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Introduction/aims: Disease progression in myotonic dystrophy (DM) is marked by milestone events when functional thresholds are crossed. DM type 2 (DM2) is considered less severe than DM type 1 (DM1), but it is unknown whether this applies uniformly to all features. We compared the age-dependent risk for milestone events in DM1 and DM2 and tested for associations with age of onset and sex.Methods: We studied a large cohort of adult participants in a national registry of DM1 and DM2. Using annual surveys from participants, we ascertained milestone events for motor involvement (use of cane, walker, ankle brace, wheelchair, or ventilatory device), systemic involvement (diabetes, pacemaker, cancer), loss of employment due to DM, and death.Results: Mean follow-up of registry participants (929 DM1 and 222 DM2 patients) was 7 years. Disability and motor milestones occurred at earlier ages in DM1 than in DM2. In contrast, the risk of diabetes was higher and tended to occur earlier in DM2 (hazard ratio [HR], 0.56; P ≤ .001). In DM1, the milestone events tended to occur earlier, and life expectancy was reduced, when symptoms began at younger ages. In DM1, men were at greater risk for disability (HR, 1.34; P ≤ .01), use of ankle braces (HR, 1.41; P = .02), and diabetes (HR, 2.2; P ≤ .0001), whereas women were at greater risk for needing walkers (HR, 0.68; P = .001) or malignancy (HR, 0.66; P ≤ .01).Discussion: Milestone events recorded through registries can be used to assess long-term impact of DM in large cohorts. Except for diabetes, the age-related risk of milestone events is greater in DM1 than in DM2. [ABSTRACT FROM AUTHOR]

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies characterized by considerable variability in severity, rates of progression and functional outcomes. Few studies follow FSHD cohorts long enough to understand predictors of disease progression and functional outcomes, creating gaps in our understanding, which impacts clinical care and the design of clinical trials. Efforts to identify molecularly targeted therapies create a need to better understand disease characteristics with predictive value to help refine clinical trial strategies and understand trial outcomes. Here we analysed a prospective cohort from a large, longitudinally followed registry of patients with FSHD in the USA to determine predictors of outcomes such as need for wheelchair use. This study analysed de-identified data from 578 individuals with confirmed FSHD type 1 enrolled in the United States National Registry for FSHD Patients and Family members. Data were collected from January 2002 to September 2019 and included an average of 9 years (range 0-18) of follow-up surveys. Data were analysed using descriptive epidemiological techniques, and risk of wheelchair use was determined using Cox proportional hazards models. Supervised machine learning analysis was completed using Random Forest modelling and included all 189 unique features collected from registry questionnaires. A separate medications-only model was created that included 359 unique medications reported by participants. Here we show that smaller allele sizes were predictive of earlier age at onset, diagnosis and likelihood of wheelchair use. Additionally, we show that females were more likely overall to progress to wheelchair use and at a faster rate as compared to males, independent of genetics. Use of machine learning models that included all reported clinical features showed that the effect of allele size on progression to wheelchair use is small compared to disease duration, which may be important to consider in trial design. Medical comorbidities and medication use add to the risk for need for wheelchair dependence, raising the possibility for better medical management impacting outcomes in FSHD. The findings in this study will require further validation in additional, larger datasets but could have implications for clinical care, and inclusion criteria for future clinical trials in FSHD. [ABSTRACT FROM AUTHOR]

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function.Methods: We studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures.Results: There was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced.Conclusions: Assessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy. [ABSTRACT FROM AUTHOR]

Introduction: The long exercise test (LET) is used to assess the diagnosis of periodic paralysis (PP), but LET methodology and normal "cutoff" values vary.Methods: To determine optimal LET methodology and cutoffs, we reviewed LET data (abductor digiti minimi motor response amplitude, area) from 55 patients with PP (32 genetically definite) and 125 controls. Receiver operating characteristic curves were constructed, and area under the curve (AUC) was calculated to compare (1) peak-to-nadir versus baseline-to-nadir methodologies and (2) amplitude versus area decrements. Using bayesian principles, we calculated optimal cutoff decrements that achieved 95% posttest probability of PP for various pretest probabilities (PreTPs).Results: AUC was highest for peak-to-nadir methodology and equal for amplitude and area decrements. For PreTP ≤ 50%, optimal decrement cutoffs (peak-to-nadir) were > 40% (amplitude) or > 50% (area).Discussion: For confirmation of PP, our data endorse the diagnostic utility of peak-to-nadir LET methodology using 40% amplitude or 50% area decrement cutoffs for PreTP ≤50%. Muscle Nerve 59:47-54, 2019. [ABSTRACT FROM AUTHOR]

Introduction: Electrical impedance myography (EIM) is a noninvasive technique for measuring muscle composition and a potential physiological biomarker for facioscapulohumeral muscular dystrophy (FSHD).Methods: Thirty-two participants with genetically confirmed and clinically affected FSHD underwent EIM in 7 muscles bilaterally. Correlations between EIM and baseline clinical measures were used to select EIM variables of interest in FSHD, and EIM and clinical measures were followed for 1 year.Results: There were no significant changes in the EIM variables. Although 50-kHZ reactance correlated the strongest with clinical measures at baseline, the 50-211-kHZ phase ratio demonstrated lower within-subject 12-month variability, potentially offering sample size savings for FSHD clinical trial planning.Discussion: EIM did not identify significant disease progression over 12 months. It is currently unclear whether this is because of limitations of the technology or the slow rate of disease progression in this cohort of FSHD patients over this period of time. Muscle Nerve 58: 213-218, 2018. [ABSTRACT FROM AUTHOR]

Introduction: In preparation for future clinical trials, we determined the reliability, relationship to measures of disease severity, and consistency across sites of the 6 Minute Walk Test (6MWT) in patients with facioscapulohumeral muscular dystrophy (FSHD).Methods: Genetically defined and clinically affected FSHD participants at 2 sites performed the 6MWT, the Timed Up and Go, and the 30 foot Go/Timed 10 meter test as measures of mobility using standard procedures.Results: Eight-six participants representing the full range of severity performed the 6MWT. The mean 6MWT distance was 404.3 meters (SD 123.9), with no difference between sites. The 6MWT was reliable (n = 25; intraclass correlation coefficient = 0.99) and demonstrated moderate to strong correlations with lower extremity strength, functional outcomes, and FSHD Clinical Score.Conclusions: The 6MWT is reliable and is associated with other measures of FSHD disease severity. Future directions include assessing its sensitivity to disease progression. Muscle Nerve 55: 333-337, 2017. [ABSTRACT FROM AUTHOR]

Introduction: In this study we determined the reliability and validity of electrical impedance myography (EIM) in facioscapulohumeral muscular dystrophy (FSHD).Methods: We performed a prospective study of EIM on 16 bilateral limb and trunk muscles in 35 genetically defined and clinically affected FSHD patients (reliability testing on 18 patients). Summary scores based on body region were derived. Reactance and phase (50 and 100 kHz) were compared with measures of strength, FSHD disease severity, and functional outcomes.Results: Participants were mostly men, mean age 53.0 years, and included a full range of severity. Limb and trunk muscles showed good to excellent reliability [intraclass correlation coefficients (ICC) 0.72-0.99]. Summary scores for the arm, leg, and trunk showed excellent reliability (ICC 0.89-0.98). Reactance was the most sensitive EIM parameter to a broad range of FSHD disease metrics.Conclusions: EIM is a reliable measure of muscle composition in FSHD that offers the possibility to serially evaluate affected muscles. Muscle Nerve 54: 696-701, 2016. [ABSTRACT FROM AUTHOR]

Introduction: As we move toward planning for clinical trials in facioscapulohumeral muscular dystrophy (FSHD), a better understanding of the clinical relationship with morphological changes in FSHD muscle biopsies will be important for stratifying patients and understanding post-therapeutic changes in muscle.Methods: We performed a prospective cross-sectional study of quadriceps muscle biopsies in 74 genetically confirmed FSHD participants (64 with FSHD type 1 and 10 with FSHD type 2). We compared a 12-point muscle pathology grade to genetic mutation, disease severity score, and quantitative myometry.Results: Pathology grade had moderate correlations with genetic mutation (rho = -0.45, P < 0.001), clinical severity score (rho = 0.53, P < 0.001), disease duration (rho = 0.31, P = 0.03), and quantitative myometry (rho = -0.47, P < 0.001). We found no difference in the frequency of inflammation between FSHD types 1 and 2.Conclusions: The pathology grade of quadriceps muscle may be a useful marker of disease activity in FSHD, and it may have a role in stratification for future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process.Methods/design: The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials.Discussion: To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics.Trial Registration: clinicaltrials.gov NCT03458832; Date of registration: 1/11/2018. [ABSTRACT FROM AUTHOR]