Publications by authors named "Jeffrey M Statland"

51 Publications

Long-term efficacy and safety of dichlorphenamide for treatment of primary periodic paralysis.

Muscle Nerve 2021 Jun 15. Epub 2021 Jun 15.

Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.

Introduction/aims: Long-term efficacy and safety of dichlorphenamide (DCP) were characterized in patients with primary periodic paralysis (PPP).

Methods: Patients with PPP in a double-blind, placebo-controlled study were randomly assigned to receive DCP 50 mg twice daily or placebo for 9 weeks, followed by a 52-week open-label DCP treatment phase (DCP/DCP and placebo/DCP populations). Efficacy (attack rate, severity-weighted attack rate) and safety were assessed in patients completing the study (61 weeks). In this post hoc analysis, efficacy and safety data were pooled from hyperkalemic and hypokalemic substudies.

Results: Sixty-three adults (age, 19-76 years) completed the double-blind phase; 47 (74.6%) of these patients completed 61 weeks. There were median decreases in weekly attack and severity-weighted attack rates from baseline to week 61 (DCP/DCP [n = 25], -1.00 [P < .0001]; placebo/DCP [n = 20], -0.63 [P = .01] and DCP/DCP, -2.25 [P < .0001]; placebo/DCP, -1.69 [P = .01]). Relatively smaller median decreases in weekly attack and severity-weighted attack rates occurred from weeks 9 to 61 among patients receiving DCP continuously (n = 26; -0.14 [P = .1] and -0.24 [P = .09]) than among those switching from placebo to DCP after 9 weeks (n = 16; -1.04 [P = .049] and -2.72 [P = .08]). Common adverse events (AEs) were paresthesia and cognition-related events, which typically first occurred within 1 month of blinded treatment initiation and in rare cases led to treatment discontinuation. Dose reductions were frequently associated with common AE resolution.

Discussion: One-year open-label DCP treatment after a 9-week randomized, controlled study confirmed long-term DCP remains safe and effective for chronic use. Tolerability issues (paresthesia, cognition-related AEs) were manageable in most patients.
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http://dx.doi.org/10.1002/mus.27354DOI Listing
June 2021

The facioscapulohumeral muscular dystrophy Rasch-built overall disability scale (FSHD-RODS).

Eur J Neurol 2021 Jul 2;28(7):2339-2348. Epub 2021 May 2.

Department of Neurology, Curaçao Medical Center, Willemstad, Curaçao.

Background And Objectives: Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient-reported Rasch-built interval scale on activity and participation for FSHD.

Methods: A pre-phase FSHD-Rasch-built overall disability scale (pre-FSHD-RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease-related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2-4 weeks; reliability studies). The pre-FSHD-RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure.

Results: The pre-FSHD-RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38-inquiry (originating from 32 items; six items split) FSHD-RODS was constructed achieving Rasch model expectations. Adequate test-retest reliability and (cross-cultural and external) validity scores were obtained.

Conclusions: The FSHD-RODS is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.
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http://dx.doi.org/10.1111/ene.14863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251612PMC
July 2021

The clinical spectrum of primary lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11;21(sup1):3-10

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Primary lateral sclerosis is a distinct entity that has recently been classified as a "restricted phenotype" of ALS. It is characterized by a pattern of isolated upper motor neuron involvement that often begins in the legs and spreads diffusely. Distinction from other conditions requires careful consideration of clinical presentation and time course of disease. Mills' Syndrome is a rare unilateral variant of primary lateral sclerosis. Cognitive and behavioral involvement may occur.
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http://dx.doi.org/10.1080/21678421.2020.1837178DOI Listing
November 2020

Challenges and opportunities for Multi-National Investigator-Initiated clinical trials for ALS: European and United States collaborations.

Amyotroph Lateral Scler Frontotemporal Degener 2021 08 3;22(5-6):419-425. Epub 2021 Feb 3.

Department of Neurology, University of Miami, Miami, Florida, USA.

An inherent challenge to clinical trials that aim to test the efficacy of experimental therapeutics for patients with amyotrophic lateral sclerosis (ALS) is the relative rarity of the disease. A promising solution to this problem is a multi-center approach that ideally includes sites distributed across a broad geographic area. In support of such an approach, the European E-RARE program and the United States National Institutes of Health (NIH) partnered to support the investigator-initiated ROCK-ALS trial (Eudra-CT-Nr.: 2017-003676-31, NCT03792490) as a multi-national collaboration between centers in Europe and North America that is led by European investigators. During the set-up of this international trial, however, a number of unanticipated legal, administrative, and financial complexities emerged that required significant adaptation of the proposed trial scheme. Here, we report our experience navigating these obstacles and describe the potential solutions that we explored. Our experience may inform future efforts to implement multi-national investigator-initiated trials that involve both European and United States centers.
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http://dx.doi.org/10.1080/21678421.2021.1879866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289747PMC
August 2021

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

EMBO Mol Med 2021 Jan 3;13(1):e12595. Epub 2020 Dec 3.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.
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http://dx.doi.org/10.15252/emmm.202012595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799365PMC
January 2021

Phenotypic diversity in an international Cure VCP Disease registry.

Orphanet J Rare Dis 2020 09 29;15(1):267. Epub 2020 Sep 29.

Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, Saint Louis, MO, 63110, USA.

Background: Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry.

Methods: Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. The results of two questionnaires with a 5-point Likert scale questions regarding to patients' disease onset, symptoms, and daily life were obtained from 59 participants (28 males and 31 females) between June 2018 and May 2020. Independent of the registry, 22 patients were examined at the Cure VCP Disease annual patient conference in 2019.

Results: In the questionnaires of the registry, fifty-three patients (90%) reported that they were with inclusion body myopathy, 17 patients (29%) with Paget's disease of bone, eight patients (14%) with dementia, two patients (3%) with amyotrophic lateral sclerosis, and a patient with parkinsonism. Thirteen patients (22%) reported dysphagia and 25 patients (42%) reported dyspnea on exertion. A self-reported functional rating scale for motor function identified challenges with sit to stand (72%), walking (67%), and climbing stairs (85%). Thirty-five (59%) patients in the registry answered that their quality of life is more than good. As for the weakness pattern of the 22 patients who were evaluated at the Cure VCP Disease annual conference, 50% of patients had facial weakness, 55% had scapular winging, 68% had upper proximal weakness, 41% had upper distal weakness, 77% had lower proximal, and 64% had lower distal weakness.

Conclusions: The Cure VCP Disease Patient Registry is useful for deepening the understanding of patient daily life, which would be a basis to develop appropriate clinical outcome measures. The registry data is consistent with previous studies evaluating VCP patients in the clinical setting. Patient advocacy groups are essential in developing and maintaining disease registries.
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http://dx.doi.org/10.1186/s13023-020-01551-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523394PMC
September 2020

Guidelines on clinical presentation and management of nondystrophic myotonias.

Muscle Nerve 2020 10 27;62(4):430-444. Epub 2020 May 27.

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications.
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http://dx.doi.org/10.1002/mus.26887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117169PMC
October 2020

Use of Capillary Electrophoresis Immunoassay to Search for Potential Biomarkers of Amyotrophic Lateral Sclerosis in Human Platelets.

J Vis Exp 2020 02 10(156). Epub 2020 Feb 10.

Department of Basic Sciences, Kansas City University of Medicine and Biosciences;

Capillary electrophoresis immunoassay (CEI), also known as capillary western technology, is becoming a method of choice for screening disease relevant proteins and drugs in clinical trials. Reproducibility, sensitivity, small sample volume requirement, multiplexing antibodies for multiple protein labeling in the same sample, automated high-throughput ability to analyze up to 24 individual samples, and short time requirement make CEI advantageous over the classical western blot immunoassay. There are some limitations of this method, such as the inability to utilize a gradient gel (4%-20%) matrix, high background with unrefined biological samples, and commercial unavailability of individual reagents. This paper describes an efficient method for running CEI in a multiple assay setting, optimizing protein concentration and primary antibody titration in one assay plate, and providing user-friendly templates for sample preparation. Also described are methods for measuring pan TDP-43 and phosphorylated TDP-43 derivative in platelet lysate cytosol as part of the initiative in blood-based biomarker development for neurodegenerative diseases.
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http://dx.doi.org/10.3791/60638DOI Listing
February 2020

Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies.

Hum Mol Genet 2020 04;29(6):1030-1043

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes-composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes-that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.
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http://dx.doi.org/10.1093/hmg/ddaa031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158378PMC
April 2020

Magnetic resonance imaging correlates with electrical impedance myography in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2020 05 22;61(5):644-649. Epub 2020 Jan 22.

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.

Introduction: Electrical impedance myography (EIM) has been proposed as a noninvasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD). Here we determine the associations of EIM variables with muscle structure measured by MRI.

Methods: We evaluated 20 patients with FSHD at two centers, comparing EIM measurements (resistance, reactance, and phase at 50, 100, and 211 kHZ) recorded from bilateral vastus lateralis, tibialis anterior, and medial gastrocnemius muscles to MRI skin and subcutaneous fat thickness, MRI T1-based muscle severity score (T1 muscle score), and MRI quantitative intramuscular Dixon fat fraction (FF).

Results: While reactance and phase both correlated with FF and T1 muscle score, 50 kHz reactance was most sensitive to muscle structure alterations measured by both T1 score (ρ = -0.71, P < .001) and FF (ρ = -0.74, P < .001).

Discussion: This study establishes the correlation of EIM with structural MRI features in FSHD and supports further evaluation of EIM as a potential biomarker in FSHD clinical trials.
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http://dx.doi.org/10.1002/mus.26792DOI Listing
May 2020

Stabilization of Early Duchenne Cardiomyopathy With Aldosterone Inhibition: Results of the Multicenter AIDMD Trial.

J Am Heart Assoc 2019 10 24;8(19):e013501. Epub 2019 Sep 24.

Nationwide Children's Hospital Columbus OH.

Background Duchenne muscular dystrophy incurs nearly universal dilated cardiomyopathy by the third decade of life, preceded by myocardial damage and impaired left ventricular strain by cardiac magnetic resonance. It has been shown that (1) mineralocorticoid receptor antagonist therapy with spironolactone attenuated damage while maintaining function when given early in a mouse model and (2) low-dose eplerenone stabilized left ventricular strain in boys with Duchenne muscular dystrophy and evident myocardial damage but preserved ejection fraction. We hypothesized that moderate-dose spironolactone versus eplerenone would provide similar cardioprotection in this first head-to-head randomized trial of available mineralocorticoid receptor antagonists, the AIDMD (Aldosterone Inhibition in Duchenne Muscular Dystrophy) trial. Methods and Results This was a multicenter, double-blind, randomized, noninferiority trial. Subjects were randomized to eplerenone, 50 mg, or spironolactone, 50 mg, orally once daily for 12 months. The primary outcome was change in left ventricular systolic strain at 12 months. Among 52 enrolled male subjects, aged 14 (interquartile range, 12-18) years, spironolactone was noninferior to eplerenone (∆strain, 0.4 [interquartile range, -0.4 to 0.6] versus 0.2 [interquartile range, -0.2 to 0.7]; =0.542). Renal and pulmonary function remained stable in both groups, and no subjects experienced serious hyperkalemia. Infrequent adverse events included gynecomastia in one subject in the spironolactone arm and facial rash in one subject in the eplerenone arm. Conclusions In boys with Duchenne muscular dystrophy and preserved left ventricular ejection fraction, spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354352.
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http://dx.doi.org/10.1161/JAHA.119.013501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806050PMC
October 2019

Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study.

BMC Neurol 2019 Sep 10;19(1):224. Epub 2019 Sep 10.

Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Ave, Rochester, NY, 14642, USA.

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.
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http://dx.doi.org/10.1186/s12883-019-1452-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734593PMC
September 2019

A pilot study of the responsiveness of wireless motion analysis in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2019 11 9;60(5):590-594. Epub 2019 Sep 9.

Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, Kansas City, Kansas.

Introduction: We determined whether instrumenting timed functional tasks with wireless inertial motion sensors were responsive to facioscapulohumeral muscular dystrophy (FSHD) progression and movement pattern changes.

Methods: Ten individuals who were clinically affected with genetically confirmed FSHD, mean age 54 years (range 42-65), performed an instrumented timed up and go (iTUG) trial at each visit, wearing six wireless inertial sensors. We determined the estimated average monthly slope of progression and 12-month change for temporal and spatial motion variables using a linear mixed effects model.

Results: For an average of 20.6 months (range 6.1-34.5), the iTUG duration stayed constant, whereas stride length, stride velocity, and trunk sagittal range of motion changed, indicating poorer performance. Arm swing changed in a compensatory direction toward the normative mean.

Discussion: This study provides preliminary evidence that iTUG motion variables could be sensitive to progression in FSHD, but this requires validation in a larger study.
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http://dx.doi.org/10.1002/mus.26681DOI Listing
November 2019

Limb-girdle muscular dystrophy: A perspective from adult patients on what matters most.

Muscle Nerve 2019 10 24;60(4):419-424. Epub 2019 Jul 24.

Department of Neurology, Virginia Commonwealth University, Richmond, Virginia.

Introduction: Limb-girdle muscular dystrophy (LGMD) consists of over 30 genetic conditions with varying clinical phenotypes primarily affecting pelvic girdle, shoulder girdle, and other proximal limb muscles. Studies focusing on the physical, mental, and social effects of this disease from the patient's perspective are limited.

Methods: Adults with LGMD were interviewed and asked to identify issues that have the greatest impact on their quality of life. Each interview was recorded, transcribed, coded, and analyzed.

Results: Participants provided 1385 direct quotes. One hundred sixty-five potential symptoms of importance were identified and grouped into 15 larger themes. The most frequently reported themes included limitations with mobility, difficulty performing activities, social role limitations, and emotional distress.

Discussion: There are multiple symptoms that alter the lives of adults with LGMD. These affect their physical, emotional, and social health, and may be amenable to medical intervention.
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http://dx.doi.org/10.1002/mus.26636DOI Listing
October 2019

FSHD1 or FSHD2: That is the question: The answer: It's all just FSHD.

Neurology 2019 05 12;92(19):881-882. Epub 2019 Apr 12.

From the Department of Neurology (N.E.J.), Virginia Commonwealth University, Richmond; and the Department of Neurology (J.M.S.), Kansas University Medical Center, Kansas City.

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http://dx.doi.org/10.1212/WNL.0000000000007446DOI Listing
May 2019

Effects of weakness of orofacial muscles on swallowing and communication in FSHD.

Neurology 2019 02 25;92(9):e957-e963. Epub 2019 Jan 25.

From the Department of Neurology (K.M., M.Y.S., A.M., J.M.S.), University of Kansas Medical Center, Kansas City; Department of Neurology (K.N.B., N.E.J.), Virginia Commonwealth University, Richmond; and Department of Neurology (K.M., B.G.M.v.E.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.

Objective: This study explores the use of quantitative data on strength and fatigability of orofacial muscles in patients with facioscapulohumeral muscular dystrophy (FSHD) and assesses the frequency of swallowing and communication difficulties and their relationship to orofacial muscle involvement.

Methods: We included 43 patients with FSHD and 35 healthy controls and used the Iowa Oral Performance Instrument (IOPI) to obtain quantitative measurements of strength and endurance of lip compression, cheek (buccodental) compression, and tongue elevation. For the assessment of swallowing and communication difficulties, we used the dysphagia-specific quality of life (SWAL-QOL) and Communicative Participation Item Bank questionnaires.

Results: Cheek compression strength was reduced in patients with FSHD compared to healthy controls. Dysphagia and difficulty with verbal communication were reported by 25% and 35% of patients, respectively, and correlated to cheek compression strength and endurance and to anterior tongue elevation endurance. Prolonged cheek compression or anterior tongue elevation endurance (decreased fatigability) made swallowing or speech problems less likely to occur.

Conclusion: Cheek compression strength is the most sensitive IOPI measure for orofacial weakness in FSHD. Orofacial weakness contributes to dysphagia and speech difficulties in FSHD, which are both common, though generally mild. Higher endurance of orofacial muscles was associated with a lower chance of dysphagia or speech problems. More research is required for further refinement of the pattern of facial muscle involvement in FSHD and to provide new insights for improvement of speech and language therapy.
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http://dx.doi.org/10.1212/WNL.0000000000007013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404471PMC
February 2019

Early onset as a marker for disease severity in facioscapulohumeral muscular dystrophy.

Neurology 2019 01 19;92(4):e378-e385. Epub 2018 Dec 19.

From the Department of Neurology (R.J.M.G., K.M., C.R.v.K., T.H.A.S., C.E.E., G.W.P., N.C.V., B.G.M.v.E.), Donders Center for Neuroscience, Radboud University Medical Center, Nijmegen; Department of Human Genetics (R.J.L.F.L., S.M.v.d.M.), Leiden University Medical Center, the Netherlands; and Department of Neurology (J.M.S.), Kansas University Medical Center, Kansas City.

Objective: To assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD).

Methods: In this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups.

Results: Twenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2-3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8-9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%).

Conclusions: Patients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.
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http://dx.doi.org/10.1212/WNL.0000000000006819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345117PMC
January 2019

Using automated electronic medical record data extraction to model ALS survival and progression.

BMC Neurol 2018 Dec 14;18(1):205. Epub 2018 Dec 14.

Department of Neurology, University of Kansas Medical Center, Kansas City, USA.

Background: To assess the feasibility of using automated capture of Electronic Medical Record (EMR) data to build predictive models for amyotrophic lateral sclerosis (ALS) outcomes.

Methods: We used an Informatics for Integrating Biology and the Bedside search discovery tool to identify and extract data from 354 ALS patients from the University of Kansas Medical Center EMR. The completeness and integrity of the data extraction were verified by manual chart review. A linear mixed model was used to model disease progression. Cox proportional hazards models were used to investigate the effects of BMI, gender, and age on survival.

Results: Data extracted from the EMR was sufficient to create simple models of disease progression and survival. Several key variables of interest were unavailable without including a manual chart review. The average ALS Functional Rating Scale - Revised (ALSFRS-R) baseline score at first clinical visit was 34.08, and average decline was - 0.64 per month. Median survival was 27 months after first visit. Higher baseline ALSFRS-R score and BMI were associated with improved survival, higher baseline age was associated with decreased survival.

Conclusions: This study serves to show that EMR-captured data can be extracted and used to track outcomes in an ALS clinic setting, potentially important for post-marketing research of new drugs, or as historical controls for future studies. However, as automated EMR-based data extraction becomes more widely used there will be a need to standardize ALS data elements and clinical forms for data capture so data can be pooled across academic centers.
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http://dx.doi.org/10.1186/s12883-018-1208-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295028PMC
December 2018

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials.

JAMA 2018 12;320(22):2344-2353

Department of Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.

Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed.

Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT.

Design, Setting, And Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016.

Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks.

Main Outcomes And Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference.

Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26).

Conclusions And Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.

Trial Registration: ClinicalTrials.gov Identifier: NCT02045667.
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http://dx.doi.org/10.1001/jama.2018.18020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583079PMC
December 2018

Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial.

Muscle Nerve 2019 02 26;59(2):201-207. Epub 2018 Nov 26.

Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 2012, Kansas City, Kansas, 66160, USA.

Introduction: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS).

Methods: We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting.

Results: There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events.

Discussion: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.
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http://dx.doi.org/10.1002/mus.26335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545236PMC
February 2019

Electrical impedance myography in facioscapulohumeral muscular dystrophy: A 1-year follow-up study.

Muscle Nerve 2018 Aug 17;58(2):213-218. Epub 2018 Apr 17.

Department of Neurology, University of Kansas Medical Center, 4330 Shawnee Mission Parkway, Suite 323 Fairway, Kansas, 66205, USA.

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.
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http://dx.doi.org/10.1002/mus.26127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105423PMC
August 2018

Using an onset-anchored Bayesian hierarchical model to improve predictions for amyotrophic lateral sclerosis disease progression.

BMC Med Res Methodol 2018 02 6;18(1):19. Epub 2018 Feb 6.

Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA.

Background: Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a rare disease with extreme between-subject variability, especially with respect to rate of disease progression. This makes modelling a subject's disease progression, which is measured by the ALS Functional Rating Scale (ALSFRS), very difficult. Consider the problem of predicting a subject's ALSFRS score at 9 or 12 months after a given time-point.

Methods: We obtained ALS subject data from the Pooled Resource Open-Access ALS Clinical Trials Database, a collection of data from various ALS clinical trials. Due to the typical linearity of the ALSFRS, we consider several Bayesian hierarchical linear models. These include a mixture model (to account for the two potential classes of "fast" and "slow" ALS progressors) as well as an onset-anchored model, in which an additional artificial data-point, using time of disease onset, is utilized to improve predictive performance.

Results: The onset-anchored model had a drastically reduced posterior predictive mean-square-error distributions, when compared to the Bayesian hierarchical linear model or the mixture model under a cross-validation approach. No covariates, other than time of disease onset, consistently improved predictive performance in either the Bayesian hierarchical linear model or the onset-anchored model.

Conclusions: Augmenting patient data with an additional artificial data-point, or onset anchor, can drastically improve predictive modelling in ALS by reducing the variability of estimated parameters at the cost of a slight increase in bias. This onset-anchored model is extremely useful if predictions are desired directly after a single baseline measure (such as at the first day of a clinical trial), a feat that would be very difficult without the onset-anchor. This approach could be useful in modelling other diseases that have bounded progression scales (e.g. Parkinson's disease, Huntington's disease, or inclusion-body myositis). It is our hope that this model can be used by clinicians and statisticians to improve the efficacy of clinical trials and aid in finding treatments for ALS.
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http://dx.doi.org/10.1186/s12874-018-0479-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801819PMC
February 2018

Facioscapulohumeral muscular dystrophy functional composite outcome measure.

Muscle Nerve 2018 Jan 30. Epub 2018 Jan 30.

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA.

Introduction: We developed an evaluator-administered functional facioscapulohumeral muscular dystrophy composite outcome measure (FSHD-COM) comprising patient-identified areas of functional burden for future clinical trials.

Methods: We performed a prospective observational study of 41 patients with FSHD at 2 sites. The FSHD-COM includes functional assessment of the legs, shoulders and arms, trunk, hands, and balance/mobility. We determined the test-retest reliability and convergent validity compared to established FSHD disease metrics.

Results: The FSHD-COM demonstrated excellent test-retest reliability (intraclass correlation coefficient [ICC] 0.96; subscale ICC range, 0.90-0.94). Cross-sectional associations between the FSHD-COM and disease duration, clinical severity, and strength were moderate to strong (Pearson correlation coefficient range |0.51-0.92|).

Discussion: The FSHD-COM is a disease-relevant, functional composite outcome measure suitable for future FSHD clinical trials that shows excellent test-retest reliability and cross-sectional associations to disease measures. Future directions include determining multisite reliability, sensitivity to change, and the minimal clinically important change in the FSHD-COM. Muscle Nerve, 2018.
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http://dx.doi.org/10.1002/mus.26088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066464PMC
January 2018

Review of the Diagnosis and Treatment of Periodic Paralysis.

Muscle Nerve 2018 04 29;57(4):522-530. Epub 2017 Nov 29.

Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522-530, 2018.
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http://dx.doi.org/10.1002/mus.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867231PMC
April 2018

Facioscapulohumeral Muscular Dystrophy.

Continuum (Minneap Minn) 2016 Dec;22(6, Muscle and Neuromuscular Junction Disorders):1916-1931

Purpose Of Review: This article describes the clinical characteristics, diagnosis, molecular pathogenesis, and treatment of facioscapulohumeral muscular dystrophy (FSHD).

Recent Findings: FSHD comprises two genetically distinct types that converge on a common downstream pathway of the expression of the toxic protein DUX4. Approximately 95% of patients have FSHD type 1 (FSHD1), in which loss of DNA repetitive elements (D4Z4 repeats) in the subtelomeric region of chromosome 4q causes decreased methylation and epigenetic derepression of DUX4, a gene contained within each D4Z4 repeat. FSHD type 2 (FSHD2) occurs through a deletion-independent mechanism but, similar to FSHD1, leads to decreased methylation and epigenetic derepression in the same region of chromosome 4q. Whereas FSHD1 is dominantly inherited, FSHD2 shows digenic inheritance, and about 80% of patients will have a mutation in the SMCHD1 gene. DUX4 lacks a polyadenylation signal, so both FSHD1 and FSHD2 only occur in the presence of permissive 4q polymorphisms, which provide a stabilizing polyadenylation sequence. FSHD is an epigenetic disease, and penetrance and severity are related to both the number of residual D4Z4 units and D4Z4 methylation.

Summary: Recent consensus guidelines outline standards for care for FSHD, and identification of potential therapeutic targets have shifted emphasis in the research community toward drug development and clinical trial planning.
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http://dx.doi.org/10.1212/CON.0000000000000399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898965PMC
December 2016

Validity of the 6 minute walk test in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2017 03 5;55(3):333-337. Epub 2016 Dec 5.

Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Avenue, Rochester, New York, 14642.

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.
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http://dx.doi.org/10.1002/mus.25251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793210PMC
March 2017

A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis.

Neurology 2016 Jul 15;87(1):57-64. Epub 2016 Jun 15.

From the Department of Biostatistics (J.H.), University of Kansas Medical Center (M.P., J.H., L.H., M.M.D., J.M.S., R.J.B.), Kansas City; University of Virginia (T.M.B.), Charlottesville; University of Texas Southwestern (S.N.), Dallas; University of Toronto (V.B.), Canada; University of California-Irvine (A.K.W., T.M.), Orange; Ohio State University (B.H.E., J.T.K.), Columbus; Phoenix Neurological Associates (D.S.), AZ; Nerve and Muscle Center of Texas (J.A.S.), Houston; University of Texas Health Science Center (C.J.), San Antonio; University of Iowa (A.S.), Iowa City; University of North Carolina (J.F.H.), Chapel Hill; Massachusetts General Hospital (N.G., W.D.), Boston; Penn State Hershey Medical Center (M.W.), Hershey, PA; University of Florida-Jacksonville (M.P.); Children's Mercy Hospital and Clinics (M. Becker), Kansas City, MO; University of Miami (M. Benatar), FL; Indiana University (R.P.), Indianapolis; Methodist Hospital System (E.S.), Houston, TX; and University of San Francisco (J.R.), CA.

Objective: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG).

Methods: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody-positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living.

Results: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4-12 prednisone AUDTC when compared to placebo (difference MTX - placebo: -488.0 mg, 95% confidence interval -2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%).

Conclusions: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials.

Classification Of Evidence: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.
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http://dx.doi.org/10.1212/WNL.0000000000002795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932232PMC
July 2016

Electrical impedance myography in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2016 10 25;54(4):696-701. Epub 2016 May 25.

Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.

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.
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http://dx.doi.org/10.1002/mus.25065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972708PMC
October 2016

Milder phenotype in facioscapulohumeral dystrophy with 7-10 residual D4Z4 repeats.

Neurology 2015 Dec 11;85(24):2147-50. Epub 2015 Nov 11.

From the Department of Neurology (J.M.S.), University of Kansas Medical Center, Kansas City; the Department of Neurology (C.M.D., R.T.), University of Rochester Medical Center, NY; the Division of Human Biology (S.J.T.), Fred Hutchinson Cancer Research Center, Seattle, WA; and the Department of Human Genetics (R.J.L.F.L., S.M.v.d.M.), Leiden University Medical Center, the Netherlands.

Objective: To examine the relationship of clinical and genetic features of patients with facioscapulohumeral muscular dystrophy (FSHD) with 7-10 residual D4Z4 repeats in a large genetically defined FSHD1 cohort.

Methods: We performed a prospective cross-sectional observational study of 74 clinically affected patients with FSHD1. Measures of clinical severity were compared between patients with 1-6 D4Z4 repeats and 7-10 repeats, and included D4Z4 CpG methylation, age at diagnosis, age-adjusted clinical severity score, a muscle pathology grade of quadriceps biopsies (0 = normal, 12 = severe dystrophic changes), quantitative myometry of biopsied muscles, global manual muscle testing scores, and frequency of wheelchair use.

Results: Twenty-eight (37.8%) participants had 7-10 D4Z4 repeats, and compared to participants with 1-6 repeats, were diagnosed 6.6 years older (p = 0.17); had lower CpG methylation than would be predicted by D4Z4 repeat size (p = 0.04); had age-adjusted clinical severity 39.8 points lower (p = 0.004); had muscle pathology grades that were 2.4 points less severe (p < 0.0001); had quantitative myometry 28.3% predicted of normal higher (p = 0.002); had global manual muscle testing scores 0.6 higher (p = 0.005); and did not require wheelchairs.

Conclusion: Patients with FSHD with 7-10 D4Z4 repeats have milder disease than other genetically defined patients with FSHD1. The lower than predicted methylation in the 7-10 residual repeat group may suggest that additional epigenetic factors play a role in the severity of disease expression.
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http://dx.doi.org/10.1212/WNL.0000000000002217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691686PMC
December 2015
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