A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1

Functional Genomics of Muscle, Nerve and Brain Disorder

Assessment of the burden of outpatient clinic and MRI-guided needle muscle biopsies as reported by patients with facioscapulohumeral muscular dystrophy

Muscle biopsies are used in clinical trials to measure target engagement of the investigational product. With many upcoming therapies for patients with facioscapulohumeral dystrophy (FSHD), the frequency of biopsies in FSHD patients is expected to increase. Muscle biopsies were performed either in the outpatient clinic using a Bergström needle (BN-biopsy) or in a Magnetic Resonance Imaging machine (MRI-biopsy). This study assessed the FSHD patients’ experience of biopsies using a customized questionnaire. The questionnaire was sent to all FSHD patients who had undergone a needle muscle biopsy for research purposes, inquiring about biopsy characteristics and burden, and willingness to undergo a subsequent biopsy. Forty-nine of 56 invited patients (88%) completed the questionnaire, reporting on 91 biopsies. The median pain score (scale 0-10) during the procedure was 5 [2-8], reducing to 3 [1-5] and 2 [1-3] after one and 24 h, respectively. Twelve biopsies (13.2%) resulted in complications, eleven resolved within 30 days. BN-biopsies were less painful compared to MRI-biopsies (median NRS: 4 [2-6] vs. 7 [3-9], p = 0.001). The burden of needle muscle biopsies in a research setting is considerate and should not be underestimated. MRI-biopsies have a higher burden compared to BN-biopsies. Neurological Motor Disorder

Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey.

OBJECTIVE: To evaluate the risk factors for the development of acute renal failure (ARF) in severe rhabdomyolysis. DESIGN: Observational historical cohort study. SETTING: General intensive care unit of a university hospital. PATIENTS: Twenty-six patients with severe rhabdomyolysis, who were admitted between July 1996 and July 2001. MEASUREMENTS AND RESULTS: Clinical and laboratory data were reviewed and groups were stratified according to presence or absence of acute renal failure. The underlying cause of rhabdomyolysis was ischemia by vascular obstruction (50%), crush injury by trauma (23%), sepsis (11.5%), heatstroke/hyperthermia (11.5%) and hyponatremia in a single patient. Mean creatine kinase (CK) level was 38,351+/-35,354 U/l on admission and rose further in all patients (mean: 59,747+/-67,514 U/l). Renal failure developed in 17 patients (65%). Serum CK levels correlated with onset of ARF, as these patients had significantly higher admission and peak serum CK concentrations. Patients with ARF had a higher mortality (59% vs 22%). CONCLUSION: In our cohort of patients with severe rhabdomyolysis the level of serum CK predicted the development of ARF. Although our results suggest that series of CK determination might be beneficial for the evaluation of the effect of therapy, the value of CK determination as a prognostic tool is limited, given the wide range of CK levels

Diagnostic yield of muscle fibre conduction velocity in myopathies

Item does not contain fulltextWe prospectively assessed diagnostic yield of muscle fiber conduction velocity (MFCV) studies in patients with signs and symptoms suggestive of a myopathy. Results were analysed with respect to the final diagnosis, and compared to the reference standard, which was qualitative electromyography (EMG), turns-amplitude analysis (TAA), and muscle biopsy. We included 125 patients, in whom a myopathy was diagnosed in 71, and a neuromuscular disorder was excluded in 54. Sensitivity of MFCV for the presence of a myopathy was 84%, and specificity 83%. Diagnostic yield of MFCV was superior to EMG, TAA, and muscle biopsy in patients with metabolic myopathies, non-dystrophic myopathies, and channelopathies. We concluded that measurement of MFCV is a quantitative EMG technique with a high diagnostic yield. In certain myopathies, MFCV may be more informative than conventional EMG examination

Muscle characteristics and altered myofascial force transmission in tenascin-X deficient mice, a mouse model of Ehlers-Danlos syndrome

Contains fulltext : 89341.pdf (publisher's version ) (Closed access)The Ehlers-Danlos syndrome is a group of inherited connective tissue disorders caused by defects in collagens or tenascin-X (TNX). Muscle involvement can be expected based on interactions between muscle and extracellular matrix molecules; however, muscle function has not yet been investigated quantitatively. This study aims to investigate effects of TNX deficiency on muscular characteristics in TNX knockout (KO) mice, a mouse model of Ehlers-Danlos syndrome. At lower muscle lengths, maximally dissected medial gastrocnemius muscle-tendon complex of TNX KO mice showed lower active force, lower maximal rate of relaxation, and longer time delay between first stimulation pulse and initial force rise, supporting the hypothesis that relatively more slack needs to be taken up, as well as more elastic length changes occurring. In addition, study of the minimally dissected lower leg muscles shows that TNX deficiency strongly affects the mechanical interaction between antagonistic, as well as synergistic, muscles, which is consistent with the concept of altered myofascial force transmission due to increased compliance of myofascial components. Altered properties of the force transmission pathways of muscle (being either part of the myotendinous or myofascial pathways) due to TNX deficiency directly affect muscle function in TNX KO mice. Such effects are likely to contribute to muscle weakness experienced by patients with Ehlers-Danlos syndrome.1 oktober 201

Longitudinal Assessment of Strength, Functional Capacity, Oropharyngeal Function, and Quality of Life in Oculopharyngeal Muscular Dystrophy

Background and Objectives Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain unknown. We aimed to examine the natural history of OPMD in a large nationwide cohort to determine clinical outcome measures that capture disease progression and can be used in future clinical trials. Methods Patients invited by their treating physicians or identified from the national neuromuscular database and invited family members were examined twice 20 months apart with fixed dynamometry; Medical Research Council (MRC) grading; maximum bite force and isometric tongue strength; Motor Function Measure (MFM); 10-step stair test; maximum swallowing, chewing, and speech tasks; and quality of life assessments. Results Disease progression was captured by 8 of 18 measures over 20 months in 43 patients with genetically confirmed OPMD. The largest deterioration was seen in deltoid muscle strength (-27% [range -17% to -37%]), followed by the quadriceps (-14% [range -6 to -23%]), iliopsoas (-12.2%), tongue (-9.9%), and MRC sum score (-2.5%). The 10-step stair test (-12.5%), MFM part D1 (-7.1%), and maximum repetition rate of /pa/ (-5.3%) showed a significant decrease as well (all p 0.05). Discussion Despite the slow disease progression of OPMD, this study showed that several outcome measures detected progression within 20 months. Deltoid muscle strength, measured by fixed dynamometry, showed the greatest decline. These longitudinal data provide clinical outcome measures that can be used as biomarkers in future clinical trials.Functional Genomics of Muscle, Nerve and Brain Disorder

Clinical and molecular overlap between myopathies and inherited connective tissue diseases

Contains fulltext : 69523.pdf (publisher's version ) (Closed access)This review presents an overview of myopathies and inherited connective tissue disorders that are caused by defects in or deficiencies of molecules within the extracellular matrix (ECM). We will cover the myopathies caused by defects in transmembrane protein complexes (dystroglycan, sarcoglycan, and integrins), laminin, and collagens (collagens VI, XIII, and XV). Clinical characteristics of several of these myopathies imply skin and joint features. We subsequently describe the inherited connective tissue disorders that are characterized by mild to moderate muscle involvement in addition to the dermal, vascular, or articular symptoms. These disorders are caused by defects of matrix-embedded ECM molecules that are also present within muscle (collagens I, III, V, IX, lysylhydroxylase, tenascin, fibrillin, fibulin, elastin, and perlecan). By focussing on the structure and function of these ECM molecules, we aim to point out the clinical and molecular overlap between the groups of disorders. We argue that clinicians and researchers dealing with myopathies and inherited connective tissue disorders should be aware of this overlap. Only a multi-disciplinary approach will allow full recognition of the wide variety of symptoms present in the spectrum of ECM defects, which has important implications for scientific research, diagnosis, and for the treatment of these disorders

Characterization of sarcoplasmic reticulum Ca(2+) ATPase pumps in muscle of patients with myotonic dystrophy and with hypothyroid myopathy

Sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA) pumps play the major role in lowering cytoplasmic calcium concentration in skeletal muscle by catalyzing the ATP-dependent transport of Ca(2+) from the cytosol to the lumen of the sarcoplasmic reticulum (SR). Although SERCA abnormalities have been hypothesized to contribute to the dysregulation of intracellular Ca(2+) homeostasis and signaling in muscle of patients with myotonic dystrophy (DM) and hypothyroid myopathy, the characterization of SERCA pumps remains elusive and their impairment is still unclear. We assessed the activity of SR Ca(2+)-ATPase, expression levels and fiber distribution of SERCA1 and SERCA2, and oligomerization of SERCA1 protein in muscle of patients with DM type 1 and 2, and with hypothyroid myopathy. Our data provide evidence that SR Ca(2+) ATPase activity, protein levels and muscle fiber distribution of total SERCA1 and SERCA2, and SERCA1 oligomerization pattern are similar in patients with both DM1 and DM2, hypothyroid myopathy and in control subjects. We prove that SERCA1b, the neonatal isoform of SERCA1, is expressed at protein level in muscle of patients with DM2 and, in lower amount, of patients with DM1. Our present study demonstrates that SERCA function is not altered in muscle of patients with DM and with hypothyroid myopathy