MEDG550/Student Activities/Myotonic Dystrophy
Myotonic dystrophy (DM) is a condition that affects muscles as well as several other parts of the body. Myotonic refers to being unable to relax muscles after contraction.[1] For example, individuals with myotonic dystrophy may have a hard time releasing their grip after holding a door knob or shaking someone's hand. It is a form of muscular dystrophy, a group of conditions that cause gradually increasing weakness and muscle loss. There are two types of myotonic dystrophy which may have different ages of onset, and have a different pattern of which muscle groups show weakness first.[1]
Features
Myotonic Dystrophy Type One
Myotonic dystrophy type one (DM1) is divided into four subtypes, congenital, juvenile, classical, or mild depending on the age symptoms first present as well as specific features.[1]
Congenital
Congenital myotonic dystrophy is a form of muscular dystrophy that can be seen at or even before birth, or during the first year of life.[2] In utero congenital myotonic dystrophy might present as having lower than normal volume of amniotic fluid surrounding the baby, and decreased movement. Newborns with congenital myotonic dystrophy will have a floppy appearance because of their overall low muscle tone (hypotonia). Weakness in the muscles of their face and jaw might cause the upper lip to appear tented. Many infants with congenital myotonic dystrophy have difficulty feeding and/or breathing and will require support to do so. Trouble relaxing muscles is typically not seen.[2]
In childhood, individuals with congenital myotonic dystrophy may be delayed reaching motor milestones such as running or jumping. Limitations in an individuals ability to learn, reason and problem solve as well as perform every day skills that would be expected for their age (intellectual disability) or trouble with reading, writing, and math (learning disorders) are common.[2]
In their teens or twenties individuals will begin to develop progressive features of the disorder.[2]
Juvenile
Onset of myotonic dystrophy after one year but before ten years of age is called juvenile or childhood-onset myotonic dystrophy.[2]
This type of myotonic dystrophy is similar to the classical type described below however signs of muscle weakness are often not seen during childhood. Children with juvenile myotonic dystrophy type I often have difficulties learning and socializing in school.[3] Approximately half of these children may have intellectual disability. Attention deficit disorder, anxiety, and mood disorders are also commonly linked to juvenile myotonic dystrophy.[2]
Classical
Classical or adult-onset myotonic dystrophy type I usually becomes apparent in adolescence or early adulthood, and less commonly the fourth decade of life.[3]
Difficulty relaxing muscles (myotonia), especially of the hand and jaw, is often the first symptom. Individuals will experience muscle weakness, particularly starting in the hands and feet. Low hand strength and trouble grasping objects, or stumbling more frequently are signs of muscle weakness.[3] A loss of muscle mass (muscle wasting) is also a defining characteristic of myotonic dystrophy. Muscle weakness and wasting are especially seen in the face, neck, arms, and legs. As a result individuals may have a characteristic look of droopy eyes, weak smile, and a thin face. Muscle weakness is slowly progressive first in these and later in other muscles.[2]
Other signs and symptoms include:
- Cataracts
- Baldness
- Trouble swallowing, alternating diarrhea and constipation, and gallstones because of weakening of the gastro-intestinal muscles
- Trouble breathing, especially during sleep leading to sleep apnea, because of weakening of the respiratory muscles.
- Excessive daytime sleepiness
- Muscle fatigue
- Thyroid problems
- Insulin insensitivity and diabetes
- Fertility issues
- Irregular heartbeat and weakening of heart muscle
Myotonic dystrophy type I is associated with a higher risk of cancer particularly of the thyroid, ovary, colon, uterus, and eye.[2]
Mild
Individuals with mild myotonic dystrophy type I may have cataracts and baldness as their only symptoms.[3] It may also be seen as mild weakness and difficulty relaxing typically after 40 years of age.[2] Heartbeat irregularities can arise in the late onset form of myotonic dystrophy type I and may be associated with reduced life expectancy.[3]
Myotonic Dystrophy Type Two
Myotonic dystrophy type two (DM2) is similar to type I in that they both present with muscle weakness, cataracts, insulin insensitivity, and heart arrhythmias.[4] Trouble relaxing muscles (myotonia) is variable in myotonic dystrophy type two and muscle weakness/ wasting are typically milder than in type one. Myotonic dystrophy type two is slowly progressive and often symptoms first appear in the third or fourth decade. There is no congenital form of myotonic dystrophy type two and intellectual disability or excessive daytime sleepiness are not seen. Life expectancy is normal. Muscle weakness typically occurs in the arms, legs and trunk of individuals with myotonic dystrophy type two rather than the hands, feet, and face as seen in type one. Type two myotonic dystrophy is associated with muscle pain and stiffness.[4]
Diagnosis
Definitive diagnosis of myotonic dystrophy type one and type two are based on genetic testing.[5] Testing should be performed in individuals with characteristic features such as muscle weakness to confirm the diagnosis.[2] The process of genetic testing is outlined below in Genetic Counselling.
Prevalence
Myotonic dystrophy is the most common muscular dystrophy diagnosis in adults. Myotonic dystrophy type one has an estimated incidence of 1/8000.[3] The incidence may be much higher in some populations such as northeastern Québec where 1/550 individuals are thought to have myotonic dystrophy type one.[6] The incidence of myotonic dystrophy type two is not well known. It is seen less frequently than type one, with the exception of some populations such as Germany and Finland.[3]
Genetic Cause
Myotonic dystrophy type one and type two are caused by changes in one of two different genes. Our genes provide the instructions needed for the cells in our body to work properly.
Our genes provide these instructions to our cells using a code of four letters, A C T and G. Sometimes when there is a change in a gene it can change those instructions. A change could be that one letter is swapped for another, or that letters are added in or taken out. In the case of myotonic dystrophy it is that there is an increase in the number a times a certain string of letters is repeat side by side within the gene. These extra repeats cause the gene to no longer work properly and so we see symptoms related to myotonic dystrophy like muscle weakness.
Type One
Myotonic dystrophy type one is caused by a change in the DMPK gene where there is an increase in the number of repeats of the letters C T G of the code in a row.[7] Typically a working copy of the gene will have 5-35 repeats of CTG. When an individual has more than 50 CTG repeats in a row in the DMPK gene we begin to see signs the gene is not working properly.[8] The severity of symptoms tends to increase, and the age symptoms first present tends to decrease with more CTG repeats. However it is difficult to predict the exact presentation of the condition for an individual based on their number of repeats as there is large overlap of the different types and wide variability between individuals.[3]
| Number of repeats | Implication[8] |
|---|---|
| 5-35 | Expected number of repeats in a working copy of the DMPK gene in healthy individuals |
| 35-49 | Individuals will not have symptoms associated with myotonic dystrophy type one but have a higher chance of having a child with a repeat length long enough to cause myotonic dystrophy (premutation carrier) |
| 50-150 | Mild |
| 100-1000 | Classical or juvenile |
| 1000 or more repeats | Cogenital myotonic dystrophy type one |
Type Two
Myotonic dystrophy type two is caused by a change in the CNBP gene. It is the result of an increased number of repeats of CCTG one after the other that cause the gene to no longer work properly. Typically a working copy of the CNBP gene will have less than 26 CCTG repeats. Individuals will myotonic dystrophy type two have been shown to have between 75 and 11000 CCTG repeats. Unlike myotonic dystrophy type one, in type two there is no link between the number or repeats and the severity of the condition or age at which symptoms first appear.[4]
Inheritance
Almost all individuals with an increased number of repeats in either their DMPK or CNBP genes will show features of myotonic dystrophy at some time in their life. However, symptoms and their severity may vary a lot even within the same family and sometimes may be so mild that they go unnoticed.[5]
Autosomal Dominant
We have two copies of all of our genes. One copy we get from our mother, and the other copy from our father. Both myotonic dystrophy type one and type two are inherited in a way which we call autosomal dominant. This that means that only one non working copy of the gene is needed for someone to have myotonic dystrophy. It does not matter whether the non working copy came from our mother or our father.
What this means is that when an individual with myotonic dystrophy, who has one non-working copy of the gene, has a child with an individual who does not have myotonic dystrophy and so has two working copies of the gene they have a 50% or 1/2 chance of having a child with myotonic dystrophy who received a working copy from their healthy parent and the non working copy from their parent with myotonic dystrophy. They also have a 50% or 1/2 chance of having a child who received a working copy of the gene from both of their parents. This child would not have muscular dystrophy.
Anticipation
In myotonic dystrophy type one it is observed that there will be an increasing number of individuals with myotonic dystrophy in consecutive generations in a family or that their symptoms become more severe or begin at an earlier age. This is called anticipation. It happens the number of repeats in the DMPK gene can change when being passed from parent to child. Often the number of repeats will increase causing the more severe features in the next generation.
Genetic Counselling
Genetic Testing
Genetic testing using involves taking a sample of blood or in some cases saliva, and sending it off to a lab for them to analyze the genetic information within the cells of that sample. In the case of myotonic dystrophy type one or type two they are looking specifically at either the DMPK gene or the CNBP gene in order to determine the number of repeats within that gene.
Diagnostic
In individuals suspected to have myotonic dystrophy type one or type two based on their features specific genetic tests looking only at the DMPK or CNBP gene will be ordered. These tests will not give you any information about other health conditions.
All individuals with myotonic dystrophy will have an increased number of repeats.
Predictive
In individuals who a close relative has had diagnosis of myotonic dystrophy confirmed by genetic testing, genetic testing before the onset of symptoms might be helpful in determining family members at risk of developing myotonic dystrophy who should begin undergoing surveillance.
Positive test results (an increase in the number of repeats in the DMPK or CNBP genes) do not allow predictions about when symptoms will be seen in asymptomatic individuals, or the severity or progression of the condition to be made.
It is not recommended that minors who are not showing symptoms of myotonic dystrophy receive predictive genetic testing as it would not greatly change their medical management. This recommendation is in place to ensure the person being tested truly wants this information and is aware of the benefits and risks associated with testing.[8]
Prenatal
If a parent has already been diagnosed with myotonic dystrophy type one testing can be done in the pregnancy to determine if the child is at risk for having myotonic dystrophy. This testing involves removing a piece of placental tissue, or amniotic fluid under ultrasound guidance in order to perform genetic testing on the cells. This procedure carries a risk of miscarriage to the pregnancy.
Congenital myotonic dystrophy type I is associated with low levels of amniotic fluid surrounding the baby which may be seen an ultrasound as well as decreased fetal movement.[1]
Women with myotonic dystrophy who are pregnant have an increased chance of complications during the pregnancy such as miscarriage, prolonged labour, and postpartum bleeding.[9]
Preconception
Preconception counselling is available to help individual affected with myotonic dystrophy and their close family members determine their risk of having a child who could develop myotonic dystrophy. Once an individual has been seen to have an increased repeat length in one of the genes associated with myotonic dystrophy type one or type two their is a 50% chance their child will develop myotonic dystrophy.
Preimplantation genetic testing (PGT-M) is an option for couples in which one individual has myotonic dystrophy and want to ensure they will have a child who does not have myotonic dystrophy. PGT-M is a process using in vitro fertilization (IVF) to create embryos which can then be tested to identify those who do not have the increased number of repeats before selecting an embryo to insert into the mother's uterus.[5]
Living with Myotonic Dystrophy (Psychosocial Considerations)
Myotonic dystrophy has been shown to impact individuals reported quality of life.[10] Fatigue was reported as one of the symptoms reported as having an impact on individuals lives.
Management
There is currently no cure for myotonic dystrophy.[9] Breathing and heart problems are responsible for 70% of deaths in myotonic dystrophy. Therefore surveillance and treatment of symptoms related to myotonic dystrophy is important to reduce mortality.[9]
Evaluation following initial diagnosis
- Neurology - baseline strength and balance
- Developmental assessment
- Eyes tested for cataracts
- ECG
- Lung function test
Surveillance
Monitoring of suspected complications
- Yearly ECG to detect abnormal heart rhythms and an echocardiogram if indicated
- Annual measurement of glucose fasting serum concentration to monitor for diabetes
- Eye examination to monitor for cataracts every two years
Treatment of manifestations/ prevention of complications
- Pacemaker or implantable cardioverter-defibrillator to monitor heart rhythm and provide a shock when individuals are experiencing dangerous irregular heart rhythms
- Non-invasive ventilation for sleep disorders related to breathing difficulties
- Physiotherapy, and/or occupational therapy related to muscle weakness
- Cataract surgery
- Medications for trouble relaxing muscles
- Treatment of diabetes
- Medications for pain management
Gene Therapy
While not currently clinically available research on targeted molecular treatments for myotonic dystrophy is currently being done in animal models.[9]
Patient Resources
Myotonic Dystrophy Foundation
Muscular Dystrophy Canada
Muscular Dystrophy Association
To find a genetics clinic closest to you, please visit www.cagc-accg.ca (Canada) or https://www.nsgc.org (United States) or speak with your primary care provider.
- ↑ 1.0 1.1 1.2 1.3 Machuca‐Tzili, L; Hilton-Jones, D (2005). "Clinical and molecular aspects of the myotonic dystrophies: A review". Muscle & Nerve. 32 (1): 1–18.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Thornton, C (2014). "Myotonic Dystrophy". Neurologic Clinics. 32 (3).
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Kamsteeg, E.J; Kress, W; Catalli, C; Hertz, J.M; Witsch-Baumgartner, M; Buckley, M.F; van Engelen, B.G.M; Schwartz, M; Scheffer, H (2012). "Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2". Eur J Hum Genet. 20 (12): 1203–1208.
- ↑ 4.0 4.1 4.2 Day, J.W; Ricker, K; Jacobsen, J.F; Ramussen, L.J; Dick, K; Kress, W; Schneider, C; Koch, M; et al. (2003). "Myotonic dystrophy type 2 Molecular, diagnostic and clinical spectrum". Neurology. 60 (4): 657–664.
- ↑ 5.0 5.1 5.2 Meola, G; Cardani, R (2015). "Myotonic dystrophies: An update on clinical aspects, genetic, pathology, and molecular pathomechanisms". BBA-Molecular Basis of Disease. 1852 (4): 594–606.
- ↑ Yotova, V; Labuda, D; Zietkiewicz, E; Gehi, D; Lovell, A; Lefebvre, J.F; Bourgeois, S; Lemieux-Blanchard, E; et al. (2005). "Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec". Human Genetics. 117 (2–3): 177–187.
- ↑ Mahadevan, M; Tsilfidis, C; Sabourin, L; Shutler, G; Amemiya, C; Jansen, G; Neville, C; Narang, M; et al. (1992). "Myotonic Dystrophy Mutation: An Unstable CTG Repeat in the 3' Untranslated Region of the Gene". Science. 255 (5049): 1253–1255.
- ↑ 8.0 8.1 8.2 The International Myotonic Dystrophy Consortium (IDMC) (2000). "New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1)". Neurology. 54 (6): 1218–1221.
- ↑ 9.0 9.1 9.2 9.3 Turner, C; Hilton-Jones, D (2015). "Myotonic dystrophy: diagnosis, management and new therapies". Current Opinion in Neurology. 27 (5): 599–606.
- ↑ Laberge, L; Mathieu, J; Auclair, J; Gagnon, E; Noreau, L; Gangon, C (2013). "Clinical, Psychosocial, and Central Correlates of Quality of Life in Myotonic Dystrophy Type 1 Patients". European Neurology. 70: 308–315.