Clinical and morphological phenotype of the filamin myopathy: a study of 31 German patients

Abstract

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.

Clinical Reasoning: A 52-year-old woman with progressive proximal weakness

“…2 The family history of respiratory compromise developing a decade after the onset of weakness as seen in our patient is typical of FLNC-MFM. Being of German descent also favors the diagnosis of FLNC-MFM, given that the founder FLNC mutation has been reported in German patients.…”

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

“…In this regard, the finding that expression of these mutants in cardiac myocytes resulted in the formation of larger protein aggregates than when expressed in C2C12 myotubes supports a model in which interaction of these mutants with tissue-specific proteins, contributes to the predominant cardiac phenotype. In this regard, it is also remarkable that about one-third of myofibrillar myopathy patients with the most frequent mutation in FLNC (the German variant, p.W2710X) are reported to have cardiac abnormalities, although only two out of 25 patients had cardiomyopathy with left ventricular dysfunction 13 . These data suggest that the clinical spectrum of the different filaminopathies is highly dependent on the site of mutation within the filamin C molecule.…”

“…Interestingly, mutations in FLNC have been previously associated with myofibrillar myopathy (MIM 609524) 12,13 . However, none of the patients diagnosed with HCM in our study showed symptoms of myofibrillar myopathy, including nine subjects older than 44 years, which is the mean age at onset reported for the most common mutation in FLNC (p.W2710X) 13 . Four HCM patients with mutations in FLNC were studied by electromyography and magnetic resonance imaging with negative results.…”

156th ENMC International Workshop: Desmin and protein aggregate myopathies, 9–11 November 2007, Naarden, The Netherlands

“…Rudolf A. Kley and Matthias Vorgerd discussing ''The phenotype of myofibrillar myopathy associated with p.W2710X mutation in filamin C in 31 German patients" had examined 31 patients from four German families to evaluate the phenotype of filaminopathy [35], a novel form of myofibrillar myopathy (MFM) [36]. All patients harboured the same p.W2710X mutation in the dimerization domain of the filamin C gene on chromosome 7q32.1.…”