Myotonic dystrophy

Myotonic dystrophy
Other names	Dystrophia myotonica,[1] myotonia atrophica,[1] myotonia dystrophica[1]
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[1]
Complications	Cataracts, intellectual disability, heart conduction problems[1][2]
Usual onset	20s to 30s[1]
Duration	Long term[1]
Types	Type 1, type 2[1]
Causes	Genetic disorder (autosomal-dominant)[1]
Diagnostic method	Genetic testing.[2]
Treatment	Braces, wheelchair, pacemakers, non invasive positive pressure ventilation[2]
Medication	Mexiletine, carbamazepine, tricyclic antidepressants, nonsteroidal anti inflammatory drugs[2]
Frequency	>1 in 8,000 people[1]

Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of long-term genetic disorders that cause progressive muscle loss and weakness.^[1] In myotonic dystrophy, muscles are often unable to relax after contraction.^[1] Other symptoms may include cataracts, intellectual disability and heart conduction problems.^[1][2] In men, there may be early balding and an inability to have children.^[1] While myotonic dystrophy can occur at any age, onset is typically in the 20s and 30s.^[1]

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).^[1] DM is typically inherited from a person's parents, following an autosomal dominant inheritance pattern,^[1] and it generally worsens with each generation.^[1] A type of DM1 may be apparent at birth.^[1] DM2 is generally milder.^[1] Diagnosis is confirmed by genetic testing.^[2]

There is no cure.^[3] Treatments may include braces or wheelchairs, pacemakers and non-invasive positive pressure ventilation.^[2] The medications mexiletine or carbamazepine can help relax muscles.^[2] Pain, if it occurs, may be treated with tricyclic antidepressants and nonsteroidal anti-inflammatory drugs (NSAIDs).^[2]

Myotonic dystrophy affects more than 1 in 8,000 people worldwide.^[1] It is the most common form of muscular dystrophy that begins in adulthood.^[1] It was first described in 1909, with the underlying cause of type 1 determined in 1992.^[2]

Signs and symptoms[]

40-year-old with myotonic dystrophy who presented with muscle wasting, bilateral cataracts, and complete heart block.

DM causes muscle weakness, earlier onset of cataracts, and myotonia, which is delayed relaxation of muscles after contraction.^[4] Cataracts can be either a cortical cataract with a blue dot appearance, or a posterior subcapsular cataract.^[5] Both DM1 and DM2 can affect the heart, lungs, gastrointestinal system, skin, endocrine, and brain.^[4] Symptoms may appear at any time from infancy to adulthood. Insulin resistance can occur.^[4] Presentation of signs and symptoms varies considerably by form (DM1/DM2), severity and even unusual DM2 phenotypes. DM1 and DM2 preferentially affect different muscles.

DM1[]

DM1 usually begins in the muscles of the hands, feet, neck, or face.^[4] It slowly progresses to involve other muscle groups, including the heart. DM1 manifestations include problems with executive function (e.g., organization, concentration, word-finding) and hypersomnia.^[4] Abnormalities in the electrical activity of the heart are common in DM1, manifesting as arrhythmias or conduction blocks.^[2] Sometimes, dilated cardiomyopathy occurs.^[2]

DM2[]

DM2 is generally milder than DM1, with generally fewer DM2 people requiring assistive devices than DM1 people.^[6] DM2 preferentially affects muscles closer to or on the torso, including the neck flexors, hip flexors, and hip extensors.^[4] Heart issues, while still potentially fatal, are less common and severe in DM2 than DM1.^[2] 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 people in the medical literature.^[7]

Genetics[]

Myotonic dystrophy is inherited in an autosomal dominant pattern.

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. Myotonic dystrophy is one of several known trinucleotide repeat disorders. Certain areas of DNA have repeated sequences of three or four nucleotides.^{[citation needed]}

A severe form of DM, 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.^[8]

DM1[]

The cause of DM1 is mutation of the DMPK gene, which is located on the long arm of chromosome 19.^[9][10] DMPK codes for myotonic dystrophy protein kinase,^[11] a protein expressed predominantly in skeletal muscle.^[12]

Histopathology of DM2. Muscle biopsy showing mild myopathic changes and grouping of atrophic fast fibres (type 2, highlighted). Immunohistochemical staining for type-1 ("slow") myosin

The mutation in DMPK consists of an abnormally increased number of cytosine-thymine-guanine (CTG) triplet repeats, termed "trinucleotide repeat expansion." Trinucleotide repeat expansion in DM1 is found at the end of the gene, in the 3' untranslated region. 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;^[13] greater than 50 repeats almost invariably is symptomatic, with some noted exceptions. Longer repeats are usually associated with earlier onset and more severe disease.^{[citation needed]}

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.^[14] Misalignments occurring during homologous recombinational repair, double-strand break repair or during other DNA repair processes likely contribute to trinucleotide repeat expansions in DM1.^[14] 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.^{[citation needed]}

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.^[15]

DM2[]

DM2 is caused by a mutation of the CNBP gene on chromosome 3.^[16] Like DM1, the mutation of DM2 is a repeat expansion, although it instead is a tetranucleotide repeat disorder involving the cytosine-cytosine-thymine-guanosine (CCTG) tetranucleotide in the first intron of CNBP.^[16][17][18]

The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats.^[16] Unlike in DM1, the size of the repeated DNA expansion in DM2 does not appear to make a difference in the age of onset or disease severity.^[13] Anticipation appears to be less significant in DM2 and most current reviews only report mild anticipation as a feature of DM2.^{[citation needed]}

Diagnosis[]

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The diagnosis of DM1 and DM2 can be difficult due to the large number of neuromuscular disorders, most of which are very rare. More than 40 neuromuscular disorders exist with close to 100 variants.^{[citation needed]}

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.

The clinical presentation for both people with DM1 and DM2 commonly differs from the conception of the diseases held by many neurologists. Clinicians who are less familiar with myotonic dystrophies may expect people with both forms to present with the more severe, classic symptoms of DM1. As a result, people may remain undiagnosed or be misdiagnosed. A useful clinical clue for diagnosis is the failure of spontaneous release of the hands following strong handshakes due to myotonia (delayed relaxation of muscles after contraction) which accompanies muscle weakness.

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.

Classification[]

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.^[19] 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.^[20] Type 2 (DM2), also known as proximal myotonic myopathy (PROMM), is rarer and generally manifests with milder signs and symptoms than DM1.^[21]

Other forms of myotonic dystrophy not associated with DM1 or DM2 genetic mutations have been described.^[13] One case which was proposed as a candidate for the "DM3" label,^[22] was later characterized as an unusual form of inclusion body myopathy associated with Paget's disease and frontotemporal dementia.^[13][17][23]

Prenatal testing[]

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.

Predictive testing[]

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.

Management[]

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.^[24] Complications relating to the cardiopulmonary system account for 70% of deaths due to DM1.^[13] Compromised lung function can, in turn, contribute to life-threatening complications during anesthesia and pregnancy.^[24]

Lung complications are the leading cause of death in DM1, warranting lung function monitoring with pulmonary function tests every 6 months.^[24] 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.^{[citation needed]}

Cardiac complications are the second leading cause of death in DM1, and commonly no symptoms are present prior to adverse events.^[24] All affected individuals are advised to have an annual or biennial ECG.^[24] Pacemaker insertion may be required for individuals with cardiac conduction abnormalities. Improving the quality of life which can be measured using specific questionnaires^[25] is also a main objective of the medical care.

Physical activity[]

There is a lack of high-quality evidence to determine the effectiveness and the safety of physical activities for people who have myotonic dystrophy.^[26] 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.^[27][26] Aerobic exercise via stationary bicycle with an ergometer may be safe and effective in improving fitness in people with DM1.^[28] 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.^[29]

Orthotics[]

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 pattern^[29] or ankle-foot-orthotics may be indicated.^[13] 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.^[13]

Mobility aids and adaptive equipment[]

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.^[13]

Prognosis[]

Life expectancy in non-congenital late-onset or adult onset DM1 is in the early 50s,^[4] with pulmonary complications being the leading cause of death, followed by cardiac complications.^[24] DM2 life expectancy has yet to be studied.^[4]

Epidemiology[]

DM1 has a prevalence of 1:2500, putting it as the most common form of muscular dystrophy.^[4] DM2 prevalence is not known, but estimated to be as high as 1:1830.^[4] These estimates were generated with genetic studies and are higher than previous estimates, which were based on signs and symptoms.^[4] DM affects males and females approximately equally.^{[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.^[1]

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.^[13] 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.

History[]

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.^[30] 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.^[31] The underlying cause of type 1 myotonic dystrophy was determined in 1992.^[2]

Research directions[]

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.^[32]

Some small studies have suggested that imipramine, clomipramine and taurine may be useful in the treatment of myotonia.^[13] 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.^[33] Human studies are planned for erythromycin. Erythromycin has been used successfully in patients with gastric issues.^[34]

References[]

External links[]

• Myotonic dystrophy at Curlie