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, 20 (7), 438-42

Inheritance Patterns and Phenotypic Features of Myofibrillar Myopathy Associated With a BAG3 Mutation

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Inheritance Patterns and Phenotypic Features of Myofibrillar Myopathy Associated With a BAG3 Mutation

Zagaa Odgerel et al. Neuromuscul Disord.

Abstract

Myofibrillar myopathies are a heterogeneous group of neuromuscular disorders characterized by disintegration of myofibrils. The inheritance pattern is commonly autosomal dominant, but there has been a striking absence of secondary cases noted in a BAG3-associated subtype. We studied three families with BAG3 p.Pro209Leu mutation showing a severe phenotype of myofibrillar myopathy and axonal neuropathy with giant axons. In one family, transmission to a pair of siblings has occurred from their asymptomatic father who showed somatic mosaicism. In two other families, neither of the parents was affected or showed detectable level of somatic mosaicism. These observations suggest that the BAG3 variant of myofibrillar myopathy may result from a spontaneous mutation at an early point of embryonic development and that transmission from a mosaic parent may occur more than once. The study underlines the importance of parental evaluation as it may have implications for genetic counseling.

Figures

Figure 1
Figure 1
Analysis of a muscle biopsy sample from a patient with BAG3 p.Pro209Leu mutation (Family 2). A, cryostat section of a muscle biopsy sample stained with NADH shows fibre diameter variability and marked irregularity of the intermyofibrillar network with many fibres showing multiple core areas. B, increased immunoreactivity for desmin under the sarcolemma and within the cytoplasm of some fibres. C, D, on EM analysis, electrondense granulofilamentous material emanating from the Z-discs.
Figure 2
Figure 2
Sural nerve morphology in a patient with BAG3 p.Pro209Leu mutation (Family 2). A, B, transverse sections show moderate loss of myelinated fibers and the presence of several giant axons (original magnification 1:200). C, teased fibre showing focal axonal enlargements.
Figure 3
Figure 3
Family structure and mutation analyses in three families affected with BAG3-associated subtype of myofibrillar myopathy. A, family pedigrees and the results of haplotype analysis with microsatellite markers from the BAG3 region on chromosome 10q. Allele identification is provided according to the number of “CA” or “TTA” repeats. BAG3 gene is located between D10S1792 and D10S1722. B, agarose gel electrophoresis of PCR-amplified exon 3 fragments of BAG3 restricted with BsaWI. The upper band is a 526-nt BsaWI-resistant fragment containing the disease-causing mutation; the middle and the lower 353-nt and 173-nt bands are portions of the restricted non-mutant fragment. C, mutant portion of the PCR-amplified exon 3 restricted with BsaWI and subjected to capillary electrophoresis.

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