Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients.
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.
Kley
Rudolf A
RA
Department of Neurology, Neuromuscular Center Ruhrgebiet, Ruhr-University Bochum, Bochum, Germany.
Hellenbroich
Yorck
Y
van der Ven
Peter F M
PF
Fürst
Dieter O
DO
Huebner
Angela
A
Bruchertseifer
Vera
V
Peters
Sören A
SA
Heyer
Christoph M
CM
Kirschner
Janbernd
J
Schröder
Rolf
R
Fischer
Dirk
D
Müller
Klaus
K
Tolksdorf
Karen
K
Eger
Katharina
K
Germing
Alfried
A
Brodherr
Turgut
T
Reum
Conny
C
Walter
Maggie C
MC
Lochmüller
Hanns
H
Ketelsen
Uwe-Peter
UP
Vorgerd
Matthias
M
D000328:Adult; D017668:Age of Onset; D001706:Biopsy; D003285:Contractile Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D018450:Disease Progression; D005260:Female; D064448:Filamins; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D018908:Muscle Weakness / Q000235:genetics; D018482:Muscle, Skeletal / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000235:genetics; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009210:Myofibrils / Q000648:ultrastructure*; D010375:Pedigree; D010641:Phenotype; D012132:Respiratory Muscles / Q000503:physiopathology
D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D008840:Microfilament Proteins