Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients
1Department of Neurology, Neuromuscular Center Ruhrgebiet, Ruhr-University Bochum, Bochum, 2Department of Human Genetics, University of Lübeck, Lübeck, 3Department of Molecular Cell Biology, University of Bonn, Bonn, 4Children's Hospital, Technical University Dresden, Dresden, 5Institute of Radiology, Ruhr-University Bochum, Bochum, 6Devision of Neuropediatrics and Muscle Disorders, University Children's Hospital Freiburg, Freiburg, 7Department of Neuropathology, University of Erlangen, Erlangen, Germany, 8Muscle Center and ALS Clinic, Kantonsspital St Gallen, St Gallen, Switzerland, 9Institute of Pathology, University of Freiburg, Freiburg, 10Department of Neurology, University Hospital Bonn, Bonn, 11Department of Neurology, Martin Luther University Halle-Wittenberg, Halle, 12Medical Clinic II, Cardiology and Angiology, Ruhr-University Bochum, Bochum and 13Friedrich Baur Institute and Department of Neurology, Ludwig Maximilians University of Munich, Munich, Germany
Correspondence to: Matthias Vorgerd, Department of Neurology, Neuromuscular Center Ruhrgebiet, BG-Kliniken Bergmannsheil, Ruhr-University Bochum, Buerkle-de-la-Camp-Platz 1, 44789 Bochum, Germany E-mail: matthias.vorgerd{at}ruhr-uni-bochum.de
Mutations in the filamin C gene (FLNC) cause a myofibrillar myopathy (MFM), morphologically characterized by focal myofibrillar destruction and abnormal accumulation of several proteins within skeletal muscle fibres. We studied 31 patients from four German families to evaluate the phenotype of filaminopathy. All patients harboured the same p.W2710X mutation in FLNC. Haplotype analysis suggested a founder mutation in these German filaminopathy families. The mean age at onset of clinical symptoms was 44 +/– 6 years (range, 24–57 years). Slowly progressive muscle weakness was mostly pronounced proximally, initially affecting the lower extremities and involving the upper extremities in the course of disease progression, similar to the distribution of weakness seen in limb-girdle muscular dystrophies (LGMD). Patients frequently developed respiratory muscle weakness. About one-third of the patients showed cardiac abnormalities comprising conduction blocks, tachycardia, diastolic dysfunction and left ventricular hypertrophy indicating a cardiac involvement in filaminopathy. Serum creatine kinase levels varied from normal up to 10-fold of the upper limit. Magnetic resonance imaging studies showed a rather homogenous pattern of muscle involvement in the lower extremities differing from that in other types of MFM. Myopathological features included perturbation of myofibrillar alignment, accumulation of granulofilamentous material similar to that seen in primary desminopathies and abnormal intracellular protein deposits typical of MFM. Decreased activities of oxidative enzymes and fibre hypertrophy seem to be early features, whereas dystrophic changes were present in advanced stages of filaminopathy. Rimmed vacuoles were detected in only a few cases. The intracellular aggregates were composed of a variety of proteins including filamin C, desmin, myotilin, Xin, dystrophin and sarcoglycans. Therapy is so far limited to symptomatic treatment. The German filaminopathy cohort, the largest group of patients studied so far, shares phenotypic features with LGMD and presents with characteristic histopathological findings of MFM.
Key Words: filamin C; FLNC mutation; phenotype; myofibrillar myopathy; muscular dystrophy
Abbreviations: FSHD, facioscapulohumeral muscular dystrophy; LGMD, limb-girdle muscular dystrophies; MFM, myofibrillar myopathy.
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Received August 17, 2007. Revised October 12, 2007. Accepted October 16, 2007.
*Present address: Institute of Human Genetics, University of Newcastle upon Tyne, UK
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