.
Limb–girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of rare muscular dystrophies that share a set of clinical characteristics. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles. LGMD usually has an autosomal pattern of inheritance. It currently has no known cure or treatment.
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation of the skeletal muscles after voluntary contraction or electrical stimulation.
Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene.
In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.
The myotonic goat or Tennessee fainting goat is an American breed of meat goat. It is characterised by myotonia congenita, a hereditary condition that may cause it to stiffen or fall over when startled. It may also be known as the fainting goat, falling goat, stiff-legged goat or nervous goat, or as the Tennessee wooden-leg goat. Four goats of this type were brought to Tennessee in the 1880s.
Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm. These areas can be spared, and muscles of other areas usually are affected, especially those of the chest, spine, abdomen, and shin. Almost any skeletal muscle can be affected in severe disease. Abnormally positioned, or winged, scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15 – 30 years. FSHD can also cause hearing loss and blood vessel abnormalities in the back of the eye.
Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they become unstable. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to chromosome instability. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.
Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles. It is a genetic disorder. The hallmark of the disease is the failure of initiated contraction to terminate, often referred to as delayed relaxation of the muscles (myotonia) and rigidity. Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some forms of the disorder, severe masseter spasm, and cramping. The condition is sometimes referred to as fainting goat syndrome, as it is responsible for the eponymous 'fainting' seen in fainting goats when presented with a sudden stimulus. Of note, myotonia congenita has no association with malignant hyperthermia (MH).
Slipped strand mispairing (SSM),, is a mutation process which occurs during DNA replication. It involves denaturation and displacement of the DNA strands, resulting in mispairing of the complementary bases. Slipped strand mispairing is one explanation for the origin and evolution of repetitive DNA sequences.
Emery–Dreifuss muscular dystrophy (EDMD) is a type of muscular dystrophy, a group of heritable diseases that cause progressive impairment of muscles. EDMD affects muscles used for movement, causing atrophy, weakness and contractures. It almost always affects the heart, causing abnormal rhythms, heart failure, or sudden cardiac death. It is rare, affecting 0.39 per 100,000 people. It is named after Alan Eglin H. Emery and Fritz E. Dreifuss.
A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.
In genetics, a dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product (progeny) of a dynamic mutation has a different likelihood of mutation than its predecessor. These mutations, typically short sequences repeated many times, give rise to numerous known diseases, including the trinucleotide repeat disorders.
Congenital myopathy is a very broad term for any muscle disorder present at birth. This defect primarily affects skeletal muscle fibres and causes muscular weakness and/or hypotonia. Congenital myopathies account for one of the top neuromuscular disorders in the world today, comprising approximately 6 in 100,000 live births every year. As a whole, congenital myopathies can be broadly classified as follows:
Bethlem myopathy is an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy, that is caused by a mutation in one of the three genes coding for type VI collagen. These include COL6A1, COL6A2, and COL6A3. Gower's sign, tiptoe-walking and contractures of the joints are typical signs and symptoms of the disease. Bethlem myopathy could be diagnosed based on clinical examinations and laboratory tests may be recommended. Currently there is no cure for the disease and symptomatic treatment is used to relieve symptoms and improve quality of life. Bethlem myopathy affects about 1 in 200,000 people.
Myotonin-protein kinase (MT-PK) also known as myotonic dystrophy protein kinase (MDPK) or dystrophia myotonica protein kinase (DMPK) is an enzyme that in humans is encoded by the DMPK gene.
Dystrophia myotonica WD repeat-containing protein is a protein that in humans is encoded by the DMWD gene.
Ying-Hui Fu is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for circadian rhythm disorders, and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California, San Francisco. She was elected to the US National Academy of Sciences in 2018.
RNA-dominant diseases are characterized by deleterious mutations that typically result in degenerative disorders affecting various neurological, cardiovascular, and muscular functions. Studies have found that they arise from repetitive non-coding RNA sequences, also known as toxic RNA, which inhibit RNA-binding proteins leading to pathogenic effects. The most studied RNA-dominant diseases include, but are not limited to, myotonic dystrophy and fragile X-associated tremor/ataxia syndrome (FXTAS).
Muscle–eye–brain (MEB) disease, also known as muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A3 (MDDGA3), is a kind of rare congenital muscular dystrophy (CMD), largely characterized by hypotonia at birth. Patients suffer from muscular dystrophy, central nervous system abnormalities and ocular abnormalities, the condition is degenerative.