Chad Heatwole

Splicing biomarkers of disease severity in myotonic dystrophy.

To develop RNA splicing biomarkers of disease severity and therapeutic response in myotonic dystrophy type 1 (DM1) and type 2 (DM2).

Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1)

Objective: To determine the most critical symptoms in a national myotonic dystrophy type 1 (DM1) population and to identify the modifying factors that have the greatest effect on the severity of these symptoms. Methods: We performed a cross-sectional study of 278 adult patients with DM1 from the national registry of patients with DM1 between April and August 2010. We assessed the prevalence and relative significance of 221 critical DM1 symptoms and 14 disease themes. These symptoms and themes were chosen for evaluation based on prior interviews with patients with DM1. Responses were categorized by age, CTG repeat length, gender, and duration of symptoms. Results: Participants with DM1 provided symptom rating survey responses to address the relative frequency and importance of each DM1 symptom. The symptomatic themes with the highest prevalence in DM1 were problems with hands or arms (93.5%), fatigue (90.8%), myotonia (90.3%), and impaired sleep or daytime sleepiness (87.9%). Participants identified fatigue and limitations in mobility as the symptomatic themes that have the greatest effect on their lives. We found an association between age and the average prevalence of all themes (p < 0.01) and between CTG repeat length and the average effect of all symptomatic themes on participant lives (p < 0.01). Conclusions: There are a wide range of symptoms that significantly affect the lives of patients with DM1. These symptoms, some previously underrecognized, have varying levels of importance in the DM1 population and are nonlinearly dependent on patient age and CTG repeat length.

The Nondystrophic Myotonias

SummaryThe nondystrophic myotonias are a heterogeneous set of rare diseases that demonstrate clinical myotonia, electrical myotonia, or both. These disorders are distinguished from myotonic dystrophy type 1 (DM-1), the more recently described proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM-2), and proximal myotonic dystrophy (a variant of DM-2) by characteristic clinical features, lack of abnormal nucleotide repeat expansions in the DM-1 and DM-2 genes, lack of cataracts and endocrine disturbances, and absence of significant histopathology in the muscle biopsy. The present article reviews each of the nondystrophic myotonias by exploring the unique clinical features, electrodiagnostic findings, diagnostic criteria, gene mutations, and response to pharmacologic therapy. These diseases are divided into those with chloride channel dysfunction (the myotonia congenita disorders) and those with sodium channel dysfunction (paramyotonia congenita, potassium-aggravated myotonia, and hyperkalemic periodic paralysis with myotonia). The variants that occur in each of these conditions are commented on. The differentiating features of the nondystrophic myotonias are summarized, and their predominant clinical, electrodiagnostic, and genetic characteristics are tabulated. For a comprehensive review of pertinent research and studies with application to diagnosis and treatment of individuals with nondystrophic myotonic disorders, the present article is best read in the context of other articles in this issue, especially those on ion channel physiology (Cannon) and pharmacology (Conte-Camerino), and on hyperkalemic periodic paralysis (Lehmann-Horn).

Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine

Objective: To develop recommendations for the evaluation, diagnosis, prognostication, and treatment of facioscapulohumeral muscular dystrophy (FSHD) from a systematic review and analysis of the evidence. Methods: Relevant articles were analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and treatment studies. Recommendations were linked to the strength of the evidence and other factors. Results and recommendations: Available genetic testing for FSHD type 1 is highly sensitive and specific. Although respiratory insufficiency occurs rarely in FSHD, patients with severe FSHD should have routine pulmonary function testing. Routine cardiac screening is not necessary in patients with FSHD without cardiac symptoms. Symptomatic retinal vascular disease is very rare in FSHD. Exudative retinopathy, however, is potentially preventable, and patients with large deletions should be screened through dilated indirect ophthalmoscopy. The prevalence of clinically relevant hearing loss is not clear. In clinical practice, patients with childhood-onset FSHD may have significant hearing loss. Because undetected hearing loss may impair language development, screening through audiometry is recommended for such patients. Musculoskeletal pain is common in FSHD and treating physicians should routinely inquire about pain. There is at present no effective pharmacologic intervention in FSHD. Available studies suggest that scapular fixation is safe and effective. Surgical scapular fixation might be cautiously offered to selected patients. Aerobic exercise in FSHD appears to be safe and potentially beneficial. On the basis of the evidence, patients with FSHD might be encouraged to engage in low-intensity aerobic exercises.

Open-Label Trial of Recombinant Human Insulin-like Growth Factor 1/Recombinant Human Insulin-like Growth Factor Binding Protein 3 in Myotonic Dystrophy Type 1

OBJECTIVE To evaluate the safety and tolerability of recombinant human insulin-like growth factor 1 (rhIGF-1) complexed with IGF binding protein 3 (rhIGF-1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1). DESIGN Open-label dose-escalation clinical trial. SETTING University medical center. PARTICIPANTS Fifteen moderately affected ambulatory participants with genetically proven myotonic dystrophy type 1. INTERVENTION Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 for 24 weeks followed by a 16-week washout period. MAIN OUTCOME MEASURES Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks receiving rhIGF-1/ rhIGFBP-3 treatment. RESULTS All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual-energy x-ray absorptiometry increased by 1.95 kg (P < .001) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (P = .002), a mean increase in HDL levels of 5.0 mg/dL (P = .03), a mean reduction in hemoglobin A(1c) levels of 0.15% (P = .03), and a mean increase in testosterone level (in men) of 203 ng/dL (P = .002) while taking rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (9 participants), as did mild transient hypoglycemia (3), lightheadedness (2), and transient papilledema (1). CONCLUSIONS Treatment with rhIGF-1/rhIGFBP-3 was generally well tolerated in patients with myotonic dystrophy type 1. Treatment with rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvement in metabolism but not increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00233519.

The diagnosis and treatment of myotonic disorders

Myotonia is a defining clinical symptom and sign common to a relatively small group of muscle diseases, including the myotonic dystrophies and the nondystrophic myotonic disorders. Myotonia can be observed on clinical examination, as can its electrical correlate, myotonic discharges, on electrodiagnostic testing. Research interest in the myotonic disorders continues to expand rapidly, which justifies a review of the scientific bases, clinical manifestations, and numerous therapeutic approaches associated with these disorders. We review the pathomechanisms of myotonia, the clinical features of the dystrophic and nondystrophic myotonic disorders, and the diagnostic approach and treatment options for patients with symptomatic myotonia. Muscle Nerve 47: 632–648, 2013

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.

Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy

Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials.

Myotonic Dystrophy Health Index: initial evaluation of a disease-specific outcome measure.

Introduction: In preparation for clinical trials we examine the validity, reliability, and patient understanding of the Myotonic Dystrophy Health Index (MDHI). Methods: Initially we partnered with 278 myotonic dystrophy type‐1 (DM1) patients and identified the most relevant questions for the MDHI. Next, we used factor analysis, patient interviews, and test–retest reliability assessments to refine and evaluate the instrument. Lastly, we determined the capability of the MDHI to differentiate between known groups of DM1 participants. Results: Questions in the final MDHI represent 17 areas of DM1 health. The internal consistency was acceptable in all subscales. The MDHI had a high test–retest reliability (ICC = 0.95) and differentiated between DM1 patient groups with different disease severities. Conclusions: Initial evaluation of the MDHI provides evidence that it is valid and reliable as an outcome measure for assessing patient‐reported health. These results suggest that important aspects of DM1 health may be measured effectively using the MDHI. Muscle Nerve 49: 906–914, 2014

Plasma exchange versus intravenous immunoglobulin for myasthenia gravis crisis: An acute hospital cost comparison study

Objective: To compare the short-term financial costs of treating a patient in myasthenia gravis crisis with intravenous immunoglobulin (IVIG) versus plasma exchange. Methods: An itemized comparative cost-minimization analysis of IVIG versus plasma exchange for myasthenia gravis crisis was performed. Calculations were based on each therapys implementation cost, associated hospitalization times, and predicted cost to treat known complications. A cost superiority determination was proposed based on the total cost profile of each therapy. Results: The difference in total cost favored IVIG over plasma exchange with an average savings of