Myotonic Dystrophy

Etiology

Myotonias are inherited disorders acquired in an autosomal dominant fashion. Both DM1 and DM2 are caused by an expansion of DNA tandem repeats, which results in an RNA gain of function mutation.[1] DM1 is caused by expansion of cytosine-thymine-guanine (CTG) repeat in the 3’-untranslated region of the DM1 protein kinase (DMPK) gene on chromosome 19q13.3.[2] DM2 results from the expansion of cytosine-cytosine-thymine-guanine (CCTG) tetranucleotide repeat located in the intron of the CCHC-type zinc finger nucleic acid-binding protein (CNB or ZNF9) gene on chromosome 3q21.3.[3]

Epidemiology

Myotonic dystrophy is the most common muscular dystrophy in people of European ancestry.[4] DM1 is more common than DM2, and globally DM has an incidence of 1 per 3000 though some regions, such as Quebec, have demonstrated an incidence of 1 per 500.[5][6][7]

Pathophysiology

The pathophysiology of DMI is related to the number of CTG repeats, with more repeats correlating with more severe disease. Those with less than 35 repeats are considered normal, and those that manifest with clinical symptoms typically have greater than 50. Maternal transmissions will often result in greater CTG expansion.[6] Additionally, the newly expanded alleles have a bias for further expansions that leads to the genetic phenomenon of anticipation when transmitted from one generation to the next. The symptoms manifest at an earlier age with each successive generation due to this phenomenon. Secondly, new alleles with varied repeat sizes are continuously generated in non-dividing cells of skeletal muscle, heart, and brain. Skeletal muscles typically have more than 2,000 expansion repeats by age 20 and 4,000 by age 40, and a proposed mechanism of symptom progression is related to the age-dependent growth of the CTG repeats.[4] In DM2, 75 or longer repeats are considered pathogenic.[8] Unlike DM1, in DM2, there is no clear correlation between the length of the CCTG expansion and clinical severity. However, similar to DM1, CTG repeats continue with age.

Histopathology

Muscle biopsy demonstrates irregularity in muscle fiber size, rows of internal nuclei, muscle fibrosis, and myofibril orientation that is perpendicular to the muscle fiber. Type I fiber atrophy can be seen along with increased intrafusal fibers.[6]

History and Physical

Myotonic dystrophy has a spectrum of clinical history and presentation, based on the number of CTG repeats present in the individual. This is a multisystem disorder that affects somatic and smooth muscles, and ophthalmological, cardiovascular, endocrine, and central nervous systems as well. It can range in presentation from lethal in infancy to being mild with the first presentation in late adulthood. DM1 is classically divided into three types: (1) congenital, (2) mild, and (3) classic. There is an additional subtype that typically presents in childhood, around the age of 10 as well. DM2 is a milder form than classic DM1.

Congenital Myotonic Dystrophy (CDM)

The congenital form presents in about 15% of cases, with fetal-onset involvement of muscle and the CNS and typically is seen in those with more than 1,000 repeats.[4] Prenatal manifestations of CDM may include reductions in fetal movement and polyhydramnios. Additionally, equinovarus and ventriculomegaly can be appreciated on fetal ultrasound.[9] The neonatal mortality rate is around 18%.[4] Those who survive into childhood or adulthood typically exhibit a characteristic tented appearance of the upper lip that results from facial diplegia. [10] Other features include marked dysarthria and expressive aphasia. Hypotonia, rather than myotonia, is a hallmark of congenital DMI since myotonia or electrical myotonia are seldom present in the first year of life. Thus respiratory involvement is frequently seen and is the principal cause of death during this period.[10]

Mild Myotonic Dystrophy

The mild form of DM1 or the oligosymptomatic form is associated with mild weakness, myotonia, and cataracts that begin between 20 to 70 years (typically after age 40 years).[4] These patients usually have normal lifespans, and their CTG repeat size ranges between 50 and 150.

Classic Myotonic Dystrophy

The classic form of DM1 usually manifests during 2, 3, or 4 decades of life. Myotonia is the primary initial symptom.[4] It is characterized by a “warm-up phenomenon” upon examination where it appears more pronounced after rest and improves with muscle activity.[11] Distal muscle weakness is the predominant symptom in classic DM1.[6] This leads to impairment of fine motor tasks involving the hands and impaired gait due to foot drop. The classic form also presents with the characteristic “myopathic face” or “hatchet face” due to weakness and wasting of the facial, levator palpebrae, and masticatory muscles.[12] As opposed to DM2, hearing loss is not frequently encountered. Cardiac conduction abnormalities are often seen. Lifespan is reduced compared to average.

Childhood Myotonic Dystrophy

The childhood (infantile) subset of DM1 typically presents around age 10. It might even be undiagnosed due to a lack of neurological symptoms unless there is a prior positive family history of DM. Initial symptoms include learning difficulties and psychosocial problems.[13] Dysarthria and hand muscle myotonia may be prominent features and might exacerbate learning difficulties. Cardiac conduction abnormalities may be diagnosed as early as age 10.

Myotonic Dystrophy Type II

DM2 typically manifests in adulthood (median age 48 years) and has a variable presentation.[14] Some physical examination findings include early-onset cataracts (younger than 50 years), varying grip myotonia, proximal muscle weakness or stiffness, hearing loss, and myofascial pain.[15] Weakness and/or myalgias are the most common initial presenting symptom and are seen in 50% of patients.[14] DM2 presents mostly with axial and proximal muscle weakness that affects the neck flexors, long finger flexors, hip flexors, and hip extensors in contrast to DM1 that typically manifests as distal muscle weakness.[15] Pain is one of the primary complaints in DM2 and is described as abdominal, musculoskeletal, and exercise-related pain. It typically fluctuates and is sometimes misdiagnosed as fibromyalgia.[16]

Evaluation

Myotonic dystrophy should be suspected in patients with symptoms of weakness, a suspected family history DM, and characteristic physical exam findings. Genetic testing for CTG repeats has replaced other modalities in the diagnosis of DM. Other diagnostic testing modalities may often be obtained prior to genetic testing and involves serum creatinine kinase, hepatobiliary function testing, muscle biopsies, and electrocardiographic findings for cardiomyopathy. 

Genetic testing

Genetic testing is performed to reveal the presence of an expanded CTG repeat in the dystrophia myotonica protein kinase (DMPK) gene and establish a definitive diagnosis. Alleles containing 5 to 34 CTG repeats are normal, and between 35 and 50 are mutable normal alleles (permutation alleles). Demonstrating full penetrance alleles of greater than 50 CTG repeats confirms the diagnosis associated with clinical manifestations. If this testing is negative and clinical suspicion is high, genetic testing specific for CCTG repeat in the ZNF9 (CNBP- Cellular nucleic acid-binding protein) gene should be pursued.[17] CCTG repeats over 75 is typical for clinical manifestation of DM2.[14]

Serum Creatine Kinase

In patients with mild disease, it may be mildly elevated but is typically normal.

Hepatobiliary Function

Elevations in the hepatobiliary enzymes alkaline phosphatase, gamma-glutamyl transferase (GGT), serum aspartate aminotransferase, and serum alanine aminotransferase can be seen in 30% to 50% of patients. Elevations do not correlate with the severity of muscle weakness, disease duration, or serum levels of creatine kinase.[18]

Electrodiagnostic Testing

Electrodiagnostic (EDX) testing has been the modality of choice for diagnosis prior to molecular testing. It has the capability to diagnose patients who are clinically asymptomatic or have subtle findings.[19] Motor nerve conduction studies (NCS) show decreased amplitude with normal latency and normal conduction velocities. Sensory nerve conduction studies are typically normal. Electromyography (EMG) typically has normal insertional activity. Early recruitment with short duration and small amplitudes motor unit potentials are observed. Myotonic discharges are highly specific and consist of spontaneous discharges that have a waxing and waning of amplitude and frequency, typically from around 150/second to 20/second.[20][21] It is shown that evaluating distal muscles is more sensitive for detecting myotonic discharges than proximal muscles.[21]

Overview of Electrodiagnostic Findings of Myotonia

• Sustained runs of positive sharp waves
• Trains of negative spikes
• Amplitudes and frequency that wax and wane producing a sound comparable to a dive bomber. This occurs due to rapid, spontaneous fluctuations in the membrane potential of muscle fibers.

Muscle Biopsy

Muscle biopsy typically reveals a morphological picture of a myopathy. The majority of biopsy findings are seen in proximal muscle groups, most notably in the biceps brachii and tibialis anterior muscles.[22] Type I fiber atrophy can be seen in early disease, along with type II fiber hypertrophy. Additional findings include irregularity in muscle fiber size, rows of internal nuclei, muscle fibrosis, and myofibril orientation that is perpendicular to the muscle fiber.

Treatment / Management

There is no curative treatment for DM. Thus, maximizing health and functional independence is the goal of supportive management. This is geared towards monitoring and treating all the medical issues associated with DM.

Medical Treatment

Cardiovascular: Cardiac monitoring with a 12-lead electrocardiogram should be performed in all patients once diagnosed with DM and annually to monitor cardiac conduction disturbances. Baseline cardiac imaging should be performed and serially every 1 to 5 years thereafter.[23]

Pulmonary: Obtaining a baseline and serial pulmonary function testing to monitor for neuromuscular respiratory failure.[24](B3)

Daytime somnolence and obstructive sleep apnea: Evaluate for sleep apnea and prescribe continuous positive airway pressure (CPAP) if required. Neurostimulants such as methylphenidate can be considered for excessive sleepiness.

Ocular involvement: Annual eye exam that includes slit-lamp examination is recommended annually. Surgical removal of cataracts that impair vision and function.[24](B3)

Obstetrics and gynecology care: A high-risk obstetrics evaluation is indicated for patients who are pregnant or considering pregnancy due to the risk of miscarriage, preterm delivery, and respiratory difficulties during pregnancy.

Endocrine issues: These patients are at increased risk of diabetes mellitus from insulin resistance; thus, a baseline and annual fasting blood glucose and hemoglobin A1C are recommended. Screening for hypothyroidism is also required. Since primary hypogonadism and erectile dysfunction are commonly seen in men with DM1, questioning about erectile dysfunction is suggested and accordingly treated if low testosterone is detected on further testing.

Myotonia: Medications that reduce sustained myotonia are used and include sodium channel blockers such as mexiletine, tricyclic antidepressants, benzodiazepines, or calcium antagonists. Sodium channel blockers are contraindicated in those with second and third-degree heart block.

Therapy

Physical and occupational therapy is recommended for strengthening weakened muscles, evaluation for orthotics, and durable medical equipment needs. Speech-language pathology (SLP) is required for dysphagia and swallowing studies or dysarthria as indicated. SLP is also utilized for intellectual disabilities and learning strategies.

Differential Diagnosis

Schwartz–Jampel Syndrome

This is a rare condition caused by a loss of function mutation of the heparan sulfate proteoglycan 2 gene (HSPG2). Unlike DM, there is no warm-up phenomenon of the myotonia. Additionally, during nerve conduction studies, the myotonic discharges lack the waxing and waning in amplitude and frequency.[25]

Hyperkalemic Periodic Paralysis (HPP)

HPP is an autosomal dominant muscle sodium channelopathy that is illustrated by episodic attacks of muscle weakness. It is due to a mutation of the SCN4A protein of skeletal muscle sodium channels located on chromosome 17q23. The attacks characteristically manifest during the first decade of life and typically last less than one hour.[26] Skipping meals, foods with high potassium content, cold temperatures, or resting post-exercise can exacerbate the attacks. Administering 2 to 10 g of potassium under supervision can be done while performing serial strength examinations every 10 to 20 minutes, which should elicit an attack of weakness.[27]

Paramyotonia Congenita (PC)

PC presents with paradoxical myotonia, which is made worse by repetitive muscle contractions and exercise. It also demonstrates increased myotonia with decreased muscle temperature.[28] The etiology is due to mutations in the sodium voltage-gated channel alpha subunit 4 gene (SCN4A).[29] PC typically presents during the first decade of life and commonly affects the facial and upper extremities muscles, with the lower extremities less affected. 

Myotonia Congenita

Myotonia congenita is an inheritable disorder of the chloride voltage-gated channel 1 gene (CLCN1) on chromosome 7q35, which encodes the chloride channel within human skeletal muscle. It has an autosomal recessive (Becker disease) and autosomal dominant (Thomsen disease) inheritance pattern. The autosomal form tends to be more severe.[30]

Conditions with Electrical Myotonia without Clinical Myotonia

• Myotubular myopathy
• Acid maltase deficiency
• Debrancher deficiency
• Inflammatory myopathies
• Hypothyroid myopathy
• Chloroquine myopathy
• Statin myopathy
• Cyclosporine myopathy

Prognosis

The prognosis of myotonic dystrophy correlates with the age of onset and the size of expansion of CTG repeats. Earlier age of onset of symptoms and a greater number of CTG repeats are linked with poorer functional outcomes and reduced survival rates.[31] Up to 50% of individuals with DM1 tend to be partially or wheelchair dependent prior to death.[32] Those with DM2 have a milder course and are typically independent of durable medical equipment or assistive devices for mobility. The leading cause of mortality in DM is neuromuscular-associated respiratory failure, followed by cardiovascular complications.[33][34]

Complications

The CTG expansions of DM affect multiple organ systems in addition to the musculoskeletal system and is associated with several complications.

Central Nervous System

• Intellectual disabilities can be seen in all types but are not universal for all types of DM. Most commonly seen in the congenital form of DM.
• Cerebrovascular accidents can occur secondary to DM associated atrial fibrillation.
• Anxiety and depression due to the loss of functional status
• Hypersomnia and sleep apnea are common due to sleep cycle dysfunctions.
• Ventriculomegaly is seen in congenital DM.

Ophthalmologic

• Cataracts are almost universal in all patients with DM and are seen early with typical onset in the ’40s. Hyperopia and astigmatism can also occur.

Cardiac

• More than 50% of patients experience cardiac abnormalities with DM, and they can occur prior to the onset of neuromuscular symptoms.[23][35]
• Common cardiac complications include:
• Atrial arrhythmias, conduction system slowing, ventricular arrhythmias, cardiomyopathy, and early-onset heart failure.

Pulmonary

• Pneumonia is common due to progressive loss of lung function and reduced lung volumes as a result of progressive neuromuscular-associated respiratory failure.
• Increased risk of anesthesia-related pulmonary complications[36]

Gastrointestinal

• Facial diplegia and oropharyngeal dysphagia can result in dysphagia and an increased risk of aspiration.
• There is also an increased incidence of gallstones and cholecystitis due to a hypertonic gallbladder sphincter.
• Transaminitis and liver enzyme elevations are seen for unknown reasons.
• Increased risk of post anesthesia aspiration due to the weakness of pharyngeal musculature.[36]

Endocrine

• Insulin insensitivity can be seen
• The loss of the seminiferous tubules results and testicular atrophy results in male infertility. 
• In women, there is an increased risk of abortion, miscarriage, pre-term birth rates, and dysmenorrhea.

Dermatologic

• Androgenic alopecia with frontal balding and increased risk of basal cell carcinoma and pilomatrixomas.[37]

Musculoskeletal

• There is a progressive loss of motor function with increased wheelchair dependency towards the end of life.
• Impairments in activities of daily living (ADLs) due to distal muscle weakness of the hands and ankle dorsiflexors.
• Myalgias are very commonly noted.