Congenital Myotonic Dystrophy

Etiology

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 19q 13.3. 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 CTG repeat expansion in the somatic cells during life due to an abnormality in the DNA repair.[6]

The severity of the disease is correlated with allele size (number of repeats) with <30 repeats in an average healthy person to >11,000 repeats in the affected person; however, mild cases were reported with long expansions.[7]

Two important terms are used in the description of autosomal dominant diseases, i.e., penetrance, and anticipation. Penetrance refers to the percentage of the individuals showing signs of the disease, from the mildest to the most severe phenotype. If all individuals who have a disease genotype exhibit the disease phenotype, then 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.[8][4][9]

In DM1, all clinical phenotypes except 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), the maternal transmission is up to ~90% of cases, and only 9-12% are paternal. The mechanism is not yet well understood; however, maternal and intrauterine environment are considered contributing factors.[3][12]

Epidemiology

Myotonic dystrophy is the most prevalent adult muscular dystrophy among the 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 systemic 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 per100 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]

Pathophysiology

Mutation in the 3′ untranslated, noncoding region of 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 skeletal muscle, whilst MBNL 2 in brain tissue. These proteins exhibit loss of function, as they are aggregated in the nucleus and unable to be utilized by the cell. Conversely, CUG-BP binds to cardiac troponin and exhibits gain of function via 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, resulting in loss of CIC-1 chloride channels through disruption of splicing. Defect in the splicing results in sustained muscle contraction with an inability to relax (myotonia).[4][12][20]

Histopathology

Muscle biopsy is required in certain cases where genetic testing comes out to be 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 and Physical

History

It includes detailed birth history, medical/surgical history, and 3-generation family history.

Clinical features associated with CMD are as follow:[4]

• 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, age 1 to 10 years: usually, they are able to walk with improvement in motor function; however, progressive weakness restarts 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.

1. Respiratory: respiratory difficulties are found in 50% of neonates and are the main cause of neonatal mortality and used to distinguish between mild and severe CDM.
2. Musculoskeletal: proximal muscle weakness in DM1 indicates a poor prognosis. The biphasic course in CMD shows improved/stable disease until adolescence/young adult with 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.
3. Cognition: cognitive impairment is one of the most common and challenging manifestations of childhood DM1. CDM patients are most affected, with IQ range 40 to 80, mean 70 (average normal 100). Cognitive impairment correlates with the severity of weakness, size of CTG repeat, and maternal transmission.
4. Sleep: excessive sleep disorder and sleep apnea may adversely affect learning, memory, high-level cognitive processing, and physical functioning, exacerbating psychomotor and cognitive delays.
5. Psychosocial: 50% of children have psychiatric diseases (phobia, depression, anxiety), and ADHD. Avoidant personality, apathy, and autistic features may be present.
6. 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.
7. Others: features of adult “classic” DM 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. 

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 the prompt release of grip, percussion with a reflex hammer, by tapping thenar, wrist extensor will produce involuntary muscle contraction with a delay in relaxation, called percussion myotonia).[23]

Evaluation

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][8][4][12]

Treatment / Management

Severe congenital myotonic dystrophy (CDM) will require intensive care mainly for feeding and respiratory support. Gastric/jejunum feeding tube, tracheostomy for mechanical ventilation, and splinting of talipes is occasionally commenced. Genetic counseling and end of life counseling are essential.[8][23][24](B3)

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,[25], and 2- Consensus Statement on Standard of Care for Congenital Muscular Dystrophies, published in 2014.[26](B3)

Neurology: disclosure of diagnosis should address five items: diagnosis, prognosis, recurrence risk, treatment plan, and family/community support. Patients should be followed by an experienced multidisciplinary team 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 and 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 an improvement in respiratory strength over time, and consideration for tracheostomy should be careful. Maintenance pulmonary therapy includes cough assist, breathe staking, etc. Pulmonary function testing includes vital capacity (<40% predict nocturnal hypoventilation), spirometry (>20% difference between sitting and supine vital capacity indicates diaphragmatic weakness and is a predictor of nocturnal hypoventilation). Other tests include peak cough flow, polysomnography, and blood gases. Pneumococcal and influenza vaccines are recommended, and palivizumab against RSV for children under two 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-ups in symptomatic patients.

Gastroenterology: serial monitoring of nutrition and growth, feeding, GI 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 advisable to consider. 

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 assisting devices to include walkers, orthotics, scooters, and wheelchairs, might 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 as children will experience progressive improvements of proximal muscle strength.

Pain Management: Patients with CMD are prone to developing contractures and can lead to painful spasms and joint pain. Adequate management of pain is important to achieve a good quality of life.[27][28][29](A1)

Surgical Care: pre-anesthesia assessment, prolonged postoperative monitoring, and combined procedures under single sedation are recommended as 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](B3)

Surveillance:[3](B3)

• Every six months: dentistry assessment
• Every year: ECG, 24-hour Holter, pulmonary function test, fasting glucose/HBA1C
• Every two years: ophthalmologic exam

Differential Diagnosis

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

Pertinent Studies and Ongoing Trials

Novel Therapies [4][24][31][32]

• 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 (pentamidine) or by inhibiting protein kinase C (involved in activating CUG-BP1) can also prevent sequestration.
• Clustered regularly interspaced short palindromic repeats (CRISPR/Cas): cleave and degrade CUG mRNA expansion.
• Others: agents to increase muscle anabolism, such as testosterone, creatine, dehydroepiandrosterone, and recombinant insulin-like growth factor (IGF-1), and myostatin inhibitors.

Prognosis

The mortality rate is up to 40% in the neonatal period due to respiratory diseases. The mean life expectancy is 45 years.[3][4]

Complications

Severe CDM will require intensive care mainly for feeding and respiratory support. Gastric/jejunum feeding tube and tracheostomy for mechanical ventilation are occasionally required.[3]