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To reveal current status of medical practice, we made a nationwide self-questionnaire survey to Japanese certified Neurologists and Child Neurologists. Most specialists seeing patients with myotonic dystrophy (DM) were aware that genetic analysis is approved in health insurance. The ratio of pre-explanation about genetic analysis was also high however written informed consent was not always obtained. Over 60% of specialists regarded motor dysfunction, conduction block/arrhythmia, heart failure, dysphagia, hypoventilation as important complications, while no more than 35% of specialists regarded hypoxia/apnea, multi-organ complications, which are feature of myotonic dystrophy, as important. Over half specialists did not check Holter electrocardiogram, sleep respiratory examination, or swallowing function regularly. This fact implied that cumbersome examinations tended to be refrained from regular assessment. Child neurologists were more aggressive in respiratory care and consultation of cardiovascular specialists. A few neurologists hesitated to introduce mechanical ventilation and tube feeding.

Myotonic dystrophy (DM) is a genetic, progressive, multisystemic disease with muscular disorder as its primary symptom. There are two types of DM (DM1 and DM2) caused by mutations in different genes, and in Japan, DM occurs with an incidence of approximately 1 in 20,000. The pathogenic mechanism underlying the disease is RNA toxicity caused by transcripts of aberrantly elongated CTG or CCTG repeats located in the 3' untranslated region or in the intron. The current treatments for DM is limited to symptomatic care. In this review, we will discuss several new therapeutic strategies based on recent studies of RNA toxicity.

Myotonic dystrophy (DM), the commonest form of muscular dystrophy in adults, is a multisystem disease caused by repeat expansions located in untranslated regions of the affected genes. Its pathogenesis results from expression of RNAs with these expanded repeats, which causes sequestration of splicing factors and thus series of splicing misregulation. An increased understanding of the disease mechanism has accelerated the development of therapeutic strategies, including correction of individual missplicing by antisense oligonucleotides (ASOs), ASO- or small molecule-mediated neutralization of the RNA toxicity by preventing sequestration of splicing factors, degradation of the toxic RNA by ASOs, and stabilization of the expanded repeats. ASOs targeting the toxic RNA have exhibited promising results in animal models, and a clinical trial has recently been launched. With the advent of clinical trials, we are confronting several challenges. As with other rare diseases, we must identify eligible patients. It may be more important in Japan to establish a standardized best practice management of currently available approaches (e.g., pacemaker use) followed by nationwide dissemination. The national DM registry, about to be launched shortly, might be a promising tool to overcome these issues and lead to improved management of DM.

No effective treatment was available for myotonic dystrophy, even in animal model. We have established a new antisense oligonucleotide delivery to skeletal muscle of mice with bubble liposomes, and led to increased expression of chloride channel (CLCN1) protein and the amelioration of myotonia. In other experiments, we also identified small molecule compounds that correct aberrant splicing of Clcn1 gene. Manumycin A corrected aberrant splicing of Clcn1 in mouse model.

The understanding of the pathomechanism of myotonic dystrophy (DM) has been greatly improved since the recognition as an mRNA disease. Pre-mRNA containing repeats sequesters or activates proteins such as MBNL and CELF that bind to an mRNA motif similar to repeat. Consequently, the regulation of mRNA splicing, a normal function of these proteins, is perturbed. Over 30 miss-splicing events have been documented including muscle chloride channel which is responsible for myotonia. Such molecular events might serve as a target for therapeutic intervention. An important genetic feature of DM is the instability of expanded repeats between generations and organs. Since pathogenesis is connected to repeat length, manipulation of the repeat expansion size (somatic instability) might be also a potential therapeutic strategy. With accumulation of pathomechanistic studies, clinical trials are highly expected. Our recent survey in Osaka Japan revealed the need of standardized management employing currently available therapies, which should be prerequisite for trials. Clinical trials for DM will face challenges including lack of reliable outcome measures and enrollment of highly restricted cohort. Global initiative to form international DM registry have been taken to facilitate natural history studies and trials. In Japan, the development of DM registry has just started.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder with variable expression. DM1 results from a trinucleotide expansion in the 3' untranslated region or the gene for myotonic dystrophy protein kinase (DMPK). Severity tends to increase and it shows a younger onset age with vertical transmission, a phenomenon known as anticipation. Congenital myotonic dystrophy (CDM) is classified as the most severe form of DM1, and its phenotype, with severe hypotonia, neonatal respiratory distress and feeding difficulties, is completely different from that of adult-onset type. Involvement of respiratory muscles may be the major cause of mortality in affected infants. Facial weakness with a tented upper lip is often recognized. If infants survive the neonatal period, muscle involvement symptoms gradually improve and most children do not require respiratory support or tube feeding. As CDM patients grow older, mental retardation or a developmental disorder becomes prominent. Furthermore, the main problems in childhood-onset DM, with an onset age under 10 years, are developmental disorders or learning disabilities, rather than muscle symptoms. Early meticulous support and cooperation with teachers are necessary. Medications such as methylphenidate may be helpful in DM1 children with attention deficit/hyperactivity disorder.

Myotonic dystrophy (DM) is the most common hereditary muscle disease in adults, caused by unstable genomic expansions of simple sequence repeats. The mutant RNA transcripts containing the expanded repeat give rise to a toxic gainoffunction by perturbing splicing factors in the nucleus, leading to the misregulation of alternative pre-mRNA splicing. Although no curative treatment exists, recent advances in research and pharmaceutical technology have provided clues for therapeutic intervention in DM. Herein, we review the RNA-dominant mechanism of DM and potential therapeutic approaches for degrading or neutralizing the toxic RNA, restoring splicing factors, correcting splicing misregulation, and stabilizing the repeat.

We studied the long-term prognosis of the patients of myotonic dystrophy with tube feeding. Subjects were 51 patients (31 male patients and 20 female patients) of typical myotonic dystrophy who were at least once admitted in our hospital. We examined the age of the introduction of tube feeding, the cause of the introduction, respiratory and motor ability at the introduction, the duration of tube feeding, the cause of death and the extension of CTG repeats in the patients. Comparing with the patients with tube feeding and the patients without it, we also examined the prognosis after the introduction of tube feeding. Tube feeding was introduced in 13 cases. The mean age of tube feeding was 57.9 +/- 8.3 years old. The mean age of death of non tube feeding group was 55.9 +/- 5.5 years old. These show tube feeding was introduced in more elderly patients. Statstically the tube feeding was effective, but poor prognosis even after the introduction of tube feeding was suggested because the mean survival time after the introduction was about 850 days. We could not find any correlation between the age of the introduction of tube feeding and the extension of CAG report.