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Danon Disease Due to a Novel LAMP2 Microduplication

  • Matthew A. Lines
  • Stacy Hewson
  • William Halliday
  • Peter J. B. Sabatini
  • Tracy Stockley
  • Anne I. Dipchand
  • Sarah Bowdin
  • Komudi SiriwardenaEmail author
Case Report
Part of the JIMD Reports book series (JIMD, volume 14)

Abstract

Danon disease is a rare X-linked disorder comprising hypertrophic cardiomyopathy, skeletal myopathy, intellectual disability, and retinopathy; mutations of the lysosome-associated membrane protein gene LAMP2 are responsible. Most affected persons exhibit “private” point mutations; small locus rearrangements have recently been reported in four cases. Here, we describe the clinical, pathologic, and molecular features of a male proband and his affected mother with Danon disease and a small LAMP2 microduplication. The proband presented at age 12 years with exercise intolerance, hypertrophic cardiomyopathy, and increased creatine kinase. Endomyocardial biopsy findings were nonspecific, showing myocyte hypertrophy and reactive mitochondrial changes. Quadriceps muscle biopsy demonstrated the characteristic autophagic vacuoles with sarcolemma-like features. LAMP2 tissue immunostaining was absent; however, LAMP2 sequencing was normal. Deletion/duplication testing by multiplex ligation-dependent probe amplification (MLPA) assay revealed a 1.5kb microduplication containing LAMP2 exons 4 and 5. RT-PCR studies were consistent with the inclusion of these two duplicated exons in the final spliced transcript, resulting in a frameshift. The proband’s mother, who had died following cardiac transplantation due to suspected myocarditis at age 35, was reviewed and was shown to be affected upon immunostaining of banked myocardial tissue. This case constitutes the second report of a pathogenic microduplication in Danon disease, and illustrates a number of potential diagnostic pitfalls. Firstly, given the imperfect sensitivity of LAMP2 sequencing, tissue immunostaining and/or MLPA should be considered as a diagnostic adjunct in the workup for this disorder. Secondly, the pathological findings in myocardium may be falsely indicative of relatively common conditions such as myocarditis.

Keywords

Intellectual Disability Hypertrophic Cardiomyopathy Endomyocardial Biopsy Pompe Disease Arrhythmogenic Right Ventricular Dysplasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Supplementary material

327082_1_En_277_MOESM1_ESM.docx (57 kb)
Supplementary Table 1 Progressive hypertrophic cardiomyopathy

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Matthew A. Lines
    • 1
  • Stacy Hewson
    • 2
  • William Halliday
    • 3
  • Peter J. B. Sabatini
    • 3
  • Tracy Stockley
    • 3
  • Anne I. Dipchand
    • 4
  • Sarah Bowdin
    • 2
  • Komudi Siriwardena
    • 2
    Email author
  1. 1.Division of Metabolics and Newborn ScreeningChildren’s Hospital of Eastern OntarioOttawaCanada
  2. 2.Department of Clinical and Metabolic GeneticsThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Pediatric Laboratory MedicineThe Hospital for Sick ChildrenTorontoCanada
  4. 4.Department of CardiologyThe Hospital for Sick ChildrenTorontoCanada

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