Survival patterns and cancer determinants in families with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non-muscular manifestations and the usual delays in the diagnosis of DM1. METHOD: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first-degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer-related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering. RESULTS: A total of 467 deaths and 337 cancers were reported amongst 1737 first-degree DM1 relatives. Mortality risk amongst relatives reported as DM1-unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1-affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk. CONCLUSION: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease-specific clinical care and surveillance.

Pigmentation phenotype, photosensitivity and skin neoplasms in patients with myotonic dystrophy.

BACKGROUND AND PURPOSE: Recent studies have suggested a possible excess risk of skin neoplasms in patients with myotonic dystrophy (DM). Risk factors related to this observation have not been defined. METHOD: Information regarding personal history of skin tumors, pigmentation phenotype, and skin reaction to sun exposure were collected from 266 DM patients who were enrolled in the US National Institutes of Health National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members. RESULTS: Seventy-seven subjects reported having skin tumors that were either benign (n = 31), malignant (n = 32) or both (n = 14). Female gender [odds ratio (OR) = 2.27, 95% confidence interval (CI) 1.02-5.05, P = 0.04], older age (OR = 1.10, 95% CI 1.05-1.16, P < 0.001) and DM1 subtype (OR = 3.42, 95% CI 1.27-9.26, P = 0.02) were associated with a malignant skin tumor. The associations between malignant skin tumors and known risk factors [light eye color (OR = 1.62, 95% CI 0.78-3.39, P = 0.20), light skin complexion (OR = 1.31, 95% CI 0.63-2.73, P = 0.48) and moderate/extensive face freckles (OR = 1.47, 95% CI 0.50-4.34, P = 0.49)] were modest. Strong, but not statistically significant, associations were noted with sunburn reactions when exposed to sunlight (OR = 4.28, 95% CI 0.91-19.95, P = 0.06, and OR = 2.19, 95% CI 0.67-7.09, P = 0.19, for sunburn with and without blistering, respectively). CONCLUSIONS: Although our study was limited by small sample size, the risk factors for malignant skin tumors in DM strongly resemble the general population. It is recommended that DM patients adhere to sun exposure protective behavior.

Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1.

OBJECTIVE: To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1). BACKGROUND: Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1. METHODS: We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials. RESULTS: There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment. CONCLUSIONS: Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1.

Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy.

BACKGROUND: In spinal muscular atrophy (SMA), weakness, decreased endurance, and fatigue limit mobility. Scales have been developed to measure function across the wide spectrum of disease severity. However, these scales typically are observer dependent, and scores are based on sums across Likert-scaled items. The Six-Minute Walk Test (6MWT) is an objective, easily administered, and standardized evaluation of functional exercise capacity that has been proven reliable in other neurologic disorders and in children. METHODS: To study the performance of the 6MWT in SMA, 18 ambulatory participants were evaluated in a cross-sectional study. Clinical measures were 6MWT, 10-m walk/run, Hammersmith Functional Motor Scale-Expanded (HFMSE), forced vital capacity, and handheld dynamometry. Associations between the 6MWT total distance and other outcomes were analyzed using Spearman correlation coefficients. A paired t test was used to compare the mean distance walked in the first and sixth minutes. RESULTS: The 6MWT was associated with the HFMSE score (r = 0.83, p < 0.0001), 10-m walk/run (r = -0.87, p < 0.0001), and knee flexor strength (r = 0.62, p = 0.01). Gait velocity decreased during successive minutes in nearly all participants. The average first minute distance (57.5 m) was significantly more than the sixth minute distance (48 m) (p = 0.0003). CONCLUSION: The Six-Minute Walk Test (6MWT) can be safely performed in ambulatory patients with spinal muscular atrophy (SMA), correlates with established outcome measures, and is sensitive to fatigue-related changes. The 6MWT is a promising candidate outcome measure for clinical trials in ambulatory subjects with SMA.

Quantitative analysis of the "warm-up" phenomenon in myotonic dystrophy type 1.

To quantitate improvement in hand-grip myotonia and muscle strength (i.e., the "warm-up" phenomenon) in myotonic dystrophy type 1 (DM1), six successive, standardized maximum voluntary isometric contractions (MVICs) were recorded on 2 separate days using a computerized isometric hand-grip myometer in 25 genetically confirmed DM1 patients and in 17 normal controls. An automated computer program placed cursors along the declining (relaxation) phase of the MVICs at 90%, 50%, and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. Mean 90% to 5% RT (a measure of myotonia) rapidly declined from 2.5 s in MVIC 1 to 0.8 s in MVIC 6 (warm-up = 1.7 s) in DM1; in controls, it remained 0.4 s for all six MVICs (warm-up = 0). In DM1, 70% of warm-up occurred between MVIC 1 and 2, almost exclusively in the terminal 50% to 5% phase of muscle relaxation. Day 1 warm-up was highly correlated with the severity of myotonia, and with day 2 warm-up. Improvement in myotonia was not accompanied by either transient paresis or improvement in PF. We conclude that, with this testing paradigm: warm-up of myotonia in DM1 can be reliably measured; is proportional to severity of myotonia; occurs rapidly, being most prominent between the first and second grips; mainly results from shortening of the terminal phase of muscle relaxation; and is not accompanied by significant warm-up in force output.

Leukocyte CTG repeat length correlates with severity of myotonia in myotonic dystrophy type 1.

OBJECTIVE: To quantitate hand muscle myotonia and to assess the relationship between CTG repeat length and myotonia in myotonic dystrophy type 1 (DM1). METHODS: First dorsal interosseous twitch and tetanic contractions evoked by single and 10-Hz ulnar nerve stimulation were recorded with a force transducer in 15 patients with genetically confirmed DM1 and 15 control subjects. An automated computer program analyzed three single and three tetanic recordings per subject on 2 successive days by placing cursors along the declining (relaxation) phase of the force recordings at 90, 50, and 5% of peak force (PF) and calculating relaxation times (RT) between these points. RESULTS: Tetanic and twitch RT was longer and PF lower in patients than subjects. RT (90 to 5%) was above the normal mean + 2.5 SD in 13 tetanic (87%) and 11 (73%) twitch patient recordings. In DM1, prolongation of RT was due mainly to delay in the terminal (50 to 5%), rather than the initial (90 to 50%) phase of relaxation, and was much greater in tetanic than single-twitch recordings. Mean test-retest variability was 19% for tetanic RT and 16% for tetanic PF. In DM1, both tetanic and twitch RT were positively correlated with leukocyte CTG repeat length. CONCLUSIONS: In DM1, myotonia of intrinsic hand muscles can be quantitated reliably by automated analysis of tetanic and twitch RT, targeting, in particular, the terminal phase of muscle relaxation after tetanic stimulation. Severity of hand muscle myotonia depends on CTG repeat length consistent with a "triplet repeat dosage" effect on chloride channel mRNA splicing and function.

A prospective natural history study of inclusion body myositis: implications for clinical trials.

Eleven patients with untreated inclusion body myositis (IBM) were prospectively studied during a 6-month period that included muscle strength, lean body mass, and muscle mass measurements. There was an overall quantifiable mean decline in percent of predicted normal muscle strength of 4% from baseline in a 6-month period, but one third of patients showed no change or slight improvements in strength. Short-term treatment trials in IBM will require large numbers of patients to detect slowing, arrest, or even slight improvement in muscle strength.

Description of a computerized health maintenance tracking system for primary care practice.

This article describes the development of a computerized health maintenance tracking system for primary care practice and its features. Research has shown existing computerized health maintenance tracking systems are unsatisfactory for the average practitioner for these reasons: (1) Data entry is slow or requires duplication of entries for billing purposes; (2) the system is linked to a totally computerized medical record that is expensive and complex to maintain; (3) health maintenance status options are limited to "YES/NO" and do not inform the practitioner of the full range of possible situations; (4) physician reminders are created only for patients with an appointment; (5) patient reminders are not generated on a regular basis regardless of appointment status; (6) it is difficult to change individual and global health maintenance schedules. The system described here downloads demographic and health maintenance data from the practice's billing system. Six health maintenance status options are available: D = done and normal, X = done but abnormal, N = not indicated, R = patient refused, E = done elsewhere, I = abnormal but inactive. A health maintenance status report is created for both the patient and provider once a year, in the month of the patient's birth unless an alternate month has been designated, regardless of the patient's appointment status. Patients are encouraged to make an appointment for overdue health maintenance procedures, unless already scheduled.