TY - JOUR
T1 - Clinical and morphological phenotype of the filamin myopathy: A study of 31 German patients
AU - Kley, Rudolf A.
AU - Hellenbroich, Yorck
AU - Van Der Ven, Peter F.M.
AU - Fürst, Dieter O.
AU - Huebner, Angela
AU - Bruchertseifer, Vera
AU - Peters, Sören A.
AU - Heyer, Christoph M.
AU - Kirschner, Janbernd
AU - Schröder, Rolf
AU - Fischer, Dirk
AU - Müller, Klaus
AU - Tolksdorf, Karen
AU - Eger, Katharina
AU - Germing, Alfried
AU - Brodherr, Turgut
AU - Reum, Conny
AU - Walter, Maggie C.
AU - Lochmüller, Hanns
AU - Ketelsen, Uwe Peter
AU - Vorgerd, Matthias
N1 - Funding Information:
R.S., R.K., M.V., D.F., P.V., A.H., J.K., M.W. and H.L. are members of the German network on muscular dystrophies (MD-NET, research project R2, 01GM0601) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany); www.md-net.org. MD-NET is a partner of TREAT-NMD (EC, 6th FP, proposal # 036825; www.treat-nmd.eu). Support by the Heimer-Stiftung e.V., Bielefeld, Germany, is appreciated. We thank Mrs A. Schreiner, Neuromuscular Center Ruhrgebiet, Bochum, for technical assistance.
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=36749069412&partnerID=8YFLogxK
U2 - 10.1093/brain/awm271
DO - 10.1093/brain/awm271
M3 - Journal articles
C2 - 18055494
AN - SCOPUS:36749069412
SN - 0006-8950
VL - 130
SP - 3250
EP - 3264
JO - Brain
JF - Brain
IS - 12
ER -