Behavioral & Cognitive Disorders
Dementia associated with amyotrophic lateral sclerosis
Aug. 11, 2023
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The myotonic dystrophies are a multisystem, autosomal dominantly inherited, highly variable muscle disease more frequent in adults. So far 2 distinct entities have been described: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) (PROMM). In this article, the authors review the clinical features, pathogenesis, and crucial management points of both myotonic dystrophy type 1 and the more recently described myotonic dystrophy type 2. This review has been updated to include the published clinical phenotype characteristics, management aspects, genetic aspects, and pathogenic mechanisms of myotonic dystrophy type 1 and type 2. The authors emphasize both the similarities and differences between the 2 forms.
• The myotonic dystrophies are the commonest cause of adult-onset muscular dystrophy.
• Myotonic dystrophy type 1 according to age of onset and symptoms is divided into 5 forms: congenital, childhood, juvenile, adult, and late-onset.
Phenotypes of DM1 and DM2 are similar, but there are some important differences, including the presence or absence of congenital form, muscles primarily affected (distal vs. proximal), involved muscle fiber types (type 1 vs. type 2 fibers), and some associated multisystemic phenotypes.
• There is currently no cure for the myotonic dystrophies but effective management significantly reduces the morbidity and mortality of patients.
• For the enormous understanding of the molecular pathogenesis of myotonic dystrophy type 1 and myotonic dystrophy type 2, these diseases are now called “spliceopathies” and are mediated by a primary disorder of RNA rather than proteins.
• Despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies.
• Gene therapy for myotonic dystrophy type 1 and myotonic dystrophy type 2 appears to be very close and the near future is an exciting time for clinicians and patients.
Myotonic dystrophies represent a group of dominantly inherited, multisystem (eye, heart, brain, endocrine, gastrointestinal tract, uterus, skin) diseases that share the core features of myotonia, muscle weakness, and early onset cataracts (before 50 years of age). Clinicians considered myotonic dystrophy to be a single disease until 1909 when Steinert and colleagues first clearly described the “classic” form of myotonic dystrophy, which was called Steinert disease (90). The gene defect responsible for myotonic dystrophy described by Steinert was discovered in 1992 and was found to be caused by expansion of a CTG repeat in the 3’ untranslated region of myotonic dystrophy protein kinase gene (DMPK), a gene located on chromosome 19q13.3, encoding a protein kinase (27; 72; 128). After the discovery of this gene defect, DNA testing revealed a group of patients with dominantly inherited myotonia, proximal more than distal weakness, and cataracts; these patients were previously diagnosed as having myotonic dystrophy of Steinert but lacked the gene defect responsible for this disease. Subsequent clinical studies of kindreds with patients having these characteristics led to new diagnostic labels for these patients: myotonic dystrophy type 2 (242), proximal myotonic myopathy (PROMM) (200; 145), or proximal myotonic dystrophy (PDM) (248). Later studies demonstrated that many of the families identified as having myotonic dystrophy type 2, PROMM, or PDM had a single disorder that results from an unstable tetranucleotide CCTG repeat expansion in intron 1 of the nucleic acid-binding protein (CNBP) gene (previously known as zinc finger 9 gene, ZNF9) on chromosome 3q21 (194; 122).
Myotonic dystrophy of Steinert, the classical form of myotonic dystrophy that results from an unstable trinucleotide repeat expansion on chromosome 19q13.3, was termed myotonic dystrophy type 1. Patients with the clinical picture of myotonic dystrophy type 2, PROMM, or PDM who have positive DNA testing for the unstable tetranucleotide repeat expansion on chromosome 3q21 were classified as having myotonic dystrophy type 2. Patients with dominantly inherited myotonia, muscle weakness, and early-onset cataracts who lack the gene defects for either myotonic dystrophy type 1 or type 2 were described (157; 249; 146). Reliability of DNA testing to establish or to exclude the diagnosis of myotonic dystrophy type 1 is close to 100% (254). However, caution is necessary in the diagnosis of myotonic dystrophy type 2. This chapter focuses on myotonic dystrophy type 1 and myotonic dystrophy type 2. The clinical spectrum for both myotonic dystrophy type 1 and myotonic dystrophy type 2 remains a work in progress in view of the fact that it has been possible to identify these disorders only recently, specifically with DNA testing. At present, much more information is available on the natural history of myotonic dystrophy type 1 than myotonic dystrophy type 2, but knowledge of myotonic dystrophy type 2 will increase at a rapid pace over the next several years.
Myotonic dystrophy type 1 (myotonic dystrophy of Steinert). Due to the wide phenotypic variability, the OMMYD-3 (Outcome Measures in Myotonic Dystrophy) consortium has defined a new myotonic dystrophy type 1 classification in 5 clinical forms based on age of onset and symptoms: congenital, infantile, juvenile, adult, and late-onset form. The 5 clinical forms differ from each other by the prevalence of the main symptoms and their time of onset as their apparition profiles. This new classification appears to be useful in the context of emerging therapeutic approaches and in harmonization of international myotonic dystrophy network activities (56). Myotonic dystrophy type 1 can present in the third decade (adult-onset) with grip myotonia, slurring of speech, trouble manipulating items, foot slapping, or weak ankles. Premature male pattern baldness also occurs, but it is not usually reported. In cases presenting in the third decade, weakness of the face muscles (inability to bury eyelashes), the long flexors of the fingers (flexor profundus muscles), the intrinsic hand muscles, and the dorsiflexors of the feet (tibialis anterior, extensor hallucis longus, and extensor digitorum longus muscles) are typically present along with myotonia. An MRI study of 20 different upper and lower leg muscles of patients with myotonic dystrophy type 1 has shown abnormal values for muscle fat fraction, muscle volume, and T2 water relaxation time reflecting putative edema (94). Fat fraction correlated with the 6-minute walk test and muscular impairment rating scale.
Myotonia occurs following a powerful isotonic contraction of the fingers or percussion of the thenar and forearm extensor muscles, which tends to be directly proportional to the severity of myotonia (123).
On clinical evaluation percussion, especially of the thenar and forearm extensor muscles, is more sensitive in detecting minimal degrees of myotonia than is grip testing. Percussion of the tongue can also reveal myotonia, but it is a cumbersome diagnostic test with no obvious advantage over percussion of hand and forearm muscles.
Myotonia, along with muscle weakness, usually contributes to the difficulties with speech, swallowing, respiration, and smooth muscle dysfunction (which include abnormal intestinal motility and uterine dysfunction). It is interesting to note that myotonia is not apparent clinically or on electrodiagnostic testing early in life in myotonic dystrophy type 1 patients. Myotonia is also difficult to detect on clinical examination in the late stages of disease, especially in wasted, weakened muscles. In a study conducted on a large population of 144 myotonic dystrophy type 1 patients, leukocyte CTG repeat length resulted to be statistically correlated with both myotonia and grip strength, which are 2 major primary neuromuscular symptoms (98). Myotonic dystrophy type 1 patients who present in the third decade usually develop progressive dysarthria, difficulty swallowing, gastric regurgitation, hypogonadism, insulin resistance, deficient release of growth hormone, hypersomnia, neuropsychological and cognitive alterations, sleep apnea, decline in forced vital capacity, and cardiac conduction disturbances (90). Lifespan may be shortened. Respiratory failure, pneumonitis, and cardiac conduction disturbances are the usual causes of death (57; 134; 90; 264).
Respiratory failure is the most common mechanism of death in patients with myotonic dystrophy due not only to progressive skeletal muscle dysfunction but also to central dysregulation of the control of breathing (189; 91). A brief overview of major sleep disorders in myotonic dystrophy patients was provided in one review: sleep disorders breathing (SDB) with the both central and obstructive sleep apneas (CSA, OSA), excessive daytime sleepiness (EDS), sleep-related movement disorders, and poor sleep quality. Possible pathogenesis and outline management were described (236). A large cohort of myotonic dystrophy type 1 patients has been widely characterized in the phenotype to assess prevalence and identify predictors of restrictive respiratory syndrome. Twenty-one adult patients with myotonic dystrophy type 1 and matched controls underwent detailed investigations with spirometry, manometry, and diaphragm ultrasound, and in addition, surface EMG of the diaphragm and oblique abdominal was performed following cortical and posterior cervical magnetic stimulation of the phrenic nerves or magnetic stimulation of lower thoracic nerve roots (92). The results of this original study showed that in myotonic dystrophy type 1, respiratory muscle weakness relates to clinical disease severity and involves respiratory and probably expiratory muscle strength. Axonal phonic nerve pathology may contribute to diaphragm dysfunction (92). A high prevalence of restrictive syndrome has been found mainly due to respiratory muscle weakness, and most of the patients showed indication to noninvasive ventilation. Data suggest that optimization of respiratory therapeutic management, particularly regarding launching of noninvasive ventilation, might help to reduce the rate of deaths due to respiratory complications in myotonic dystrophy type 1 (205). Noninvasive ventilation has been found to significantly improve ventilation and oxygenation starting from the first night of treatment, and follow-up revealed stable normoxia and normocapnia without deterioration of sleep outcomes for up to 52 months (235). Trunk muscles in myotonic dystrophy type 1 patients show significant higher levels of fat infiltration and reduced muscle size compared to age and gender matched controls. Fat infiltration is associated with reduced muscle strength, mobility, balance, and lung function, although muscle size is associated with reduced muscle strength and lung function. These findings are of importance for clinical management of the disease (234).
The heart is commonly involved in myotonic dystrophy type 1 patients, and cardiac disorders are also an important cause of premature death in these patients (263). Patients with myotonic dystrophy type 1 typically manifest conduction defects, ventricular dysfunctions, and supraventricular and ventricular arrhythmias (263). Sudden death prevention is central and relies on annual follow-up and prophylactic permanent pacing in patients with conduction defect on ECG and/or infrahisian blocks on electrophysiological study. Implantable cardiac defibrillator therapy may be indicated in patients with ventricular tachyarrhythmia (264). The first case of a myotonic dystrophy type 1 patient with type 1 Brugada ECG pattern has been reported (180), suggesting that the combination of ECG abnormalities commonly seen in both myotonic dystrophy type 1 and Brugada syndrome may share a common pathophysiologic pathway, perhaps due to the loss-of-function of the sodium channel SCN5A (71; 180). Overt cardiomyopathy is relatively rare, although cardiac MRI studies suggest that more subtle changes in myocardial trabeculation and mass are more common than previously recognized (45). Physicians dealing with myotonic dystrophy type 1 may take into consideration that cardiac MRI in patients without apparent cardiac disease may show increase in cardiac extracellular volume and decrease in strain as signs of early cardiac pathology (05).
Sleep may also be impaired in myotonic dystrophy type 1 patients. Excessive daytime sleepiness is seen in 33.1% of these patients and tends to be proportional to the amount of muscular impairment. In addition, myotonic dystrophy type 1 patients often have longer sleep periods (more than 10 hours), excessive daytime sleep, difficulty falling asleep, and somnolence after meals; this is similar to patients with idiopathic hypersomnia (112). Periodic limb movements in myotonic dystrophy type 1 are also frequently associated (203). In a large cohort of Canadian myotonic dystrophy type 1 patients followed for 9 years, the predicting factors of daytime sleepiness and fatigue were modifiable factors as BMI, psychological distress, hypothyroidism, and sleep habits (113).
Severe vitamin D deficiency is common in myotonic dystrophy type 1 and it is associated with secondary hyperparathyroidism, and primary hyperparathyroidism, though rare, may occur. Therefore, greater attention should be given to vitamin D status in order to administer an appropriate replacement therapy (168). Moreover, patients with myotonic dystrophy type 1 have a higher incidence of hypercalcemia compared to the general population (97) and higher fragility fractures in myotonic dystrophy type 1 versus myotonic dystrophy type 2, whereas hip osteopenia was more prominent in myotonic dystrophy type 2 (169).
Early onset posterior subscapular cataract (less than 50 years of age) is considered a characteristic feature of myotonic dystrophy type 1 and is known to be a key feature for timely diagnosis (262). Early detection of Christmas tree cataract also constitutes a common ophthalmologic finding in myotonic dystrophy type 1 patients (165). Occurrence of cataracts before the age of 50 years should alert the clinician to consider myotonic dystrophy. Retinal degenerative changes have also been documented pathologically (14). New findings of retinal changes by spectral domain optical coherence tomography (OCT) in a cohort of myotonic dystrophy type 1 patients have been described (03). They are consistent with typical retinal pigment epithelium changes and abnormalities of the vitreoretinal interface, particularly epiretinal membranes, resulting in central macular thickness. Both inner and outer retinal alterations are associated with increasing age, suggesting a premature aging of the retina in myotonic dystrophy type 1.
Gastrointestinal manifestations are common in myotonic dystrophy type 1 patients, affecting their quality of life, with a relatively high frequency of gallbladder removal occurring at a younger age compared to normal population. In a study that analyzed the progression of gastrointestinal manifestations, the most common changes reported by myotonic dystrophy type 1 patients were new reports of stomach ulcers and trouble swallowing (95). In these patients the greater risk of a gastrointestinal manifestation has been associated with higher body mass index and longer disease duration. A study conducted on a cohort of 152 patients with myotonic dystrophy type 1 revealed that 32% of the study population reported faecal incontinence, which has changed their lifestyle (186). In one study, a gender-related prevalence and severity of gastrointestinal manifestations was documented in myotonic females versus males, who showed high serum GPT and γGT levels (179).
Myotonic dystrophy type 1 patients have a clear age-related decline of cognitive functions as demonstrated through detailed neuropsychological studies, linguistic levels, praxis evaluations, and executive task evaluations. Cognitive deficits may include a variable combination of global cognitive impairment with involvement across different domains, including social cognition, memory, visuospatial functioning, and recognition of emotions conveyed by facial expression and body postures (160; 29; 118). The level of decline does not tend to correlate with either the number of CTG repeats or the severity of muscle weakness (149; 277; 76). These studies give support for proposals on a possible degenerative brain process (148).
Advanced MRI studies demonstrated across the brain a widespread white matter disruption and a multifocal gray matter volume loss by using various single MRI techniques, including diffusion tensor imaging and voxel-based morphometry, with correlations found between corresponding quantitative MRI parameters and triplet expansion, neuropsychological tests, and the severity of muscular involvement (11; 269; 148; 280; 278; 37; 279; 228; 220; 284; 255). Abnormal patterns of brain connectivity have also been reported in myotonic dystrophy type 1 patients and have been demonstrated to account for patients’ personality traits (230; 226; 225). A work on 31 patients with myotonic dystrophy type 1 shows that in myotonic dystrophy type 1 a prominent deficit of decision-making, which is critical for succeeding in social and professional life, might be related to increased connectivity between ventral tegmental area (VTA) and brain areas critically involved in the reward/punishment system and social cognition. These findings suggest a potential dopaminergic function as potential target for pharmacological and nonpharmacological interventions in myotonic dystrophy type 1 (229). An abnormal cortical thickness associated with deficits in social cognition was found by MRI-3T in 30 patients with myotonic dystrophy type 1. This study confirms the presence of widespread brain changes associated with cognitive impairment in myotonic dystrophy type 1 patients (227). Volumetric analysis by neuroimaging has revealed a reduced intracranial volume in myotonic dystrophy type 1 subjects compared with controls, and some morphological differences observed are associated with CTG repeat length, indicating plausible links to key myotonic dystrophy type 1 symptoms including cognitive deficits and excessive daytime somnolence (256).
Nevertheless, the mechanistic links between the genetic abnormalities, the pathomolecular mechanisms, and CNS involvement remain elusive at the moment. The identification of adequate biomarkers of brain involvement in myotonic dystrophy type 1 is of great importance as CNS outcomes measures are necessary for upcoming gene therapy clinical trials (75; 74; 138; 82). In 1 study, it has been observed that identification of outcome measures with good specificity for brain involvement in myotonic dystrophy type 1 is challenging because complex cognitive assessments may be compromised by peripheral muscle weakness, and self-reported questionnaires may be influenced by mood and insight. This highlights the need for further large, longitudinal studies to identify and validate objective measures, which may include imaging biomarkers and cognitive measures not influenced by motor speed (87). A paper shows a distinct pattern of brain atrophy and its progression over time of a decade in pediatric and adult onset in 21 myotonic dystrophy type 1 patients (9 with pediatric onset, 12 with adult-late onset). These findings indicate a possible neurodevelopment origin of brain abnormalities in myotonic dystrophy type 1, along with the existence of additional neurodegenerative process (111).
Myotonic dystrophy type 1 can also present with severe symptoms in newborns. This presentation is termed congenital myotonic dystrophy. Babies typically have generalized weakness and hypotonia, respiratory failure or insufficiency, feeding difficulty, and clubfoot deformity. Children with congenital myotonic dystrophy have 25% mortality rate in the first year if their disease is severe enough to warrant prolonged ventilation (30). Based on current information, congenital myotonic dystrophy occurs only in myotonic dystrophy type 1 and does not develop in myotonic dystrophy type 2. No clinical electrophysiologic myotonia is apparent in infants with congenital myotonic dystrophy. Children with congenital myotonic dystrophy demonstrate impaired orofacial functioning that affects communication and swallowing (21). A study shows a positive correlation between methylation, particularly upstream of the CTG repeat, and maternal inheritance in congenital myotonic dystrophy-affected individuals, indicating that DMPK methylation may account for the maternal bias for congenital myotonic dystrophy transmission (18; 114). Careful evaluation of the mother is helpful in establishing the diagnosis and demonstrating the presence of myotonia (percussion and grip) and weakness (long flexors of the fingers and dorsiflexors of the feet). Electromyographic study of the mother is also useful. Without a careful evaluation of the mother, the underlying cause of the illness in the infant may be missed, and an opportunity for future preventive therapy in both the infant and the mother will be lost. The cause of the hypotonia, feeding difficulty, and respiratory problems can be erroneously ascribed solely to perinatal factors, such as germinal matrix hemorrhage or eventration of the diaphragm, both of which occur in congenital myotonic dystrophy (90).
Babies with congenital myotonic dystrophy type 1 who survive the newborn period (and those who have less severe weakness as infants and elude diagnosis) typically have intellectual disability, learning disabilities, behavior problems, toilet training delay, and slowed motor development. In 1 study, detailing brain magnetic resonance imaging findings in neonates and children with congenital myotonic dystrophy type 1 and white matter abnormalities have even been found in the neonatal period (173). Fortunately, these children usually have improvement in all these limitations throughout childhood and during their early teens. Motor function improves during the first decade, is most pronounced during the first 6 years, reaches a plateau during adolescence, and starts to deteriorate in the beginning of the second decade (109). Unlike other neuromuscular diseases, older children (3 to 13 years old) with congenital myotonic dystrophy type 1 have a muscle mass closer to age-matched controls, consistent with the clinical profile of increasing strength in childhood (38). Later in the second or in the third decade patients with congenital myotonic dystrophy type 1 begin to show progressive weakness. A decrease in muscle strength has been observed more pronounced in the distal than in the proximal muscle groups (109). Superimposed on the skeletal muscle and brain manifestations that persist from congenital myotonic dystrophy type 1, patients also develop a clinical picture resembling that of typical patients with myotonic dystrophy type 1. A preliminary study found a prevalence of 25.8% congenital myotonic dystrophy pediatric patients with cardiac abnormalities (231).
Patients with patent symptoms occurring during the first decade will be assigned to infantile myotonic dystrophy type 1 whereas children with onset between 10 and 20 years of age will be classified as a juvenile form of myotonic dystrophy type 1 (65). Neurocognitive dysfunction is a hallmark of the childhood forms of myotonic dystrophy type 1 (infantile and juvenile onset forms), with age of onset after 1 year. This dysfunction is comprehensive of neuropsychiatric problems, such as predominantly inactive subtype of attention deficit hyperactive disorders or autism spectrum disorders (10; 64; 09). As with the congenital type, children with childhood-onset myotonic dystrophy type 1 (infantile and juvenile forms) will develop muscle symptoms at an older age, causing physical disabilities comparable to the severe adult-onset type 1 disease (66; Echenne et al 2013). The juvenile form with age of onset after 11 years of age is characterized by school and behavioral problems and is often underrecognized. These childhood forms have to be considered as a CNS disease rather than a muscular or systemic disease (66). A neuroimaging study of brain in children and adolescents suggests a relationship between white matter damage and working memory (278).
A multicenter study has been conducted to genotypically and phenotypically characterize a large pediatric myotonic dystrophy type 1 cohort (314 children: 55% congenital, 31% infantile, 14% juvenile form), and thus provide a solid frame of data for future evidence-based health management (116).
Myotonic dystrophy type 1 has the most variable clinical features of the myotonic dystrophies. It can present late in life with only cataracts, baldness, or occasionally heart block (late-onset oligosymptomatic form). These complaints are often attributed to aging or coronary disease. Muscle weakness in such cases is often mild or absent, and diagnosis of myotonic dystrophy type 1 may not be considered.
Gender is an unrecognized factor influencing myotonic dystrophy type 1 clinical profile and severity of the disease, however, in a cross-sectional analysis of main multiorgan clinical parameters in 1409 adult myotonic dystrophy type 1 patients it has been reported that gender may impact on myotonic dystrophy type 1 phenotype and severity with worse socioeconomic consequences of the disease and higher morbidity and mortality in males (63). Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder, and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems and had a higher mortality rate. This study indicates that gender should be considered in the design of both stratified medical management and clinical trials.
Myotonic dystrophy type 2 (PROMM; proximal myotonic myopathy). There are no distinct clinical subgroups in myotonic dystrophy type 2, and clinical presentation comprises a continuum ranging from early adult-onset severe forms to very late-onset mild forms that are difficult to differentiate from normal aging. Only 2 cases of neonatal forms have been reported so far in the literature: 1 of these patients had reduced intrauterine movements and muscle hypotonia after birth (110), and the second had only congenital talipes equinovarus without any other clinical sign (197). At present, there is no evidence of a congenital or childhood form of myotonic dystrophy type 2 (54). Contrary to myotonic dystrophy type 1, in myotonic dystrophy type 2, anticipation has been described only with clinical criteria in a few families, but no longer CCTG repeat expansions in patients with earlier age at onset have been observed (219; 54; 221). Myotonic dystrophy type 2 typically presents in adulthood and has variable manifestations such as early onset cataracts (less than 50 years of age), various grip myotonias, thigh muscle stiffness, muscle pain, and weakness (in hip flexors, hip extensors, or long flexors of the fingers) (200; 242; 201; 145; 55; 136; 157; 54). These complaints often appear between 20 and 50 years of age. Posterior subscapular cataract before 50 years of age is a characteristic feature of myotonic dystrophy type 2, and early onset cataract can be a presenting feature of the disease, preceding all other symptoms (166). Pain is a common as well as a highly relevant problem for many patients with myotonic dystrophy type 2, with an estimated lifetime prevalence of 76% and a negative effect on quality of life (258). Patients and their care providers ascribe the symptoms to overuse of muscles, “pinched nerves,” “sciatica,” arthritis, or fibromyalgia. In comparison to other chronic muscle disorder patients, proximal myotonic dystrophy type 2 patients more frequently describe a pain that is sometimes reported to be exercise-related, temperature-modulated, and palpation-induced (81). Younger patients may complain of stiffness or weakness when running up steps, whereas they infrequently complain of cramps. The muscle pain in myotonic dystrophy type 2 has no consistent relationship to exercise or to the severity of myotonia found on clinical examination. The pain, which tends to come and go without obvious cause, usually fluctuates in intensity and distribution over the limbs. It can last for days to weeks. This pain seems qualitatively different from the muscle and musculoskeletal pain that occurs in patients with myotonic dystrophy type 1. In a study on qualitative as well as quantitative aspects of pain in patients with myotonic dystrophy type 2, it has been observed that mechanical hyperalgesia is the main finding present in the rectus femoris, trapezius, and thenar, suggestive of at least a peripheral mechanism of pain (258). Pain appears to be most often located symmetrically in the proximal limbs (258). Myotonic dystrophy type 2 scored significantly lower than myotonic dystrophy type 1 on the bodily pain scale, indicating more body pain in myotonic dystrophy type 2. This finding has a high disease impact on physical as well as on mental health functioning (243), and on professional performance (237). A transcriptomic analysis performed on 12 muscle biopsy specimens obtained from myotonic dystrophy type 2 patients has identified 14 muscle genes significantly up- or down-regulated in myalgic patients compared to nonmyalgic myotonic dystrophy type 2 patients. These data support the idea that molecular changes in the muscles of myotonic dystrophy type 2 patients are associated with muscle pain and suggest that muscle-specific molecular pathways might play a significant role in myalgia (153). Identifying the molecular source of pain pathophysiology should greatly facilitate the development of mechanism-based therapeutic strategies to treat musculoskeletal pain.
Early in the presentation of myotonic dystrophy type 2, there is only mild weakness of hip extension, thigh flexion, and finger flexion. Myotonia of grip and thigh muscle stiffness varies from minimal to moderate severity over days to weeks. Direct percussion of forearm extensor and thenar muscles is the most sensitive clinical test for myotonia in myotonic dystrophy type 2. Myotonia of grip is sometimes prominent and often has a jerky quality that seems to differ from that in myotonic dystrophy type 1 and the nondystrophic myotonias. Myotonia is often less apparent in myotonic dystrophy type 2 than in patients with myotonic dystrophy type 1.
In cases of late onset myotonic dystrophy type 2, myotonia may appear only on electromyographic testing after examination of several muscles (201; 54). Facial weakness is mild in myotonic dystrophy type 2 as is muscle wasting in the face and limbs. Weakness of neck flexors is frequent. Trouble arising from a squat is common, especially as the disease progresses.
Calf muscle hypertrophy occasionally is prominent (200; 242; 201).
Other manifestations, such as excessive sweating, hypogonadism, glucose intolerance, cardiac conductions disturbances, cognitive alterations, and neuropsychological alterations, may also occur and worsen over time (55; 143; 54; 144). Sleep complaints and breathing disorders are also frequent in myotonic dystrophy type 2 (204).
The cardiac manifestations of myotonic dystrophy type 2 patients have been found to cause sudden death. In a population of 297 German myotonic dystrophy type 2 patients, 4 had cardiac sudden death before the age of 45. Of these 4 patients, 3 were asymptomatic, all had histologically proven dilated cardiomyopathy, and 2 had conduction system fibrosis (223).
A study on frequency and progression of cardiac and muscle involvement in a large cohort of patients with myotonic dystrophy type 2 demonstrated that the frequency and severity of cardiac involvement and muscle weakness are reduced in myotonic dystrophy type 2 compared to myotonic dystrophy type 1 and that progression is slower and less severe (214). Nevertheless, careful cardiac evaluation is recommended to identify patients at risk for potential cardiac major arrhythmia. A retrospective study comprised of 62 adult patients with myotonic dystrophy type 2 showed that cardiac conduction and rhythm defects are relatively rare in myotonic dystrophy type 2, although diastolic dysfunction is common, suggesting that regular ECG and echocardiography screening is needed in these patients (181). Cardiovascular magnetic resonance demonstrates that in myotonic dystrophy type 2 patients subclinical myocardial injury was already detectable in preserved left ventricular ejection fraction. Moreover, extracellular volume was also increased in regions with no focal fibrosis and myocardial fibrosis was related to conduction abnormalities (218).
Patients with both myotonic dystrophy type 1 and type 2 have lower scores on frontal lobe functioning tests compared to controls and have an increased prevalence of avoidant personality disorders (144). In a study aimed to analyze personality patterns in a cohort of myotonic dystrophy type 1 and type 2 patients, no significant personality impairments have been observed in patients with myotonic dystrophy type 2, and the most common clinical symptoms observed in these patients were anxiety and somatization (170). In patients with type 2 disease, conventional brain MRI findings can be entirely normal. However, in advanced stages or more severe cases, diffuse white-matter changes can be present although be less pronounced than or different to that in myotonic dystrophy type 1 (202; 148). It has been reported that the main transcranial sonography finding in myotonic dystrophy type 2 patients is brainstem raphe hypoechogenicity, which is associated with fatigue and excessive daytime sleepiness. In addition, substantia nigra hyperechogenicity and increased diameter of the third ventricle has been observed (192). The type of cognitive impairment that occurs in myotonic dystrophy type 2 is similar to but less severe than that of myotonic dystrophy type 1. A specific type of “avoidant” personality and a significant impairment in frontal lobe function (especially limited ability to perform executive functions) have been observed in myotonic dystrophy type 1 and type 2 patients, although these abnormalities were milder in myotonic dystrophy type 2 patients (144). Similar observations have been reported in a study performed in a larger cohort of myotonic dystrophy type 2 patients (183). In conclusion there are clinical, neuropsychological, and neuroimaging data that support the hypothesis of central nervous system involvement also in myotonic dystrophy type 2 (141).
As in myotonic dystrophy type 1, gastrointestinal manifestations are common in myotonic dystrophy type 2 patients, affecting their quality of life. A study on progression of gastrointestinal manifestations in these patients reports that during the 5 years of follow-up, the most common changes are the development of trouble swallowing and constipation and that female patients demonstrate a greater risk of a gastrointestinal manifestation (95). A relatively high frequency of cholecystectomy on average before 45 years of age is also reported (95).
It has been reported that hearing impairment is a frequent symptom in myotonic dystrophy type 2 patients and that the sensorineural hearing impairment is located in the cochlea (257). This suggests it is important to perform audiometry when hearing impairment is suspected in order to propose early hearing rehabilitation with hearing aids when indicated.
In a study conducted on a large cohort of 307 genetically-confirmed myotonic dystrophy type 2 patients, a profound gender and age influence on the phenotype has emerged, emphasizing that female gender and aging may be associated with a higher disease burden (150). Indeed, it appears that with aging, there is a tendency towards the worsening of weakness, whereas myalgia and myotonia tend to decrease. Females seem to be more severely affected than men as they show more frequently muscle weakness, multisystem involvement, and need of using walking aids. This study suggests that these age- and gender-specific differences should be considered in diagnostics, management, and future clinical studies of myotonic dystrophy type 2.
It has been observed that metabolic syndrome is common in myotonic dystrophy type 2 patients but not more frequent than in healthy subjects. However, treatment of metabolic disturbances may reduce cardiovascular complications and improve quality of life in patients with myotonic dystrophy type 2.
Body composition assessed by DEXA (dual-energy x-ray absorptiometry) reveals that patients with myotonic dystrophy type 1 and type 2 have similar total body mass, bone mineral content, fat mass, and lean tissue mass. Patients with myotonic dystrophy type 2 have less visceral fat deposition than those affected by myotonic dystrophy type 1. Also, right rib bone mineral density was lower in myotonic dystrophy type 2 patients (182).
Myotonic dystrophy type 1 (myotonic dystrophy of Steinert). As a general rule patients having onset of symptoms in childhood and early adulthood develop more severe manifestations of myotonic dystrophy type 1 and have larger CTG repeat expansions in their leucocyte DNA (90). Myotonia is usually the first clinical sign in myotonic dystrophy type 1, and it usually becomes symptomatic before distal weakness becomes a problem. Progression of muscle weakness (facial, pharyngeal, and distal limb muscles) occurs gradually, typically over 2 or more decades. But some individuals develop more rapid muscle wasting in the presence of chronic medical problems, such as recurrent gastrointestinal dysfunction, diabetes, or prolonged infection. In 1 study, the average annual strength decline using manual muscle testing was .95% (135). Mildly affected individuals may have only minimal or no clinical myotonia and weakness and do not develop symptoms until late middle age. Early onset cataracts, baldness, or cardiac conduction disturbance may be their only signs of myotonic dystrophy type 1.
The life threatening complications in myotonic dystrophy type 1 are primarily respiratory (respiratory failure) and cardiac (heart block, other serious conduction disturbances) (57; 134). These serious complications can occur in patients with and without severe muscle wasting and weakness. Sudden cardiac events appear to be related to age of the patient, duration of disease, and male gender, but not to CTG repeat expansion (209). However, in 1 study, the size of the CTG expansion has been associated with a worse long-term outcome, including a higher incidence of sudden and total death (44). Respiratory insufficiency is often precipitated by pneumonia or aspiration.
The predisposing factors involved in cardiac arrhythmias are less clear. There is agreement that cardiac complications in myotonic dystrophy type 1 develop more frequently in patients with more severe neuromuscular symptoms. One investigation found lower mean left ventricular contraction velocities in myotonic dystrophy type 1 patients with more severe neuromuscular involvement (73). There is conflicting evidence on the importance of CTG repeat length with regard to cardiac conduction, arrhythmias, and survival in myotonic dystrophy type 1 patients (274). Reports show a correlation between conduction disturbance and the size of the CTG repeat (86). In particular, larger CTG expansion in the blood of myotonic dystrophy type 1 patients is associated with the development of conduction system defect, left ventricular dysfunction, and supraventricular arrhythmias (44). Moreover, motor function and CTG repeat length has been found to be significantly correlated with left ventricular diastolic dysfunction in patients with myotonic dystrophy type 1 (167). Significantly higher levels of both serum cTnT and cTnI have been observed in patients with myotonic dystrophy type 1 and type 2 compared with controls, suggesting that these factors might represent a helpful serum biomarker to "predict" cardiac risk in myotonic dystrophy disease (252; 88). Moreover, myotonic dystrophy type 1 and type 2 patients having ECG abnormalities show NT-proBNP serum levels higher than those seen in patients with normal ECG, suggesting that NT-pro-BNP levels may be considered to be used clinically to identify myotonic dystrophy patients at increased risk of developing myocardial conduction abnormalities (251). Although left ventricular dysfunction is a major prognostic determinant in myotonic dystrophy type 1, patients with preserved left ventricular ejection fraction exhibit significantly altered left ventricular global longitudinal strain as compared with controls (79). This parameter could be a predictive factor of sudden cardiac death, and myotonic dystrophy type 1 patients with impaired longitudinal strain could benefit from improved and appropriate therapeutic management. Ischemic stroke may occur in patients with myotonic dystrophy type 1 and is associated with atrial fibrillation (283). A high prevalence of myocardial fibrosis was demonstrated in a cardiovascular magnetic resonance (CMR) study on 52 myotonic dystrophy type 1 patients; however, no association between cardiovascular magnetic resonance myocardial fibrosis with late gadolinium enhancement (CMR-LGE) and surface conduction abnormality has been found (36).
Myotonic dystrophy type 2 (proximal myotonic myopathy). Overall the prognosis for patients with myotonic dystrophy type 2 is more favorable than for individuals with myotonic dystrophy type 1 (201; 157; 54). Patients usually have a slower, less severe, and less widespread progression of muscle weakness and less muscle wasting. There does not seem to be a more severe phenotype associated with the homozygotic form of this disease (221). As in myotonic dystrophy type 1, patients with myotonic dystrophy type 2 who have an earlier onset of symptoms have an earlier onset of myotonia and weakness (219). The natural history of myotonic dystrophy type 2 remains to be fully defined, but present information indicates that most patients have a normal lifespan. Respiratory failure, hypersomnia, and recurrent aspiration or pneumonia are not common in myotonic dystrophy type 2 (244). Cardiac conduction disturbances occur (157), but they are less frequent compared to myotonic dystrophy type 1 (142; 223). An investigation using a variety of standard tests of autonomic function (response to Valsalva maneuver, deep breathing, change in posture, grip, analysis of heart rate variability) reveals no major abnormalities in patients with myotonic dystrophy type 2 myopathy (70).
Myotonic dystrophy type 1 (myotonic dystrophy of Steinert). A 41-year-old man presented to our clinic for difficulty with manipulating objects and with gait problems that had started about 4 years prior to the evaluation. More specifically, he complained of falls from tripping on the ground (for example on carpet edges). Moreover, he reported that since he was 16 years old he noticed stiffness in his hands after grip that was worsening over the years. His mother died due to sudden death at the age of 50 years. Past history and review of systems were remarkable for diabetes and excessive daytime sleepiness. He underwent a study that revealed the presence of sleep-disordered breathing; therefore, he started to use assisted nocturnal ventilation with a partial benefit on daytime sleepiness. His neurologic examination revealed baldness, mild facial weakness, and tongue myotonia. Moreover, there was evidence of weakness of neck, deep finger, and of the feet muscles. Action and percussion myotonia was present in both hands with a warm up phenomenon. Electromyography showed myotonic discharges in abductor pollicis brevis and subsequent genetic analysis confirmed the abnormal expansion of CTG repeats (range 600 to 800) in the 19q13.3 DMPK gene. A check of the major system involved in myotonic dystrophy type 1 allowed the diagnosis of an initial cataract and a bundle branch block. He started therapy with mexiletine 200 mg 3 times a day with improvement of stiffness and he began to use ankle-foot orthoses to help gait and prevent falls. In the follow-up, an episode of loss of consciousness occurred. The cardiologic evaluation and the electrocardiographic monitoring showed an impairment of conduction parameters; thus, the patient underwent an artificial pacemaker implantation with improvement of the symptoms.
Myotonic dystrophy type 2 (proximal myotonic myopathy). A 59-year-old woman with no known family history of neuromuscular disease presented to the clinic for a progressive impairment of walking. She said that she walked “dragging” her legs and she found it difficult to stand up from a chair. She did not complain of any symptoms in the upper limbs except for a mild and proximal stiffness in both the arms, more severe on the right side. Her symptoms started almost 30 years earlier and they worsened after she had been pregnant. She first experienced difficulty climbing up stairs and getting on the bus unless she had something to hold on to. Later she had several falls and complained that it was difficult to walk. The clinical neurologic examination showed proximal weakness but no action nor percussion myotonia were detected. Past history and systems review were remarkable for cholecystectomy and appendicectomy, bilateral cervical lymphadenopathy of unknown origin, cataract in both eyes, thyroid nodules, struma, 2 episodes of loss of consciousness, and several lipothymic episodes, idiopathic artery hypertension, and right bundle branch block. Family history showed an early onset cataract and difficulty climbing stairs in her father. She had never presented to a neurologist until 57 years of age when blood tests performed after a treatment with torvastatine showed high CPK levels of serum creatine phosphokinase. Abnormal values persisted after the treatment was discontinued. She underwent an electromyography that showed myotonic discharges in both upper and lower limbs and a motor polyneuropathy. Because genetic analysis was negative for myotonic dystrophy type 1 a muscle biopsy was performed. The biopsy showed a myopathic pattern with preferential type II fibers atrophy, abnormal number of central nuclei centralization, and several nuclear clumps; the fluorescence in situ hybridization with (CAGG)5 probe on muscle biopsy sections detected nuclear foci confirming the diagnosis of myotonic dystrophy type 2. Subsequent genetic analysis showed an abnormal tetranucleotide CCTG expansion (range 5000 to 6000).
Myotonic dystrophy type 1 results from an unstable CTG repeat expansion in the 3’ non-coding region of the gene for a serine and threonine kinase (myotonic dystrophy type 1 protein kinase, DMPK) on chromosome 19q13.3 (27; 72; 128). The cause of the unstable CTG repeat expansion is unknown; however, it is thought to occur during gametogenesis and is more extensive when coming from a female carrier (61). CCG, CTC, and GGC repetitions interspersed within the 3′ or 5’ end of the CTG expansion have been reported in myotonic dystrophy type 1 patients with a prevalence of 3% to 5% (26; 185). Direct observation of de novo interruptions across 1 or several generations in myotonic dystrophy type 1 families have been reported (26; 25; 185; 50). Interruptions have also been detected at the 5' end of the CTG array (25). Interruptions within the DMPK expanded alleles might have a stabilizing effect on the mutational dynamics and can modulate the severity of symptoms in myotonic dystrophy type 1 patients (26; 25; 185; 50). A study has provided firm evidence that various types and patterns of repeat interruptions confer stability to DMPK expansions in somatic cells, predisposing myotonic dystrophy type 1 patients to develop disease later than average. These data support the assumption that repeat interruptions can act as a genetic modifier of myotonic dystrophy type 1 phenotype (184; 147). Because patients with variant repeats may have unusually mild symptoms, identification of these individuals has important implications for genetic counselling and patient stratification in clinical trials. In 1 study, 2 myotonic dystrophy type 1 families with apparent contractions and no worsening of myotonic dystrophy type 1 symptoms in 2 and 3 successive maternal transmissions have been described (246). In these families, patients with multiple CCG interruptions or a new unique CAG interruption at the 5′ end of the CTG repeat expansion have been detected, suggesting that these 2 types of interruptions are associated with successive maternal CTG repeat contractions and low somatic instability. These results suggest that a single modification in CTG repeat expansions is sufficient to alter the CTG repeat dynamics in myotonic dystrophy type 1 patients by mechanisms yet to be discovered. Several observations raise the possibility that environmental or external factors may influence the development of pathologic enlargement of CTG repeats at the myotonic dystrophy type 1 locus (187; 282).
Normal individuals have 5 to 37 CTG repeats in leucocyte DNA. Repeat lengths of 38 to 50 are considered premutation alleles, whereas 51 to 100 repeats are protomutations, both of which show increased instability toward expansions. Carriers of premutations or protomutations present no or few mild symptoms, such as cataracts. Research suggests that premutations in the upper normal range of CTG sizes become pathologically enlarged within a few generations (133; 01). Patients with myotonic dystrophy type 1 have a wide range of CTG repeat sizes; more severely affected individuals have repeat sizes in the thousands (90). Late onset cases may have minimal skeletal muscle manifestations of myotonic dystrophy type 1 and these individuals typically have small repeat expansions (less than 100 CTG repeats) (90). Those patients with onset in the second or third decades (early middle-life) in general have more prominent symptoms on initial examination and have larger expansion sizes that extend over a wide range. Infants with congenital myotonic dystrophy typically have expansions of more than 800 CTG repeats (90). Strict correlation between genotype and phenotype appeared to be unreliable because there is overlap in the CTG repeat enlargements between groups with classical adult onset and childhood onset myotonic dystrophy type 1 (90). Moreover, the dynamic nature of the expansion makes correlation of genotype and phenotype even more challenging because, over the years, the CTG repeat size in circulating leucocytes from the same individual increases (90). One study attempted to correlate CTG repeat length with progressive myotonic dystrophy type 1 phenotypes; CTG repeat tract length has been measured and screened for interrupting variant repeats in 192 participants from a well-characterized Canadian cohort. Using statistical models that include confounding factors, the analysis has revealed a strong correlation between myotonic dystrophy type 1 genotype and respiratory function and skeletal muscle power (164). To determine the suitability of saliva DNA as a source for myotonic dystrophy type 1 genotyping, small pool-PCR has been used to perform a detailed quantitative study of the somatic mutational dynamics of the CTG repeat in saliva and blood DNA from 40 myotonic dystrophy type 1 patients. The modal allele length in saliva resulted only moderately higher in saliva, and data indicate that saliva constitutes an accessible, noninvasive, and suitable DNA sample source for performing genetic studies in myotonic dystrophy type 1 (47).
Tissue mosaicism adds a further challenge to genotype-phenotype correlations. The repeat size is larger in DNA from skeletal and cardiac muscle compared to that from leucocytes (90), and there is no reliable way to predict the size of the repeat in a given target tissue based on its size in circulating leucocytes. However, it is tempting to propose that the tendency of the myotonic dystrophy type 1 gene to expand and its greater size in certain target tissues exert a determining influence in the variation in clinical severity and in the distribution of manifestations that occurs in individual patients with myotonic dystrophy type 1. However, the general rule remains that the size of the repeat expansion in circulating leucocyte DNA correlates with rate of progression and severity of muscle manifestations. One example of the relationship between CTG repeat size and disease severity in myotonic dystrophy is the phenomenon of anticipation, best exemplified by congenital myotonic dystrophy (90). Anticipation is the earlier onset of more severe clinical manifestations in offspring of affected individuals. In congenital myotonic dystrophy type 1 there is a dramatic enlargement in the size of the CTG repeat with severe symptoms in the infant. Evidence suggests that CTG repeat enlargement in the myotonic dystrophy type 1 gene occurs to a greater degree in the eggs than in the sperm of affected individuals, and that this accounts for the almost exclusive restriction of cases of congenital myotonic dystrophy to children of mothers with myotonic dystrophy type 1 (90). However, the size of the CTG repeat usually increases progressively in successive generations in the eggs of females and the sperm of males who carry the myotonic dystrophy type 1 mutation. Studies of male mice in a transgenic mouse model of myotonic dystrophy type 1 (CTG expansions of 300 to 338 repeats) have shown that germinal expansions occur in spermatogonia and that the length of the CTG repeat does not change between spermatogonia and mature spermatozoa. The size of the CTG repeat expansions in sperm increases with age and probably results from the accumulation of expansions over lifetime as spermatogonia undergo mitotic divisions or as DNA repair mechanisms operate repeatedly on these cells. Further study of these mice indicate that the function of the DNA mismatch repair enzyme MSH2 (muts (E coli) homolog 2; colon cancer gene) is necessary to have the repeat enlargement and suggests that the mechanism underlying the CTG repeat instability is a meiosis-independent event (217). The important idea these results convey is that the mechanisms responsible for instability in germ line and somatic tissues may be identical. Given the important role that DNA mismatch repair genes play in mediating expansions in mouse models, modifier gene effects with 13 DNA mismatch gene polymorphisms (1 each in MSH2, PMS2, MSH6, and MLH1; and 9 in MSH3) have been tested. The data obtained suggest that MSH3 is a key player in generating somatic variation in myotonic dystrophy type 1 patients and further highlight MSH3 as a potential therapeutic target (151).
There are no examples of point mutations in the myotonic dystrophy type 1 gene locus that have caused the clinical picture of myotonic dystrophy type 1. There is evidence in a mouse model that the manifestations of myotonic dystrophy type 1 may result largely from the CTG repeat expansion alone (129) without involvement of the DMPK gene or of flanking genes. The molecular pathology of myotonic dystrophy type 1 is in large part likely to result from a toxic effect of the abnormally expanded RNA that accumulates in the nuclei of target tissues (131; 193; 245; 130).
Myotonic dystrophy type 2 results from an unstable tetranucleotide repeat expansion, CCTG in intron 1 of the nucleic acid-binding protein (CNBP) gene (previously known as zinc finger 9 gene, ZNF9) on chromosome 3q21 (194; 122; 17; 121). The cause for the unstable expansion is unknown. In contrast to the (CTG)n repeat in myotonic dystrophy type 1, in myotonic dystrophy type 2/proximal myotonic myopathy the (CCTG)n repeat is a part of the complex repetitive motif (TG)n(TCTG)n(CCTG)n, and the (CCTG)n repeat tract is generally interrupted in healthy range alleles by 1 or more GCTG, TCTG, or ACTG motifs, whereas it is typically uninterrupted in the expanded alleles (122; 17; 16).
The size of the (CCTG)n repeat is below 30 repeats in normal individuals, whereas the range of expansion sizes in myotonic dystrophy type 2 patients is huge (16). The smallest reported mutations vary between 55 and 75 CCTG (122; 16) and the largest expansions have been measured to be about 11,000 repeats (122). The expanded myotonic dystrophy type 2 alleles show marked somatic instability, with significant increase in length over time (122; 54), thus the threshold size of the disease-causing mutation remains to be determined. The size of the CCTG repeat appears to increase over time in the same individual, and, like myotonic dystrophy type 1, this is a dynamic gene defect (54). These 2 genetic findings complicate the correlation between genotype and phenotype. The gene mutation responsible for myotonic dystrophy type 2 appears to have arisen from a Northern European founder (17; 121), but single-kindred Afghan (221) and Japanese (210) cases have been described. Both mutations are believed to have occurred after migration out of Africa, between 120,000 and 60,000 years ago. The age of the myotonic dystrophy type 2 founder mutation has been estimated at 4000 to 12000 years (about 200 to 540 generations) (17). The molecular pathomechanism leading to the manifestations of myotonic dystrophy type 2 is felt to be similar to that in myotonic dystrophy type 1 and relates to a toxic effect of the abnormally expanded RNA that accumulates in the muscle nuclei (131; 193; 245; 130; 35).
The fact that 2 repeat sequences located in entirely different genes can cause such similar disease features implies a common pathogenic mechanism. The clinical and molecular parallels between myotonic dystrophy type 1 and type 2 strongly suggest that the mutant RNAs containing the repeat expansions that accumulate in the cell nuclei as foci are responsible for the pathological features common to both disorders. It is now clear that the gain-of-function RNA mechanism is the predominant cause of myotonic dystrophy pathogenesis in which the CUG and CCUG repeats alter cellular function of several RNA-binding proteins. It has been demonstrated that mutant CUG and CCUG RNAs are very stable due to a deficiency of RNA helicase p68 (102). The expanded CUG and CCUG RNA form hairpins, imperfect double-stranded structures that lead to dysregulation of 2 important RNA-binding proteins: muscleblind like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1), which are antagonist regulators of alternative splicing of various genes (240; 53). Data demonstrate that MBNL1-containing foci in myotonic dystrophy type 2 cells also sequester snRNPs and hnRNPs, splicing factors involved in the early phases of transcript processing (68; 176), thus strengthening the hypothesis that a general alteration of pre-mRNA posttranscriptional pathway could be at the basis of the multifactorial phenotype of myotonic dystrophy type 2 patients. In myotonic dystrophies, the downregulation of MBNL1, due to its sequestration in mutant RNA foci, and the upregulation of CUGBP1 result in abnormal expression of embryonic isoforms in adult tissues. The alteration of pre-mRNA processing strengthens the hypothesis of a spliceopathy that leads to an expression of isoforms inadequate for a particular tissue or developmental stage (163; 139). Another RNA-binding protein, Staufen1 (Stau1), has been found increased in skeletal muscle of myotonic dystrophy type 1 mouse models and patients (196). It has been demonstrated that Stau1 regulates several alternative splicing events in both control and myotonic dystrophy type 1 myoblasts, suggesting that Stau1 may act as a disease modifier in myotonic dystrophy type 1 (24). However, there is no direct evidence of a cause-effect relationship between symptoms and missplicing, and it is now clear that spliceopathy may not fully explain the multisystemic disease spectrum. In both myotonic dystrophy type 1 and type 2, missplicing of insulin receptor gene (INSR) was associated with insulin resistance. However, Renna and colleagues reported that post-receptor insulin signal transduction via both IRS1-Akt/PKB and Ras-ERK pathway is impaired in myotonic dystrophy skeletal muscle, thus contributing to insulin resistance observable in myotonic dystrophy type 1 and type 2 patients (199). Moreover, myotonic dystrophy skeletal muscle exhibits a lower expression of the insulin receptor in type 1 fibers, contributing to the defective activation of the insulin pathway (198). It is now clear that the molecular pathomechanism of myotonic dystrophies is more complex than actually suggested (Sznajder and Swanson 2019).
miRNAs are small, noncoding RNA modulating gene expression at the posttranscriptional level, and their expression and intracellular distribution are deregulated in many human diseases, including muscular dystrophies (67; 83; 77; 175; 84). Both in myotonic dystrophy type 1 and in myotonic dystrophy type 2 it has been demonstrated that the highly regulated pathways of miRNA are altered in skeletal muscle, potentially contributing to myotonic dystrophy pathogenetic mechanisms (77; 175; 84). The misregulation of miR-1 observed in the hearts of people with myotonic dystrophy type 1 and type 2 may contribute to the cardiac dysfunctions observed in patients (195). The significant reduction of miR-1 in myotonic dystrophy cardiac muscle appears to be caused by the expression of expanded CUG repeats and subsequent MBNL1 nuclear sequestration (195). Interestingly, several miRNAs have been found deregulated in peripheral blood plasma from patients affected by myotonic dystrophy type 1 (177; 178; 107; 108). The levels of these miRNAs, alone or in combination, correlate with both skeletal muscle strength and creatine kinase (178). However, in a study on the expression of 175 known serum miRNAs in myotonic dystrophy type 1 blood samples, none of the miRNA analyzed show consistent differences in serum expression between patients and controls and, thus do not result in useful serum biomarkers for myotonic dystrophy type 1 (69). A deregulation of microRNA in skeletal muscle and plasma from myotonic dystrophy type 2 patients has been also reported (84; 178). The identification of minimally invasive analytical biomarkers for myotonic dystrophies and the established potential of circulating miRNAs as prognostic and diagnostic biomarkers are particularly important to monitor myotonic dystrophies progression and the effectiveness of new drug treatments. Although it seems clear that miRNA pathway is disrupted in myotonic dystrophies, the functional implications of this dysregulation require further investigation. To identify “functional” miRNAs actually engaged in mRNA/target inhibitions relevant for myotonic dystrophy type 1 disease mechanisms, the RISC-associated RNAs have been analyzed in muscle biopsies from myotonic dystrophy type 1 patients. Among the 24 miRNA/mRNA correlations identified, functionally relevant miRNA/mRNA interactions have been identified in skeletal muscles, and in particular, the dysfunction of couple miR-29c/ASB2 has been demonstrated (31). miR-23b and miR-218 have been identified as downregulators of MBNL1 and MBNL2 in HeLa cells. Antagonists of these miRNAs enhance MBNL protein levels, rescue pathogenic missplicing events in myotonic dystrophy type 1 myoblasts, and improve splicing alterations, histopathology, and myotonia in the HSALR mice. These data provide evidence for therapeutic blocking of the miRNAs that control muscleblind-like protein expression in myotonic dystrophy (39). A pilot study indicates that another class of noncoding RNAs, circular RNAs (circRNAs), are dysregulated in myotonic dystrophy type 1 skeletal muscle. Out of 9 tested, 4 transcripts showed an increased circular fraction (CDYL, HIPK3, RTN4_03, and ZNF609), and their circular fraction values correlated with skeletal muscle strength and with splicing biomarkers of disease severity, and they displayed higher values in more severely affected patients. Increased circular fractions of RTN4_03 and ZNF609 have also been observed in differentiated myogenic cell lines from myotonic dystrophy type 1 patients (261).
A novel molecular mechanism that may contribute to the pathogenesis of myotonic dystrophies has been described by Zu and collaborators (286). RNA transcripts containing expanded CAG or CUG repeats can be translated in the absence of a starting ATG, and this noncanonical translation, called repeat associated non-ATG translation (RAN-translation), occurs across expanded repeats in all reading frames to produce potentially toxic homopolymeric proteins (171; 286). RAN-translation results in the accumulation of polyglutamine (polyGln) nuclear aggregates in myotonic dystrophy type 1 mouse tissues and human cardiac myocytes, leukocytes, and myoblasts not detectable in control tissues (286). RAN-translation products appear to be toxic to cells and may contribute to myotonic dystrophy type 1 pathology. It has been demonstrated that RAN-translation also occurs across transcripts containing the myotonic dystrophy type 2 CCUG or CAGG expansion mutation, producing tetra-repeat expansion proteins with a repeating Leu-Pro-Ala-Cys (LPAC) or Gln-Ala-Gly-Arg (QAGR) motif (285). Both LPAC and QAGR RAN proteins accumulate in myotonic dystrophy type 2 human autopsy brains in distinct patterns. For LPAC, cytoplasmic aggregates are found in neurons, astrocytes, and glia in the gray matter regions of the brain. In contrast, QAGR RAN protein accumulation, which is nuclear, is found primarily in oligodendrocytes located in white matter regions of the brain. Moreover, it has been evidenced that RAN protein accumulation can be modulated by MBNL1 levels and that nuclear sequestration of CCUG, CUG, or CAG RNAs decrease steady-state levels of RAN proteins (285). These data suggest that RAN-translation may be common to both myotonic dystrophy type 1 and type 2 and that RAN proteins may be responsible for some of the CNS features of myotonic dystrophies.
It has been hypothesized that DNA methylation contributes to disease development and progression and explains part of the phenotypic variability reported in myotonic dystrophy type 1 (126; 18). It has been observed that DNA methylation at the DMPK gene locus contributes to variability of both muscular strengths and respiratory profiles in myotonic dystrophy type 1 and that these associations are independent of the CTG repeat length. These results, thus, provide evidence that measuring DNA methylation might help to predict progression of the disease and to establish a more reliable prognosis for those patients (117).
To help understand the molecular mechanism and facilitate research into myotonic dystrophy type 1, 120 RNASeq transcriptomes have been generated from skeletal and heart muscle derived from healthy and myotonic dystrophy type 1 biopsies and autopsies. Splicing and gene expression, tissue-specific changes in RNA processing, and uncovered transcriptome changes have been analyzed. Moreover, a web resource has been created at to be maximally accessible to investigators who would like to rapidly browse RNAseq read coverage across the genome and access previously computed gene expression (266). The web resource can be accessed at the following site: http://DMseq.org .
Another open question in the field of myotonic dystrophies is to clarify the pathomechanisms underlying the phenotypic differences between myotonic dystrophy type 1 and type 2. Clinical signs in myotonic dystrophy type 1 and type 2 are similar, but there are some distinguishing features: myotonic dystrophy type 2 is generally less severe and lacks a prevalent congenital form. This suggests that other cellular and molecular pathways are involved besides the shared toxic-RNA gain of function hypothesized. An important step forward in understanding the differences between myotonic dystrophy type 1 and type 2 has been made. Indeed, rbFOX1 has been reported as a novel RNA binding protein that specifically binds to expanded CCUG repeats, but not to expanded CUG repeats. rbFOX1 is enriched in skeletal muscle, heart, and brain and is involved in the regulation of various aspects of mRNA metabolism. In the study, it has been demonstrated that rbFOX1 co-localizes with CCUG RNA foci in muscle cells and skeletal muscle tissues of individuals with myotonic dystrophy type 2, but not with CUG RNA foci in myotonic dystrophy type 1 samples (224). Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats, and its overexpression partly releases MBNL1 from sequestration within CCUG RNA foci in muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing, and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of myotonic dystrophy type 2 (224).
Several studies have revealed a role for CNBP in myotonic dystrophy type 2. CNBP deletion in several animal models results in severe brain and muscle phenotypes and other abnormalities similar to those seen in myotonic dystrophy type 2 (42; 02; 43; 272). These defects can be rescued by reintroduction of wild-type levels of CNBP, suggesting that a loss of CNBP function likely contributes to myotonic dystrophy type 2. Two reports using cell models describe a reduction of the rate of protein translation in myotonic dystrophy type 2 muscle cells due to a decrease of CNBP protein levels in myotonic dystrophy type 2 myoblasts and adult muscle (100) and due to the interaction of CCUG repeats with cytoplasmic multiprotein complexes, which dysregulate translation and degradation of proteins in patients (211). Sammons and colleagues report that CNBP activity is reduced in myotonic dystrophy type 2 human myoblasts leading to a decrease in CNBP activation of IRES-mediated translation of the human ODC and suggest that CNBP activity may contribute to myotonic dystrophy type 2 phenotype (213). Moreover, the reduction of CNBP expression has been reported in myotonic dystrophy type 2 muscle biopsies but not in myotonic dystrophy type 1, thus explaining some of the phenotypic disparities between both types of myotonic dystrophies (32). Taken together, these data suggest that myotonic dystrophy type 2 pathology may be due to a combination of an RNA gain of function and CNBP loss of function.
The role of CUGBP1 in myotonic dystrophy type 2 is particularly intriguing, with contradictory results being reported (120; 174; 211; 32). Cardani and colleagues demonstrated that this protein is overexpressed in muscle biopsies from patients affected by the adult classical form of myotonic dystrophy type 1 but not in muscle from myotonic dystrophy type 2 patients, suggesting that sequestration of MBNL1 evidently has a central role in splicing misregulation in both types of myotonic dystrophies, whereas CUGBP1 overexpression might be an additional pathogenic mechanism in myotonic dystrophy type 1 not shared by myotonic dystrophy type 2 (32). However, it has been shown that that MBNL1 overexpression in a mouse model of RNA toxicity (DM200) is not effective in reversing myotonic dystrophy type 1 phenotypes such as myotonia and cardiac conduction abnormalities. Also, the mice do not show improvement in function assays such as grip strength or treadmill running, and MBNL1 overexpression notably increases muscle histopathology and results in variable rescue of a number of splicing targets (281).
Myotonic dystrophy type 1 and 2 are degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness and atrophy. However, the cause for the muscle weakness and wasting in myotonic dystrophies is still unclear. Patients with myotonic dystrophy type 2, in contrast to patients with classic myotonic dystrophy type 1, usually have only mild muscle wasting. However, there is an uncommon adult-onset variant of myotonic dystrophy type 2 termed proximal myotonic dystrophy, which causes severe wasting of proximal arm and thigh muscles as the illness progresses (248). Moreover, there is still no mechanistic explanation for the histopathological features characteristic of myotonic dystrophies, which include fiber atrophy-hypertrophy, increased number of central nuclei, and presence of fibers with nuclear clumps. It is known that most muscle symptoms can be explained by pathomechanistic effects of toxic RNA and spliceopathy. However, aberrations in DNA replication and transcription of the myotonic dystrophy loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient’s lifetime (08). Vihola and collaborators investigated the molecular basis of muscle weakness and wasting and the differences in muscle phenotype between myotonic dystrophy type 1 and type 2. They identified differences in muscle gene expression and splicing between myotonic dystrophy type 1 and type 2 patients. In particular, the aberrant splicing isoform of TNNT3 is twice as frequent in myotonic dystrophy type 2 compared to myotonic dystrophy type 1. Moreover, in myotonic dystrophy type 1 and type 2, a different protein expression pattern has been found in the highly atrophic fibers (259). Potential molecular mechanisms underlying skeletal muscle loss has been studied in a skeletal muscle-specific mouse model of myotonic dystrophy type 1 (CUG960) showing progressive skeletal muscle wasting. RNA-seq and protein array analysis indicate that the balance between anabolic and catabolic pathways that normally regulate muscle mass may be disrupted by deregulation of PDGFRβ signaling and PI3K/AKT and AMPK pathways. Renna and colleagues reported that IRS1-Akt/PKB and Ras-ERK pathway are impaired in myotonic dystrophy skeletal muscle, leading to a lower activation of mTOR and to an increase in MuRF1 and Atrogin-1/MAFbx expression, possibly explaining myotonic dystrophy skeletal muscle fiber atrophy (198). Similar changes has been detected in skeletal muscle of myotonic dystrophy type 1 patients (152). A role of disruption of PI3K/AKT pathway in myotonic dystrophy type 1 muscle pathology has also been reported by Timchenko and collaborators (102; 271). Using the HSALR mouse model of myotonic dystrophy type 1, they observed an increase of active GSK3β in skeletal muscle of mice, prior to the development of skeletal muscle weakness. Inhibition of GSK3β reduced muscle weakness and myotonia, corrected atrophy, normal fiber size, and reduced central nuclei (102; 271). Correction of GSK3β with small molecule inhibitor of GSK3, Tideglusib, not only normalizes the GSK3β-CUGBP1 pathway but also reduces the mutant DMPK mRNA in myoblasts from patients with adult and congenital myotonic dystrophy type 1. Moreover, the correction of this pathway with Tideglusib increases postnatal survival and improves growth and neuromotor activity of DMSXL mice. Concerning myotonic dystrophy type 2, skeletal muscle phenotype has been studied in heterozygous Cnbp KO mice and in human muscle samples (270). The study demonstrates that CNBP protein expression is reduced in cytoplasm of myotonic dystrophy type 2 muscle fibers, and it is predominantly localized at membrane level where its interaction with α-dystroglycan is increased compared to controls. These findings suggest that alterations of CNBP in myotonic dystrophy type 2 might cause muscle atrophy, not only via misregulation of mRNA but also via protein-protein interactions with membrane proteins affecting myofiber membrane function (270).
Brain function is compromised in myotonic dystrophies, but the underlying mechanisms are not fully understood. By using transgenic mouse models, it has been found that the major pathological changes in the myotonic dystrophy brain result from disruption of the MBNL-2-mediated developmental splicing program (41). A study on myotonic dystrophy type 1 brain mechanisms conducted on DMSXL mouse model and human patients demonstrates glial molecular abnormalities affecting neuronal activity through neuroglial miscommunication (232). Moreover, a global proteomics approach revealed downregulation of the GLT1 glutamate transporter, providing exciting therapeutic perspectives through the modulation of GLT1 levels and glutamate signalling (232).
Myotonic dystrophy type 1 is the most prevalent form of adult muscular dystrophy and has an estimated prevalence ranging from 5 to 20 per 100,000 (90). Certain regions of the world have a greater prevalence, such as Saguenay-Lac St Jean region of Quebec, Canada (162 per 100,000), Norbotten in Northern Sweden, the Basque region of Spain, and Istria region of Croatia (90). A few areas rarely have myotonic dystrophy type 1, such as southern China, Thailand, Australia, the Pacific Islands, and sub-Saharan Africa (90).
Myotonic dystrophy type 2 appears to have a lower prevalence than myotonic dystrophy type 1 and primarily affects populations with a Northern European heritage (121). For myotonic dystrophy type 2, there are currently no established prevalence estimates; myotonic dystrophy type 2 is generally thought to be rarer than myotonic dystrophy type 1, but large-scale population studies to confirm this have not been performed. In Germany, 267 mutation-verified molecular diagnoses were made between 2003 and 2005 compared with 277 myotonic dystrophy type 1 diagnoses within the same period. These data suggest that myotonic dystrophy type 2 appears to be more frequent than previously thought, with most myotonic dystrophy type 2 patients currently undiagnosed with symptoms frequently occurring in the elderly population (238). However, many patients in older generations with myotonic dystrophy type 1 or type 2 with milder symptoms are clearly undiagnosed. It is noteworthy that recessive mutations in the chloride channel gene CLCN1, which have a high frequency in the general population, can act as modifiers in patients with myotonic dystrophy type 2 disease by amplification of their myotonia (239; 33; 172). Meola’s group has identified myotonic dystrophy type 2 patients presenting an atypical phenotype characterized by early and severe myotonia without mutation on the CLCN1 gene but with mutations on SCN4A gene (28; 140; 23). Thus, both CLCN1 and SCN4A mutations may contribute to exaggerate the myotonia in myotonic dystrophy type 2 (140).
Myotonic dystrophy type 1 (myotonic dystrophy of Steinert). Genetic counseling is part of the multidisciplinary management of myotonic dystrophy patients. Myotonic dystrophy is an autosomal dominant disease with almost complete penetrance. Therefore, in 50% of cases the proband's offspring inherit the mutation and develop features of the disease. Moreover, due to instability of the CTG repeat expansion in the disease, the anticipation phenomena is described, ie, the offspring can show more severe phenotype than parents. A major role of genetic counseling is reproductive counseling, especially in the evaluation of the risk of having a child with congenital myotonic dystrophy. The estimated risk of a congenital myotonic dystrophy pregnancy is about 10% to 40% (106). Some authors found a major risk if the mother has multisystem involvement or if her symptoms start before 30 years of age (273; 106). Martorell and colleagues found 12 asymptomatic females with congenital myotonic dystrophy children (132). Cobo and collaborators found the risk of having a congenital myotonic dystrophy child to be 59% if the repeat size is greater than 300 and 10% if it is smaller (46).
Prenatal testing. It is possible to make a prenatal diagnosis determining the size of CTG repeat expansion from fetal cells obtained by amniocenteses (16th week) or through chorionic villus sampling (12th week). It is important to have molecular confirmation of myotonic dystrophy type 1 in both parents before performing the procedure (Martorell et al. 2007). It is not possible to predict exactly the phenotype of the fetus. Normally if an expansion over 1000 is found there is a high probability of congenital myotonic dystrophy.
Preimplantation genetic diagnosis. Preimplantation genetic testing of in vitro-fertilized embryos followed by selective transfer to the mother’s uterus of unaffected embryos is a feasible solution to increase the chances of an unaffected pregnancy. Standard repeat-spanning or flanking PCR to detect the normal DMPK allele of the affected parent is commonly employed in preimplantation genetic testing for myotonic dystrophy type 1 due to reliability issues in detecting the expanded allele, especially when performed directly on the limited genetic material of single cells (58). A robust strategy for preimplantation genetic testing for myotonic dystrophy type 1 that can be applied to virtually any at-risk couple has been proposed (119). This strategy combines detection of the CTG repeat expansion by bidirectional TP-PCR with linked haplotype analysis generated from a dodecaplex marker panel after whole-genome amplification. The aim of this strategy is to provide direct detection of the expansion mutation when present, while concurrently providing haplotype based diagnostic confirmation for virtually any preimplantation genetic test case. The use of multiple microsatellite markers also mitigates the risk of ambiguous haplotype phasing arising from insufficient informative markers.
Myotonic dystrophy type 2 (proximal myotonic myopathy). In myotonic dystrophy type 2, as in myotonic dystrophy type 1, it is possible to make prenatal diagnosis through the same procedures. However, it is seldom requested due to the absence of the congenital form and the less severe phenotype presented in myotonic dystrophy type 2.
Myotonic dystrophy type 1 and myotonic dystrophy type 2 share a similar pathogenetic mechanism and for several years the presence of common features in muscular and multisystemic involvement have been emphasized. Nowadays, advances in understanding myotonic dystrophy type 2 allow us to find clinical differences between the 2 disorders.
It seems that several factors other than splicing alteration modulate the clinical features of the diseases.
One of the most debated arguments is the presence, or not, of anticipation in myotonic dystrophy type 2. In fact it is well known that in myotonic dystrophy type 1 CTG expansion may increase in length during meiosis and mitosis leading to an earlier and more severe phenotype in successive generation. Indeed in myotonic dystrophy type 1 onset and disease severity correlate with repeat length. However, in myotonic dystrophy type 2 there is not a clear correlation between repeat size and disease severity and no evidence of an anticipation phenomenon has been demonstrated (219; 54; 221). Only a debated case of congenital myotonic dystrophy type 2 has been described so far with an expansion size similar between son and mother (110).
The clinical spectrum presents slight but important differences between the 2 diseases.
Muscle weakness is the main feature of both diseases but it shows a different pattern of muscles involvement. Adult onset myotonic dystrophy type 1 starts like a distal myopathy (deep finger flexor, wrist extensor, ankle dorsiflexor) that involves also facial and neck flexor muscle, whereas in myotonic dystrophy type 2 the pelvic girdle is 1 of the first areas where weakness is noticed. Moreover, muscular atrophy is more severe in myotonic dystrophy type 1 than in myotonic dystrophy type 2 except in proximal myotonic dystrophy variant where marked atrophy, and absent of clinical myotonia, it can mimic spinal muscle atrophy (248; 206).
Clinical myotonia is more severe in myotonic dystrophy type 1 than in myotonic dystrophy type 2 and electrical myotonia presents different features between the 2 forms, as an easier evocability and the presence of waxing-waning discharges in myotonic dystrophy type 1, compared to more difficult evocability and the waning discharges in myotonic dystrophy type 2 (124).
From a histopathological point of view, previous studies showed similar pattern characterized by fibers size variation, nuclear internalization, and nuclear clumps. Over the years several authors have identified a more characteristic pattern in myotonic dystrophy type 2 compared to myotonic dystrophy type 1, which consists of a prevalent type 2 fibers atrophy and nuclear internalization (260; 20; 188).
Multisystemic involvement as well as muscular features present slight differences between the 2 forms. At a cardiac level myotonic dystrophy type 1 patients are more often affected by conductive disturbances, whereas myotonic dystrophy type 2 patients have a prominent left ventricular dysfunction (265). Meola and colleagues showed that myotonic dystrophy type 2 patients have a more favorable prognosis than myotonic dystrophy type 1 patients (142) whereas Wahbi and colleagues found an overall risk of myotonic dystrophy type 2 comparable to myotonic dystrophy type 1 (265).
The clinical spectrum of endocrine involvement presents differences between the 2 forms in terms of a higher prevalence of hypogonadism in myotonic dystrophy type 1 and insulin resistance in myotonic dystrophy type 2.
A dysexecutive syndrome caused by frontal lobe dysfunction is a frequent feature of adult myotonic dystrophies although it seems to be less prominent and less severe in myotonic dystrophy type 2 patients (141).
Nondystrophic myotonias caused by sodium or chloride channelopathies are distinguished from myotonic dystrophy type 1 and myotonic dystrophy type 2 based on normal muscle strength and by lack of muscle wasting or other systems involvement. Having the patient squeeze his or her eyes closed 4 to 5 times consecutively is helpful in identifying paradoxical myotonia. Paradoxical myotonia is myotonia that worsens with repeated muscle contractions. This type of myotonia is not characteristic of the myotonic dystrophies. Paradoxical myotonia favors a diagnosis of sodium channel myotonia caused by a mutation in the skeletal muscle sodium channel (154; 155).
One typical presentation for patients with undiagnosed myotonic dystrophy is to complain of muscle weakness, muscle stiffness, or muscle pain without obvious diagnostic findings on clinical examination.
The gold standard for establishing the diagnoses of myotonic dystrophy type 1 and myotonic dystrophy type 2/proximal myotonic myopathy is to demonstrate the presence of abnormal expansions of CTG repeats in the 19q13.3 DMPK gene and of CCTG repeats in the 3q21 zinc finger protein 9 (ZNF9/CNBP) gene involved with myotonic dystrophy type 2. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy type 1 and type 2 have been published (103). Standard leucocyte DNA testing is available for myotonic dystrophy type 1 (254). However, the observation of myotonic dystrophy type 1 patients presenting interrupted allele has practical consequences for myotonic dystrophy type 1 molecular genetic test. Indeed, variant repeats with extreme GC contents yield false negatives in both repeat primed PCR and standard PCR based approaches to diagnostics. For this reason bidirectional triplet primed PCR (TP-PCR) should be included in the routine diagnostic protocol used for myotonic dystrophy type 1 testing because it is very sensitive to detect myotonic dystrophy type 1 expansions presenting variant repeats (216; 59). A commercial kit based on the bidirectional TP-PCR approach, the FastDM1TM DMPK sizing kit, has been validated to be used in diagnostic myotonic dystrophy type 1 testing (115).
Leucocyte DNA testing is also available for myotonic dystrophy type 2, but previous DNA analysis for diagnosing myotonic dystrophy type 2 and proximal myotonic myopathy may have missed as many as 20% of affected individuals (54). As for myotonic dystrophy type 1, a new ready to use genetic test has been validated to identify the myotonic dystrophy type 2 disease, with the advantage to reduce errors that can be introduced using homemade reagents (253). However, the myotonic dystrophy type 2 diagnostic odyssey is complicated by the difficulties to develop an accurate, robust, and cost-effective method for a routine molecular assay (140).
A more practical tool for myotonic dystrophy type 2 diagnosis than the complex genotyping procedure is via in situ hybridization detection of nuclear accumulations of CCUG-containing RNA in myotonic dystrophy type 2 muscle biopsy using specific probes (35; 212). Moreover, because MBNL1 is sequestered by mutant RNA foci, it is possible to visualize the nuclear accumulation of MBNL1 by immunofluorescence on muscle sections. However, although MBNL1 represents a histopathological marker of myotonic dystrophies, it does not allow one to distinguish between myotonic dystrophy type 1 and myotonic dystrophy type 2 (34). Another tool to investigate muscle weakness and wasting is muscle imaging with MRI. In type 1 disease, initial changes are seen in the soleus and medial gastrocnemius; these muscles in the lower legs are completely replaced by fatty infiltration (degenerative changes). It has been reported that MRI of tibialis anterior could be a "surrogate measure" in myotonic dystrophy type 1 (137). The MRI techniques will help to identify asymptomatic patients or patients with only minimal clinical abnormalities; information that clarifies the natural history and prognosis of the disease; and a pharmacologic action in this muscle group. Finally, another advantage that the MRI provides is its ability to assess each individual muscle group and demonstrate subtle changes in muscle structure. In type 2 disease, early muscular changes develop in the anterior vastus group of thigh muscles, with relative sparing of the rectus femoris (250).
Myotonic dystrophy type 1 (myotonic dystrophy of Steinert). The basic approach to treatment in myotonic dystrophy type 1 is symptomatic. Bracing with ankle-foot orthoses or high top shoes, motorized scooters, wheelchairs, serial monitoring of ECG (with focus on PR interval to identify first degree block or more concerning conduction disturbances), serial monitoring of force vital capacity (measurements supine as well as sitting are helpful to detect diaphragm weakness), and consultations with physical therapy, occupational therapy, orthopedics, ophthalmology, pulmonary medicine, and cardiology are the usual components of symptomatic therapy. A multidisciplinary approach to prevent falls should be implemented, as myotonic dystrophy type 1 patients are 10 times more likely to fall or stumble compared to healthy cohorts (276). A team-based multifactorial approach with multifactorial addresses, including exercises and peer-learning of different strategies in dynamic balance challenges, could maybe reduce fall risk when the distal muscles are weak, and so could an appropriate ankle-foot orthotic device (89).
Despite recent advances in the molecular pathophysiology of cardiac involvement and arrhythmias in myotonic dystrophy type 1, gaps in our knowledge limit optimal approaches to rhythm management. It is not uniformly accepted that the use of prophylactic pacemakers or implantable cardioverter defibrillators may benefit these patients. Indeed, sudden death has been observed in patients with pacemakers or implantable cardioverter defibrillators. Thus, it is justifiable to consider a randomized trial of prophylactic device implants in patients at high cardiac risk given that many are receiving devices based on uncertain data (85).
There is currently no consensus on standardized respiratory diagnostic and management protocols, perhaps because it is generally assumed that myotonic dystrophy type 1 is a slowly progressive disorder with an unknown long-term rate of change in respiratory function (241). However, physicians should carefully assess respiratory symptoms and perform minimal lung function screening as recommended (215), keeping in mind that respiratory impairment is a major cause of death in this population. Myotonic stiffness in paraspinal muscles, myotonia affecting speech and swallowing, and grip myotonia occasionally become persistent and burdensome for patients, and a trial of antimyotonia therapy is helpful. Double blind randomized trials comparing different antimyotonia medications are limited, but medications such as mexiletine, phenytoin, and acetazolamide deserve consideration (62). Data describe results from 7 week, randomized, double-blind, crossover trials in 2 groups of 30 DM1 patients and indicates that mexiletine in 150 mg and 200 mg dosages given 3 times daily is effective, well-tolerated, and safe (125). Other data from small single studies have given some indication that clomipramine and imipramine may have short-term benefit and that taurine may have long term benefit in treating myotonia (247). For patients whose speech production is altered from myotonia, a warm-up period can often improve symptoms (60).
Aerobic training exercises have been found to be both safe and effective in improving overall fitness in myotonic dystrophy patients (162). It has been reported in a pilot study that functional electrical stimulation might also be a safe and valid tool to improve muscle function in muscles severely compromised in which no other restorative options are available (48). The effects on muscle function of metformin, a well-known antidiabetic drug, have been tested in a small-scale monocentric phase II study (19). At the maximal tolerated dose, metformin provided a promising effect on the mobility and gait abilities of myotonic patients.
Cataracts need serial monitoring and, at some point, may require removal. Cases of recurrent capsular opacification requiring multiple capsulorhexis have been described in postoperative myotonic dystrophy patients (80). Treatment of testosterone deficiency (testosterone patch, injections) and insulin resistance (oral agents, including thiazolidinediones) need to be coordinated with the primary care physician and endocrinologist. Hypersomnia deserves aggressive treatment because it may lead to loss of job productivity and social isolation. Therapeutic trials suggest that modafinil is helpful (51; 127; 96) and previous reports indicate that methylphenidate may also reduce hypersomnolence (90). A polysomnographic exam should be considered in patients with severe fatigue as a correctable sleep-related abnormality may be contributing to the patient’s symptoms (49). Behavioral problems in childhood may require medication and counseling (90). Problems with executive type functions and with interpersonal relationships in adult life (12; 144) may require counseling, medication, and vocational rehabilitation (90). Chronic gastrointestinal dysfunction (hyper and hypomotility) requires dietary assessment (small meal size, lower fat), treatment of gastroesophageal reflux (elevate head of bed; avoid late evening meals), and medication trials, including antimyotonia therapy (90). A number of therapeutic trials have occurred to treat various manifestations of myotonic dystrophy type 1, but no specific treatment has been identified for the muscle wasting, eye, heart, brain, gastrointestinal, or endocrine problems. A review has summarized the previous therapeutic trials (158).
A multicenter, single-blind, randomized trial has been conducted with the aim to determine whether cognitive behavioral therapy optionally combined with graded exercise compared with standard care alone improves the health status of patients with myotonic dystrophy type 1. Cognitive behavioral therapy focuses on addressing reduced patient initiative, increasing physical activity, optimizing social interaction, regulating sleep-wake patterns, coping with pain, and addressing beliefs about fatigue and myotonic dystrophy type 1. Data from this prospective trial of severely fatigued adult patients with myotonic dystrophy type 1 have shown that cognitive behavioral therapy increased patients’ capacity for activity and participation compared with standard care alone (161). From the OPTIMISTIC study, it was found that a behavioral intervention targeting physical activity increased lower extremity muscle cross-sectional area in 14 myotonic dystrophy type 1 patients, preferentially in healthy-appearing muscle (93).
Genetic counseling is available in myotonic dystrophy type 1, and there is a useful database for providing risk assessment to apparently normal siblings and other at risk family members (90). Many affected individuals have limited interest in counseling, and this is likely to relate, in part, to the personality characteristics and avoidant behavior that often develops in myotonic dystrophy type 1 (90; 144).
Patients with myotonic dystrophy type 1 are at increased risk of cancer and early death (22). Epitheliomas and pilomatricomas have been reported in patients with type 1 disease (90). In a cross-sectional study derived from the United Kingdom myotonic dystrophy registry, 12.4% of the myotonic dystrophy type 1/type 2 patients reported at least 1 benign tumor, and 6.2% reported at least 1 malignant tumor. Skin cancers are the most commonly reported malignant tumors in this study (07; 267). For some cancers (endometrium, ovary, brain, and colon), risk is as high as 7-fold. A study investigates the association of diabetes type 2, metformin, and cancer risk in a large cohort of 913 myotonic dystrophy type 1 patients and in an age-sex and clinic matching cohort of 12,316 myotonic dystrophy type 1 free controls from the United Kingdom database. The results show an association between diabetes type 2 and cancer risk in myotonic dystrophy type 1 patients and provide new insights into the possible benefits of metformin use in myotonic dystrophy type 1 (06).
At the end of 2018, the Myotonic Dystrophy Foundation recruited 66 international clinicians experienced in myotonic dystrophy type 1 patient care to develop consensus-based care recommendations. The methodology used for the project has generated a 4-page quick reference guide and a comprehensive 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments (13).
The Myotonic Dystrophy Foundation recruited clinicians from the United States, Canada, and Europe who have experience in treatment of children with myotonic dystrophy type 1 to develop consensus-based recommendations. The recommendations are designed to standardize the care of children with a multisystemic disorder that leads to significant morbidity and mortality (101).
Myotonic dystrophy type 2 (proximal myotonic myopathy). In general the management of myotonic dystrophy type 2 is similar to myotonic dystrophy type 1, but there is less need for supportive care like bracing, scooters, or wheelchairs. Cataracts require monitoring, and serial monitoring of ECG is necessary to check for covert arrhythmia. Disturbances in cardiac rhythm are less frequent in myotonic dystrophy type 2, but abnormalities do occur (157; 54). Hypogonadism and insulin resistance need monitoring as in myotonic dystrophy type 1. Myotonia tends to be less marked and less troublesome in myotonic dystrophy type 2, but in specific circumstances, especially if muscle stiffness is frequent and persistent, antimyotonia therapy with mexiletine is helpful. Cognitive difficulties also occur in myotonic dystrophy type 2, as in myotonic dystrophy type 1, and appear to be associated with decreased cerebral blood flow to frontal and anterior temporal lobes (143) and decreased brain volume (40; 04; 70). The changes are less severe than in myotonic dystrophy type 1. Their etiology is unknown but may relate to the toxic effect of intranuclear accumulations of abnormally expanded RNA. Management of these brain symptoms is similar to that for myotonic dystrophy type 1.
A frequent and difficult problem in myotonic dystrophy type 2 is the peculiar muscle pain described earlier. The exact mechanism underlying the pain is unknown, and there is no well-established effective treatment. Carbamazepine or mexiletine along with nonsteroidal antiinflammatory medications ameliorate this pain in some patients. However, others with severe pain may require opiates on a regular basis to obtain relief. Fortunately, this peculiar muscle pain is not typical in myotonic dystrophy type 1. Guidelines on diagnosis and management have been published (250). Care considerations and management issues on the wide spectrum of disease manifestations in myotonic dystrophy type 2 have been published by a consortium of international experts (222).
Treatments on the horizon. In recent years Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated system (Cas) methodology had a huge impact on research and gene therapy development by its ability to accurately target a specific locus in the genome of eukaryotes (105). In particular, the most straightforward application of CRISPR/Cas9 in myotonic dystrophy type 1 is to remove the genetic cause of disease by precise excision of the expansion mutation; from a therapeutic point of view, this excision approach is feasible in myotonic dystrophy type 1 because the (CUG)n repeat is not part of the DMPK open reading frame (191; 15). Using the CRISPR/Cas9 gene-editing system, the repeat expansions have been removed in myotonic dystrophy type 1 cell models, therefore, preventing nuclear foci formation and splicing alterations (190; 52; 268). However, if these strategies are effective and safe, ex vivo in cells and in vivo in patients cannot be concluded at this moment and more research is warranted.
Myotonic dystrophy type 1 (myotonic dystrophy of Steinert). It is possible to make an accurate prenatal diagnosis of an affected fetus and to determine the size of the CTG repeat expansion (90). If the mother has myotonic dystrophy type 1, it is possible based on the size of the repeat to estimate the risk that the pregnancy will lead to an affected infant and whether the infant is likely to have congenital myotonic dystrophy type 1 (90). Mothers with myotonic dystrophy type 1 are at increased risk of having spontaneous abortion, polyhydramnios, prolonged first stage of labor, retained placenta, and postpartum hemorrhage (90). A study of women with myotonic dystrophy found that out of 64 gestations, 4% were ectopic, 9% had placenta previa, 13% had perinatal urinary tract infections, and 19% ended in preterm labor. There was no noted increase in miscarriage or preeclampsia compared to a sample population (208). Given the above conditions, in conjunction with an elevated risk of maternal cardiac arrhythmias and anesthetic complications, close obstetric monitoring should be utilized for the pregnant myotonic dystrophy patient.
Myotonic dystrophy type 2 (proximal myotonic myopathy). Studies of prenatal diagnosis using sensitive DNA testing for myotonic dystrophy type 2 myopathy (54) are theoretically possible and more information is likely to become available in the near future.
If a mother has myotonic dystrophy type 2 with only minimal symptoms at the time of her pregnancy, she may have an increased risk of developing myotonia and weakness in the later stages of the pregnancy (159; 54). In 1 study of 96 pregnancies in 42 myotonic dystrophy type 2 women, it was found that 21% of the women had their first myotonic symptoms during their pregnancy. Additionally, 17% of their pregnancies ended in miscarriages, and 27% ended in preterm labor (207). Two reports suggest that the symptoms that develop during pregnancy reverse after delivery (159; 54), but more information is necessary to make such a prediction with certainty.
Myotonic dystrophy type 1 (myotonic dystrophy of Steinert). Patients with myotonic dystrophy type 1 have increased sensitivity to sedative medications, especially barbiturates and opiates, and have paradoxical reactions to depolarizing muscle relaxants (90; 275). There is an increased risk of postoperative apnea following general anesthesia (90; 154), and it is prudent to monitor patients with oximetry for 24 hours after general anesthesia to assure full recovery of their baseline respiratory function. Patients who have significantly low forced vital capacity measurement prior to general anesthesia are at increased risk of hypoventilation and postoperative atelectasis (90; 156). In selected cases, the anesthesiologist and surgeon may choose to delay extubation and maintain ventilator support of the patient, especially in surgeries that require several days of postoperative pain control with opiates. Aggressive pulmonary physical therapy, use of assisted cough device treatments, nasal bilevel positive airway pressure, and careful postoperative monitoring are often needed, and coordination of care with pulmonary medicine and respiratory therapy consultants is necessary.
There is also an increased risk of cardiac arrhythmia following general anesthesia in patients with myotonic dystrophy type 1 (90). Cardiology consultation is useful if arrhythmia develops to advise about treatment because myotonic dystrophy type 1 patients sometimes display an unexpected, undesirable reaction to certain medications (90).
Myotonic dystrophy type 2 (proximal myotonic myopathy). One study of a large number of individuals with myotonic dystrophy type 2 has found no significant problems with the ability of patients to tolerate general anesthesia (54). In a report of a large German patient cohort, the overall frequency of severe complications was 0.6% (2 of 340). The overall lower risk seems to be predominantly related to the minor respiratory involvement in myotonic dystrophy type 2 than in myotonic dystrophy type 1 (104).
Twenty-eight years have passed since the (CTG)n repeat expansion mutation was discovered in patients with myotonic dystrophy type 1, and 19 years ago the (CCTG)n mutation was identified in type 2 disease. Emerging data indicate that molecular pathomechanisms are much more complex than could have been envisioned when the respective mutations were just identified. RNA toxicity clearly has a major role, yet spliceopathy alone does not seem to fully account for all aspects of the multisystemic phenotype in myotonic dystrophies. Other pathomechanisms consistent with the toxic RNA model probably entail regulation of gene expression and translation and various cellular stress pathways, and extend beyond the nucleus to the cytoplasm. Nevertheless, it is important to emphasize that despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies.
Although treatment of myotonic dystrophy type 1 and myotonic dystrophy type 2 is currently limited to supportive therapies, new therapeutic approaches based on pathogenic mechanisms may become feasible in the near future.
Preclinical experimental therapies for myotonic dystrophy involve animal models and have focused on the use of antisense oligonucleotides (ASOs), small interfering molecules, ribozymes, and engineered small nuclear RNAs (78). IONIS-DMPKRx trials started in 2015 on human patients affected by myotonic dystrophy type 1. The phase 2 study was completed in June 2016 (NCT02312011). It was a blinded, placebo-controlled study of 48 myotonic dystrophy type 1 patients. Study medication was given subcutaneously once weekly over 6 weeks. The study was safe even at higher dosage. However, the drug failed to achieve the target tissue concentration of antisense oligonucleotide to be necessary to knockdown DMPK mutant allele. In October 2018, the AMO Pharma Limited sponsored a randomized, double-blind study to evaluate the efficacy and safety of tideglusib versus placebo for the treatment of children and adolescents (aged 6 to 16 years) with congenital and childhood myotonic dystrophy type 1. A phase 2 study on 16 patients of AMO-02 was safe and well tolerated (NCT02858908). This study suggests a potential treatment for congenital and childhood onset type 1 myotonic dystrophy (99).
The future holds great promise for advances in translational research in myotonic dystrophy type 1 and myotonic dystrophy type 2. The teamwork will expedite the development of targeted therapies and improve the lives of patients and their families (155).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Giovanni Meola MD
Dr. Meola of Casa di Cura Igea-Milan has no relevant financial relationships to disclose.See Profile
Emma Ciafaloni MD FAAN
Dr. Ciafaloni of the University of Rochester received honorariums and consulting fees for serving on advisory boards and/or as a consultant for Alexion, Avexis, Biogen, PTC Therapeutics, Ra Pharma, Strongbridge Biopharma PLC, and Wave; and for serving on a speakers' bureau for Biogen. Dr Ciafaloni also received research and/or grant support from Orphazyme, Santhera, and Sarepta.See Profile
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