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1.  The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease 
Brain  2011;134(12):3527-3543.
Myotonic dystrophy types 1 and 2 are progressive multisystemic disorders with potential brain involvement. We compared 22 myotonic dystrophy type 1 and 22 myotonic dystrophy type 2 clinically and neuropsychologically well-characterized patients and a corresponding healthy control group using structural brain magnetic resonance imaging at 3 T (T1/T2/diffusion-weighted). Voxel-based morphometry and diffusion tensor imaging with tract-based spatial statistics were applied for voxel-wise analysis of cerebral grey and white matter affection (Pcorrected < 0.05). We further examined the association of structural brain changes with clinical and neuropsychological data. White matter lesions rated visually were more prevalent and severe in myotonic dystrophy type 1 compared with controls, with frontal white matter most prominently affected in both disorders, and temporal lesions restricted to myotonic dystrophy type 1. Voxel-based morphometry analyses demonstrated extensive white matter involvement in all cerebral lobes, brainstem and corpus callosum in myotonic dystrophy types 1 and 2, while grey matter decrease (cortical areas, thalamus, putamen) was restricted to myotonic dystrophy type 1. Accordingly, we found more prominent white matter affection in myotonic dystrophy type 1 than myotonic dystrophy type 2 by diffusion tensor imaging. Association fibres throughout the whole brain, limbic system fibre tracts, the callosal body and projection fibres (e.g. internal/external capsules) were affected in myotonic dystrophy types 1 and 2. Central motor pathways were exclusively impaired in myotonic dystrophy type 1. We found mild executive and attentional deficits in our patients when neuropsychological tests were corrected for manual motor dysfunctioning. Regression analyses revealed associations of white matter affection with several clinical parameters in both disease entities, but not with neuropsychological performance. We showed that depressed mood and fatigue were more prominent in patients with myotonic dystrophy type 1 with less white matter affection (early disease stages), contrary to patients with myotonic dystrophy type 2. Thus, depression in myotonic dystrophies might be a reactive adjustment disorder rather than a direct consequence of structural brain damage. Associations of white matter affection with age/disease duration as well as patterns of cerebral water diffusion parameters pointed towards an ongoing process of myelin destruction and/or axonal loss in our cross-sectional study design. Our data suggest that both myotonic dystrophy types 1 and 2 are serious white matter diseases with prominent callosal body and limbic system affection. White matter changes dominated the extent of grey matter changes, which might argue against Wallerian degeneration as the major cause of white matter affection in myotonic dystrophies.
PMCID: PMC3235566  PMID: 22131273
myotonic dystrophy; neuropsychology; MRI; DTI; VBM
2.  Electrophysiological evaluation of oropharyngeal swallowing in myotonic dystrophy 
OBJECTIVE—Oropharyngeal dysphagia is a common feature of patients with myotonic dystrophy and is not usually perceived due to their emotional deficits and lack of interest. The aim was to show the existence and frequency of subclinical electrophysiological abnormalities in oropharyngeal swallowing and to clarify the mechanisms of dysphagia in myotonic dystrophy.
METHODS—Eighteen patients with myotonic dystrophy were examined for oropharyngeal phase of swallowing by clinical and electrophysiological methods. Ten patients had dysphagia whereas 11 patients had signs and symptoms reflecting CNS involvement. Four patients with myotonia congenita and 30 healthy volunteers served as controls. Laryngeal movements were detected by means of a piezoelectric sensor. EMG activities of the submental muscle (SM-EMG) and needle EMG of the cricopharyngeal muscle of the upper eosophageal sphincter (CP-EMG) were also recorded during swallowing.
RESULTS—In about 70% of the patients with myotonic dystrophy, the existence of oropharyngeal dysphagia was indicated objectively by means of the technique of "dysphagia limit" and by clinical evaluation. Duration of the swallowing reflex as defined by the laryngeal relocation time (0-2 time interval) and submental muscle excitation as a part of the swallowing reflex (A-C interval) were significantly prolonged in patients with myotonic dystrophy, especially in dysphagic patients. Triggering time of the swallowing reflex (A-0 interval) also showed significant prolongation, especially in the patients having both dysphagia and CNS involvement. During swallowing, CP muscle activity was abnormal in 40% of the patients with myotonic dystrophy.
CONCLUSION—Both myopathic weakness and myotonia encountered in oropharyngeal muscles play an important part in the oral and the pharyngeal phases of swallowing dysfunction in myotonic dystrophy. It was also suggested that CNS involvement might contribute to the delay of the triggering of the swallowing reflex and some abnormal EMG findings in the CP sphincter, resulting in oropharyngeal dysphagia in myotonic dystrophy.

PMCID: PMC1737233  PMID: 11181860
3.  Non-dystrophic myotonia: prospective study of objective and patient reported outcomes 
Brain  2013;136(7):2189-2200.
Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.
PMCID: PMC3692030  PMID: 23771340
non-dystrophic myotonia; SCN4A; CLCN1; myotonia; paramyotonia
4.  Apathy and hypersomnia are common features of myotonic dystrophy 
OBJECTIVES—Myotonic dystrophy is a disease characterised by myotonia and muscle weakness. Psychiatric disorder and sleep problems have also been considered important features of the illness. This study investigated the extent to which apathy, major depression, and hypersomnolence were present. The objective was to clarify if the apathy reported anecdotally was a feature of CNS involvement or if this was attributable to major depression, hypersomnolence, or a consequence of chronic muscle weakness.
METHODS—These features were studied in 36 adults with non-congenital myotonic dystrophy and 13 patients with Charcot-Marie-Tooth disease. By using patients with Charcot-Marie-Tooth disease as a comparison group the aim was to control for the disabling effects of having an inherited chronic neurological disease causing muscle weakness. Standardised assessment instruments were used wherever possible to facilitate comparison with other groups reported in the medical literature.
RESULTS—There was no excess of major depression on cross sectional analysis in these patients with mild myotonic dystrophy. However, apathy was a prominent feature of myotonic dystrophy in comparison with a similarly disabled group of patients with Charcot-Marie-Tooth disease (clinician rated score; Mann Whitney U test, p=0.0005). Rates of hypersomnolence were greater in the myotonic dystrophy group, occurring in 39% of myotonic dystrophy patients, but there was no correlation with apathy.
CONCLUSION—These data suggest that apathy and hypersomnia are independent and common features of myotonic dystrophy. Apathy cannot be accounted for by clinical depression or peripheral muscle weakness and is therefore likely to reflect CNS involvement. These features of the disease impair quality of life and may be treatable.

PMCID: PMC2170039  PMID: 9576545
5.  Decreased insulin sensitivity of forearm muscle in myotonic dystrophy. 
Journal of Clinical Investigation  1978;62(4):857-867.
Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.
PMCID: PMC371838  PMID: 701484
6.  Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2 
European Journal of Human Genetics  2012;20(12):1203-1208.
Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age and have a more severe course (anticipation). In myotonic dystrophy type 2 (DM2), no anticipation is described, but cardiac conduction abnormalities as in DM1 are observed and patients with DM2 additionally have muscle pain and stiffness. Both DM1 and DM2 are caused by unstable DNA repeats in untranslated regions of different genes: A (CTG)n repeat in the 3'-UTR of the DMPK gene and a (CCTG)n repeat in intron 1 of the CNBP (formerly ZNF9) gene, respectively. The length of the (CTG)n repeat expansion in DM1 correlates with disease severity and age of onset. Nevertheless, these repeat sizes have limited predictive values on individual bases. Because of the disease characteristics in DM1 and DM2, appropriate molecular testing and reporting is very important for the optimal counseling in myotonic dystrophy. Here, we describe best practice guidelines for clinical molecular genetic analysis and reporting in DM1 and DM2, including presymptomatic and prenatal testing.
PMCID: PMC3499739  PMID: 22643181
7.  Ocular motor myotonic phenomenon in myotonic dystrophy 
Objective: To detect disconjugate ocular motor abnormalities and a possible extraocular muscle myotonic phenomenon in patients with myotonic dystrophy (MyD).
Methods: The magnetic scleral search coil technique was used to record monocularly the small (25°) and large (50°) saccades, which were paced to two interstimulus intervals (ISIs), one short (1 s), the other long (5 s). The case study comprised 20 patients with MyD, 10 patients with multiple sclerosis (MS), and 10 controls. The amplitude, duration, peak velocity, and skewness of the velocity profile (ratio between the acceleration and the deceleration periods) of each saccade were measured. The disconjugate parameters (difference between the two eyes of the same measure), and the myotonic parameter (the maximal (as absolute value) short-long ISI difference between the same measures) were considered.
Results: The disconjugate parameters were the same in all three groups. The mean values of myotonic parameters found in patients with MyD for duration (for both small and large target displacements) and skewness (for small target displacements only) differed from those found for both the MS and the control groups. Additionally, the occurrence of individual patients presenting with abnormal duration and skewness parameters was higher in the MyD than in the MS group. In patients with MyD, the saccade duration was longer for long than for short ISI; the effect derived from a prolongation of the acceleration period, which manifested as an increase in skewness.
Conclusion: The results can be explained by a combination of the myotonic and the warm up phenomena. A delay in the relaxation (myotonia) of the extraocular muscle may be more evident after a long fixation period (long ISI) and it may improve by increasing saccade pacing (short ISI-warm up). This phenomenon is slight, and is unlikely to affect saccade performance significantly, but it may provide some insight into the nature of the disorder affecting extraocular and skeletal muscles in myotonic dystrophy.
PMCID: PMC1737732  PMID: 11796775
8.  Age of Onset of RNA Toxicity Influences Phenotypic Severity: Evidence from an Inducible Mouse Model of Myotonic Dystrophy (DM1) 
PLoS ONE  2013;8(9):e72907.
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. It is caused by an expanded (CTG)n tract in the 3′ UTR of the Dystrophia Myotonica Protein Kinase (DMPK) gene. This causes nuclear retention of the mutant mRNA into ribonuclear foci and sequestration of interacting RNA-binding proteins (such as muscleblind-like 1 (MBNL1)). More severe congenital and childhood-onset forms of the disease exist but are less understood than the adult disease, due in part to the lack of adequate animal models. To address this, we utilized transgenic mice over-expressing the DMPK 3′ UTR as part of an inducible RNA transcript to model early-onset myotonic dystrophy. In mice in which transgene expression was induced during embryogenesis, we found that by two weeks after birth, mice reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, muscle weakness, histopathology and mRNA splicing defects. Notably, these defects were more severe than in adult mice induced for an equivalent period of exposure to RNA toxicity. Additionally, the utility of the model was tested by over-expressing MBNL1, a key therapeutic strategy being actively pursued for treating the disease phenotypes associated with DM1. Significantly, increased MBNL1 in skeletal muscle partially corrected myotonia and splicing defects present in these mice, demonstrating the responsiveness of the model to relevant therapeutic interventions. Furthermore, these results also represent the first murine model for early-onset DM1 and provide a tool to investigate the effects of RNA toxicity at various stages of development.
PMCID: PMC3764231  PMID: 24039817
9.  Chronic muscle stimulation improves muscle function and reverts the abnormal surface EMG pattern in Myotonic Dystrophy: a pilot study 
To date, in Myotonic Dystrophy type 1 (DM1) the rehabilitative interventions have always been aimed at muscle strengthening, increasing of fatigue resistance and improving of aerobic metabolism efficiency whereas the electrical membrane fault has always been addressed pharmacologically. Neuromuscular electrical stimulation (NMES) is a useful therapeutic tool in sport medicine and in the rehabilitation of many clinical conditions characterized by motor impairment such as stroke, cerebral palsy and spinal cord injury.
The aim of our pilot study was to evaluate the effects of chronic electrical stimulation both on functional and electrical properties of muscle in a small group of DM1 patients.
Five DM1 patients and one patient with Congenital Myotonia (CM) performed a home electrical stimulation of the tibialis anterior muscle lasting 15 days with a frequency of two daily sessions of 60 minutes each. Muscle strength was assessed according to the MRC scale (Medical Research Council) and functional tests (10 Meter Walking Test, 6 Minutes Walking Test and Timed Up and Go Test) were performed. We analyzed the average rectified value of sEMG signal amplitude (ARV) to characterize the sarcolemmal excitability.
After the treatment an increase of muscle strength in those DM1 patients with a mild strength deficit was observed. In all subjects an improvement of 10MWT was recorded. Five patients improved their performance in the 6MWT. In TUG test 4 out of 6 patients showed a slight reduction in execution time. All patients reported a subjective improvement when walking. A complete recovery of the normal increasing ARV curve was observed in 4 out of 5 DM1 patients; the CM patient didn’t show modification of the ARV pattern.
NMES determined a clear-cut improvement of both the muscular weakness and the sarcolemmal excitability alteration in our small group of DM1 patients. Therefore this rehabilitative approach, if confirmed by further extensive studies, could be considered early in the management of muscular impairment in these patients. An attractive hypothesis to explain our encouraging result could be represented by a functional inhibition of SK3 channels expressed in muscle of DM1 subjects.
PMCID: PMC3765215  PMID: 23938156
Myotonic dystrophy type 1; Neuromuscular electrical stimulation (NMES); Rehabilitation; SK = small conductance Ca-activated K + channels
10.  Sleep disturbances in myotonic dystrophy type 2 
European neurology  2012;68(6):377-380.
Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep disordered breathing (SDB), hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) data. Eight patients (five women, three men) with DM2 were identified. Excessive daytime sleepiness (EDS) was seen in six patients (75%), insomnia in five (62.5%), and excessive fatigue in four (50%). Obstructive sleep apnea was diagnosed in three of five patients studied with PSG (60%). Respiratory muscle weakness was present in all six patients (100%) who received pulmonary function testing. Four of eight (50%) met criteria for diagnosis of restless legs syndrome (RLS). The clinical spectrum of DM2 may include a wide range of sleep disturbances. Although respiratory muscle weakness was frequent, sustained sleep-related hypoxia suggestive of hypoventilation was not seen in our patients. Further prospective studies are needed to examine the frequency and scope of sleep disturbances in DM2.
PMCID: PMC4259012  PMID: 23108384
myotonic dystrophy type 2; DM2; excessive daytime sleepiness; EDS; fatigue; OSA; RLS
11.  Polysomnography in Patients With Obstructive Sleep Apnea 
Executive Summary
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario.
Clinical Need: Target Population and Condition
Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies.
The Technology Being Reviewed
There is no ‘gold standard’ for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs.
In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as “The Sleep Book.” The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered.
Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective.
Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value.
At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments.
Review Strategy
There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature.
To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed.
Diffusion of Sleep Laboratories
To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases.
Summary of Findings
Literature Review
A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study.
Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men.
Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups.
Diagnostic Value of Polysomnography
It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined.
Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population.
Obstructive Sleep Apnea and Obesity
Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m2) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals.
Obstructive Sleep Apnea and Cardiovascular Diseases
Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values.
A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m2; range = 32.30–68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension.
Health Technology Assessments, Guidelines, and Recommendations
In April 2005, the Centers for Medicare and Medicaid Services (CMS) in the United States published its decision and review regarding in-home and in-lab sleep studies for the diagnosis and treatment of OSA with CPAP. In order to cover CPAP, CMS requires that a diagnosis of OSA be established using PSG in a sleep laboratory. After reviewing the literature, CMS concluded that the evidence was not adequate to determine that unattended portable sleep study was reasonable and necessary in the diagnosis of OSA.
In May 2005, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) published a review of guidelines for referral of patients to sleep laboratories. The review included 37 guidelines and associated reviews that covered 18 applications of sleep laboratory studies. The CCOHTA reported that the level of evidence for many applications was of limited quality, that some cited studies were not relevant to the recommendations made, that many recommendations reflect consensus positions only, and that there was a need for more good quality studies of many sleep laboratory applications.
As of the time of writing, there are 97 licensed sleep laboratories in Ontario. In 2000, the number of sleep studies performed in Ontario was 376/100,000 people. There was a steady rise in sleep studies in the following years such that in 2004, 769 sleep studies per 100,000 people were performed, for a total of 96,134 sleep studies. Based on prevalence estimates of the Wisconsin Sleep Cohort Study, it was estimated that 927,105 people aged 30 to 60 years have sleep-disordered breathing. Thus, there may be a 10-fold rise in the rate of sleep tests in the next few years.
Economic Analysis
In 2004, approximately 96,000 sleep studies were conducted in Ontario at a total cost of ~$47 million (Cdn). Since obesity is associated with sleep disordered breathing, MAS compared the costs of sleep studies to the cost of bariatric surgery. The cost of bariatric surgery is $17,350 per patient. In 2004, Ontario spent $4.7 million per year for 270 patients to undergo bariatric surgery in the province, and $8.2 million for 225 patients to seek out-of-country treatment. Using a Markov model, it was concluded that shifting costs from sleep studies to bariatric surgery would benefit more patients with OSA and may also prevent health consequences related to diabetes, hypertension, and hyperlipidemia. It is estimated that the annual cost of treating comorbid conditions in morbidly obese patients often exceeds $10,000 per patient. Thus, the downstream cost savings could be substantial.
Considerations for Policy Development
Weight loss is associated with a decrease in OSA severity. Treating and preventing obesity would also substantially reduce the economic burden associated with diabetes, hypertension, hyperlipidemia, and OSA. Promotion of healthy weights may be achieved by a multisectorial approach as recommended by the Chief Medical Officer of Health for Ontario. Bariatric surgery has the potential to help morbidly obese individuals (BMI > 35 kg/m2 with an accompanying comorbid condition, or BMI > 40 kg/m2) lose weight. In January 2005, MAS completed an assessment of bariatric surgery, based on which OHTAC recommended an improvement in access to these surgeries for morbidly obese patients in Ontario.
Habitual snorers with excessive daytime sleepiness have a high pretest probability of having OSA. These patients could be offered a therapeutic trial of CPAP to diagnose OSA, rather than a PSG. A majority of these patients are also obese and may benefit from weight loss. Individualized weight loss programs should, therefore, be offered and patients who are morbidly obese should be offered bariatric surgery.
That said, and in view of the still evolving understanding of the causes, consequences and optimal treatment of OSA, further research is warranted to identify which patients should be screened for OSA.
PMCID: PMC3379160  PMID: 23074483
12.  Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy 
PLoS Genetics  2013;9(6):e1003430.
Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.
Author Summary
The intracellular organization of muscle fibers relies on a complex membrane system important for muscle structural organization, maintenance, contraction, and resistance to stress. Amphiphysin 2, encoded by BIN1, plays a central role in membrane sensing and remodelling and is involved in intracellular membrane trafficking in different cell types. The ubiquitously expressed BIN1, altered in centronuclear myopathy (CNM) and myotonic dystrophy (DM), possesses a muscle-specific exon coding for a phosphoinositide binding domain. We identified splice mutations affecting the muscle-specific BIN1 isoform in humans and dogs presenting a clinically and histopathologically comparable highly progressive centronuclear myopathy. Our functional and ultrastructural data emphasize the importance of amphiphysin 2 in membrane remodeling and suggest that the defective maintenance of the triad structure is a primary cause for the muscle weakness. The canine Inherited Myopathy of Great Danes is the first faithful mammalian model for investigating other potential pathological mechanisms underlying centronuclear myopathy and for testing therapeutic approaches.
PMCID: PMC3675003  PMID: 23754947
13.  Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland 
Myotonic dystrophy (DM) is the most common adult-onset muscular dystrophy with an estimated prevalence of 1/8000. There are two genetically distinct types, DM1 and DM2. DM2 is generally milder with more phenotypic variability than the classic DM1. Our previous data on co-segregation of heterozygous recessive CLCN1 mutations in DM2 patients indicated a higher than expected DM2 prevalence. The aim of this study was to determine the DM2 and DM1 frequency in the general population, and to explore whether the DM2 mutation functions as a modifier in other neuromuscular diseases (NMD) to account for unexplained phenotypic variability. We genotyped 5535 Finnish individuals: 4532 normal blood donors, 606 patients with various non-myotonic NMD, 221 tibial muscular dystrophy patients and their 176 healthy relatives for the DM2 and DM1 mutations. We also genotyped an Italian idiopathic non-myotonic proximal myopathy cohort (n=93) for the DM2 mutation. In 5496 samples analyzed for DM2, we found three DM2 mutations and two premutations. In 5511 samples analyzed for DM1, we found two DM1 mutations and two premutations. In the Italian cohort, we identified one patient with a DM2 mutation. We conclude that the DM2 mutation frequency is significantly higher in the general population (1/1830; P-value=0.0326) than previously estimated. The identification of DM2 mutations in NMD patients with clinical phenotypes not previously associated with DM2 is of particular interest and is in accord with the high overall prevalence. On the basis of our results, DM2 appears more frequent than DM1, with most DM2 patients currently undiagnosed with symptoms frequently occurring in the elderly population.
PMCID: PMC3137497  PMID: 21364698
myotonic dystrophy; mutation frequency; prevalence; population
14.  Laboratory Test Abnormalities are Common in Polymyositis and Dermatomyositis and Differ Among Clinical and Demographic Groups 
Given the difficulties regarding the interpretation of common laboratory test results in polymyositis (PM) and dermatomyositis (DM) in clinical practice, we assessed their range of abnormalities, differences among phenotypes and interrelationships in a large referral population.
We retrospectively assessed 20 commonly measured blood laboratory tests in 620 well-defined PM/DM patients at different stages of illness and treatment to determine the frequency, range of abnormalities and correlations among clinical, gender, racial and age phenotypes.
Myositis patients at various stages of their disease showed frequent elevations of the serum activities of creatine kinase (51%), alanine aminotransferase (43%), aspartate aminotransferase (51%), lactate dehydrogenase (60%), aldolase (65%) and myoglobin levels (48%) as expected. Other frequent abnormalities, however, included elevated high white blood cell counts (36%), low lymphocyte counts (37%), low hematocrit levels (29%), low albumin levels (22%), high creatine kinase MB isoenzyme fractions (52%), high erythrocyte sedimentation rates (33%) and high IgM and IgG levels (16% and 18%, respectively). Many of these tests significantly differed among the clinical, gender, racial and age groups. Significant correlations were also found among a number of these laboratory tests, particularly in the serum activity levels of creatine kinase, the transaminases, lactate dehydrogenase and aldolase.
Laboratory test abnormalities are common in PM/DM. Knowledge of the range of these expected abnormalities in different myositis phenotypes, gender and age groups and their correlations should assist clinicians in better interpretation of these test results, allow for a clearer understanding what level of abnormality warrants further evaluation for liver or other diseases, and may avoid unnecessary laboratory or other testing.
PMCID: PMC3377888  PMID: 22723809
Myositis; phenotypes; laboratory testing.
15.  Clinical and laboratory predictive markers for acute dengue infection 
Early diagnosis of dengue virus infection during the febrile stage is essential for adjusting appropriate management. This study is to identify the predictive markers of clinical and laboratory findings in the acute stage of dengue infection during a major outbreak of dengue virus type 1 that occurred in southern Taiwan during 2007. A retrospective, hospital-based study was conducted at a university hospital in southern Taiwan from January to December, 2007. Patient who was reported for clinically suspected dengue infection was enrolled. Laboratory-positive dengue cases are confirmed by enzyme-linked immunosorbent assay of specific dengue IgM, fourfold increase of dengue-specific IgG titers in convalescent serum, or by reverse transcription-polymerase chain reaction (RT-PCR) of dengue virus.
The suspected dengue cases consist of 100 children (≤ 18 years) and 481 adults. Among the 581 patients, 67 (67%) children and 309 (64.2%) adults were laboratory-confirmed. Patients who had laboratory indeterminate were excluded. Most cases were uncomplicated and 3.8% of children and 2.9% of adults developed dengue hemorrhagic fever or dengue shock syndrome (DHF/DSS). The overall mortality rate in those with DHF/DSS was 7.1%, and the average duration of hospitalization was 20 days. The most common symptoms/signs at admission were myalgia (46.8%), petechiae (36.9%) and nausea/vomiting (33.5%). The most notable laboratory findings included leukopenia (2966 ± 1896/cmm), thrombocytopenia (102 ± 45 × 103/cmm), prolonged activated partial thromboplastin time (aPTT) (45 ± 10 s), and elevated serum levels of aminotransferase (AST, 166 ± 208 U/L; ALT, 82 ± 103 U/L) and low C - reactive protein (CRP) (6 ± 11 mg/L). Based on the clinical features for predicting laboratory-confirmed dengue infection, the sensitivities of typical rash, myalgia, and positive tourniquet test are 59.2%, 46.8%, and 34.2%, while the specificities for above features are 75.4%, 53.5% and 100%, respectively. The positive predictive value (PPV) for combination of leukopenia, thrombocytopenia (< 150 × 103/cmm), elevated aminotransferase (AST/ALT > 1.5) and low CRP (< 20 mg/L) is 89.5%, while the negative predictive value is 37.4%. Furthermore, the PPV of the combination was increased to 93.1% by adding prolonged aPTT (>38 secs).
Leukopenia, thrombocytopenia, elevated aminotransferases, low CRP and prolonged aPTT, were useful predictive markers for early diagnosis of dengue infection during a large outbreak in southern Taiwan.
PMCID: PMC4015130  PMID: 24138072
Dengue; Early diagnosis; Predictive markers
16.  Patterns of serum laboratory monitoring for safety and efficacy in patients on chronic statin therapy 
To describe safety and efficacy laboratory monitoring of statin therapy at the University of Colorado Hospital Outpatient Clinics over a period of 3 years prior to the revised United States Food and Drug Administration statin labeling.
This retrospective, observational study evaluated serum laboratory monitoring for safety and efficacy of statin therapy between July 2008 and June 2011. Adult patients prescribed chronic statin therapy were included. The primary objective of this study was to describe the frequency of outpatient liver function tests, lipid panels, and creatine kinase for patients on chronic statin therapy.
A total of 143 patients met study criteria. Over a 3-year period, the mean maximum frequency of measurements per patient of serum hepatic transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was higher than lipid panel measurements (5.2 ± 4.4 and 4.2 ± 2.0 respectively, p = 0.021). Only 22 of 143 patients (15.4%) had an elevation in ALT or AST. All elevations were less than three times the upper limit of normal and statin therapy was continued without changes in response to these elevations. Creatine kinase, though not a routine monitoring test, was infrequently measured (mean maximum frequency of measurements per patient 0.3 ± 0.8).
Serum hepatic transaminases were routinely monitored in patients treated with chronic statin therapy. Given the absence of significant serum hepatic transaminase elevations, and clinician response to minor elevations, our data indicate that routine serum laboratory evaluations for statin toxicity are excessive.
PMCID: PMC4110821  PMID: 25083247
drug therapy monitoring; dyslipidemia; hepatic transaminases; hydroxyl-3-methyl-glutaryl coenzyme A reductase inhibitors; statin
17.  The Effect of Automated Alerts on Provider Ordering Behavior in an Outpatient Setting 
PLoS Medicine  2005;2(9):e255.
Computerized order entry systems have the potential to prevent medication errors and decrease adverse drug events with the use of clinical-decision support systems presenting alerts to providers. Despite the large volume of medications prescribed in the outpatient setting, few studies have assessed the impact of automated alerts on medication errors related to drug–laboratory interactions in an outpatient primary-care setting.
Methods and Findings
A primary-care clinic in an integrated safety net institution was the setting for the study. In collaboration with commercial information technology vendors, rules were developed to address a set of drug–laboratory interactions. All patients seen in the clinic during the study period were eligible for the intervention. As providers ordered medications on a computer, an alert was displayed if a relevant drug–laboratory interaction existed. Comparisons were made between baseline and postintervention time periods. Provider ordering behavior was monitored focusing on the number of medication orders not completed and the number of rule-associated laboratory test orders initiated after alert display. Adverse drug events were assessed by doing a random sample of chart reviews using the Naranjo scoring scale.
The rule processed 16,291 times during the study period on all possible medication orders: 7,017 during the pre-intervention period and 9,274 during the postintervention period. During the postintervention period, an alert was displayed for 11.8% (1,093 out of 9,274) of the times the rule processed, with 5.6% for only “missing laboratory values,” 6.0% for only “abnormal laboratory values,” and 0.2% for both types of alerts. Focusing on 18 high-volume and high-risk medications revealed a significant increase in the percentage of time the provider stopped the ordering process and did not complete the medication order when an alert for an abnormal rule-associated laboratory result was displayed (5.6% vs. 10.9%, p = 0.03, Generalized Estimating Equations test). The provider also increased ordering of the rule-associated laboratory test when an alert was displayed (39% at baseline vs. 51% during post intervention, p < 0.001). There was a non-statistically significant difference towards less “definite” or “probable” adverse drug events defined by Naranjo scoring (10.3% at baseline vs. 4.3% during postintervention, p = 0.23).
Providers will adhere to alerts and will use this information to improve patient care. Specifically, in response to drug–laboratory interaction alerts, providers will significantly increase the ordering of appropriate laboratory tests. There may be a concomitant change in adverse drug events that would require a larger study to confirm. Implementation of rules technology to prevent medication errors could be an effective tool for reducing medication errors in an outpatient setting.
A computerized order entry system that alerted providers to potential problems was shown to be able to influence prescribing practice
PMCID: PMC1198038  PMID: 16128621
18.  Dengue: profile of hematological and biochemical dynamics 
The objective of this study was to correlate laboratory tests during the evolution of dengue fever, comparing frequencies between the different clinical forms in order to use test results to predict the severity of the disease.
This is an observational, descriptive and retrospective study of 154 patients with clinical and serological diagnoses of dengue fever who, in the period from January to May 2008, were admitted in a tertiary state hospital in the city of Fortaleza that is a referral center for infectious diseases. The patients were allocated to two groups according to age: under 15 years old (n = 66) and 15 years or older (n = 88). The tests analyzed were blood count, platelet count, and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations.
Thrombocytopenia and elevated transaminases were observed in patients with classic dengue fever. The main laboratory abnormalities found in dengue hemorrhagic fever were thrombocytopenia, hemoconcentration and elevated transaminases, similar to severe dengue with the exception of hemoconcentration. Most laboratory abnormalities started on the 3rd day but were more evident on the 5th day with restoration of values by the 11th day; this was more prominent in under 15-year-olds and with the more severe clinical forms.
These results are relevant in assessing the disease because they can be used as markers for more severe forms and can help by enabling the adaptation of the therapeutic conduct to the needs of individual patients.
PMCID: PMC3459605  PMID: 23049382
Dengue/blood; Dengue hemorrhagic fever/diagnosis; Dengue virus; Prognosis; Clinical laboratory techniques; Hematologic tests
19.  Ascertainment of myotonic dystrophy through cataract by selective screening. 
Journal of Medical Genetics  1995;32(7):519-523.
Myotonic dystrophy (DM) almost always results from the expansion of an unstable (CTG)n repeat. The mutation can be detected directly. Affected patients with cataracts may have minimal additional signs of the disorder, but all are at risk of life threatening complications. We have studied the efficacy of detecting new families with myotonic dystrophy by selectively screening cataract patients. Selection criteria were: age under 60 with no obvious precipitating factor (except non-insulin dependent diabetes mellitus (NIDDM)); patients of any age with other signs suggestive of myotonic dystrophy detected by the ophthalmologist. Ninety-six patients were tested prospectively; 17 others under 55 were screened retrospectively. All patients were counselled by a clinical geneticist before testing. The patients' DNA was analysed using the DNA probe/restriction enzyme combinations GB2.6/EcoRI, KB1.4/BglI and polymerase chain reaction (PCR). Six patients have been found to have a mutation, three (3.1%) in the prospective group and three (17.6%) in the retrospective group. Three of these patients had minimal myotonic dystrophy and three had classical DM.
PMCID: PMC1050543  PMID: 7562963
20.  Does cytosine-thymine-guanine (CTG) expansion size predict cardiac events and electrocardiographic progression in myotonic dystrophy? 
Heart  2001;86(4):411-416.
OBJECTIVE—To assess whether the size of the cytosine-thymine-guanine (CTG) expansion mutation in myotonic dystrophy predicts progression of conduction system disease and cardiac events.
DESIGN—Longitudinal study involving ECG and clinical follow up over (mean (SD)) 4.8 (1.8) and 6.2 (1.9) years, respectively, of patients stratified by CTG expansion size (E0 to E4).
PATIENTS—73 adult patients under annual review in a regional myotonic dystrophy clinic. Patients were grouped into E0/E1 (n = 25), E2 (n = 34), and E3/E4 (n = 14).
RESULTS—The proportion of patients with a QRS complex > 100 ms at baseline increased with the size of the CTG expansion (EO/E1, 4%; E2, 12%; E3/E4, 36%; p = 0.02). This trend was more pronounced at follow up (E0/E1, 4%; E2, 21%; E3/E4, 57%; p = 0.0004). The rate of widening of the QRS complex (ms/year) was similarly related to the size of the mutation (EO/E1, 0.4 (1.3); E2, 1.4 (2.5); E3/E4, 1.5 (1.6); p = 0.04). First degree atrioventricular block was present in 23% of patients at baseline and 34% at follow up, with no significant relation to expansion size. Seven patients suffered a cardiac event during follow up (sudden death in two, permanent pacemaker insertion in three, chronic atrial arrhythmia in two), of whom six were in CTG expansion group E2 or greater. Patients who experienced a cardiac event during follow up had more rapid rates of PR interval increase (9.9 (11.1) v 1.6 (2.9) ms/year; p = 0.008) and a trend to greater QRS complex widening (3.6 (4.5) v 0.9 (1.5) ms/year; p = 0.06) than those who did not.
CONCLUSIONS—Larger CTG expansions are associated with a higher rate of conduction disease progression and a trend to increased risk of cardiac events in myotonic dystrophy.

Keywords: myotonic dystrophy; atrioventricular block; delayed intraventricular conduction; cytosine-thymine-guanine expansion
PMCID: PMC1729946  PMID: 11559681
21.  Increased Cancer Risks in Myotonic Dystrophy 
Mayo Clinic Proceedings  2012;87(2):130-135.
To estimate cancer risks for patients with myotonic dystrophy, given that increased risks for neoplasms in association with myotonic dystrophy type 1 and type 2 have been suggested in several studies but the risks of cancers have not been quantified.
Patients and Methods
A cohort of 307 patients with myotonic dystrophy identified from medical records of Mayo Clinic in Rochester, MN, from January 1, l993, through May 28, 2010, was retrospectively analyzed. We estimated standardized incidence ratios (SIRs) of specific cancers for patients with myotonic dystrophy compared with age- and sex-specific cancer incidences of the general population. Age-dependent cumulative risks were calculated using the Kaplan-Meier method.
A total of 53 cancers were observed at a median age at diagnosis of 55 years. Patients with myotonic dystrophy had an increased risk of thyroid cancer (SIR, 5.54; 95% confidence interval [CI], 1.80-12.93; P=.001) and choroidal melanoma (SIR, 27.54; 95% CI, 3.34-99.49; P<.001). They may also have an increased risk of testicular cancer (SIR, 5.09; 95% CI, 0.62-18.38; P=.06) and prostate cancer (SIR, 2.21; 95% CI, 0.95-4.35; P=.05). The estimated cumulative risks at age 50 years were 1.72% (95% CI, 0.64%-4.55%) for thyroid cancer and 1.00% (95% CI, 0.25%-3.92%) for choroidal melanoma. There was no statistical evidence of an increased risk of brain, breast, colorectal, lung, renal, bladder, endometrial, or ovarian cancer; lymphoma; leukemia; or multiple myeloma.
Patients with myotonic dystrophy may have an increased risk of thyroid cancer and choroidal melanoma and, possibly, testicular and prostate cancers.
PMCID: PMC3498332  PMID: 22237010
22.  Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies 
Acta Myologica  2013;32(3):154-165.
Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. DM1 may present in four different forms: congenital, early childhood, adult onset and late-onset oligosymptomatic DM1. Congenital DM1 is the most severe form of DM characterized by extreme muscle weakness and mental retardation. In DM2 the clinical phenotype is extremely variable and there are no distinct clinical subgroups. Congenital and childhood-onset forms are not present in DM2 and, in contrast to DM1, myotonia may be absent even on EMG. Due to the lack of awareness of the disease among clinicians, DM2 remains largely underdiagnosed. The delay in receiving the correct diagnosis after onset of first symptoms is very long in DM: on average more than 5 years for DM1 and more than 14 years for DM2 patients. The long delay in the diagnosis of DM causes unnecessary problems for the patients to manage their lives and anguish with uncertainty of prognosis and treatment.
PMCID: PMC4006279  PMID: 24803843
Myotonic dystrophy type 1 (Dm1); myotonic dystrophy type 2 (Dm2); management
23.  Prolonged Corrected QT Interval in Patients with Myotonic Dystrophy Type 1 
Background and Purpose
Sudden cardiac death is one of the leading causes of death in patients with myotonic dystrophy type 1 (DM1). It has been proposed that a prolonged QT interval is associated with sudden cardiac death in several neurological diseases, including multiple system atrophy, idiopathic Parkinson's disease, and diabetic autonomic neuropathy. However, analyses of the corrected QT (QTc) interval in DM1 patients are rare in the literature. The purposes of this study were to determine the association between the QT interval and DM1, and the affecting factors.
Thirty-nine patients diagnosed with DM1 through genetic testing were enrolled. The QTc interval (calculated using Bazett's formula: QTc=QT/√RR) was compared between these patients and 39 normal healthy controls. The clinical and laboratory factors affecting QTc interval in the patient group were investigated.
The QTc interval was significantly longer in the DM1 group (411.2±44.7 msec, mean±SD) than in the normal control group (355.6±20.6 msec). Intragroup analysis revealed that a prolonged QTc interval in DM1 patients was associated with being female and older, having a longer disease duration, and exhibiting abnormal electrocardiography findings.
The higher incidence of sudden cardiac death in the DM1 population is associated with the observed prolonged QTc interval in those patients.
PMCID: PMC3722470  PMID: 23894242
myotonic dystrophy; corrected QT interval; Bazett's formula; sudden cardiac death
24.  Evoked myotonia can be “dialed-up” by increasing stimulus train length in Myotonic Dystrophy Type 1 
Muscle & nerve  2010;41(2):191-196.
It is unknown how evoked myotonia varies with stimulus frequency or train length, or how it compares to voluntary myotonia in myotonic dystrophy type 1 (DM1).
First dorsal interosseous (FDI) tetanic contractions evoked by trains of 10–20 ulnar nerve stimuli at 10–50 Hz were recorded in 10 DM1 patients and 10 normals. For comparison, maximum voluntary handgrip contractions were also recorded. An automated computer program placed cursors along the declining (relaxation) phase of the force recordings at 90 and 5% of peak force (PF) and calculated relaxation times (RTs) between these points.
For all stimulus frequencies and train lengths, evoked RTs were much shorter, and evoked PFs were much greater in normals than in DM1. In normals, evoked RT was independent of stimulus frequency and train length, while in DM1, RT was longer for train lengths of 20 stimuli (mean:9 seconds in DM1; 0.20 in normals) than for 10 stimuli (mean:3 seconds in DM1, 0.19 in normals), but it did not change with stimulus frequency. In both groups, PF increased greatly as stimulus frequency rose from 10 to 50 Hz but only slightly as train length rose from 10 to 20 stimuli. Voluntary handgrip RT (mean:1.9 seconds) was less than evoked FDI RT (mean:9 seconds).
In DM1, evoked RT can be “dialed up” by increasing stimulus train length. Evoked myotonia testing utilizing a stimulus paradigm of at least 20 stimuli at 30–50 Hz may be useful in anti-myotonic drug trials, particularly when grip RT is normal or equivocal.
PMCID: PMC4122294  PMID: 19750543
myotonia; myotonic dystrophy; handgrip; relaxation time
25.  Clinical and genetic analysis of the first known Asian family with myotonic dystrophy type 2 
Journal of Human Genetics  2014;59(3):129-133.
Myotonic dystrophy type 2 (DM2) is more common than DM1 in Europe and is considered a rare cause of myotonic dystrophies in Asia. Its clinical course is also milder with more phenotypic variability than DM1. We herein describe the first known Asian family (three affected siblings) with DM2 based on clinical and genetic analyses. Notably, two of the affected siblings were previously diagnosed with limb-girdle muscular dystrophy. Myotonia (the inability of the muscle to relax) was absent or only faintly present in these individuals. The third sibling had grip myotonia and is the first known Asian DM2 patient. The three DM2 siblings share several systemic characteristics, including late-onset, proximal-dominant muscle weakness, diabetes, cataracts and asthma. Repeat-primed PCR across the DM2 repeat revealed a characteristic ladder pattern of a CCTG expansion in all siblings. Southern blotting analysis identified the presence of 3400 repeats. Further DM2 studies in Asian populations are needed to define the clinical presentation of Asian DM2 and as yet unidentified phenotypic differences from Caucasian patients.
PMCID: PMC3973124  PMID: 24430576
Asian; CCTG repeat; clinical spectrum; haplotype; limb-girdle muscular dystrophy; myotonia; myotonic dystrophy type 2 (DM2)

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