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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 filam...

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Published in:Brain (London, England : 1878) England : 1878), 2007-12, Vol.130 (12), p.3250-3264
Main Authors: Kley, Rudolf A., Hellenbroich, Yorck, van der Ven, Peter F. M., Fürst, Dieter O., Huebner, Angela, Bruchertseifer, Vera, Peters, Sören A., Heyer, Christoph M., Kirschner, Janbernd, Schröder, Rolf, Fischer, Dirk, Müller, Klaus, Tolksdorf, Karen, Eger, Katharina, Germing, Alfried, Brodherr, Turgut, Reum, Conny, Walter, Maggie C., Lochmüller, Hanns, Ketelsen, Uwe-Peter, Vorgerd, Matthias
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container_issue 12
container_start_page 3250
container_title Brain (London, England : 1878)
container_volume 130
creator Kley, Rudolf A.
Hellenbroich, Yorck
van der Ven, Peter F. M.
Fürst, Dieter O.
Huebner, Angela
Bruchertseifer, Vera
Peters, Sören A.
Heyer, Christoph M.
Kirschner, Janbernd
Schröder, Rolf
Fischer, Dirk
Müller, Klaus
Tolksdorf, Karen
Eger, Katharina
Germing, Alfried
Brodherr, Turgut
Reum, Conny
Walter, Maggie C.
Lochmüller, Hanns
Ketelsen, Uwe-Peter
Vorgerd, Matthias
description 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.
doi_str_mv 10.1093/brain/awm271
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M. ; Fürst, Dieter O. ; Huebner, Angela ; Bruchertseifer, Vera ; Peters, Sören A. ; Heyer, Christoph M. ; Kirschner, Janbernd ; Schröder, Rolf ; Fischer, Dirk ; Müller, Klaus ; Tolksdorf, Karen ; Eger, Katharina ; Germing, Alfried ; Brodherr, Turgut ; Reum, Conny ; Walter, Maggie C. ; Lochmüller, Hanns ; Ketelsen, Uwe-Peter ; Vorgerd, Matthias</creator><creatorcontrib>Kley, Rudolf A. ; Hellenbroich, Yorck ; van der Ven, Peter F. M. ; Fürst, Dieter O. ; Huebner, Angela ; Bruchertseifer, Vera ; Peters, Sören A. ; Heyer, Christoph M. ; Kirschner, Janbernd ; Schröder, Rolf ; Fischer, Dirk ; Müller, Klaus ; Tolksdorf, Karen ; Eger, Katharina ; Germing, Alfried ; Brodherr, Turgut ; Reum, Conny ; Walter, Maggie C. ; Lochmüller, Hanns ; Ketelsen, Uwe-Peter ; Vorgerd, Matthias</creatorcontrib><description>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.</description><identifier>ISSN: 0006-8950</identifier><identifier>EISSN: 1460-2156</identifier><identifier>DOI: 10.1093/brain/awm271</identifier><identifier>PMID: 18055494</identifier><identifier>CODEN: BRAIAK</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Adult ; Age of Onset ; Biological and medical sciences ; Biopsy ; Contractile Proteins - genetics ; Disease Progression ; Diseases of striated muscles. Neuromuscular diseases ; DNA Mutational Analysis - methods ; Female ; filamin C ; Filamins ; FLNC mutation ; Humans ; Magnetic Resonance Imaging ; Male ; Medical sciences ; Microfilament Proteins - genetics ; Middle Aged ; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis ; Muscle Weakness - genetics ; Muscle, Skeletal - ultrastructure ; Muscular Atrophy - genetics ; Muscular Diseases - genetics ; Muscular Diseases - pathology ; Muscular Diseases - physiopathology ; muscular dystrophy ; Mutation ; myofibrillar myopathy ; Myofibrils - ultrastructure ; Neurology ; Pedigree ; Phenotype ; Respiratory Muscles - physiopathology</subject><ispartof>Brain (London, England : 1878), 2007-12, Vol.130 (12), p.3250-3264</ispartof><rights>The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2007</rights><rights>2008 INIST-CNRS</rights><rights>The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 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M.</creatorcontrib><creatorcontrib>Fürst, Dieter O.</creatorcontrib><creatorcontrib>Huebner, Angela</creatorcontrib><creatorcontrib>Bruchertseifer, Vera</creatorcontrib><creatorcontrib>Peters, Sören A.</creatorcontrib><creatorcontrib>Heyer, Christoph M.</creatorcontrib><creatorcontrib>Kirschner, Janbernd</creatorcontrib><creatorcontrib>Schröder, Rolf</creatorcontrib><creatorcontrib>Fischer, Dirk</creatorcontrib><creatorcontrib>Müller, Klaus</creatorcontrib><creatorcontrib>Tolksdorf, Karen</creatorcontrib><creatorcontrib>Eger, Katharina</creatorcontrib><creatorcontrib>Germing, Alfried</creatorcontrib><creatorcontrib>Brodherr, Turgut</creatorcontrib><creatorcontrib>Reum, Conny</creatorcontrib><creatorcontrib>Walter, Maggie C.</creatorcontrib><creatorcontrib>Lochmüller, Hanns</creatorcontrib><creatorcontrib>Ketelsen, Uwe-Peter</creatorcontrib><creatorcontrib>Vorgerd, Matthias</creatorcontrib><title>Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients</title><title>Brain (London, England : 1878)</title><addtitle>Brain</addtitle><description>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. 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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. 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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.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>18055494</pmid><doi>10.1093/brain/awm271</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record>
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source Oxford Journals Online
subjects Adult
Age of Onset
Biological and medical sciences
Biopsy
Contractile Proteins - genetics
Disease Progression
Diseases of striated muscles. Neuromuscular diseases
DNA Mutational Analysis - methods
Female
filamin C
Filamins
FLNC mutation
Humans
Magnetic Resonance Imaging
Male
Medical sciences
Microfilament Proteins - genetics
Middle Aged
Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis
Muscle Weakness - genetics
Muscle, Skeletal - ultrastructure
Muscular Atrophy - genetics
Muscular Diseases - genetics
Muscular Diseases - pathology
Muscular Diseases - physiopathology
muscular dystrophy
Mutation
myofibrillar myopathy
Myofibrils - ultrastructure
Neurology
Pedigree
Phenotype
Respiratory Muscles - physiopathology
title Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients
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