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.
Earlier age of onset and severity roughly correlates with number of CTG repeats, which increases with successive generations, known as genetic anticipation. 3-37 repeats are normal, 38-49 “premutation” (asymptomatic but possibly expanding), mild, late adult onset disease 50-150, “classic” early adult 150-1000, congenital nearly 1000 copies or more.
Epidemiology including risk factors and primary prevention
DM1 of all severities affects about 11/100,000 people worldwide, and congenital cases are about one tenth of these. Males and females are equally affected, but transmission in severe congenital cases is typically maternal. Mothers may be mildly affected or asymptomatic and are commonly undiagnosed. Genetic counseling once a parent is identified as having a mutation or premutation includes explaining the 50% recurrence risk, and advising that prenatal or pre-implantation testing is possible.
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, causing dysfunctional transcription of a variety of genes, not only reducing the DMPK transcript itself on the affected allele, but also affecting multiple organ systems, most notably skeletal muscles via CLCN (chloride channel 1) and TNNT3 (troponin 3) but also 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)
Earliest symptoms are reduced fetal movement and polyhydramnios. Very severely involved newborns with dysphagia and ventilator dependence may not survive the neonatal period; most affected surviving infants improve, developing head and trunk control and becoming ambulatory, though with global developmental delay and intellectual disability in 50-60%.
Hypotonia, generalized muscular atrophy, clubfoot, and myopathic facies are usual presenting features. Premature delivery is common and the condition can be mistaken for cerebral palsy or coexist with it. Myotonia is usually clinically absent in infancy, and may or may not be present electromyographically.
Lifespan is into adulthood but shortened, averaging mid-forties. People with premutation should remain asymptomatic with normal life span, 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
- Distal weakness and myotonia tend to progress, with foot drop, temporal wasting, symptomatic and sometimes painful cramping and difficulty releasing grip.
- Cardiac: conduction defects in up to 90%, dilated cardiomyopathy more rarely.
- GI: dysphagia, constipation, gallstones, mildly elevated LFT
- 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: Ptosis, “Christmas tree” cataracts, usually not symptomatic until thirties; hyperopia and astigmatism more common in children.
- Endocrine: thyroid dysfunction, insulin resistance with eventual type 2 diabetes, male infertility due to testicular atrophy.
- Respiratory: weakness and dysphagia may progress; hypersenitivity to respiratory depressants and severe reaction to succinylcholine with hyperthermia and hyperkalemia, somewhat distinct from malingnant hyperthermia, can complicate surgery and anesthesia.
2. ESSENTIALS OF ASSESSMENT
Inquire about possibly affected family members, with a focus on maternal symptoms; include pregancy and birth history, other premature deliveries in siblings.
Ascertain nutritional status and feeding history, duration and type of respiratory support in the neonatal period, frequent respiratory infection, and acquisition of motor milestones.
Suspect the condition when a weak, hypotonic infant has marked or subtle facial weakness, with “carp” or “tented” mouth configuation, clubfoot with or without hip dislocation, and assess for signs and symptoms of respiratory insufficiency and dysphagia. Check mother for grip myotonia or delay or unusual maneuver to relase grip, and look for temporal muscle atrophy, flat facies or limited facial expression. DTRs may vary. Sensation should be normal. Ptosis or abnormal EOM may be present. Scalp or other pilomatrixomas or epitheliomas may be noted.
Typical fine and gross motor function and developmental testing and clinical ADL scales would be informative, along with gait observation and manual muscle testing once the child can cooperate. Formal neurosychological and psychoeducational testing should be used later on to guide programming.
CPK is usually mildly elevated (hundreds). EMG and biopsy are non-specific myopathic and not usually indicated. Definitive test 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 occsionally 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, and spine x-ray if scoliosis is clinically noted later on.
Supplemental assessment tools
Pulmonary function testing, EKGs and echocardiograms should be followed regularly. Polysomnography and formal dysphagia evaluation and swallowing videofluoroscopy should be done for any possible nutritional or respiratory symptoms. Formal audiologic exam should be done. Most standards of care indicate EKG should be annual at a minimum, and fasting blood glucose and/or hemoglobin A1c should be followed at least annually as well. A Holter monitor can be placed if the EKG is equivocal or if cardiac symptoms are reported. Ophthalmologic evaluation every two years is recommended.
Early predictions of outcomes
Infants who require long-term ventilatory support typically make limited progress and remain total care; others will typically improve their motor abilities with therapy but special educational needs should be anticipated. Wheelchair use may be necessary for long distances in about half of affected adults due to fatigue or progressive weakness.
Level surfaces for ambulation and limited requirement for stair climbing or long distances 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 and assistance provided in making applications. The MDA can help.
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, to encourage them to seek care for themselves and avoid provoking unmerited guilt for transmitting a genetic condition or being unaware of it.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Owing to great variation in severity and occurrence of specific complications, there has not been an overarching guideline published for DM1. Basic screenings to be done regardless of symptoms are noted under Supplemental Assessment Tools above. A major consideration is that many symptoms may be related to underlying diagnosis of DM1, and knowledge about this on the part of primary care physicians may be limited. Many adults tend to chronically tolerate symptoms rather than receive medical assessment and management, particularly fatigue and sleep disturbances, and they often prioritize caring for an affected child over their own needs.
At different disease stages
- Confirm diagnosis, implications for parents
- Assess respiratory sufficiency, dysphagia
- Educate about long-term medical care needs, surgical/anesthetic risks
- Orthopedic 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 mexilitene or anticonvulsant (off-label)
- Treat attention deficit and hypersomnolence with stimulants
- Provide neuropsych assessments, help to develop appropriate Section 504 plans or IEPs, advocacy for services and accomodations
- Follow cardiopulmonary status, preventing sudden death, cardiac failure, aspiration or other 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, cardiologist, pulmonologist, endocrinologist, GI, sleep medicine, genetics/genetic counselor, PT, OT, speech therapy, nutritionist social work, psychology, and communication with primary care or medical home physician; MDA or other clinic setting with advance coordination of screening tests and ancillary services as possible is ideal.
Patient & family education
Families should understand the 50-50 chance with each pregnancy involving an affected parent, and worsening severity with each succeeding generation. It should be emphasized every generation requires good medical care to optimize lifespan and function along the lines described above, with the avoidance of the few specific medications that may cause harm.
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 necessary, with observance of least restrictive environment and avoidance of homebound services that are not medically necessary. 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.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
Cutting edge concepts and practice
ISIS-DMPKRx is an antisense molecule which targets and silences the DMPK toxic mRNA and is in early stage clinical trials for safety and tolerability for adults with DM1; the approach has been successful in a mouse model. Adults age 20-65 can be referred via information on clinicaltrials.gov to consider becoming subjects, and must be infertile or using reliable contraception and not taking an anti-myotonia agent in order to participate.
Studies of neuropsychological correlation with fMRI and advanced imaging strategies and of biomarkers to guide treatment and research are also in progress.
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
Optimal strategies for management of cognitive, ventilation and sleep-wake disorders have not been determined, and a myotonic-dystrophy specific care guideline or measure of function or quality of life remains to be developed. A blinded, randomized controlled trial is underway on the efficacy of mexiletine.
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Groh WJ, Groh MR, Saha C, et al. Electrocardiographic abnormalities and sudden death in myotonic dystrophy type 1. N Engl J Med. 2008;358:2688–2697.
Kamsteeg E-J, Kress W, Catalli C, et al. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2. European Journal of Human Genetics. 2012;20(12):1203-1208. doi:10.1038/ejhg.2012.108.
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Original Version of the Topic:
Desiree Roge, MD. Congenital Myotonic Dystrophy. Publication Date: 2011/11/10.
Vikki A. Stefans, MD
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