Diagnosis and Management of Myotonic Dystrophy Type 1.

This JAMA Insights discusses the signs and symptoms, diagnosis, and treatment of myotonic dystrophy type 1.

Distrofia miotónica tipo 1: 13 años de experiencia en un hospital terciario. Estudio clínico y epidemiológico. Correlación genotipo-fenotipo / Myotonic dystrophy type 1: 13 years of experience at a tertiary hospital. Clinical and epidemiological study and genotype-phenotype correlation

Introducción: Se desconoce la incidencia de la distrofia miotónica tipo 1 (DM1), enfermedad con gran variedad fenotípica, en nuestra región. El objetivo de nuestro trabajo es estimar la incidencia de DM1 en nuestro centro (referencia en Aragón) e identificar las características propias de nuestra población (correlación genotipo-fenotipo). Métodos: Estudio descriptivo retrospectivo de 459 pacientes clasificados según número de repeticiones CTG en: normal (5-35), premutado (36-50), protomutado (51-80), pequeñas expansiones (81-150), intermedias (151-1.000) y grandes (> 1.000). Además, según el fenotipo mostrado, se categorizaron como: no afectos (5-50 CTG), forma leve o asintomática (51-150 CTG), clásica (151-1.000 CTG) y severa (> 1.000 CTG). Resultados: La incidencia de DM1 fue de 20,61 (IC 95%: 19,59-21,63) casos por millón de individuos-año. Se evidenció una correlación inversa entre el número de CTG y la edad al diagnóstico genético (ρ = −0,547; IC 95%: −0,610 a −0,375; p < 0,001). El CTG5 fue el alelo polimórfico más frecuente en sanos. Del total de afectos, el 28,3% presentaron la forma leve o asintomática, el 59,1% la forma clásica y el 12,6% la forma severa. El 35,1% presentaron herencia materna, el 59,4% herencia paterna y el 5,5% herencia incierta. En las formas leves la calvicie frontal en varones fue el rasgo fenotípico más prevalente, junto con miotonía y cataratas, mientras que en la clásica predominó la ptosis palpebral, la debilidad facial, las alteraciones en la voz y la pronunciación, la miotonía y la sensación de cansancio/somnolencia. Conclusiones: La incidencia de DM1 es relevante en Aragón. La revisión multidisciplinar del fenotipo de pacientes con DM1 es clave para un diagnóstico precoz y medicina personalizada.(AU)

Introduction: The incidence of myotonic dystrophy type 1 (DM1), a disease with great phenotypic variety, in our region is unknown. This study aims to estimate the incidence of DM1 at our hospital (a reference centre in Aragon, Spain) and to identify the characteristics of our population (genotype-phenotype correlation). Methods: Retrospective, descriptive study of 459 patients classified according to the number of CTG repeats, as follows: normal (5-35), premutation (36-50), protomutation (51-80), small expansions (81-150), intermediate expansions (151-1000), and large expansions (> 1000). Furthermore, according to clinical phenotype, patients were categorised as unaffected (5-50 CTG repeats), mild form or asymptomatic (51-150), classical form (151-1000), and severe form (> 1000). Results: The incidence of DM1 was 20.61 cases per million person-years (95% CI: 19.59-21.63). An inverse correlation was observed between the number of CTG repeats and the age at genetic diagnosis (ρ = −0.547; 95% CI: −0.610 to −0.375; P < .001). CTG5 was the most frequent polymorphic allele in healthy individuals. Of all patients with DM1, 28.3% presented the mild or asymptomatic form, 59.1% the classical form, and 12.6% the severe form. Inheritance was maternal in 35.1% of cases, paternal in 59.4%, and uncertain in 5.5%. In mild forms, frontal balding in men was the most prevalent phenotypic trait, as well as myotonia and cataracts, while in the classical form, ptosis, facial weakness, voice and pronunciation alterations, myotonia, and fatigue/sleepiness were most frequent. Conclusions: The incidence of DM1 in Aragon is significant. Multidisciplinary study of the phenotype of patients with DM1 is key to early diagnosis and personalised management.(AU)

Cardiac Pathology in Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.

Cognitive Deficits in Myopathies.

Myopathies represent a wide spectrum of heterogeneous diseases mainly characterized by the abnormal structure or functioning of skeletal muscle. The current paper provides a comprehensive overview of cognitive deficits observed in various myopathies by consulting the main libraries (Pubmed, Scopus and Google Scholar). This review focuses on the causal classification of myopathies and concomitant cognitive deficits. In most studies, cognitive deficits have been found after clinical observations while lesions were also present in brain imaging. Most studies refer to hereditary myopathies, mainly Duchenne muscular dystrophy (DMD), and myotonic dystrophies (MDs); therefore, most of the overview will focus on these subtypes of myopathies. Most recent bibliographical sources have been preferred.

Screening for early symptoms of respiratory involvement in myotonic dystrophy type 1 using the Respicheck questionnaire.

Symptoms of respiratory involvement are frequently present but overlooked by patients with Myotonic Dystrophy type 1 (DM1). A respiratory symptom checklist was designed to test whether a DM-specifically designed checklist to detect symptoms of respiratory involvement (The Respicheck Questionnaire) could help patients be more aware of their respiratory problems, if any, and help clinicians in identifying potential candidates for intervention. The Respicheck questionnaire was administered to 58 consecutive adult-onset patients with genetically determined DM1 who did not complain of respiratory involvement per history at enrollment. Based on respiratory function test results patients were divided into 3 groups: A, (n = 17) having no signs of respiratory involvement; B (n = 13), patients having borderline results on respiratory assessments and having no need for respiratory intervention; C, (n = 28) patients having respiratory impairment requiring intervention. Respiratory test results and Respicheck scores were analyzed. Respicheck total score and subscales correlated positively with global respiratory impairment. Respicheck appears to be able to discriminate between patients having a higher level of respiratory dysfunction from those having a lower risk of respiratory involvement. This might allow to better target efforts and resources in respiratory management in DM1.

Clinical implication of maximal voluntary ventilation in myotonic muscular dystrophy.

Patients with myotonic muscular dystrophy type 1 (DM1) tend to exhibit earlier respiratory insufficiency than patients with other neuromuscular diseases at similar or higher forced vital capacity (FVC). This study aimed to analyze several pulmonary function parameters to determine which factor contributes the most to early hypercapnia in patients with DM1.We analyzed ventilation status monitoring, pulmonary function tests (including FVC, maximal voluntary ventilation [MVV], and maximal inspiratory and expiratory pressure), and polysomnography in subjects with DM1 who were admitted to a single university hospital. The correlation of each parameter with hypercapnia was determined. Subgroup analysis was also performed by dividing the subjects into 2 subgroups according to usage of mechanical ventilation.Final analysis included 50 patients with a mean age of 42.9 years (standard deviation = 11.1), 46.0% of whom were male. The hypercapnia was negatively correlated with MVV, FVC, forced expiratory volume in 1 second (FEV1), and their ratios to predicted values in subjects with myotonic muscular dystrophy type 1. At the same partial pressure of carbon dioxide, the ratio to the predicted value was lowest for MVV, then FEV1, followed by FVC. Moreover, the P values for differences in MVV and its ratio to the predicted value between ventilator users and nonusers were the lowest.When screening ventilation failure in patients with DM1, MVV should be considered alongside other routinely measured parameters.

[Palatal myoclonus associated with myotonic dystrophy type 1]. / Mioclonia palatina asociada a distrofia miotonica de tipo 1.

TITLE: Mioclonia palatina asociada a distrofia miotonica de tipo 1.

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes.

Myotonic dystrophy (DM) is the most common autosomal dominant muscular dystrophy and encompasses both skeletal muscle and cardiac complications. DM is nucleotide repeat expansion disorder in which type 1 (DM1) is due to a trinucleotide repeat expansion on chromosome 19 and type 2 (DM2) arises from a tetranucleotide repeat expansion on chromosome 3. Developing representative models of DM in animals has been challenging due to instability of nucleotide repeat expansions, especially for DM2, which is characterized by nucleotide repeat expansions often greater than 5,000 copies. To investigate mechanisms of human DM, we generated cellular models of DM1 and DM2. We used regulated MyoD expression to reprogram urine-derived cells into myotubes. In this myogenic cell model, we found impaired dystrophin expression, in the presence of muscleblind-like 1 (MBNL1) foci, and aberrant splicing in DM1 but not in DM2 cells. We generated induced pluripotent stem cells (iPSC) from healthy controls and DM1 and DM2 subjects, and we differentiated these into cardiomyocytes. DM1 and DM2 cells displayed an increase in RNA foci concomitant with cellular differentiation. iPSC-derived cardiomyocytes from DM1 but not DM2 had aberrant splicing of known target genes and MBNL sequestration. High-resolution imaging revealed tight association between MBNL clusters and RNA foci in DM1. Ca2+ transients differed between DM1- and DM2 iPSC-derived cardiomyocytes, and each differed from healthy control cells. RNA-sequencing from DM1- and DM2 iPSC-derived cardiomyocytes revealed distinct misregulation of gene expression, as well as differential aberrant splicing patterns. Together, these data support that DM1 and DM2, despite some shared clinical and molecular features, have distinct pathological signatures.

rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences.

Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 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 DM2.

Quantitative Methods to Monitor RNA Biomarkers in Myotonic Dystrophy.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are human neuromuscular disorders associated with mutations of simple repetitive sequences in affected genes. The abnormal expansion of CTG repeats in the 3'-UTR of the DMPK gene elicits DM1, whereas elongated CCTG repeats in intron 1 of ZNF9/CNBP triggers DM2. Pathogenesis of both disorders is manifested by nuclear retention of expanded repeat-containing RNAs and aberrant alternative splicing. The precise determination of absolute numbers of mutant RNA molecules is important for a better understanding of disease complexity and for accurate evaluation of the efficacy of therapeutic drugs. We present two quantitative methods, Multiplex Ligation-Dependent Probe Amplification and droplet digital PCR, for studying the mutant DMPK transcript (DMPKexpRNA) and the aberrant alternative splicing in DM1 and DM2 human tissues and cells. We demonstrate that in DM1, the DMPKexpRNA is detected in higher copy number than its normal counterpart. Moreover, the absolute number of the mutant transcript indicates its low abundance with only a few copies per cell in DM1 fibroblasts. Most importantly, in conjunction with fluorescence in-situ hybridization experiments, our results suggest that in DM1 fibroblasts, the vast majority of nuclear RNA foci consist of a few molecules of DMPKexpRNA.

Magnetic resonance imaging of leg muscles in patients with myotonic dystrophies.

Magnetic resonance imaging (MRI) of muscles has recently become a significant diagnostic procedure in neuromuscular disorders. There is a lack of muscle MRI studies in patients with myotonic dystrophy type 1 (DM1), especially type 2 (DM2). To analyze fatty infiltration of leg muscles, using 3.0 T MRI in patients with genetically confirmed DM1 and DM2 with different disease durations. The study comprised 21 DM1 and 10 DM2 adult patients. Muscle MRI was performed in axial plane of the lower limbs using T1-weighted (T1w) sequence. Six-point scale by Mercuri et al. was used. Fatty infiltration registered in at least one muscle of lower extremities was found in 71% of DM1 and 40% of DM2 patients. In DM1 patients, early involvement of the medial head of gastrocnemius and tibialis anterior muscles was observed with later involvement of other lower leg muscles and of anterior and posterior thigh compartments with relative sparing of the rectus femoris. In DM2, majority of patients had normal MRI findings. Early involvement of lower legs and posterior thighs was found in some patients. Less severe involvement of the medial head of the gastrocnemius compared to other lower leg muscles was also observed, while involvement of proximal muscles was rather diffuse than selective. It seems that both in DM1 and DM2 some muscles may be affected before weakness is clinically noted and vice versa. We described characteristic pattern and way of progression of muscle involvement in DM1 and DM2.

Enfermedad de Steinert congénita, la forma más grave de distrofia miotónica tipo 1 / Congenital Steinert disease, the most serious form of type 1 myotonic dystrophy

Introducción. La enfermedad de Steinert congénita es la forma más grave de distrofia miotónica tipo 1, caracterizada fundamentalmente por hipotonía muscular y dificultades para la alimentación. Se hereda de forma autosómica dominante y presenta el fenómeno de anticipación, siendo la penetrancia mayor en generaciones sucesivas y, por tanto, formas más graves. Presentamos un caso de una forma congénita de enfermedad de Steinert en el contexto de familia afecta. Caso clínico. Embarazo controlado con diagnóstico fetal de enfermedad de Steinert (+ 110 copias CTG). Cesárea electiva a las 38 semanas. Apgar 3/7/8. La madre y hermana de 2 años, enfermedad de Steinert. En la exploración destaca hipotonía y debilidad muscular generalizada, con movimientos escasos y facies hipomímica. Reflejo de succión débil e hiporreflexia osteotendinosa. Precisa ventilación mecánica invasiva durante 21 días, posteriormente ventilación no invasiva nocturna hasta los 3 meses de vida. Precisa sonda orogástrica para la alimentación durante el primer mes, después progresivamente tolerancia oral con buena coordinación succión-deglución-respiración y adecuada ganancia ponderoestatural. Actualmente con 6 meses y medio, presenta retraso del desarrollo neuromadurativo global, persistiendo la hipotonía generalizada. En seguimiento multidisciplinar por especialistas, centro de atención temprana y pediatra de Atención Primaria. Conclusiones. La gravedad de la forma neonatal de la enfermedad de Steinert requiere un seguimiento por el pediatra de Atención Primaria y equipo multidisciplinar para detectar posibles complicaciones que pueden llevar incluso a la muerte temprana. Actualmente el consejo genético es esencial para la planificación familiar y poder evitar la transmisión de la enfermedad a generaciones sucesivas. Por un lado, se puede realizar estudio genético de los embriones de manera preimplantacional para posteriormente transferirlos de manera selectiva sin la mutación, mediante técnicas de fecundación in vitro. Por otro lado, también es posible el estudio genético fetal mediante biopsia corial en el primer trimestre de la gestación, como en el caso presentado, pudiéndose realizar interrupción voluntaria del embarazo

Introduction. Congenital Steinert's disease is the most serious form of type 1 myotonic dystrophy, characterized mainly by muscle hypotonia and feeding difficulties. It is inherited autosomically dominant and presents the phenomenon of anticipation, being the major penetrance in successive generations and therefore, more serious forms. We present a case of a congenital form of Steinert's disease in the affected family context. Clinical case. Pregnancy controlled with fetal diagnosis of Steinert's disease (+ 110 CTG copies). Cesarean elective at 38 weeks. Apgar 3/7/8. The mother and sister of 2 years old have also Steinert's disease. Exploration highlights hypotonia and generalized muscle weakness, with scarce movements and hypomimic facies; weak suction reflexion and osteotendinous hyporreflexia. It requires invasive mechanical ventilation for 21 days, later non-invasive night ventilation up to 3 months of life. It needs an orogastric tube for feeding during the first month, then progressively oral tolerance with good coordination, suction-swallowingbreathing and adequate ponderoestatural gain. Currently, with 6 months of life, she presents a delay in global neuromadurative development, persisting generalized hypotonia. In multidisciplinary follow-up by specialists, early care center and primary care pediatrician. Conclusions. The severity of the congenital form of Steinert's disease requires follow-up by the primary care pediatrician and multidisciplinary team to detect possible complications that can lead to even early death. Currently genetic counseling is essential for family planning and to prevent the transmission of the disease to successive generations. On the one hand, it is possible to carry out a genetic study of the embryos in a pre-implantation manner and then transfer them selectively without the mutation, by in vitro fertilization techniques. On the other hand, fetal genetic study by corial biopsy in the first trimester of pregnancy is also possible, as in the case presented, being able to voluntary interruption of pregnancy

Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.

The broad clinical spectrum of myotonic dystrophy type 1 (DM1) creates particular challenges for both medical care and design of clinical trials. Clinical onset spans a continuum from birth to late adulthood, with symptoms that are highly variable in both severity and nature of the affected organ systems. In the literature, this complex phenotype is divided into three grades (mild, classic, and severe) and four or five main clinical categories (congenital, infantile/juvenile, adult-onset and late-onset forms), according to symptom severity and age of onset, respectively. However, these classifications are still under discussion with no consensus thus far. While some specific clinical features have been primarily reported in some forms of the disease, there are no clear distinctions. As a consequence, no modifications in the management of healthcare or the design of clinical studies have been proposed based on the clinical form of DM1. The present study has used the DM-Scope registry to assess, in a large cohort of DM1 patients, the robustness of a classification divided into five clinical forms. Our main aim was to describe the disease spectrum and investigate features of each clinical form. The five subtypes were compared by distribution of CTG expansion size, and the occurrence and onset of the main symptoms of DM1. Analyses validated the relevance of a five-grade model for DM1 classification. Patients were classified as: congenital (n=93, 4.5%); infantile (n=303, 14.8%); juvenile (n=628, 30.7%); adult (n=694, 34.0%); and late-onset (n=326, 15.9%). Our data show that the assumption of a continuum from congenital to the late-onset form is valid, and also highlights disease features specific to individual clinical forms of DM1 in terms of symptom occurrence and chronology throughout the disease course. These results support the use of the five-grade model for disease classification, and the distinct clinical profiles suggest that age of onset and clinical form may be key criteria in the design of clinical trials when considering DM1 health management and research.

In vivo assessment of muscle membrane properties in myotonic dystrophy.

INTRODUCTION: Myotonia in myotonic dystrophy types 1 (DM1) and 2 (DM2) is generally attributed to reduced chloride-channel conductance. We used muscle velocity recovery cycles (MVRCs) to investigate muscle membrane properties in DM1 and DM2, using comparisons with myotonia congenita (MC). METHODS: MVRCs and responses to repetitive stimulation were compared between patients with DM1 (n = 18), DM2 (n = 5), MC (n = 18), and normal controls (n = 20). RESULTS: Both DM1 and DM2 showed enhanced late supernormality after multiple conditioning stimuli, indicating delayed repolarization as in MC. Contrary to MC, however, DM1 showed reduced early supernormality after multiple conditioning stimuli, and weak DM1 patients also showed abnormally slow latency recovery after repetitive stimulation. CONCLUSIONS: These findings support the presence of impaired chloride conductance in both DM1 and DM2. The early supernormality changes indicate that sodium currents were reduced in DM1, whereas the weakness-associated slow recovery after repetitive stimulation may provide an indication of reduced Na(+) /K(+) -ATPase activation. Muscle Nerve 54: 249-257, 2016.

Peripheral nerve involvement in myotonic dystrophy type 2 - similar or different than in myotonic dystrophy type 1?

INTRODUCTION: Multisystem manifestations of myotonic dystrophies type 1 (DM1) and 2 (DM2) are well known. Peripheral nerve involvement has been reported in DM1 but not in genetically confirmed DM2. The aim of our study was to assess peripheral nerve involvement in DM2 using nerve conduction studies and to compare these results with findings in DM1. METHODS: We prospectively studied patients with genetically confirmed DM2 (n=30) and DM1 (n=32). All patients underwent detailed neurological examination and nerve conduction studies. RESULTS: Abnormalities in electrophysiological studies were found in 26.67% of patients with DM2 and in 28.13% of patients with DM1 but the criteria of polyneuropathy were fulfilled in only 13.33% of patients with DM2 and 12.5% of patients with DM1. The polyneuropathy was subclinical, and no correlation was found between its presence and patient age or disease duration. CONCLUSIONS: Peripheral nerves are quite frequently involved in DM2, but abnormalities meeting the criteria of polyneuropathy are rarely found. The incidence of peripheral nerve involvement is similar in both types of myotonic dystrophy.

Frontostriatal dysexecutive syndrome: a core cognitive feature of myotonic dystrophy type 2.

The aim of this study was to assess cognitive status in a large group of patients with myotonic dystrophy type 2 (DM2) compared to type 1 (DM1) subjects matched for gender and age, using a comprehensive battery of neuropsychological tests. Thirty-four genetically confirmed adult DM2 patients were recruited and matched for gender and age with 34 adult-onset DM1 subjects. All patients underwent detailed classic pen and pencil neuropsychological investigation and also computerized automated battery-CANTAB. More than half of DM2 patients had abnormal results on executive tests [Intra/Extradimensional Set Shift (IED), Stockings of Cambridge (SOC)] and verbal episodic memory (Ray Auditory Verbal Learning Test). Regarding DM1, abnormal results in more than 50 % of subjects were achieved in even ten tests, including visuospatial, language, executive, cognitive screening and visual memory tests. Direct comparison between patient groups showed that lower percentage of DM2 patients had abnormal results on following tests: Addenbrooke's Cognitive Examination-Revised, Raven Standard Progressive Matrices, Block Design, copy and recall of Rey-Osterieth Complex Figure, number of categories and perseverative responses on Wisconsin Card Sorting Test and Boston Naming Test (p < 0.01), as well as Trail Making Test-B and Spatial Span (p < 0.05). Our results showed significant dysexecutive syndrome and certain impairment of episodic verbal memory in DM2 patients that are reflective of frontal (especially frontostriatal) and temporal lobe dysfunction. On the other hand, dysexecutive and visuospatial/visuoconstructional deficits predominate in DM1 which correspond to the frontal, parietal (and occipital) lobe dysfunction.

Diagnostic odyssey of patients with myotonic dystrophy.

The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. This report analyzes the diagnostic delay (time from onset of first symptom to diagnosis) in a large sample of myotonic dystrophy (DM) patients enrolled in the US National Registry [679 DM type 1 (DM1) and 135 DM type 2 (DM2) patients]. Age of onset averaged 34.0 ± 14.1 years in DM2 patients compared to 26.1 ± 13.2 years in DM1 (p < 0.0001). The most common initial symptom in DM2 patients was leg weakness (32.6 %) compared to grip myotonia in DM1 (38.3 %). Pain was reported as the first symptom in 11.1 % of DM2 and 3.0 % of DM1 patients (p < 0.0001). Reaching the correct diagnosis in DM2 took 14 years on average (double the time compared to DM1) and a significantly higher percentage of patients underwent extended workup including electromyography, muscle biopsies, and finally genetic testing. DM patients who were index cases experienced similar diagnostic delays to non-index cases of DM. Further evaluation of how to shorten these diagnostic delays and limit their impact on burdens of disease, family planning, and symptom management is needed.

Myotonic dystrophy: from bench to bedside.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant disorders classically characterized by muscle weakness, myotonia, and early-onset cataracts. Patients may also experience dysfunction of the heart, brain, gastrointestinal, endocrine, skin, and respiratory systems. The pathogenesis of myotonic dystrophy is related to trinucleotide (DM1) and tetranucleotide (DM2) repeat expansions that produce toxic mutant mRNA with subsequent interference of RNA-splicing mechanisms. Optimal disease management includes symptomatic care, screens for asymptomatic disease, counseling, and a multidisciplinary approach. The authors review the pathogenesis, clinical features, diagnostic tests, and standard management of DM1 and DM2 and outline promising clinical research for patients with these disorders.

The myotonic dystrophies: molecular, clinical, and therapeutic challenges.

Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterised by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified. Myotonic dystrophy type 1 (also known as Steinert's disease) was first described more than 100 years ago, whereas myotonic dystrophy type 2 was identified only 18 years ago, after genetic testing for type 1 disease could be applied. Both diseases are caused by autosomal dominant nucleotide repeat expansions. In patients with myotonic dystrophy type 1, a (CTG)(n) expansion is present in DMPK, whereas in patients with type 2 disease, there is a (CCTG)(n) expansion in CNBP. When transcribed into CUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in a spliceopathy of downstream effector genes. The prevailing paradigm therefore is that both disorders are toxic RNA diseases. However, research indicates several additional pathogenic effects take place with respect to protein translation and turnover. Despite clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are distinct disorders requiring different diagnostic and management strategies.

Myotonic dystrophies and the heart.

Myotonic dystrophy (MD) is a neuromuscular disorder of autosomal dominant inheritance, which is categorized by 2 main sub-types: type 1 (MD1) and type 2 (MD2). This disease is characterized by myotonia and various multisytemic complications, most commonly of the cardiac, endocrine, and central nervous systems. In addition, cardiac abnormalities contribute to a significant morbidity and mortality in these patients. The cardiac abnormalities common to MD1 are conduction defects, such as first-degree atrioventricular block, arrhythmias, and other less common manifestations such as heart failure, ischemic heart disease, and mitral valve prolapse. Although these cardiac manifestations are also common in MD2, another complication that has been linked to MD2 is cardiomyopathy. Further study needs to be performed to better understand the pathology and management of these cardiac disorders associated with MD.