Browse the corpus

Congenital myotonic dystrophy (CMD) is an autosomal dominant neuromuscular disorder with multisystem involvement. It is a subtype of myotonic dystrophy type 1. Features include severe hypotonia and generalized muscle weakness; myotonia is classically absent in infancy. This activity will review clinical features, pathophysiology, and management strategies in CMD. It also highlights the importance of the interprofessional team in achieving the best outcomes in patients suffering from CMD. Objectives: Describe the incidence of congenital myotonic dystrophy (CMD). Summarize the causes of congenital myotonic dystrophy (CMD). Outline the clinical features of congenital myotonic dystrophy (CMD). Summarize how an interprofessional team is critical for the symptoms management, surveillance, and family support of patients with congenital myotonic dystrophy (CMD). Access free multiple choice questions on this topic.

Congenital myotonic dystrophy (CMD) is an autosomal dominant disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene on chromosome 19q13.3. It extends well beyond muscle disease; affected individuals may develop cataracts, cardiac conduction abnormalities, insulin resistance, and, in the congenital form, developmental disabilities.[1] Two major forms are recognized: myotonic dystrophy type 1 (DM1), also known as Steinert disease, and myotonic dystrophy type 2 (DM2), which generally has a milder course. As with other trinucleotide repeat expansion disorders, severity correlates with the number of repeats.[2][3] CMD has an estimated incidence of 1 in 47,619 live births, with neonatal mortality reaching up to 40%. Severe cases follow a distinct “biphasic” natural history in which affected newborns often experience improvement or stabilization of symptoms during infancy, only to develop adult-onset manifestations later in life.[4]

Congenital myotonic dystrophy is caused by the repeat expansion of trinucleotide "CTG" (cytosine-thymine-guanine) in the 3'-untranslated region of the myotonia dystrophy protein kinase (DMPK) gene located on chromosome 19q13.3. Myotonic dystrophy type 2 is caused by a CCTG expansion in intron 1 of the ZNF9 (e zinc finger protein 9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.[5] Variability in the clinical expression of DM1 is thought to be caused by somatic mosaicism due to instability of the CTG repeat expansion in somatic cells during life, due to an abnormality in the DNA repair.[6] The severity of the disease correlates with allele size (number of repeats), with <30 repeats in an average healthy person and >11,000 repeats in an affected person; however, mild cases have been reported with long expansions.[7] Two important terms used to describe autosomal dominant diseases are penetrance and anticipation. Penetrance is the percentage of individuals who show signs of the disease, ranging from the mildest to the most severe phenotype. If all individuals with a disease genotype exhibit the disease phenotype, the disease is said to be 'fully penetrant' or to have a penetrance of 100%. Anticipation refers to the increased disease severity and decreased age of onset in successive generations.[4][8][9] In DM1, all clinical phenotypes, except the premutation, exhibit full penetrance and anticipation.[10][11] Full penetrance alleles of more than 50 are associated with disease manifestations. In CMD, repeats are usually more than 1000, compared to less than 37 in normal individuals, and 38-49 in premutation allele patients (asymptomatic). Offspring of premutation patients can inherit longer repeats, increasing the risk of disease and decreasing the age of onset in the next generations (anticipation). Contrary to the classic (adult) pattern, maternal transmission accounts for 90% of cases, and only 9-12% are paternal. The mechanism is not yet well understood; however, the maternal and intrauterine environments are considered contributing factors.[3][12]

Myotonic dystrophy is the most prevalent adult muscular dystrophy among people of European ancestry, with a minimum prevalence of 11.84/100,000[13][14] The incidence of CMD is 1 in 47619 live births, higher in specific areas (Quebec, Canada) [4] Spain - 0.08 per 10,000 live births [15] Canada - 2.1 in 100,000 (1 in 47,619) live births [16] South Africa - 3 per 100,000 live births [17] Taiwan 0.46/100,000 inhabitants (adult type) [18] In a systematic review, the prevalence of all muscular dystrophies was 19.8 to 25.1 per 100,000 person-years. Myotonic dystrophy (0.5 to 18.1 per 100,000), Duchenne muscular dystrophy (1.7 to 4.2), and facioscapulohumeral muscular dystrophy (3.2 to 4.6 in 100,000) were the most common types.[19]

A mutation in the 3′ untranslated, noncoding region of the DMPK gene, located on chromosome 19q13.3, results in the expansion of DNA (CTG) repeats. Transcription of DNA results in a mutant RNA that disrupts the splicing of CUG binding protein (CUG-BP) and Musclebind-like protein (MBNL). This leads to the sequestration of splicing factors forming ribonuclear inclusions. In turn, this disturbs cellular signaling and causes toxic effects on muscle metabolism and RNA processing. This process is known as spliceopathy. MBNL 1 protein is abundant in skeletal muscle, whilst MBNL 2 is in brain tissue. These proteins exhibit loss of function because they aggregate in the nucleus and cannot be utilized by the cell. Conversely, CUG-BP binds cardiac troponin and exhibits a gain-of-function, leading to increased activation and phosphorylation. Elevated levels result in cardiac abnormalities and abnormal insulin receptor function, elucidating the risk of diabetes. It also inhibits myoblast differentiation, leading to a loss of CIC-1 chloride channels through splicing disruption. A splicing defect results in sustained muscle contraction and an inability to relax (myotonia).[4][12][20]

A muscle biopsy is required in certain cases where genetic testing is inconclusive. Microscopy can show increased internalized nuclei (boxcar appearance), ring fibers, sarcoplasmic masses, and type 1 fiber atrophy with a pyknotic clump and type 2 fiber hypertrophy in DM1 and type 2 fiber atrophy in DM2.[21][22] Electron Microscopy Appearance: Sarcoplasmic masses composed of disorganized myofibrils, dilated sarcoplasmic reticulum, and free ribosomes.

History It includes detailed birth history, medical/surgical history, and 3-generation family history. Clinical features associated with CMD are as follows: Prenatal: polyhydramnios, reduced fetal movements, preterm delivery <36 weeks, small for gestational age. Neonatal: hypotonia, hyporeflexia, muscle weakness (distal > proximal), neck muscle weakness (flexion), myopathic facies (ptosis, facial diplegia, atrophy of temporalis muscles, tent-shaped mouth), contractures, arthrogryposis, scoliosis, talipes equinovarus, visual impairment (cataract, lens opacification), respiratory distress, weak cough, sleep apnea, pulmonary hypoplasia, bronchopulmonary dysplasia, raised right hemidiaphragm, pneumothorax, recurrent infections/otitis media, aspiration pneumonia, feeding and sucking difficulties, gastroparesis, GERD, constipation/diarrhea, fecal incontinence, increased sensitivity to anesthesia (due to respiratory muscle compromise and central dysregulation of breathing), cardiac conduction disturbances, valve defects (mitral), and early death. Infancy and childhood, ages 1 to 10 years: usually able to walk with improvement in motor function; however, progressive weakness recurs in the 2nd decade. Myotonia (by 10 years of age), intellectual disability (50-60%), autism, ADHD, psychiatric disorders, vision problems (hyperopia, astigmatism, cataract), excessive daytime sleepiness, cardiac and endocrine complications. Respiratory: respiratory difficulties are found in 50% of neonates and are the leading cause of neonatal mortality, and are used to distinguish between mild and severe CDM. Musculoskeletal: Proximal muscle weakness in DM1 is associated with a poor prognosis. The biphasic course in CMD shows improved/stable disease until adolescence/young adulthood, followed by gradual deterioration. Complications of muscle weakness may include scoliosis and contractures, producing foot deformity and toe walking. Bulbar muscle weakness may produce swallowing, speech, and language difficulties. Cognition: cognitive impairment is one of the most common and challenging manifestations of childhood DM1. CDM patients are most affected, with an IQ range of 40 to 80 and a mean of 70 (average normal: 100). Cognitive impairment correlates with the severity of weakness, size of CTG repeat, and maternal transmission.

Musculoskeletal: Proximal muscle weakness in DM1 is associated with a poor prognosis. The biphasic course in CMD shows improved/stable disease until adolescence/young adulthood, followed by gradual deterioration. Complications of muscle weakness may include scoliosis and contractures, producing foot deformity and toe walking. Bulbar muscle weakness may produce swallowing, speech, and language difficulties. Cognition: cognitive impairment is one of the most common and challenging manifestations of childhood DM1. CDM patients are most affected, with an IQ range of 40 to 80 and a mean of 70 (average normal: 100). Cognitive impairment correlates with the severity of weakness, size of CTG repeat, and maternal transmission. Sleep: excessive sleep disorder and sleep apnea may adversely affect learning, memory, high-level cognitive processing, and physical functioning, exacerbating psychomotor and cognitive delays. Psychosocial: 50% of children have psychiatric diseases (phobia, depression, anxiety), and ADHD. Avoidant personality, apathy, and autistic features may be present. Cancer: There is an increased risk of cancer in patients with type 1 myotonic dystrophy, including thyroid, uterine, choroidal melanoma, colon, testicular, prostate, and basal cell cancer. Others: features of adult “classic” myotonic dystrophy are not evident in childhood, including cataracts, significant cardiac disorders, and diabetes mellitus. Lens pathology is evident in 40% and can predict future cataract. Conduction disturbances observed on ECG, or valve abnormalities, may be symptomatic. Hypothyroidism, hypogonadism, growth hormone abnormalities, and androgen insensitivity are rare. In contrast, testicular atrophy and infertility are common in CDM males, as are irregular menses in CDM females.[4]

Others: features of adult “classic” myotonic dystrophy are not evident in childhood, including cataracts, significant cardiac disorders, and diabetes mellitus. Lens pathology is evident in 40% and can predict future cataract. Conduction disturbances observed on ECG, or valve abnormalities, may be symptomatic. Hypothyroidism, hypogonadism, growth hormone abnormalities, and androgen insensitivity are rare. In contrast, testicular atrophy and infertility are common in CDM males, as are irregular menses in CDM females.[4] Physical Exam: vital signs, weight, height, and head circumference measurements are essential. Comprehensive neonatal exam looking for dysmorphic features, contractures, scoliosis, pulmonary and cardiac evaluation for abnormal chest rise, or murmurs. Abdominal exam for organomegaly, back for scoliosis, the musculoskeletal system for contractures, detailed neurological exam assessing mental status, cranial nerves (myopathic facies, ptosis, dysphagia, weak cry/cough/gag, respiratory failure), motor (axial and appendicular hypotonia, frog-like posture, decreased movements), reflexes, Babinski response, sensory, coordination, and primitive reflexes. Examine mother (myopathic facies; shake hand as myotonia prevents prompt grip release; percussion with a reflex hammer: tapping the thenar; wrist extensor produces involuntary muscle contraction with delayed relaxation, called percussion myotonia).[23]

Molecular Genetic Testing (first line): targeted analysis of the DMPK gene appears positive for a heterozygous pathogenic variant in nearly 100% of affected individuals. If the diagnosis is uncertain, the panel can be completed. The multigene panel can include testing for the DMPK CTG repeat expansion and other disorders of interest, depending on the laboratory. Serum CK: normal to mildly elevated. Muscle Biopsy (if negative genetic testing): increased internalized nuclei (boxcar appearance), ring fibers, sarcoplasmic masses, and type 1 fiber atrophy with a pyknotic clump. Electromyography: records myopathic units (distal muscles), fibrillation potentials, and positive sharp waves. Fast runs of single-fiber discharges approaching the pattern of myotonic discharges are seen, without typical waxing and waning electrical myotonia. Brain MRI: may show ventricular dilatation, cortical atrophy, hypoplasia of the corpus callosum, and white matter abnormalities.[2][4][2][8][12]

Severe congenital myotonic dystrophy (CDM) requires intensive care, mainly for feeding and respiratory support. Gastric/jejunum feeding tube, tracheostomy for mechanical ventilation, and splinting of talipes are occasionally commenced. Genetic counseling and end-of-life counseling are essential.[8][23][24] Thereafter, a multidisciplinary team approach is critical for symptom management, surveillance, and family support. The following recommendations are acquired from Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1 published in 2019, and 2- Consensus Statement on Standard of Care for Congenital Muscular Dystrophies, published in 2014.[25][26] Neurology: disclosure of diagnosis should address 5 items: diagnosis, prognosis, recurrence risk, treatment plan, and family/community support. An experienced multidisciplinary team should follow patients in the neuromuscular clinic. Routine surveillance every 3 to 4 months for infants less than 12 months, and 4 to 6 months in toddlers of more than 12 months. Allied health teams include nurses, physical and occupational therapists, speech-language therapists, social workers, and genetic counselors. Focusing on the financial burden and psychosocial aspects is vital. Referral to ophthalmology and other services, as discussed below, is recommended. Respiratory: the primary goal is to monitor respiratory function, decrease secretions, and manage assisted ventilation. There is often improvement in respiratory strength over time, and careful consideration of tracheostomy should be given. Maintenance pulmonary therapy includes cough assist, breathing stacking, etc. Pulmonary function testing includes vital capacity (<40% predicts nocturnal hypoventilation) and spirometry (>20% difference between sitting and supine vital capacity indicates diaphragmatic weakness and predicts nocturnal hypoventilation). Other tests include peak cough flow, polysomnography, and blood gases. Pneumococcal and influenza vaccines are recommended, and palivizumab against RSV is recommended for children under 2 years of age. Cardiology: arrhythmias, myopathies, and structural cardiac diseases can present with lethargy, dyspnea, pallor, palpitations, and syncope. Twice-yearly assessment is required, with closer follow-up for symptomatic patients.

Respiratory: the primary goal is to monitor respiratory function, decrease secretions, and manage assisted ventilation. There is often improvement in respiratory strength over time, and careful consideration of tracheostomy should be given. Maintenance pulmonary therapy includes cough assist, breathing stacking, etc. Pulmonary function testing includes vital capacity (<40% predicts nocturnal hypoventilation) and spirometry (>20% difference between sitting and supine vital capacity indicates diaphragmatic weakness and predicts nocturnal hypoventilation). Other tests include peak cough flow, polysomnography, and blood gases. Pneumococcal and influenza vaccines are recommended, and palivizumab against RSV is recommended for children under 2 years of age. Cardiology: arrhythmias, myopathies, and structural cardiac diseases can present with lethargy, dyspnea, pallor, palpitations, and syncope. Twice-yearly assessment is required, with closer follow-up for symptomatic patients. Gastroenterology: serial monitoring of nutrition and growth, feeding, gastrointestinal motility (GERD, dysmotility, constipation), and oral care is recommended. Feeding tubes with or without Nissen fundoplication, laxatives, antacids, proton pump inhibitors, antiemetics, and probiotics are all advisable. Malocclusion, teeth crowding, caries, and gingival hyperplasia (prolonged NPO) should prompt an orthodontist evaluation. Orthopedics and Rehabilitation: conservative or surgical interventions are required to manage joint contractures, scoliosis, foot, and spine deformities. Bracing, serial splinting, and assistive devices, including walkers, orthotics, scooters, and wheelchairs, may be required to facilitate standing/walking/sitting. Yearly evaluation is recommended, more frequent in younger children, to assess motor development and function. Physical activity is essential for children as they experience progressive improvements in proximal muscle strength. Pain Management: Patients with CMD are prone to developing contractures, which can lead to painful spasms and joint pain. Effective pain management is important for achieving a good quality of life.[27][28][29]

Orthopedics and Rehabilitation: conservative or surgical interventions are required to manage joint contractures, scoliosis, foot, and spine deformities. Bracing, serial splinting, and assistive devices, including walkers, orthotics, scooters, and wheelchairs, may be required to facilitate standing/walking/sitting. Yearly evaluation is recommended, more frequent in younger children, to assess motor development and function. Physical activity is essential for children as they experience progressive improvements in proximal muscle strength. Pain Management: Patients with CMD are prone to developing contractures, which can lead to painful spasms and joint pain. Effective pain management is important for achieving a good quality of life.[27][28][29] Surgical Care: pre-anesthesia assessment, prolonged postoperative monitoring, and combined procedures under single sedation are recommended for children at higher risk for complications. Avoidance of specific agents, including inhaled sedation (halothane), IV sedation (thiopentone), muscle relaxants (succinylcholine, vecuronium), neostigmine, and some chemotherapy, is essential. Propofol-induced pain can induce myotonia.[8] Psychiatry: Patients with CMD with their disability are prone to develop depression and anxiety, and must have a psychiatry/psychologist referral as part of multidisciplinary care.[30] Surveillance: Every 6 months: dentistry assessment Every 1 year: ECG, 24-hour Holter, pulmonary function test, fasting glucose/HBA1C Every 2 years: ophthalmologic exam [3]

Differential diagnoses of congenital myotonic dystrophy include the following: Prader-Willi syndrome Temple syndrome Congenital myopathies (multiminicore, nemaline, and centronuclear) [8] Hereditary inclusion body myopathy Welander distal myopathy Limb-girdle muscular dystrophy types 2B (dysferlinopathy) and 2L

Novel Therapies Antisense Oligonucleotides (AONs): work by degrading the CUG expansion, or by binding to CUG expansion to inhibit RNA sequestration and sites for abnormal MBNL binding. Recombinant Adeno-associated viral (rAAV): stimulates overexpression of MBNL1 to prevent sequestration. Inhibition of CUG-BP1 activity via small molecules (such as pentamidine) or by inhibiting protein kinase C (which activates CUG-BP1) can also prevent sequestration. Clustered regularly interspaced short palindromic repeats (CRISPR/Cas): cleave and degrade CUG mRNA expansion. Others: agents that increase muscle anabolism, such as testosterone, creatine, dehydroepiandrosterone, and recombinant insulin-like growth factor (IGF-1), as well as myostatin inhibitors.[4][24][31][32]

Patient education considerations for congenital myotonic dystrophy include: Congenital myotonic dystrophy (CMD) is a multisystem disease affecting many organs in the body. A mutation in the DMPK gene causes it. Infants appear weak and sometimes require help with breathing and feeding. It is usually diagnosed by genetic testing for the targeted gene. There is no cure, but multiple teams follow the patient for symptom management, surveillance, and family support. Unfortunately, the mortality rate is up to 40% in the neonatal period secondary to respiratory failure.

Key facts to keep in mind about congenital myotonic dystrophy include: Congenital myotonic dystrophy (CMD) is an autosomal dominant neuromuscular disorder with multisystem involvement. It is a subtype of myotonic dystrophy type 1. Features include severe hypotonia and generalized muscle weakness; myotonia is classically absent in infancy. Severe CDM requires intensive care, mainly for feeding and respiratory support. Gastric/jejunum feeding tube, tracheostomy for mechanical ventilation, and splinting of talipes are occasionally commenced. A mutation in the DMPK gene, located on chromosome 19q13.3, results in the expansion of DNA (CTG) repeats. Targeted molecular genetic testing of the DMPK gene appears positive for a heterozygous pathogenic variant in nearly 100% of affected individuals. The multidisciplinary team approach is critical for symptom management, surveillance, and family support. The mortality rate is up to 40% in the neonatal period due to respiratory diseases. The mean life expectancy is 45 years.

As discussed previously, a multidisciplinary team approach is critical for symptom management, surveillance, and family support. Consensus-based care recommendations for congenital and childhood-onset myotonic dystrophy type 1 were published in 2019, and the 2014 Consensus Statement on Standard of Care for Congenital Muscular Dystrophies summarized guidelines for inpatient care.[25][26] Future clinical trials include: Natural History: Trial Readiness and Endpoint Assessment in Congenital Myotonic Dystrophy (TREAT_CDM): Children with CDM aged 0-15 are to be enrolled, with baseline and 1-year visits to evaluate physical and cognitive function and quality of life, to extend understanding of disease progression. Treatment: Efficacy and Safety of Tideglusib in Congenital Myotonic Dystrophy. Randomized, double-blind, placebo-controlled trials of tideglusib versus placebo in the treatment of children and adolescents 6 to 16 years of age with congenital DM1. The outcome is a change in Clinician-Completed Congenital DM1 Rating Scale (CDM1-RS) after 22 weeks.