Myotonia is essentially failure of muscle relaxation following contraction, leading to clinical spasm and specific patterns of prolonged electrophysiological activity. If of muscular origin, it is characterized on EMG by a distinctive pattern of rapid spontaneous firing of muscle fibers waxing and waning in frequency and amplitude, while in neuromyotonia this may occur in irregular bursts.1Clinically, it can manifest as stiffness in affected muscles, inability to relax after voluntary contraction, classically an inability to promptly and easily release after a strong grip, or percussion myotonia reflecting muscle irritability. The underlying pathology for myotonia is dysfunction of ion channels on the muscle membranes, while neuromyotonia is the result of spontaneously occurring peripheral nerve discharges.2 This article will focus on myotonia disorders.
The majority of conditions with myotonia are hereditary (genetic) and may be congenital or appearing later in life. Hereditary myotonia is commonly divided into dystrophic and nondystrophic types. Nonhereditary or acquired myotonia can be drug induced or occur in the setting of other conditions such as hypothyroidism. As noted, myotonia is not a single disease entity. A clinical presentation of true myotonia is always associated with electrophysiologic myotonia. However, the converse is not always true, as certain myopathies demonstrate myotonic discharge on EMG without clinical myotonia.3,4
Though presentation may be similar, there are electrophysiologically distinct conditions associated with abnormal sustained muscle contraction, such as myokymia, continuous motor activity, complex repetitive spontaneous discharges including bizarre high-frequency discharges, fibrillations, fasciculations, or electrically silent contracture. These other conditions which lack true electrophysiological myotonia may referred to as neuromuscular hyperexcitability disorders or “pseudomyotonia”.5 Pseudomyotonia is generally characterized by delayed relaxation after maximal voluntary contraction with neuromyotonia discharges.6 Specific treatment for each of these disorders differs substantially. Examples include
- McArdle’s disease (glycogenosis type V) is a disorder of glycogen metabolism, can be difficult to distinguish from a myotonic disorder clinically due to increasing muscle stiffness with exertion, with paraspinal fibrillations and sometimes contracture, is treated with carbohydrate and exercise management.
- Hoffman’s disease with CPK elevation, with myoedema or muscle hypertrophy and complex spontaneous discharges sometimes including true myotonia, due to hypothyroidism.
- Brody myopathy is an autosomal recessive disorder of relaxation in fast twitch muscle associated with deficiency of ATP2A1, the sarcoplasmic reticulum calcium ATPase responsible for reuptake of calcium post contraction. It typically presents with exercise–induced initially painless contracture or cramp. Dantrolene and calcium channel blockers are usually helpful. On EMG, myotonic discharges are typically absent.
- Tetanus shows continuous discharge of motor subunits and shortening of refractory periods between action potentials. Strychnine poisoning is also a close mimic clinically. Both occur due to loss of function of spinal inhibitory neurons. Tetany related to hypocalcemia may include high frequency doublet and triplet discharges.
- Stiff-person syndrome presents with progressive rigidity and waxing and waning spasm with stimulation, primarily of proximal muscles, sometimes with myoclonus. EMG shows continuous involuntary motor unit activity that is abolished during sleep. It is most commonly due to anti-GAD antibodies which affect GABAergic neurons and may be associated with thyroiditis or type I diabetes. First line treatment is benzodiazepines. If symptoms persist, adding levetiracetam or pregabalin is recommended. Second line includes oral baclofen. Refractory cases may be treated with intrathecal baclofen, IVIG or plasmapheresis, though recovery is often incomplete.7
- Isaacs syndrome, aka Isaacs-Merton syndrome, Morvan syndrome (if associated with encephalopathy) and cramp-fasciculation syndrome constitute a group of peripheral nerve hyperexcitability (PNH) disorders.6 Classic Isaacs syndrome is an acquired autoimmune disorder, characterized by continuous muscle fiber activity on EMG that persists during sleep, and also shows fasciculations, neuromyotonia, myokymia, and complex repetitive discharges. Etiology is paraneoplastic or other autoimmune, having associations with VGKC, LGI1 and CASPR antibodies, thymoma, SCLC and other conditions. It has been called acquired neuromyotonia to emphasize the neurogenic basis of the continuous muscle activity.6,8 The possible mechanism of axonal nodal excitability due to greater persistent sodium channel conductance is supported by the effectiveness of the sodium channel blocking anticonvulsants (phenytoin, carbamazepine).6 It is also treated with gabapentin, plasmapheresis and/or immune suppression as well. Some sources consider KCNA1 mutations causing episodic ataxia plus neuromyotonia and myokymia as a hereditary cause of this condition, and it may respond to magnesium supplementation.9
- Hyperekplexia syndromes, which are primarily hereditary and related to glycine signaling, most commonly GLRA1, are sometimes referred to as stiff-baby syndrome because of early presentation with excess generalized stiffness, but later are more characterized by exaggerated startle and are the basis of the “jumping Frenchman syndrome.” Rarely this can be acquired due to brainstem encephalitis. EMG does not show abnormal potentials but abnormal spread and occurrence of muscular activities. It often responds to clonazepam and other anticonvulsants.
Some medications cause or aggravate EMG myotonia with or without clinical myotonia, including the herbicide 2,4-dichlorophenoxyacetate, chloroquine, colchicine, asthma medications, such as terbutaline, fenoterol, beta-adrenergic agonist inhalers, some immunosuppressants, including penicillamine and cyclosporine, lipid lowering agents such as HMG-CoA reductase inhibitors, clofibrate, and 20, 25-diazacholesterol (currently not used therapeutically in humans.)10 Monocarboxylic acids and anthracene-9-carboxylic acid can also cause myotonia.10 Heavy metal exposure is reported as a possible cause in a few sources. Treatment is to stop exposure whenever possible.
Electrophysiologic myotonia may also be seen in association with other disorders:
- Metabolic: acid maltase deficiency (Pompe’s disease) which is treatable with enzyme replacement therapy, and debrancher enzyme deficiency type III aka Forbes-Cori disease.
- Inflammatory: Dermatomyositis/polymyositis is treated with immunosuppression, primarily corticosteroids.
- Inclusion body myopathies, either idiopathic or hereditary forms such as the autosomal recessive GNE myopathy or Paget disease of bone with dementia due to heterozygous mutation of the VCP gene for valosin-containing protein; none of those have specific pharmacological treatment at this time.
- Congenital myopathies, especially centronuclear or myofibrillar.
- Muscular dystrophies such as Emery-Dreifuss or DNAJB6 myopathy
- Schwartz-Jampel syndrome, a complicated dwarfism syndrome aka chondrodystrophic myotonia, is due to biallelic perlecan (HSPG2) mutation. The EMG findings closely resemble neuromyotonia or CRDs.3 The spasms may be treatable with anticonvulsants such as phenytoin or carbamazepine or antiarrhythmics such as mexiletine, procainamide, quinidine or quinine. Modalities such as massaging, warming and stretching may be helpful. The blepharospasm can benefit from botulinum toxin injection or surgery.
- Neuromyotonia and axonal neuropathy (NMAN) due to biallelic HINT1 mutation, also treatable with phenytoin or carbamazepine.
- Systemic disorders: malignant hyperpyrexia, severe hypothyroidism.
- Cases of severe denervation of anti-MuSK myasthenia gravis.3,5
The rest of this article will focus on the true primary myotonic disorders.
Detailed pathoanatomy/physiology and etiologies
Hyperexcitability of skeletal muscle fibers can be due to alterations in voltage gated chloride, sodium, calcium, or potassium channels. In the nondystrophic disorders, skeletal muscle chloride (CLCN1) or sodium channel gene (SCN4A) mutations alter the channel structure and function that lead to muscle membrane hyperexcitability.5 They can present with symptoms of muscle stiffness, pain, fatigue and weakness.
In myotonic dystrophy, the toxic RNA produced by the excess repeats in a gene leads to defective mRNA splicing of the chloride channels, along with other more widespread gene expression in other organs causing a complex multisystem disease.
Specific myotonic disorders – dystrophic
Myotonic Dystrophy Type I and II are autosomal dominant disorders caused by expansion of repeat genes. Type 1 having much greater anticipation or worsening in terms of earlier onset and greater severity with each generation. They affect about 1 in 8,000 people worldwide with DM1 being the most prevalent. The toxic RNA interferes with regulation of splicing and transcription most notably of CLCN1, via binding and inactivating muscleblind-like proteins particularly MBNL1.11,12
- Myotonic Dystrophy Type I (DM1) aka Steinert disease
- Myotonic Dystrophy type II (DM2) aka PROMM (proximal myotonic myopathy)
DM1 is the most common adult-onset muscular dystrophy but can present at any age; its severity and earlier age of onset are roughly proportional to the number of CTG repeats in the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19q13, which tends to expand with each generation. Normally there are fewer than 35-37 repeats; the premutation range with risk of disease transmission though asymptomatic is 38-50, adult-onset cases may have 50 to several hundred, and younger onset cases several hundred to over 1000. The congenital form of the disease, known as Congenital Myotonic Dystrophy (CDM1), is the most severe variant of the disease with CTG repeats usually > 1000. CDM1 is essentially always maternally transmitted, and some mothers are unaware of their condition. This is because male fertility is affected in more severe cases, while in affected females, fertility is preserved even though mothers have myotonia and myopathic facies and may even be cognitively affected enough that childcare is delegated to a grandparent who is either unaffected or very mildly symptomatic. While very large CTG expansions are typically observed in CDM1, this association is not universal.13 However, there is data to suggest that the likelihood of a child being born with CDM1 rises proportionally with the size of the repeat expansion in the mother, particularly if the number of CTG repeats exceeds 300.14
CDM1 manifests prenatally with symptoms that differ from adult-onset DM1 and has a high incidence of perinatal mortality. These infants may be hypotonic with marked myopathic facies, bilateral clubfoot, respiratory weakness, inability to feed with oral and pharyngeal dysphagia, and are often premature due to maternal effects of the condition. This can be mistaken for cerebral palsy or may coexist with cerebral palsy due to the prematurity. Cases with pediatric onset are typically associated with significant intellectual disability and learning differences, attention deficit and psychological disorders, but higher level executive functions including judgement and organizational skills are often affected in adults as well.15
For DM2 the repeat expansion is a CCTG in CNBP gene (cellular nucleic-acid-binding protein, formerly ZNF9) on chromosome 3q21. There is a founder effect for increased prevalence in some geographical areas, most notably in Finland. Though repeat numbers can be much higher, anywhere from over 75 to over 10,000, severity of the condition is much less clearly related and the expansion size tends to be more stable over generations. Age of onset is always in adulthood and there is no congenital form.
The clinical manifestations of these disorders are protean and myotonia may or may not be the clinically most important feature.
Cardiac involvement is a significant and frequent manifestation of DM1, affecting an estimated 75-80% of patients with a spectrum of symptoms that range from mild ECG changes to severe arrhythmias leading to sudden death. Cardiac causes account for up to one-third of mortality in these patients.14 Many adults eventually require pacemaker placement. Accelerated atherosclerosis is also noted in many cases.
Cataracts are nearly universal in adults, usually developing around 50-60 years of age, and the history of cataract before age 50 in prior generations may be a clue to diagnosis.
Insulin resistance is high and type 2 diabetes with onset in early middle age is common. Other endocrinopathies may occur, especially hypothyroidism and hypogonadism.
Disturbance of circadian rhythm with poor sleep and daytime somnolence is very common. Obstructive and/or central sleep apnea contributes to this when present, but low neurologic arousal is a primary issue. Cognitive dysfunction and psychiatric issues, as well as restrictive pulmonary disease due to respiratory muscle weakness are rare in DM2 but common for DM1.
Sensorineural hearing loss commonly occurs in adulthood in 20-30% of cases. DM is also associated with an increased risk of cancer.
Anesthetic considerations are present with risk of a malignant hyperthermia (MH)-like condition and predisposition to severe respiratory depression.
Weakness in DM1 primarily affects distal muscles, but it also impacts muscles involved in neck, face, mastication, swallowing, and speech. The progression of weakness is slow, estimated at a rate of 1% to 3% per year.14
With DM2 most patients are able to function, work, and perform activity of daily living through adulthood, though tremors are prominent and muscle weakness becomes more severe at age 60-85. Life expectancy is much closer to normal. Cardiopulmonary disease can be life-limiting for adults with DM1.
Essentials of Assessment
Providers should inquire about symptoms such as pain, cramping, weakness, and limitation of mobility. DM1 typically impacts the distal muscles more severely, which can present with difficulty releasing grip. However, patients may have developed effective, and even subconscious strategies for avoiding this issue. Proximal muscle pain and weakness are more common in DM2. A thorough review of systems is needed to address all organs with special attention to cardiac, endocrine, special sensory, gastrointestinal, respiratory and sleep symptoms. Family history should include any neuromuscular disease, cataracts and heart disease or arrhythmias with onset age. Taking into account a person’s birth, developmental and academic history, along with occupational background and disability status, is also crucial.
Clinically, myotonia is best tested by having a patient make a tight fist and then try to open hands quickly. In the case of myotonia, there will be a few second delay in hand opening. Similarly, after forced eye closure there will be delay in eyelid opening. 3 Percussion of thenar eminence, wrist extensors, quadriceps, gastrocnemius or tongue, are classically used to test for percussion myotonia. Symptoms of myotonia are generally exacerbated aggravated by the cold.
On ophthalmologic examination, the presence of iridescent posterior subcapsular opacities is almost pathognomonic. Ptosis and strabismus may also be noted.
DM1: Characteristic facial appearance with frontal balding, atrophy in the temporal muscles, facial weakness and myopathic lack of expression, with ptosis and tented upper lip when more severe. Speech intelligibility may be affected and may be worsened in patients with hearing loss. Assessing cognitive versus audiologic reasons for difficulty following commands may be challenging. Distal muscles are more affected and reflexes may be brisk with hypertonia, but Babinski reflexes will usually be downgoing. There is often a “warm up” phenomenon where myotonia improves with repeat activation. Gait may reveal poor balance, subtalar deviation, and sometimes foot drop. Heel cord or hamstring tightness may be identified. Sensory and motor neuropathy may occur but is usually mild unless there is long-standing diabetes, which can be detected by vibratory and position sense testing. Low sperm count with infertility are common.
DM2: There may be a jerky or ratchet quality to grip.16 Pain, unrelated to myotonia, occurring spontaneously or tenderness elicited by palpation is common in proximal muscle groups. Proximal muscles are more affected than distal muscles or facial muscles. Cognitive deficits, when present, are generally mild.
Clinical functional assessment
Difficulty with ambulation, climbing stairs, manual dexterity, opening or closing eyelids and releasing a handshake, can be socially embarrassing. Issues with employability, self-care and household management should be assessed.
Laboratory testing for diagnosis should include creatinine kinase, which will be modestly elevated or possibly within upper limits of normal. Abnormal liver function tests are frequent in DM1 and DM2. Additionally, specific genetic testing can be conducted for DM1 alone initially, and if the results are negative, then testing for DM2 should follow. Annual or semi-annual follow-up of fasting blood sugar or hemoglobin A1c is absolutely necessary, and lipid panels should be monitored, along with thyroid stimulating hormone and follicular stimulating hormone.
Annual EKG, Holter monitor if symptomatic, periodic echocardiogram, monitoring of pulmonary function and sleep study are also recommended.
Muscle biopsy may be abnormal particular for dystrophic versus non-dystrophic myotonias, but is typically non-specific. Electrodiagnosis is not necessary if the clinical phenotype is present and genetic tests confirm the diagnosis. Biopsy findings for DM1 may include small type I fibers, sarcoplasmic masses, ring fibers and internalized nuclei. For DM2, there may be atrophic type 2 fibers and nuclear clumps. Other dystrophic features such as degeneration-regeneration, necrosis and inflammation are not generally observed.
Electrodiagnosis is more essential if there is concern for pseudomyotonia or other disorders. Note that myotonia may not be present in the infant or young child with DM1 initially. Electrodiagnostically, the myotonia is classic and has been likened to hearing a revving engine or dive bomber airplane. Morphologically, the spontaneous muscle fiber action potentials have characteristics of positive waves or fibrillations10 firing at 20 to 80 Hz that wax and wane in amplitude and frequency, which can be stimulated by voluntary contraction, motor nerve stimulation, mechanical percussion or just the needle.14 Characteristic results with short and long exercise tests help to differentiate between the various causes of myotonia. Myotonia in DM1 is more easily evoked in most muscles compared to in DM2 where it is more easily evoked in proximal muscles, such as vastus lateralis and tensor fascia lata. Amplitudes of CMAP and myotonic potentials increase with exercise and decrease with rest.3
MRI of muscles shows fatty hypertrophy correlating with clinical weakness. Brain MRI may show widespread white matter changes. Ventriculomegaly and white matter abnormalities are commonly seen in CDM1 and may be detected prenatally on fetal MRI.19 In DM1 the soleus and medial gastrocnemius are most affected and affected first, and in DM2 vastus lateralis is first affected with involvement of erector spinae and gluteus maximus also common.
Rehabilitation Management and Treatments
Available or current treatment guidelines
There is an AAN publication by 66 experts in collaboration with the MDF (Myotonic Dystrophy Foundation) regarding comprehensive treatment guidelines for adults with DM1.18 Briefly, multidisciplinary treatment with education, genetic counseling, physical, occupational and speech therapy as well as multispecialty medical monitoring and treatment for associated conditions is the standard of care. There is no medication specifically approved for this condition but there is evidence for safety and efficacy for treatment of myotonia when it affect function. Mexiletine maybe considered in the absence of cardiac contraindications,20 but recent clinical trial showed that mexiletine does not significantly change 6-minute walk distance at 6 months.21
It is recommended to evaluate at least annually for swallowing and speech difficulties, mobility, balance, and falls, activities of daily living and activities in home, school, work, and community. 20 Low-intensity exercise and exercise testing with ECG monitoring prior to beginning an exercise training program in DM1 patients are recommended.22.
The most common causes of mortality are cardiac and pulmonary issues; referral to cardiology, pulmonology, and/or sleep medicine consultations are recommended. Cardiac management is defined in detail by an AHA publication. 23 Cardiology can assist with use of both stimulant and anti-myotonic medications. Hypersomnolence can be frequently the initial presenting symptoms, and are thought to be primarily caused by a central dysfunction of sleep-wake regulation rather than poor sleep, but sleep-related breathing disorders, sleep fragmentation, and restless legs symptoms may also occur.24 PFT showing significant restrictive disease or peak cough flow under 270 l/min should trigger pulmonology referral. There is some evidence for treatment excessive daytime sleepiness with either methylphenidate or modafinil; 24melatonin is not contraindicated and can be tried for insomnia. Precautions are needed during and post anesthesia as patients have a risk for an MH-like reaction and high sensitivity to respiratory depressants such as benzodiazepines and opioids. Weak bulbar muscles, prolonged gastric emptying time, and blunted response to C02 may require awake extubation, postoperative noninvasive support, and careful use of supplemental oxygen. Muscle relaxants and hyperkalemia should be avoided and regional anesthesia is preferred when possible. Cognitive status is also relevant to surgical tolerance and recovery.25
Endocrine systems dysfunctions require annual plus symptomatic monitoring of glycemic status and hepatic function (GGT, bilirubin and alkaline phosphatase to avoid alarm due to mildly elevated SGPT and SGOT which are enzymes also found in muscle), and thyroid function (T4 and TSH) testing and lipid profiles every three years or if symptomatic. Recommendations for moderate active exercise, both resistance and cardiovascular, would appear to be safe and may improve insulin sensitivity and reduce risks of frailty and debility, though strength benefits may not be dramatic and care should be taken not to increase fatigue in individuals who are already active. Gastrointestinal complaints are also frequent and may be severe, often requiring GI specialist, speech therapist, and nutritionist input for dysphagia, constipation or diarrhea. Dermatologic concerns include susceptibility to pilomatrixoma which may require surgical excision. Ophthalmologic evaluation is required at least annually including slit lamp examination. Ptosis crutches or surgery are options. Pregnant women require referral to high risk obstetrics. Psychological, psychiatric and social screening are also needed.
Genetic counseling and options for in vitro fertilization and pre-implantation diagnosis may reduce the 50% transmission risk, which may not be well understood even in large affected families.
For pediatric patients, school situation and appropriateness of individualized educational plans and/or section 504 accommodations is an additional concern, as well as transition to adulthood and possible needs for full or limited guardianship depending on individual neuropsychological assessment. Maximizing independence and continence require assessment and encouragement for caregivers.
Translation into practice and clinical pearls
Despite the multiple pathologies of this condition, diagnosis is often delayed for adults and even for children. Average time from onset of symptoms to diagnosis is over 5 years for DM1, and over 14 years for DM2, likely due to subtler symptoms and less clinician awareness.Diagnostic workup should be considered even if patients are taking medications with known myotonia-aggravating potential as they can unmask an underlying disease. Cataracts and diabetes at a young age should prompt consideration. Be aware that symptoms vary, even with identical repeat numbers in the same family generation.26
Specific myotonic disorders – non-dystrophic (ion channel)
Definition and Etiology: These conditions in general are more benign and do not have the complex comorbidities as seen with the myotonic dystrophies and have either autosomal recessive or dominant transmission without anticipation.
Two types of non-dystrophic myotonia include: chloride channelopathies and sodium channelopathies. Diagnosis is based on history and examination, presence of electrical myotonia and genetic testing.5
Chloride Channel Disorders: CLCN1-associated Myotonia Congenita.5 Thomsen disease refers to autosomal dominant and Becker disease to autosomal recessive cases, with the latter being generally more severe but with considerable overlap. These present with muscle stiffness which may improve with exercise (“warm-up phenomenon”) and aggravation with cold, but on particular response to dietary intake. There may be neonatal to young adult onset. Diffuse muscular hypertrophy may be notable, but without the expected supra-normal or high normal strength that might be expected from appearance. This is not as marked as in the “infant Hercules syndrome” associated with Kocher–Debré–Semelaigne syndrome, adrenogenital syndrome, or myostatin mutations. Episodic muscle weakness often lasts a few seconds when initiating movement.5 Mild fixed proximal weakness may develop.
Sodium Channel Disorders: SCN4a-associated phenotypes include a range of symptomatology which are allelic but were defined clinically as different entities until their genetic basis was known. They can be subdivided as paramyotonia congenita (PMC), sodium channel myotonia (SCM), hyperkalemic periodic paralysis (HyperPP) and severe neonatal episodic laryngospasm (SNEL). 5 PMC refers to the “paradoxical” situation where the myotonia is aggravated by exercise, but still cold-aggravated. SCM is characterized as a purely myotonic disorder with additional features such as myotonia fluctuans (fluctuating myotonia), myotonia permanens (permanent myotonia) or acetazolamide -responsive myotonia. Myotonia fluctuans and permanens refer to variable symptoms during rest post-exercise versus more persistent severe symptoms that may interfere with respiration. SNEL are very severe infantile onset cases with muscle hypertonia, episodic laryngospasm (myotonia aggravated by crying and cold exposure) and life-threatening respiratory involvement. Flecainide has been reported as a treatment for myotonia permanens with SNEL onset.27 Potassium-aggravated myotonias include both SCM and HyperPP. HyperPP is characterized by episodes of weakness lasting hours to days, triggered by fasting, exercise or potassium ingestion.5 Hypertrophy is not usually a prominent feature of any of these conditions, but mild persistent proximal weakness may also develop.
Calcium and potassium channel disorders
Hypokalemic periodic paralysis, usually without myotonia, is associated with CACNA1S as an autosomal dominant disorder, which may also confer susceptibility to malignant hyperthermia and hyperthyroid-related periodic paralysis; the latter is also associated with mutation in KCNJ8. HOKPP is precipitated by carbohydrate ingestion and rest after exercise and helped by potassium supplementation.
Cutting Edge/Emerging Issues and Unique Concepts
All of these conditions are covered under the MDA umbrella, both dystrophic and non-dystrophic. Children and families can benefit from support groups and information available through this organization as well as the specialized clinical centers, and children up to age 16 can attend special camps where their condition or disability will be little or no obstacle to participation, often for no charge and with medical and nursing staff available. Registries for both DM1 and DM2 and online support including web sites and social media groups are available as well, and clinical studies for natural history, pulmonary interventions and new drugs continue primarily for DM1. Clinical trials are ongoing in order to assess the efficacy of several novel medications, ranging from repurposing of existing medications (metformin, erythromycin) to novel small molecules, antisense technology, and genome modification using CRISPR based gene editing technologies.28,29
Gaps in Evidence-Based Knowledge
Genotype-phenotype correlations and variable penetrance remain somewhat mysterious. Better studies of benefits of exercise including specific types are needed, as well as additional studies ideally leading to FDA indication and wider formulary coverage for commonly used drugs targeting symptoms.
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- Rauchenzauner M, Frühwirth M, Hecht M, et. al. A Novel Variant in the HINT1 Gene in a Girl with Autosomal Recessive Axonal Neuropathy with Neuromyotonia: Thorough Neurological Examination Gives the Clue. Neuropediatrics. 2016 Apr;47(2):119-22. doi: 10.1055/s-0035-1570493. Epub 2016 Jan 13. PMID: 26760849.
- Miller, Timothy. Differential Diagnosis of Myotonic Disorders. Muscle Nerve 37: 293–299, 2008.
- Ghosh PS, Sorenson EJ. Use of Clinical and Electrical Myotonia to Differentiate Childhood Myopathies. J Child Neurol. 2015 Sep;30(10):1300-6.
- Stunnenberg BC, LoRusso S, Arnold WD, et. al. Guidelines on clinical presentation and management of nondystrophic myotonias. Muscle Nerve. 2020 Oct;62(4):430-444.
- Bashford J, Chan WK, Coutinho E, et.al. Demystifying the spontaneous phenomena of motor hyperexcitability. Clin Neurophysiol. 2021 Aug;132(8):1830-1844. doi: 10.1016/j.clinph.2021.03.053. Epub 2021 May 13. PMID: 34130251.
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- Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, MoxleyRT, et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 2002;10:35–44.
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- Douniol M, et.al, Psychiatric and cognitive phenotype in children and adolescents with myotonic dystrophy, Eur Child Adolesc Psychiatry. 2009;18(12):705-15. http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2012.04379.x/epdf
- Meols, Giovannit and Cardani, Rosanna. Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism. J Neuromuscul Dis. 2015 Jul 22; 2(Suppl 2): S59–S71.
- Peric, S., Maksimovic, R., Banko, B. et al. Magnetic resonance imaging of leg muscles in patients with myotonic dystrophies. J Neurol 264, 1899–1908 (2017). https://doi.org/10.1007/s00415-017-8574-0
- Franc, Daniel T. et al. Cerebral and muscle MRI abnormalities in myotonic dystrophy. Volume 22, ISSUE 6, P483-491, June 01, 2012. https://doi.org/10.1016/j.nmd.2012.01.003
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- Ashizawa T, Gagnon C, Groh WJ, et al. Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurol Clin Pract. 2018 Dec;8(6):507-520.
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- Thornton CA, Moxley RT 3rd, Eichinger K, et al. Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial. Lancet Neurol. 2023 Mar;22(3):218-228.
Original Version of the Topic
Heakyung Kim, MD, Hannah Aura Shoval, MD, Jahannaz Dastgir, MD. Congenital and Acquired Myotonia. 9/22/2015.
Previous Revision(s) of the Topic
Vikki A. Stefans, MD. Congenital and Acquired Myotonia. 7/10/2020.
Yuxi Chen, MD
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Michael Hagen, MD
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Marco Lawandy, DO
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Jessi Yu, MD
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