Danon Disease Presenting with Slowly Progressive Cardiomyopathy and Harboring a Novel Missense Variant in the Lysosome-associated Membrane Protein Type 2 (LAMP-2) Gene

Figures

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  Figure 1.. Clinical course, plain chest X-ray images, and echocardiographic findings. It was initially characterized by mild left ventricular hypertrophy and partial ventricular aneurysms; however, his slowly declined over a decade after catheter ablation and pacemaker implantation. The cardiothoracic ratio also increased over time on plain chest radiographs. CRTD: cardiac resynchronization therapy with defibrillator, LVEF: left ventricular ejection fraction, LVEDD: left ventricular end-diastolic diameter, LVESD: left ventricular end-systolic diameter

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  Figure 2.. A pedigree and molecular genetic analysis. A: Pedigree of the family with Danon disease. Circle indicates female, and squares indicate male. Black symbols indicate affected individuals, and white symbols indicate unaffected individuals. The proband is indicated by an arrow. Slashed symbols indicate the deceased members. AFL: atrial flutter, CAVB: complete atrioventricular block, CHF: congestive heart failure, CRTD: cardiac resynchronization therapy with defibrillator, PMI: pacemaker implantation, SCD: sudden cardiac death. B: Deoxyribonucleic acid (DNA) sequence analysis of lysosome-associated membrane protein type 2 (LAMP-2) in the proband. A hemizygous nucleotide transition from T to A at nucleotide position 62 in LAMP-2 occurred in the proband. C: Electrophoresis of the reverse transcription polymerase chain reaction (RT-PCR) products from the proband and control using 1F and 2R primers. D: Direct sequencing of the RT-PCR fragment from the proband demonstrates c.62T>A substitution and no exon-skipping messenger ribonucleic acid (mRNA).

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  Figure 3.. Pathological findings of a skeletal muscle biopsy. A: Hematoxylin and Eosin (H&E) staining showed a few fibers demonstrated sarcolemmal indentation and had small basophilic granular structures. B: Enzymatic activity of acetylcholinesterase (AChE) was found. C: On modified Gomori trichrome (mGT), no ragged red fibers or rimmed vacuoles were observed. Immunohistochemical staining revealed positive findings of β-dystroglycan (D) and dystrophin (E). F: Lysosome-associated membrane protein type 2 (LAMP-2) expression was completely absent.

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  Figure 4.. Pathological findings of an endomyocardial biopsy. A: Hematoxylin and Eosin (H&E) staining showed thickening of the endomyocardium. B: Masson’s trichrome staining showed interstitial fibrosis. C: Diastase-digested material positive for periodic acid-Schiff (PAS) staining was locally identified. D: Lysosome-associated membrane protein type 2 (LAMP-2) expression was completely absent. Many p62- (E) and ubiquitin-positive aggregates (F) were observed.

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  Figure 5.. Electron microscopic findings of endomyocardial biopsy. Electron microscopy revealed an increase in the number of collagen fibers and mitochondrial proliferation. Although not numerous, some autophagic vacuoles with autophagic materials and glycogen granules were observed. AVSF: autophagic vacuoles with unique sarcolemmal feature, MF: myofibrils, MT: mitochondria