title: Danon disease: intrafamilial phenotypic variability related to a novel LAMP-2 mutation.
abstract: Danon disease is an X-linked lysosomal disorder, characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation. We report a family with a novel mutation, in which the mother and her three sons were affected with various clinical presentations. A massive hypertrophy of the left ventricle was the predominant feature in the three male patients, with different degrees of severity of cardiac symptoms, from isolated palpitations to cardiac failure and sudden death. Muscle pain and weakness were also variable, but constantly associated with increased plasma CK levels. Finally, the male patients had variable degree of a mental retardation. The mother had an attenuated phenotype, limited to a mild hypertrophic cardiomyopathy with premature ventricular contractions diagnosed during her 40's. Microscopy examination of skeletal muscle biopsy, performed in the youngest patient, demonstrated atrophic myofibers with intracytoplasmic vacuoles suggesting lysosomal glycogen storage disease. Immunohistochemistry analyses in muscle specimen showed no detectable Lysosomal-Associated Membrane Protein-2 (LAMP-2), in keeping with the diagnosis of Danon disease. However, a very low expression of a shortened LAMP-2 protein could be evidenced by Western-blot in the patient's fibroblasts. Molecular investigations identified a novel splicing mutation (IVS6 + 1delG) in the LAMP-2 gene. This case report highlights the intrafamilial variability of Danon disease phenotype. In this case, morphological examination of muscle biopsy, showing lysosomal storage myopathy, and immunohistochemistry analyses can provide key elements for orienting etiologic investigations.
authors.affiliation: Service de Médecine Pédiatrique, CHRU de Tours, Université François Rabelais, Tours, France.
authors.forename: Sarah-Louise
authors.initials: SL
authors.lastname: Cottinet
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bergemer-Fouquet
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Frédérique
authors.initials: F
authors.lastname: Sabourdy
authors.forename: Zoha
authors.initials: Z
authors.lastname: Maakaroun-Vermesse
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: Alain
authors.initials: A
authors.lastname: Chantepie
authors.forename: François
authors.initials: F
authors.lastname: Labarthe
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D005260:Female; D014644:Genetic Variation; D052120:Glycogen Storage Disease Type IIb / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008607:Intellectual Disability / Q000235:genetics; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D008247:Lysosomes / Q000473:pathology; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D010641:Phenotype
chemical_list: C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins