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Novel diagnostic features of dysferlinopathies

Authors

  • Xiomara Q. Rosales MD,

    1. Department of Pediatrics, Neuromuscular Division, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
    3. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
    4. Department of Neurology, Neuromuscular Division, Ohio State University, Columbus, Ohio, USA
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  • Julie M. Gastier-Foster PhD,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
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  • Sarah Lewis HT, ASCP,

    1. Department of Pediatrics, Neuromuscular Division, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
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  • Malik Vinod PhD,

    1. Department of Pediatrics, Neuromuscular Division, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
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  • Devon L. Thrush MS,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
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  • Caroline Astbury PhD,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
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  • Robert Pyatt PhD,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
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  • Shalini Reshmi PhD,

    1. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
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  • Zarife Sahenk MD, PhD,

    1. Department of Pediatrics, Neuromuscular Division, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
    3. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
    4. Department of Neurology, Neuromuscular Division, Ohio State University, Columbus, Ohio, USA
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  • Jerry R. Mendell MD

    Corresponding author
    1. Department of Pediatrics, Neuromuscular Division, Nationwide Children's Hospital, Columbus, Ohio, USA
    2. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
    3. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
    4. Department of Neurology, Neuromuscular Division, Ohio State University, Columbus, Ohio, USA
    • Department of Pediatrics, Neuromuscular Division, Nationwide Children s Hospital, Columbus, Ohio, USA
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Abstract

Reports of dysferlinopathy have suggested a clinically heterogeneous group of patients. We identified specific novel molecular and phenotypic features that help distinguish dysferlinopathies from other forms of limb-girdle muscular dystrophy (LGMD). A detailed history, physical exam, and protein and mutation analysis of genomic DNA was done for all subjects. Five of 21 confirmed DYSF gene mutations were not previously reported. A distinct “bulge” of the deltoid muscle in combination with other findings was a striking feature in all patients. Six subjects had atypical calf enlargement, and 3 of these exhibited a paradoxical pattern of dysferlin expression: severely reduced by direct immunofluorescence with overexpression on Western blots. Six patients showed amyloid deposits in muscle that extended these findings to new domains of the dysferlin gene, including the C2G domain. Correlative studies showed colocalization of amyloid with deposition of dysferlin. The present data further serve to guide clinicians facing the expensive task of molecular characterization of patients with an LGMD phenotype. Muscle Nerve 42: 14–21, 2010

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