Brain Advance Access originally published online on April 17, 2007
Brain 2007 130(6):1485-1496; doi:10.1093/brain/awm039
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Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum of adult-onset, dominant myopathies are associated with the desmin mutation R350P
1Friedrich Baur Institute, Department of Neurology and 7Institute for Clinical Radiology, Ludwig Maximilians University of Munich, 2Children's Hospital, Technical University, Dresden, 3Muscle center and ALS clinic, Kantonspital St Gallen, Switzerland, 4Center of Biochemistry, University of Cologne, 5Department of Neurology, Ruhr-University of Bochum, 6Institute for Human Genetics, University of Würzburg, Germany and 8Hoffmann-La Roche and CNS Research, Basel, Switzerland
Corresponding to: Hanns Lochmüller MD, Friedrich-Baur-Institute, Marchioninistrasse 17, 81377 Munich, Germany E-mail: hanns.lochmueller{at}med.uni-muenchen.de
In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named ‘scapuloperoneal syndrome type Kaeser’ (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype–phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absent.
Key Words: myofibrillar myopathy; scapuloperoneal syndrome; desminopathy; desmin-related myopathy
Abbreviations: EM, electron microscopy; EMG, electromyography; Gd-DTPA, gadolinium-diethyltriaminepentaacetic acid; LGMD, limb girdle muscular dystrophy; MRI, magnetic resonance imaging
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Received January 12, 2007. Revised February 8, 2007. Accepted February 12, 2007.
*These authors contributed equally to this work.
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