Myotonic dystrophy
Encyclopedia
Myotonic dystrophy is a chronic, slowly progressing, highly variable inherited multisystemic disease
. It is characterized by wasting of the muscles (muscular dystrophy
), cataract
s, heart conduction defects, endocrine changes, and myotonia
. Myotonic dystrophy can occur in patients of any age. Genetically the disease is autosomal dominant.
Two types of adult onset myotonic dystrophy exist. Type 1 (DM1), also called Steinert's disease, has a severe congenital form and a milder childhood-onset form. Myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM), is due to a different mechanism than DM1 and generally manifests with milder signs and symptoms.
Other forms of myotonic dystrophy (DM3, DM4, and DMX) may also exist. One recent case was proposed as a candidate for the "DM3" label, but was later characterized as a form of Paget's disease
.
diagnosed in adults. Myotonic dystrophy affects at least 1 in 8,000 people worldwide. The prevalence of the two types of myotonic dystrophy varies among different geographic and ethnic populations. In most populations, type 1 appears to be more common than type 2. However, recent studies suggest that type 2 may be as common as type 1 among people in Germany and Finland.
, 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 et 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.
Symptoms and signs classically associated with DM1 are generally more mild and involve the smooth muscle (including G.I. symptoms), hypersomnia
(daytime sleepiness), muscle wasting, dysphagia
, and respiratory insufficiency. In addition, DM1 may manifest with a cognitive abnormalities including developmental delays, learning problems, language
, speech, behaviour, apathy
or hypersomnia. Cognitive manifestations for DM2 include problems with executive function (e.g., organization, concentration, word-finding) and hypersomnia. Conduction abnormalities are more common in DM1 than DM2, but all patients are advised to have an annual ECG. Both types are also associate with insulin resistance
.
DM2 is generally milder than DM1, with generally fewer DM2 patients requiring assistive devices than DM1 patients. In addition, 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.
Myotonic dystrophy is a genetic
condition which is inherited in an autosomal dominant pattern and thus will be passed along to 50% of a carrier's offspring, on average.
Myotonic dystrophy is one of several known trinucleotide repeat disorders. Certain areas of DNA
have repeated sequences of two or three nucleotides.
, a protein expressed predominantly in skeletal muscle. The gene is located on the long arm of chromosome 19
.
In DM1, there is a repeat of the triplet cytosine
-thymine
-guanine
(CTG) in the DMPK gene. The number of repeats varies greatly, but the average number in a healthy person is between 5 and 37. Additional trinucleotide repeats inserted during cell division
can produce protein instability. Consequently, the repeat size of an individual with DM1 will become larger usually during gametogenesis
or early embryonic development. This explains the phenomenon
of anticipation
, as each child of an affected adult will have a larger expansion than their parent. Individuals with larger expansions have an earlier onset of the disorder and a more severe phenotype
.
. The specific defect is a repeat of the cytosine-cytosine-thymine-guanosine (CCTG) tetranucleotide in the ZNF9 gene. As it involves the repeat of four nucleotides, it is not a trinucleotide repeat disorder, but rather a tetranucleotide repeat disorder.
The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats. 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. Anticipation appears to be less significant in DM2 and most current reviews only report mild anticipation as a feature of DM2.
As a result, patients 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, patients 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 phenotype
s.
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.
Even though there is presently no cure for DM and management is currently symptom based, a precise diagnosis is still necessary because of multiple other problems that may develop over time, e. g. 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.
, 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, aerobic exercise training, and foot drop.
Recent research has provided more information on the underlying molecular pathophysiologic mechanisms 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. 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.
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 7th biennial meeting IDMC-7 took place in Wurzburg, Germany September 9–12, 2009. The 8th biennial meeting will take place in Clearwater, Florida, USA November 30-December 3, 2011.
, while the ZNF9 gene for DM2 is found on chromosome 3
. Genetic tests, including prenatal testing, are available for both confirmed forms. Molecular testing is considered the gold standard
of diagnosis. Further forms of myotonic dystrophy (DM3, DM4, and DMX) are suspected by researchers with possible defects on chromosome 16
and chromosome 21
.
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
. It is characterized by wasting of the muscles (muscular dystrophy
Muscular dystrophy
Muscular dystrophy is a group of muscle diseases that weaken the musculoskeletal system and hamper locomotion. Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue.In the 1860s, descriptions of boys who...
), cataract
Cataract
A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
s, heart conduction defects, endocrine changes, and myotonia
Myotonia
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed...
. Myotonic dystrophy can occur in patients of any age. Genetically the disease is autosomal dominant.
Classification
| Type | Gene | Repeat | Anticipation | Severity |
|---|---|---|---|---|
| DM1 | DMPK | CTG | Yes | Moderate-severe |
| DM2 | ZNF9 | CCTG | Minimal/none | Mild-moderate |
Two types of adult onset myotonic dystrophy exist. Type 1 (DM1), also called Steinert's disease, has a severe congenital form and a milder childhood-onset form. Myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM), is due to a different mechanism than DM1 and generally manifests with milder signs and symptoms.
Other forms of myotonic dystrophy (DM3, DM4, and DMX) may also exist. One recent case was proposed as a candidate for the "DM3" label, but was later characterized as a form of Paget's disease
Paget's disease
Sir James Paget, a surgeon and pathologist, described several diseases, including:* Paget's disease of bone * Paget's disease of the breast* Paget-Schroetter disease* Extramammary Paget's disease...
.
Epidemiology
Myotonic dystrophy is the most common form of muscular dystrophyMuscular dystrophy
Muscular dystrophy is a group of muscle diseases that weaken the musculoskeletal system and hamper locomotion. Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue.In the 1860s, descriptions of boys who...
diagnosed in adults. Myotonic dystrophy affects at least 1 in 8,000 people worldwide. The prevalence of the two types of myotonic dystrophy varies among different geographic and ethnic populations. In most populations, type 1 appears to be more common than type 2. However, recent studies suggest that type 2 may be as common as type 1 among people in Germany and Finland.
Symptoms and signs
Presentation of symptoms and signs varies considerably by form (DM1/DM2), severity and even unusual DM2 phenotypes. DM1 patients often present with myotoniaMyotonia
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed...
, disabling distal weakness and severe cognitive problems. DM2 patients commonly present with muscle pain, stiffness
Stiffness
Stiffness is the resistance of an elastic body to deformation by an applied force along a given degree of freedom when a set of loading points and boundary conditions are prescribed on the elastic body.-Calculations:...
, fatigue, or the development of proximal lower extremity weakness (Day et 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
Ptosis (eyelid)
Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
), 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.
Symptoms and signs classically associated with DM1 are generally more mild and involve the smooth muscle (including G.I. symptoms), hypersomnia
Hypersomnia
Hypersomnia is a disorder characterized by excessive amounts of sleepiness.There are two main categories of hypersomnia: primary hypersomnia and recurrent hypersomnia...
(daytime sleepiness), muscle wasting, dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
, and respiratory insufficiency. In addition, DM1 may manifest with a cognitive abnormalities including developmental delays, learning problems, language
Language
Language may refer either to the specifically human capacity for acquiring and using complex systems of communication, or to a specific instance of such a system of complex communication...
, speech, behaviour, apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
or hypersomnia. Cognitive manifestations for DM2 include problems with executive function (e.g., organization, concentration, word-finding) and hypersomnia. Conduction abnormalities are more common in DM1 than DM2, but all patients are advised to have an annual ECG. Both types are also associate with insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
.
DM2 is generally milder than DM1, with generally fewer DM2 patients requiring assistive devices than DM1 patients. In addition, 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.
Genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
condition which is inherited in an autosomal dominant pattern and thus will be passed along to 50% of a carrier's offspring, on average.
Myotonic dystrophy is one of several known trinucleotide repeat disorders. Certain areas of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
have repeated sequences of two or three nucleotides.
DM1
In DM1, the affected gene is called DMPK, which codes for myotonic dystrophy protein kinaseMyotonic dystrophy protein kinase
Myotonin-protein kinase also known as myotonic dystrophy protein kinase or dystrophia myotonica protein kinase is an enzyme that in humans is encoded by the DMPK gene.- Function :...
, a protein expressed predominantly in skeletal muscle. The gene is located on the long arm of chromosome 19
Chromosome 19 (human)
125px|rightChromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active...
.
In DM1, there is a repeat of the triplet cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
-thymine
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
-guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
(CTG) in the DMPK gene. The number of repeats varies greatly, but the average number in a healthy person is between 5 and 37. Additional trinucleotide repeats inserted during cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
can produce protein instability. Consequently, the repeat size of an individual with DM1 will become larger usually during gametogenesis
Gametogenesis
Gametogenesis is a biological process by which diploid or haploid precursor cells undergo cell division and differentiation to form mature haploid gametes. Depending on the biological life cycle of the organism, gametogenesis occurs by meiotic division of diploid gametocytes into various gametes,...
or early embryonic development. This explains the phenomenon
Phenomenon
A phenomenon , plural phenomena, is any observable occurrence. Phenomena are often, but not always, understood as 'appearances' or 'experiences'...
of anticipation
Anticipation (genetics)
In genetics, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders such as...
, as each child of an affected adult will have a larger expansion than their parent. Individuals with larger expansions have an earlier onset of the disorder and a more severe phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
DM2
DM2 is caused by a defect of the ZNF9 gene on chromosome 3Chromosome 3 (human)
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs and represents about 6.5 percent of the total DNA in cells....
. The specific defect is a repeat of the cytosine-cytosine-thymine-guanosine (CCTG) tetranucleotide in the ZNF9 gene. As it involves the repeat of four nucleotides, it is not a trinucleotide repeat disorder, but rather a tetranucleotide repeat disorder.
The repeat expansion for DM2 is much larger than for DM1, ranging from 75 to over 11,000 repeats. 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. 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 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.As a result, patients 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
Primary care physician
A primary care physician, or PCP, is a physician/medical doctor who provides both the first contact for a person with an undiagnosed health concern as well as continuing care of varied medical conditions, not limited by cause, organ system, or diagnosis....
to a neurologist
Neurologist
A neurologist is a physician who specializes in neurology, and is trained to investigate, or diagnose and treat neurological disorders.Neurology is the medical specialty related to the human nervous system. The nervous system encompasses the brain, spinal cord, and peripheral nerves. A specialist...
for diagnosis. Depending on the presentation of symptoms, patients 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 phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s.
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.
Even though there is presently no cure for DM and management is currently symptom based, a precise diagnosis is still necessary because of multiple other problems that may develop over time, e. g. 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.
Management
There is currently no cure for or treatment specific to myotonic dystrophy. Complications of the disease, including heart problems, cataracts, and other abnormalities, can be treated but not cured. However there are medical interventions and medications that may relieve some of the symptoms such as myotoniaMyotonia
Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by the slow relaxation of the muscles after voluntary contraction or electrical stimulation. Generally, repeated effort is needed to relax the muscles, and the condition improves after the muscles have warmed...
, 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, aerobic exercise training, and foot drop.
Recent research has provided more information on the underlying molecular pathophysiologic mechanisms 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
Antisense therapy
Antisense therapy is a form of treatment for genetic disorders or infections.When the genetic sequence of a particular gene is known to be causative of a particular disease, it is possible to synthesize a strand of nuc acid that will bind to the messenger RNA produced by that gene and inactivate...
hold hope for more effective targeted treatments for the future. Altered splicing of the muscle-specific chloride channel 1 (ClC-1) has been shown to cause the myotonic phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
of DM1 and is reversible in mouse models using Morpholino
Morpholino
In molecular biology, a Morpholino is a molecule in a particular structural family that is used to modify gene expression. Morpholino oligomers are an antisense technology used to block access of other molecules to specific sequences within nucleic acid...
antisense to modify splicing
Splicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
of ClC-1 mRNA.
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 7th biennial meeting IDMC-7 took place in Wurzburg, Germany September 9–12, 2009. The 8th biennial meeting will take place in Clearwater, Florida, USA November 30-December 3, 2011.
Screening
Screening for the repeat expansions on the DMPK gene for DM1 is targeted at chromosome 19Chromosome 19 (human)
125px|rightChromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active...
, while the ZNF9 gene for DM2 is found on chromosome 3
Chromosome 3 (human)
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs and represents about 6.5 percent of the total DNA in cells....
. Genetic tests, including prenatal testing, are available for both confirmed forms. Molecular testing is considered the gold standard
Gold standard
The gold standard is a monetary system in which the standard economic unit of account is a fixed mass of gold. There are distinct kinds of gold standard...
of diagnosis. Further forms of myotonic dystrophy (DM3, DM4, and DMX) are suspected by researchers with possible defects on chromosome 16
Chromosome 16 (human)
125px|rightChromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs and represents just under 3 % of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic...
and chromosome 21
Chromosome 21 (human)
Chromosome 21 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. The trisomy of the 21st chromosome causes Down Syndrome...
.
External links
- GeneReview/NCBI/NIH/UW entry on Myotonic Dystrophy Type 1
- GeneReview/NCBI/NIH/UW entry on Myotonic Dystrophy Type 2
- Searchable database at Dutch Neuromuscular Research
- 140th ENMC International Workshop 2006 Myotonic Dystrophy DM2/PROMM and other Myotonic dystrophies]
- Information from the Myotonic Dystrophy Foundation
- Information from the International Myotonic Dystrophy Organization (IMDO)
- MDSG Information
- Information from the Neuromuscular Disease Center
- DM Toolbox Research tools for Myotonic Dystrophy from the Marigold Foundation