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Danon disease is caused by mutations in the lysosome-associated membrane protein-2 gene, LAMP2, located on the X chromosome. Female carriers with LAMP2 mutations most often present with late onset cardiomyopathy and slow disease progress; however, there are unusual cases that emerge early and show a more severe disease course. We investigated the explanted heart and skeletal muscle biopsies in two girls, aged ten and thirteen years, who underwent cardiac transplantation because of hypertrophic cardiomyopathy secondary to LAMP2 mutations and a 41-year old female with late-onset familial LAMP2 cardiomyopathy with more typical clinical phenotype. The two girls in contrast had clinical features that mimicked severe primary hypertrophic cardiomyopathy caused by mutations in genes encoding sarcomeric proteins. Immunohistochemistry in cardiac muscles showed a remarkable pattern with lack of LAMP2 protein in large regions including thousands of cardiomyocytes that also showed myocyte hypertrophy, lysosomal enlargement and disarray. In other equally large regions there were preserved LAMP2 expression and nearly normal histology. The skeletal muscle biopsy revealed no pathological changes. An uneven distribution of LAMP2 protein may cause deleterious effects depending on which regions of the myocardium are lacking LAMP2 protein in spite of an overall moderate reduction of LAMP2 protein. This may be a more common mechanism behind early aggressive disease in females than an overall skewed X-chromosome inactivation in the tissue.

Original publication

DOI

10.1016/j.nmd.2015.03.005

Type

Journal article

Journal

Neuromuscul Disord

Publication Date

06/2015

Volume

25

Pages

493 - 501

Keywords

Cardiomyopathy, Danon disease, Female carriers, LAMP2, X-chromosome inactivation, Adolescent, Adult, Age of Onset, Child, Disease Progression, Female, Glycogen Storage Disease Type IIb, Humans, Lysosomal-Associated Membrane Protein 2, Muscle, Skeletal, Myocardium, Sequence Analysis