DiagnosisClinical DiagnosisMyotonic dystrophy type 1 (DM1) is suspected in adults with the following: Muscle weakness, especially of the distal leg, hand, neck, and face Myotonia (sustained muscle contraction), which often manifests as the inability to quickly release a hand grip (grip myotonia) and which can be demonstrated by tapping a muscle (e.g., the thenar muscles) with a reflex hammer (percussion myotonia) Posterior subcapsular cataracts detectable as red and green iridescent opacities on slit lamp examination DM1 is suspected in neonates with some combination of the following:Hypotonia Facial muscle weakness Generalized weakness Positional malformations including club foot Respiratory insufficiency TestingNon-molecular testing that has been used in the past to establish the diagnosis of DM1 currently has little role in diagnosis and is primarily used if molecular testing of DMPK does not identify the CTG repeat expansion and other myopathies are being considered. Tests include the following: Electromyography (EMG). A needle electrode placed in the muscle of an affected adult records myotonic discharges and myopathic-appearing motor units, predominantly in distal muscles. Electrical myotonic discharges are not usually seen during infancy, but fast runs of single fiber discharges approaching the pattern of myotonic discharges are suggestive. Serum CK concentration. Serum CK concentration may be mildly elevated in individuals with DM1 with weakness, but is normal in asymptomatic individuals. Muscle biopsy. Pathologic features observed on muscle biopsy include rows of internal nuclei (having a box car appearance), ring fibers, sarcoplasmic masses, type I fiber predominance and atrophy, fibrosis and fatty infiltration, and a greatly increased number of intrafusal muscle fibers [Thornton 2002]. Molecular Genetic Testing Gene. DMPK is the only gene in which mutations are known to cause myotonic dystrophy type 1 (DM1). Essentially 100% of individuals with DM1 have an increased number (i.e., an expansion) of the CTG trinucleotide repeat in DMPK. Allele sizes. Reference ranges for allele sizes were established by the Second International Myotonic Dystrophy Consortium (IDMC) in 1999 [International Myotonic Dystrophy Consortium 2000, Moxley & Meola 2008] See Prior [2009] and Kamsteeg et al [2012] for technical standards and guidelines for testing. Normal alleles: 5-34 CTG repeats Mutable normal (premutation) alleles: 35-49 CTG repeats. Individuals with CTG expansions in the premutation range have not been reported to have symptoms, but their children are at increased risk of inheriting a larger repeat size and thus having symptoms [Martorell et al 2001]. Full penetrance alleles: >50 CTG repeats. Full penetrance alleles are associated with disease manifestations. See Published Guidelines.Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Myotonic Dystrophy Type 1View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityDMPKTargeted mutation analysisCTG trinucleotide repeat expansion100% 2Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing to quantitate the number of DMPK CTG trinucleotide repeats is performed by PCR analysis, which reliably detects expanded alleles with about 100-150 CTG repeats. Detection of larger CTG expansions requires Southern blot analysis. Testing StrategyTo confirm/establish the diagnosis in a proband. A diagnostic algorithm for evaluating patients with myotonia is described by Moxley & Meola [2008]. Molecular genetic testing of DMPK is the basis of diagnosis of DM1. Non-molecular testing used in the past to establish the diagnosis of DM1 currently has little role in diagnosis; it is primarily used if molecular testing of DMPK does not identify the CTG repeat expansion. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with mutations in DMPK.}

Natural HistoryClinical findings in myotonic dystrophy type 1 (DM1) span a continuum from mild to severe. Udd & Krahe [2012] provide an excellent overview of all aspects of DM1. The clinical findings have been categorized into three somewhat overlapping phenotypes (mild, classic, and congenital) that generally correlate with CTG repeat size (Table 2). The CTG repeat ranges for the phenotypes in Table 2 have considerable overlap and caution must be used in predicting disease severity on the basis of CTG repeat size [Gharehbaghi-Schnell et al 1998, International Myotonic Dystrophy Consortium 2000, Harper 2001, Moxley & Meola 2008].Table 2. Correlation of Phenotype and CTG Repeat Length in Myotonic Dystrophy Type 1View in own windowPhenotypeClinical Signs CTG Repeat Size ^1, 2 Age of OnsetAverage Age of DeathMutable normal (premutation) None 35 to 49 NA ³ NA ³ Mild Cataracts
Mild myotonia 50 to ~150 20 to 70 yrs60 yrs to normal life spanClassic Weakness
Myotonia
Cataracts
Balding
Cardiac arrhythmia
Others ~100 to ~1000 10 to 30 yrs48 to 55 yrs Congenital Infantile hypotonia
Respiratory deficits
Intellectual disability
Classic signs present in adults >1000 ⁴ Birth to 10 yrs45 yrs ⁵ From de Die-Smulders et al [1998], Mathieu et al [1999], International Myotonic Dystrophy Consortium [2000] 1. CTG repeat sizes are known to overlap between phenotypes.2. Normal CTG repeat size is 5-34.3. NA = not applicable4. Redman et al [1993] reported a few individuals with congenital DM1 with repeats between 730 and 1000. 5. Does not include neonatal deathsMild DM1Individuals with mild DM1 may have only cataract, mild myotonia, or diabetes mellitus. They may have fully active lives and a normal or minimally shortened life span [Arsenault et al 2006]. Classic DM1Within this range of CTG repeat size, only a rough correlation with severity of symptoms exists. Individuals with CTG repeat sizes in the 100-to-1000 range usually develop classic DM1 with muscle weakness and wasting, myotonia, cataracts, and often cardiac conduction abnormalities. While the age of onset for classic DM1 is typically in the 20s and 30s (and less commonly after age 40 years), classic DM1 may be evident in childhood, when subtle signs such as myotonic facies and myotonia are observed.Muscle. In individuals with classic DM1, the predominant symptom is distal muscle weakness, leading to foot drop/gait disturbance and difficulty with performing tasks requiring fine dexterity of the hands. The typical facies is mainly caused by weakness of the facial and levator palpebrae muscles. Myotonia may interfere with daily activities such as using tools, household equipment, or doorknobs. Handgrip myotonia and strength may improve with repeated contractions (the so-called warm-up phenomenon) [Logigian et al 2005]. The warm-up phenomenon can also improve dysarthric speech [de Swart et al 2004].Fatigue is a common finding [Kalkman et al 2005].Cardiac. Cardiac conduction defects of varying degrees of severity are common. In one series, 90% of individuals had conduction defects. These defects are a significant cause of early mortality in individuals with DM1, sometimes associated with sudden death. Less commonly, cardiomyopathy may occur [Bassez et al 2004, Chebel et al 2005, Dello Russo et al 2006, Gagnon et al 2007, Sovari et al 2007, Breton & Mathieu 2009, Mörner et al 2010, Petri et al 2012, Turkbey et al 2012].GI. Smooth muscle involvement may produce dysphagia, constipation, intestinal pseudo-obstruction, or diarrhea [Bellini et al 2006]. Orophayngeal dysphagia and swallowing problems have been studied by Ercolin et al [2013].Gallstones occur as a result of increased tone of the gall bladder sphincter.Liver function tests (e.g., transaminases) are often elevated for unclear reasons [Heatwole et al 2006].Cognition and CNS changes. Minor intellectual deficits are present in some individuals, but in others intelligence may be incorrectly assumed to be reduced because of the dull facial expression. Age-related cognitive decline has been reported in some adults [Modoni et al 2004, Gaul et al 2006, Sansone et al 2007, Modoni et al 2008]. Frontal-parietal lobe deficits have been documented on formal testing [Sistiaga et al 2010].Avoidant, obsessive-compulsive, and passive-aggressive personality features have been reported [Delaporte 1998, Winblad et al 2005].Anxiety and depression are often seen and general quality of life can be seriously impaired [Antonini et al 2006].Hypersomnia and sleep apnea are other well-recognized manifestations that appear later [Rubinsztein et al 1998, Laberge et al 2009]. Excessive daytime sleepiness is often caused by a central dysfunction of sleep regulation, but all types of sleep disorders have been reported [Dauvilliers & Laberge 2012]. Fifty percent of 40 individuals with DM1 had obstructive sleep apnea [Pincherle et al 2012].Brain MRI may demonstrate mild cortical atrophy and white matter abnormalities. The white matter changes can be diffuse and extensive [Minnerop et al 2011, Wozniak et al 2013].At autopsy brain neurons may contain tau-associated neurofibrillary tangles [Maurage et al 2005, Oyamada et al 2006]. Nerve. An axonal peripheral neuropathy may add to the weakness but may be uncommon [Krishnan & Kiernan 2006, Bae et al 2008]. Peric et al [2013] found evidence of neuropathy by nerve conduction studies in one third of 111 individuals with DM1. Eye. Cataracts can eventually be observed as having characteristic multi-colored “Christmas tree” appearance by slit lamp examination in nearly all affected individuals. They may cause visual symptoms at any age, but usually in the 30s-40s. Some affected individuals have ophthalmoplegia.Endocrine. Endocrinopathies including hyperinsulinism, thyroid dysfunction, diabetes mellitus, calcium dysregulation, testicular atrophy, and possible abnormalities in growth hormone secretion can be observed, although they are rarely clinically significant. Infertility may occur in otherwise asymptomatic persons [Garcia de Andoin et al 2005, Matsumura et al 2009]. The largest published study of these endocrine abnormalities is that of Orngreen et al [2012].Skin. Pilomatrixomata and epitheliomas can occur, especially on the scalp, and can be confused with sebaceous cysts [Geh & Moss 1999, Cigliano et al 2005]. Cancer risk. Win et al [2012] found that individuals with DM1 may be at increased risk for thyroid cancer, choroidal melanoma, and possibly testicular and prostate cancers. Additional studies are needed. Disease course. Rarely, after several decades of disease, DM1 progresses to the point of wheelchair confinement. Weakness/myotonia of the diaphragm and a susceptibility to aspiration increase the risk for respiratory compromise, usually in individuals with advanced disease [Roses 1997]. Several studies have evaluated life span and mortality in DM1 (Table 2) [de Die-Smulders et al 1998, Mathieu et al 1999]. The most common causes of death are pneumonia/respiratory failure, cardiovascular disease, sudden death/arrhythmia, and neoplasms. In the study of de Die-Smulders et al [1998] 50% of individuals with DM1 were either partially or totally wheelchair bound shortly before death. The cumulative probability of 15-year survival in Belgrade was 50% [Mladenovic et al 2006]. Both early age of onset and decreased survival correlate with larger CTG repeat expansions [Groh et al 2011].Congenital DM1A transmission ratio distortion at conception favors transmission of larger CTG repeats than those present in the parent [Dean et al 2006]. The mother is almost always the parent who transmits the larger repeat, although transmission by the father has been reported [Zeesman et al 2002]. Presence of a large repeat may lead to earlier onset and more severe disease, known as congenital DM1 [De Temmerman et al 2004, Rakocevic-Stojanovic et al 2005]. Congenital DM1 often presents before birth as polyhydramnios and reduced fetal movement.After delivery, the main features are severe generalized weakness, hypotonia, and respiratory compromise. Typically, affected infants have an inverted V-shaped (also termed 'tented or 'fish'-shaped) upper lip, which is characteristic of significant facial diplegia (weakness). Mortality from respiratory failure is common. Surviving infants experience gradual improvement in motor function. Affected children are usually able to walk; however, a progressive myopathy occurs eventually, as in the classic form [Harper 2001]. These individuals may develop any of the typical features of DM1 including weakness, myotonia, cataracts, and cardiac problems.Intellectual disability is present in 50%-60% of individuals with congenital DM1. The cause of the intellectual disability is unclear, but cerebral atrophy and ventricular dilation are often evident at birth. Intellectual disability may result from a combination of early respiratory failure and a direct effect of the DMPK mutation on the brain [Spranger et al 1997, Ekström et al 2009]. Autism spectrum disorder may be observed [Ekström et al 2008]. Douniol et al [2012] have reported common mood/anxiety disorders, impaired attention, and abnormal visual-spatial abilities. Children with DM1 may have low visual acuity, hyperopia, or astigmatism [Ekström et al 2010].

Differential DiagnosisTable 3. Myotonic Dystrophy: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype
MIM NumberGene/LocusGene/Locus
MIM NumberMyotonic dystrophy 1 160900 DMPK, DM, DMK 605377Myotonic dystrophy 2 602668 ZNF9, CNBP1, DM2, PROMM 116955 Data from Online Mendelian Inheritance in ManThe distinction between myotonic dystrophy type 1 (DM1) and other inherited myopathies is made by determining the number of CTG repeats in DMPK.Myotonic dystrophy type 2 (DM2) is characterized by myotonia (90% of affected individuals) and muscle dysfunction (weakness, pain, and stiffness) (82%), and less commonly by cardiac conduction defects, iridescent posterior subcapsular cataracts, insulin-insensitive type 2 diabetes mellitus, and testicular failure. Although myotonia has been reported during the first decade, onset is typically in the third decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and weakness of the neck flexors and finger flexors. Subsequently, weakness occurs in the elbow extensors and the hip flexors and extensors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. A detailed comparison between DM1 and DM2 has been reported [Turner & Hilton-Jones 2010]. CNBP (ZNF9) is the only gene in which mutations are known to cause myotonic dystrophy type 2. CNBP intron 1 contains a complex repeat motif, (TG)n(TCTG)n(CCTG)n. Expansion of the CCTG repeat causes DM2. The number of CCTG repeats in expanded alleles ranges from approximately 75 to more than 11,000, with a mean of approximately 5000 repeats. The detection rate of a CNBP CCTG expansion is more than 99% with the combination of routine PCR, Southern blot analysis, and the "PCR repeat assay." Inheritance is autosomal dominant.No other genetic causes of multisystem myotonic dystrophies have been identified, although they likely exist. The International Myotonic Dystrophy Consortium (IDMC) has agreed that any newly identified multisystem myotonic dystrophies will be sequentially named as forms of myotonic dystrophy. One family posited to have DM3 [Le Ber et al 2004] was subsequently shown to have an unusual presentation of inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFTD) [Udd et al 2006], caused by mutations in VCP. If the DMPK CTG repeat length is in the normal range and if DM2 has been excluded by molecular genetic testing of CNBP, further testing with EMG, serum CK concentration, and/or muscle biopsy is often warranted to evaluate for other causes of muscle disease. The differential diagnosis for hereditary distal myopathies includes hereditary inclusion body myopathy (IBM), hereditary myofibrillar myopathy (MFM), distal muscular dystrophy (e.g., Miyoshi, Nonaka, Welander, Markesbery-Griggs), and the limb-girdle muscular dystrophies.Other hereditary disorders associated with myotonia are myotonia congenita (also called Thomsen disease or Becker disease), caused by mutations in CLCN1, paramyotonia congenita and its variants, caused by mutations in SCN4A, and hyperkalemic periodic paralysis, caused by mutations in SCN4A.Occasionally, DM1 has been misdiagnosed as motor neuron disease (see Spinal Muscular Atrophy and Spinal and Bulbar Muscular Atrophy), cerebral palsy, nonspecific intellectual disability, or, because of 'masked face' and slow movements, parkinsonism.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Mild DM1Classic DM1Congenital DM1

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in children diagnosed with congenital myotonic dystrophy type 1 (DM1), the following evaluations are recommended:Baseline neurologic examination Baseline ophthalmologic examination Assessment of motor skills Assessment of cognitive ability Medical genetics consultationTo establish the extent of disease and needs in adults with classic DM1, the following evaluations are recommended:Baseline neurologic examination Baseline examination by an ophthalmologist familiar with the iridescent posterior subcapsular cataract characteristic of DM1 Assessment of thyroid function ECG, Holter monitoring, and echocardiogram to evaluate syncope, palpitations, and other symptoms of potential cardiac origin Assessment of strength [Whittaker et al 2006] Assessment of cognitive ability Fasting blood glucose determination Medical genetics consultationTreatment of ManifestationsNo specific treatment exists for the progressive weakness in individuals with DM1.A physiatrist, occupational therapist, or physical therapist can help evaluate affected individuals regarding the need for ankle-foot orthoses, wheelchairs, or other assistive devices as the disease progresses. Orthopedic surgery may benefit children with musculoskeletal deformities [Canavese & Sussman 2009].Increased weakness in DM1 has been associated with both hypothyroidism and certain cholesterol-lowering medications (i.e. statins), so that some strength can return if these causative factors are eliminated.Myotonia in DM1 is typically mild to moderate and rarely requires treatment [Ricker et al 1999]. Anecdotally, some individuals have responded to mexilitene or carbamazepine. Logigian et al [2010] found mexilitene 150-200 mg TID effective and safe for treating myotonia.Pain management can be an important part of DM1 treatment. Different medications and combinations of medications work for some individuals, although none has been routinely effective; medications that have been used include mexilitene, gabapentin, nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose thyroid replacement, low-dose steroids, and tricyclic antidepressants. When used as part of a comprehensive pain management program, low-dose analgesics may provide relief.Consultation with a cardiologist is appropriate for individuals with cardiac symptoms or ECG evidence of arrhythmia because fatal arrhythmias can occur prior to other symptoms in individuals with DM1. More advanced, invasive electrophysiologic testing of the heart may be required [Sovari et al 2007].Cataracts can be removed if they impair vision. Recurrence after surgery has been reported [Garrott et al 2004].Males with low serum concentration of testosterone require hormone replacement therapy if they are symptomatic. In most cases, surgical excision of pilomatrixoma including clear margins and its overlying skin is the preferred treatment [Cigliano et al 2005].An extensive review found no evidence for treatment of hypersomnia with routine psychostimulants [Annane et al 2006].Prevention of Secondary ComplicationsVeyckemans & Scholtes [2013] have reviewed the anesthetic management of individuals with DM1. Choice of induction agents, airway care, local anesthesia, and neuromuscular blockade were found to minimize complications during surgery in individuals with DM1. Cardiac pacemakers or implantable cardioverter-defibrillators may prevent life-threatening arrhythmias [Wahbi et al 2012, Facenda-Lorenzo et al 2013].Gagnon et al [2013] presented evidence that obesity, tobacco smoking, physical inactivity and alcohol/illicit drug consumption are lifestyle risk factors associated with more severe DM1 phenotypes.SurveillanceThe following are appropriate:Annual ECG to detect asymptomatic cardiac conduction defects. Some centers perform annual 24-hour Holter monitoring of individuals with DM1 who do not have cardiac symptoms [Sá et al 2007, Sovari et al 2007, Cudia et al 2009]. Tissue Doppler monitoring has also been proposed [Parisi et al 2007, Wahbi et al 2012]. Annual measurement of fasting serum glucose concentration and glycosylated hemoglobin concentration, with treatment for diabetes mellitus if indicated [Matsumura et al 2009]Ophthalmologic examination every two years to evaluate for cataract formation Attention to nutritional status including mastication and trouble eating [Motlagh et al 2005, Engvall et al 2009, Umemoto et al 2009]Polysomnographic follow-up of sleep complaints [Kumar et al 2007]Agents/Circumstances to AvoidStatins used to lower cholesterol may sometimes cause muscle pain and weakness. Mathieu et al [1997] noted that “[n]umerous cases of perioperative complications in patients with DM have been reported. Hazards have been associated with the use of thiopentone, suxamethonium, neostigmine, and halothane. A retrospective study of perioperative complications was conducted for 219 patients who had their first surgery under general anesthesia at the Chicoutimi Hospital. The overall frequency of complications was 8.2% (18 of 219). Most complications (16 of 18) were pulmonary, including five patients with acute ventilatory failure necessitating ventilatory support, four patients with atelectasis, and three patients with pneumonia. Using multivariate analysis, [the authors] found that the risk of perioperative pulmonary complications (PPC) was significantly higher after an upper abdominal surgery and for patients with a severe muscular disability, as assessed by the presence of proximal limb weakness. The likelihood of PPC was not related to any specific anesthetic drug. Because of the increased risk of PPC, careful monitoring during the early postoperative period, protection of the upper airways, chest physiotherapy, and incentive spirometry are mandatory in all symptomatic patients with DM, particularly those with a severe muscular disability or those who have undergone an upper abdominal surgery.”Malignant hyperthermia during anesthesia including the use of vecuronium [Nishi et al 2004] has been reported in DM1 but is very uncommon [Kirzinger et al 2010]. (See Malignant Hyperthermia Susceptibility.)Aggressive doxorunbicin-based chemotherapy for lymphoma in a person with DM1 produced sudden atrial fibrillations [Montella et al 2005]. Evaluation of Relatives at RiskIt is appropriate to offer molecular genetic testing to at-risk adult relatives to allow early diagnosis and treatment of cardiac manifestations, diabetes mellitus, and cataracts.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Women with DM1 are at risk for complications during pregnancy including increased spontaneous abortion rate, premature labor, prolonged labor, retained placenta, placenta previa, and postpartum hemorrhage [Zaki et al 2007, Argov & de Visser 2009]. Special surveillance during pregnancy of women with DM1 includes ultrasound examination; evaluation for placenta previa; and anticipation of possible polyhydramnios, prolonged labor, and/or need for delivery by cesarean section [Argov & de Visser 2009]. Complications related to the presence of congenital DM1 in the fetus include reduced fetal movement and polyhydramnios. There is an increase in the rates of caesarean births and preterm deliveries [Awater et al 2012].Therapies Under InvestigationTreatment trials of myotonia are few in number and not carefully conducted [Trip et al 2006]. Ideas for new pharmacologic approaches are reviewed by Wheeler [2008] and by Foff & Mahadevan [2011] including RNA and small molecule approaches. Gao & Cooper [2013] discuss the potential use of antisense oligonucleotides.Heatwole et al [2011] reported no increase in muscle strength or function in a pilot study of recombinant human insulin-like growth factor; however, they recommended that a larger control trial be performed. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherModerate-intensity strength training does no harm, but it is unclear whether it offers measurable benefits [van der Kooi et al 2005]. A controlled study of an exercise program for DM1 showed neither beneficial nor detrimental effects [Kierkegaard et al 2011].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Myotonic Dystrophy Type 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDMPK19q13​.32Myotonin-protein kinaseDMPK homepage - Mendelian genesDMPKData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Myotonic Dystrophy Type 1 (View All in OMIM) View in own window 160900MYOTONIC DYSTROPHY 1; DM1 605377DYSTROPHIA MYOTONICA PROTEIN KINASE; DMPKNormal allelic variants. DMPK has 14 exons covering approximately 13 kb of genomic DNA Normal allelic variants have 5-34 CTG repeats. Alleles with 35-49 CTG repeats are normal mutable (or premutation) alleles. Individuals with CTG expansions in the premutation range have not been reported to have symptoms, but their children are at increased risk of inheriting a larger repeat size and thus having symptoms [Martorell et al 2001]. Pathologic allelic variants. Myotonic dystrophy type 1 (DM1) appears to be caused by a single mutational mechanism: expanded CTG trinucleotide repeat (>49). Other types of mutations (e.g., point mutations, deletions, insertions) in DMPK have not been reported to be associated with DM1. The CTG repeat that is expanded in DM1 lies in the 3' untranslated region of DMPK. Abnormal repeat lengths may reach several thousand, particularly in individuals with congenital DM1. Table 4. Selected DMPK Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change Reference SequencesNormalc.*224_226CTG(5-34) ¹
(normal range 5-34 CTG repeats)NANM_001081563​.1
NP_001075032​.1c.*224_226CTG(35-49) ^{1(normal mutable range 35-49 CTG repeats)Pathologicc.*224_226CTG(50-?) 1(full-penetrance mutant alleles <50 CTG repeats)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). NA = not applicable1. The CTG variant is in the 3’untranslated region of the gene (indicated by *), with the first nucleotide after the stop codon numbered as *1. Parentheses indicate the range of numbers of the CTG repeats, here indicating normal alleles range from 5-34 repeats. A specific single allele with five repeats would be designated as c.*224_226CTG[5].Normal gene product. Myotonin-protein kinase (DMPK), a 69-kd serine-threonine protein kinase, has been localized to specialized cell structures in heart and skeletal muscle that are associated with intercellular conduction and impulse transmission. It is closely related to cyclic-AMP-dependent protein kinases and to Rho-binding kinases. DMPK may interact with a GTP-binding protein that is a regulatory subunit of myosin phosphatase. Abnormal gene product. The effect of the CTG repeat remains complex and many issues are being clarified [Fiszer & Krzyzosiak 2013]. The effects of an expanded CTG repeat may occur via abnormal RNA transcript processing. Two homologous RNA CUG-binding proteins (CUG-BP and MBNL1 [muscleblind]) have been identified. These proteins are mutually antagonistic mediators of a subgroup of alternative splicing events that are disrupted in DM, in which embryonic forms of some proteins now predominate. These proteins include a chloride channel, resulting in myotonia; the insulin receptor, resulting in increased risk of diabetes mellitus; and microtubule-associated protein tau, encoded by MAPT, a gene associated with cognitive function [Savkur et al 2001, Mankodi et al 2002, Kanadia et al 2003, Ranum & Day 2004, Day & Ranum 2005, Cooper 2006, Leroy et al 2006, Wheeler & Thornton 2007].}