Danon disease: Gender differences in presentation and outcomes Michela Brambatti a,1 , Oren Caspi a,1 , Alessandro Maolo a , Elliott Koshi a , Barry Greenberg a , Matthew R.G. Taylor b , Eric D. Adler a, ⁎ ,2 a Division of Cardiology, University of California San Diego, San Diego, CA, USA b Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver, CO, USA abstract article info Article history: Received 7 December 2018 Accepted 2 January 2019 Available online 16 February 2019 Background: Danon disease (DD) is a rare X-linked autophagic vacuolar myopathy, characterized by high penetrance and severe cardiomyopathy. Because of its rarity, the natural history (NH) is uncertain. Objectives: We aimed to describe disease variability and outcomes through a systematic review of all published DD cases. Methods: Among 83 manuscripts in MEDLINE and EMBASE on DD cases published until October 2017, we identified 146 patients with positive genetic testing for DD or positive muscle biopsy in a relative of a genetically diagnosed proband. Results: 56 females and 90 males were identified. 92.5% of patients had cardiac abnormalities. Females presented with either hypertrophic cardiomyopathy (HCM, 70.3%) or dilated cardiomyopathy (DCM, 29.3%) whereas males presented with HCM 96.2% of the time. The composite outcome of death, heart transplant or ventricular assist devices occurred equally in both sexes (32% of females and 37% of males, p = 0.60) but later in females (median age 38 years) than in males (median age 21 years, p b 0.001). Whereas women present with isolated cardiac disease 73% of the time, in males DD was frequently multisystemic and presented as a triad of cognitive impairment, skeletal myopathy, and HCM in 42% of patients. Conclusions: In this first systematic review of DD, we confirmed the severe morbidity and mortality associated with disease in both sexes. Women presented with both HCM and DCM and generally with isolated cardiac disease, whereas in men DD usually presented as HCM and was frequently multi-systemic. Further prospective NH studies will be required to confirm these findings. © 2019 Elsevier B.V. All rights reserved. Keywords: Danon disease LAMP2 mutation Hypertrophic cardiomyopathy Dilated cardiomyopathy Genetic testing Gender 1. Introduction Danon Disease (DD) is a rare, X-linked vacuolar myopathy caused by mutations in the Lysosomal-Associated Membrane Protein 2 (LAMP2) gene. The LAMP-2 protein is integral to cellular autophagy, and its ab- sence or reduced expression results in intracytoplasmic vacuoles contain- ing autophagic material [1,2]. Sequelae of DD include cardiac and skeletal myopathies, neurodegeneration, and pigmentary retinopathy. The exact prevalence of DD is unknown but is generally believed to as high as 5% of all cases of pediatric hypertrophic cardiomyopathy (HCM) [3]. Al- though no specific diagnostic criteria have been established, the diagnosis is usually made by identifying a mutation in LAMP2 in the context of either a typical clinical triad (cardiomyopathy, skeletal myopathy, and cognitive impairment) or pathognomonic findings of vacuolar myopathy after a skeletal or cardiac muscle biopsy. As in other rare diseases, delayed diagnosis and misdiagnosis are common [4]. Because of the rarity of this condition, a high degree of uncertainty remains in regards with its clinical presentation and the natural history. Since DD is X-linked, the disease generally arises earlier in males, who typically die or require heart transplantation (HTx) in the second or third decade of life due to progressive heart failure (HF) [5,6]. This phe- nomenon is presumably related to the hemizygous male status of the LAMP2 gene, with many mutations leading to a complete absence of the LAMP-2 protein. Notably, specific cases of severely affected females have also been described [7,8], possibly caused by non-random or de- fective X-inactivation [9]. As DD can be misdiagnosed as sarcomeric HCM, it is critical to under- stand the variable ways DD can present itself so that providers can dis- tinguish the separate clinical entities that require different management strategies [10]. Furthermore, recent insights into the molecular mecha- nisms [2,11–13] and potential therapeutic targets of DD may lead to the initiation of clinical trials. However, before clinical trials are started a International Journal of Cardiology 286 (2019) 92–98 Abbreviations: DD, Danon disease; HCM, hypertrophic cardiomyopathy; DCM, dilated cardiomyopathy; HTx, heart transplantation; LVAD, left ventricular assist device; Q1, first quartile; Q3, third quartile; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; LV, left ventricle. ⁎ Corresponding author. E-mail address: eradler@ucsd.edu (E.D. Adler). 1 Dr. Brambatti and Dr. Caspi contributed equally to this work. 2 Address: 300 Campus Point Dr. #7411, La Jolla, CA 92037, USA. https://doi.org/10.1016/j.ijcard.2019.01.020 0167-5273/© 2019 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard