- Congenital myotonic dystrophy is the most severe form of myotonic dystrophy type 1 (DM1, aka Steinert disease), an autosomal dominant disorder caused by an unstable cytosine-thymine-guanine (CTG) trinucleotide repeat in the myotonic dystrophy protein kinase (DMPK) gene, chromosome 19q13.2-q13.3.
- It is a progressive neuromuscular, central nervous system, and multisystem disease.
- It is also the most common inherited neuromuscular disorder of adults and may be the most common disorder of skeletal muscle.
- Of note, there is a myotonic dystrophy (DM2) that is less severe and not associated with congenital forms.
- Age of onset and severity of disease correlate with the number of CTG repeats. Subjects without the disease may have the normal amount of 3-37 repeats.
- Slightly higher number of repeats (38-49) is known as a premutation as the individual is asymptomatic, but repeats are possibly expanding.
- Mild, late adult onset disease is associated with 50-150 repeats.
- The classic early adult manifestation 150-1000 repeats.
Any amount of 1000 or more repeats are seen only with congenital DM1.
Epidemiology including risk factors and primary prevention
- Myotonic dystrophy has a worldwide incidence of 1 per 7500 to 8000.
- Congenital cases (DM1) take place in about 2.1 to 28.6 /100,000 live births.
- Although males and females are equally affected by DM1, maternal inheritance is typically associated with the congenital form. Mothers may be mildly affected or asymptomatic and are commonly undiagnosed.
- If a parent is detected to have positive molecular testing for DM1, a first-degree family member has a 50% risk of being affected. Advisement for prenatal or pre-implantation testing is possible. Fetal cell DNA can be assessed at 15-18 weeks of gestation and chorionic villus sampling can be done at 10-12 weeks of gestation to test for DM1.
The DMPK repeats, located in the 3′ untranslated region of the gene, are believed to produce a toxic RNA which is retained in cell nuclei. This leads to dysfunctional transcription of a variety of genes, not only reducing the DMPK transcript itself on the affected allele, but also affecting multiple organ systems. Organ systems affected include skeletal muscles via CLCN (chloride channel 1) and TNNT3 (troponin 3), heart, eye, smooth muscle, brain, and hormonal pathways particularly those involved in circadian rhythm and insulin sensitivity. The role of having a reduced amount of the DMPK protein itself, a serine-threonine protein kinase, is unclear.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
- Premature delivery is common in congenital DM1 and the condition can be mistaken for or even coexist with cerebral palsy.
- Myotonia is usually clinically absent in infancy and may or may not be present electromyographically.
- Earliest symptoms are reduced fetal movement, talipes equinovarus, and polyhydramnios.
- Initial symptoms include hypotonia (as opposed to myotonia), generalized atrophy, and myopathic facies such as tented upper lip, high-arched palate, and triangular-shaped mouth.
- 50% develop neonatal respiratory distress and require mechanical ventilation.
- Additionally, due to oromotor weakness, there is failure to thrive as well. These neonates require tube feedings.
- Very severely involved newborns may not survive the neonatal period.
- Even if the infants are able to be weaned off from the ventilator and become ambulatory, most have developmental delay. Developmental delays are seen with motor milestones, speech, and feeding, and intellectual disability is seen in 50-60% of these patients.
- Behavioral disorder such as ADHD and autistic are also seen in these children.
- Weakness is typically seen first in distal muscles and later in more proximal muscles. This is in contrast to many dystrophies which present with proximal weakness first.
- Children typically require bracing for ambulation but can become wheelchair dependent due to progression of weakness.
- Decline is due to progressive loss of functional muscle fibers, decreased endurance, pulmonary function, and cardiac impairment.
Lifespan is into adulthood but shortened, averaging mid-forties. 25% of patients die before 18 months of age and 50% die before the mid-30s. Younger age of onset, more severe muscle weakness, and cardiac arrhythmias are associated with increased risk of death.
People with premutation should remain asymptomatic with normal life span, whereas mildly affected individuals may have near-normal life expectancy into at least their sixties, and “classic” cases average late forties to fifties.
Specific secondary or associated conditions and complications
- Musculoskeletal: Distal weakness and myotonia tend to progress, with foot drop, temporal wasting, symptomatic and sometimes painful cramping and difficulty releasing grip (known as grip myotonia).
- Cardiac: conduction defects occur in up to 90%, while dilated cardiomyopathy happens more rarely.
- GI: dysphagia, especially when younger, constipation, delayed gastric emptying, gallstones, mildly elevated LFTs.
- CNS: Fatigue, hypersomnia, central and obstructive sleep apnea, early age-related cognitive decline in some adults, lower full-scale IQ and frontal-parietal deficits on formal testing; higher risk of ADD, anxiety, depression, and other pathologic personality traits. Limited facial expression should not be mistaken for dullness or depression.
- Ophthalmologic: Palpebral ptosis, and “Christmas tree” cataracts, usually not symptomatic until thirties; hyperopia and astigmatism being more common in children.
- Endocrine: thyroid dysfunction, insulin resistance with eventual type 2 diabetes, male infertility due to testicular atrophy.
- Respiratory: Sleep apnea syndrome, weakness and dysphagia may progress, hypersensitivity to respiratory depressants and severe reaction to succinylcholine with hyperthermia and hyperkalemia, somewhat distinct from malignant hyperthermia, which can complicate surgery and anesthesia.
- Dermatology: Seborrheic Dermatitis
- HEENT: Cavities, gingivitis
- OBGYN: High risk-pregnancies
- Oncology: Shown to have increased risk of malignancy
Essentials of Assessment
Important historical information includes understanding:
- Prenatal risk factors (infections, drug/toxin exposures, thyroid disease, maternal body mass index)
- Family history of similar conditions
- Perinatal history (as indicated by APGAR scores, birth weight and history of asphyxia)
- Comprehensive developmental history including ages at which developmental milestones were met or if any were lost
- Loss of achieved milestones suggests a neurodegenerative condition.
- Nutritional status and feeding history
- Duration and type of respiratory support
- Frequency of respiratory infection
- Atypical behavior for age
- Excessive fatigue or hypersomnia
- In adults, consider asking about a history of infertility or requirement for an endocrinologist’s care.
- Weak, hypotonic infant.
- Marked or subtle facial weakness, with “carp” or “tented” mouth configuration.
- Clubfoot with or without hip dislocation.
- Signs and symptoms of respiratory insufficiency and dysphagia.
- Grip myotonia, temporal muscle atrophy, flat facies, or limited facial expression.
- Percussion myotonia as well with percussion of the thenar eminence with a reflex. hammer resulting in thumb adduction and flexion.
- Sensation is often normal.
- Ptosis or abnormal EOM may be present.
- Scalp or other pilomatrixomas or epitheliomas may be noted.
- Cardiac exam for abnormal rhythm should be performed.
- Adults may have frontal pattern balding, cataracts, and/or testicular atrophy.
- Assess for distal atrophy in older patients.
- Typical fine and gross motor function developmental testing, and clinical ADL scales.
- Gait observation and manual muscle testing once the child can cooperate.
- Formal neuropsychological and psychoeducational testing should be done later on to guide programming.
- The Muscular Impairment Rating Scale may be beneficial for assessment.
- CPK is usually mildly elevated (hundreds).
- EMG does not always have a myotonic pattern.
- Biopsy may be non-specific.
- The gold standard test for diagnosis is DMPK molecular genetics for number of CTG repeats.
- Avoid more expensive panels including DM2 and myotonia congenita genes as those conditions would not clinically be in the differential for affected infants.
- Neuroimaging can be normal or may show mild cortical atrophy and occasionally white matter abnormalities. In some cases, there will be periventricular leukomalacia as this occurs as a complication of prematurity.
- Pelvic x-ray for developmental hip dysplasia should be considered if clinical signs or hypertonia are present.
- Spine x-ray if scoliosis is clinically noted.
Supplemental assessment tools
- Pulmonary function testing, (especially FVCs).
- EKGs (annually), and echocardiograms (every 3-5 years) should be followed regularly. A Holter monitor can be placed if the EKG is equivocal or if cardiac symptoms are reported.
- Given high risk for sleep apnea syndrome, polysomnography should be done.
- Formal dysphagia evaluation and swallowing video fluoroscopy should be done for any possible nutritional or respiratory symptoms.
- Formal audiologic exam should be performed.
- Fasting blood glucose and/or hemoglobin A1c should be followed at least annually as well.
- Thyroid tests should be done annually.
- Ophthalmologic evaluation every two years is recommended given the high risk of cataracts.
- Lipid profile every 6-12 months.
- Vitamin D can be tested annually.
- Typical oncologic screening should be done.
Early predictions of outcomes
Infants who require long-term ventilatory support typically make limited progress and require significant levels of assistance. Other infants typically improve in their motor abilities with therapy; but special educational needs should be anticipated.
- Level surfaces for ambulation and limited requirement for stair climbing or long-distance ambulation would be an appropriate practical consideration.
- Generator availability and adequate power outlets for respiratory support or CPAP should be assured.
- Maintaining a warm environment in surgical areas minimizes risks of muscle dysfunction that can occur with shivering.
Social role and social support system
Cognitive effects of parent’s disease can lead to difficulties with low income, organizing or providing care, and keeping follow-up appointments. A disproportionate number of affected children are in grandparental care. Waiver, respite, case management, and similar supports should be sought out and assistance be provided in making applications. MDA offers many services that could fill these needs.
It is very important to realize many parents and most grandparents have gone unrecognized as having DM1 themselves, and the subject must be approached cautiously and gently. This may encourage them to seek care for themselves and avoid provoking unmerited guilt for transmitting a genetic condition or being unaware of their condition.
Rehabilitation Management and Treatments
Available or current treatment guidelines
Guidelines are based on the different medical complications that can occur due to the congenital myotonic dystrophy. These include:
- Assessment of neurological involvement via motor testing.
- Performing functional tests such as six-minute walk tests and hand grip.
- Following up with questions about limitations of ambulation and transfers.
- There is continued research regarding level of intensity of therapies. Current evidence supports a moderate; however, submaximal level of aerobic exercise. Excessive exercise should be avoided. For many patients, aerobic exercise is difficult given their muscle weakness and likely poor endurance. Aquatic therapies can be considered for those with low overall strength.
- As patients get weaker, different bracing options should be considered. It is advised to continue contracture prevention; however, wheelchair dependence likely occurs in the setting of weakness, not contractures. Contractures are typically due to poor positioning and some are inevitable.
- Prompt surgery and bracing may prolong ambulation by 2-3 years and decrease lower extremities contractures. There are increased energy costs afterwards too.
- For myotonic symptoms, mexiletine has been shown to be effective (dose 100-200 mg three times daily). However, it may have an arrhythmogenic effect. Other medications include phenytoin, carbamazepine, clomipramine, imipramine, amitriptyline, nifedipine, flecainide, acetazolamide, and taurine.
- Pain is a common complaint and should be addressed with analgesics.
- Many patients present with fatigue and modafinil 50 -200 mg 1-2 times per day may be helpful. The Epworth sleepiness scale should be done as well. Arrythmias should be assessed and treated per cardiology team. Patients may require ICDs or pacemakers as appropriate.
- Pulmonary conditions should be addressed annually including with spirometry, and with influenza and pneumococcal vaccinations. Patients may require CPAP or other forms of non-invasive ventilation.
- Gastrotomy tubes may need to be placed for dysphagia. Gallstones are usually treated conventionally, prokinetics are used for delayed gastric emptying.
- Pregnant patients should follow with a high-risk pregnancy team.
- Cognitive impairments can be assessed via neuropsychological testing and should be addressed with such.
- Patient will need to be followed by ophthalmology as cataracts may need to be removed. Blepharoplasty is performed for palpebral ptosis, etc.
At different disease stages
- Confirm diagnosis, implications for parents
- Genetic counseling as required
- Assess respiratory insufficiency, dysphagia
- Assess developmental delay
- Educate about long-term medical care needs, surgical/anesthetic risks
- Orthopedic and physiatric management including bracing, scoliosis surveillance, contracture management
- Refer for early intervention and therapy
- Avoid overwork/overfatigue of distal muscles
- Consider orthotic management for gait correction, support of weak or painful feet and ankle muscles
- Treat symptomatic myotonia with mexiletine or anticonvulsant (off-label)
- Treat attention deficit and hypersomnolence with stimulants
- Provide neuropsychology assessments, help to develop appropriate Section 504 plans or IEPs, advocacy for services and accommodations
- Follow cardiopulmonary status, to prevent sudden death, cardiac failure, aspiration or pneumonia (include flu shots annually)
- Detect progression to diabetes; note statin medication should be avoided, though other usual glycemic control and risk management appropriate
- Prevent undernutrition or obesity
- Encourage parental self-care, support for aging caregivers
- Encourage participation in community, MDA, special camp settings, self-advocacy
- Prepare adolescents for transition to adult care, aid in obtaining guardianship when appropriate
Pre-terminal or end of life care
- Provide for home health care and equipment needs as appropriate; be aware of need to modify opiate and anxiolytic protocols
Coordination of care
Specialists may include physiatrist, orthopedist, cardiologist, pulmonologist, endocrinologist, GI, sleep medicine, genetics/genetic counselor, PT, OT, SLP, nutritionist, social worker, and psychologist. Communication with primary care or medical home physician; MDA or other clinic setting with advanced coordination of screening tests and ancillary services as possible is ideal.
Patient & family education
- Families should understand the 50% chance of having an affected child with each pregnancy involving an affected parent, and worsening severity with each succeeding generation.
- Every generation requires good interdisciplinary medical care to optimize lifespan and function along the lines described above, with the avoidance of the few specific medications that may cause harm. These include succinylcholine, rocuronium, remifentanil, sedatives, and opioids.
- There is also a Myotonic Dystrophy Family Registry to enter that helps identify participants for research studies and clinical trials. This can be found on clinicaltrials.gov.
Measurement of Treatment Outcomes including those that are impairment-based, activity participation-based and environmentally based
- Wee-FIM, CHART, and any standardized tool for mobility, ADL, and health-related QOL could be used.
- ADL independence should be expected.
- Participation in regular classroom education with integration is usually ideal. Even if special education resources are needed, observance of least restrictive environment and avoidance of homebound services that are not medically necessary should be considered.
- Participation in online disease-specific support groups and registries could also be a measure of successful education and engagement.
Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
- Consider circumstances of the entire family when caring for children with early onset disease, particularly health and participation of caregivers facing related health issues with their own progression.
- Differentiate congenital DM1 from SMA or other causes of hypotonia on the basis of clinical presentation, targeting the optimal genetic diagnostic strategy.
- Provide direct help and/or referrals for the entire spectrum of physiological and psychosocial deficits associated with this condition to optimize well-being and desired outcomes.
Cutting Edge/ Emerging and Unique Concepts and Practice
- Small molecule therapeutics, antisense oligonucleotide (ASO)-based therapy, and genome editing targeting DNA, RNA, or downstream signaling pathways are being trialed.
- Measurements of spliced RNA products, used as biomarkers, are being assessed as well to assist with tracking disease response.
- Tideglusib, a selective and irreversible glycogen synthase kinase 3 inhibitor is undergoing clinical trial and is in the recruitment phase. Participants aged => 6 and <=16 years old are being recruited. More information can be found on clinicaltrials.gov.
- Agents affecting production and degradation of RNA particles, reducing toxicity of the repeats have had promising results preclinically.
Gaps in the Evidence- Based Knowledge
As of now, treatments are for symptoms and clinical conditions that develop subsequently to DM1, but there are no current disease modifying treatments. Some are in clinical trials as above. A specific myotonic-dystrophy measure of function or quality of life remains to be developed although the Individualized Neuromuscular Quality of Life Questionnaire appears to be a good proxy.
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Original Version of the Topic
Desiree Roge, MD. Congenital Myotonic Dystrophy. 11/10/2011
Previous Revision(s) of the Topic
Vikki A. Stefans, MD. Congenital Myotonic Dystrophy. 5/5/2016
Jeremy Roberts, MD
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Ray Stanford, MD
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Amy Tenaglia, MD
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Vera Tsetlina, MD
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