JACC: CARDIOVASCULAR IMAGING VOL. -, NO.

-, 2020
ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-878X/$36.00

PUBLISHED BY ELSEVIER

iMAIL cardiomyopathy is misclassified as sarcomeric hy-

pertrophic cardiomyopathy (HCM) in young boys and
is under-recognized in females who can present with
Cardiac Magnetic Resonance Imaging in isolated HCM or dilated cardiomyopathy (DCM) (2).
Danon Disease Cardiomyopathy Identifying DD may aid selection for implantable
cardioverter-defibrillator, heart transplantation, and
DD-targeted gene therapy development trials (3).
Danon Disease (DD) is a rare, X-linked and highly The Natural History of Danon Disease is a global
penetrant vacuolar myopathy caused by the multi-center observational study approved by the
Lysosomal-Associated Membrane Protein-2 (LAMP-2) University of California, San Diego Institutional Re-
primary deficiency (1). LAMP-2 cardiomyopathy is the view Board (4). The largest DD cohort with cardiac
most common and high-risk manifestation of DD. It magnetic resonance (CMR) to date is hereby pre-
often manifests with sudden cardiac death, sented (n ¼ 12; males: 5 [42%]; median age: 13 years
arrhythmias and early-onset heart failure. DD [10 to 15 years]; mean body mass index 23 

F I G U R E 1 Proposed CMR Gender-Related Phenotypes and Specific Imaging Sign of Danon Disease LAMP-2 Cardiomyopathy

A Male HCM Phenotype Female HCM Phenotype Female DCM Phenotype

IVS 15 mm IVS 32 mm IVS 20 mm

LVEDVi 80 ml/m2 LVEDVi 69 ml/m2 LVEDVi 140 ml/m2
RV 2 mm RV 10 mm RV 8 mm
Concentric LVH Asymmetric LVH with RV hypertrophy Asymmetric LVH with LV dilation

Extensive LGE with mid septum sparing

(A) The 3 gender-related phenotypes of Danon Disease (DD) cardiomyopathy are presented in the short-axis mid-ventricular slice of 3 example patients. Concentric left
ventricular hypertrophy (LVH) was the most common phenotype in males (hypertrophic cardiomyopathy [HCM] phenotype, male, 15 years of age). Asymmetric LVH
was more common in females and associated with right ventricular (RV) hypertrophy (HCM phenotype, female 12 years of age). Left ventricular (LV) dilation with
systolic dysfunction was present only in females (dilated cardiomyopathy [DCM] phenotype, female 14 years of age). (B) Late gadolinium enhancement (LGE) short-
axis images in an example DD female with DCM phenotype. Although DD cardiomyopathy had various LGE patterns and distributions, LGE was always sparing the
mid-interventricular septum (orange arrow, 100% of LGE patients, proposed specific DD sign). Other common characteristics were the presence of LGE at the LV-RV
insertion points (yellow arrow, 75% of LGE patients) and RV-LGE in females (blue arrow). The presented cardiac magnetic resonance (CMR) characteristics may help
increase DD imaging suspicion in HCM and DCM phenotypes.
2 iMail
5 kg/m 2). DD diagnosis was performed with genetic
testing and confirmed on muscle biopsy in genetic
variants of uncertain significance. CMR scans were
anonymized, centralized, and analyzed by an expe-
rienced reader blinded to demographic and clinical
parameters.
Phenotypical sex differences (Figure 1A) and a
particular pattern of extensive late gadolinium
enhancement (LGE) with mid-interventricular
septum sparing (Figure 1B) may help distinguish DD
from other cardiomyopathies. Although DD in males
typically presents at a young age with various degrees
of cardiac involvement, myopathy, and cognitive
deficit (1), heterozygotes females have variable X-
linked expression and can present later in life without
extra-cardiac symptoms, making their diagnosis
additionally challenging (5). Recognizing DD imaging
characteristics can aid clinical suspicion of this het-
erogeneous genetic syndrome.
The most frequent DD cardiomyopathy manifesta-
tion was left ventricular hypertrophy (LVH) either
isolated in 8 or with dilation in 2 patients (Figure 1A).
Two patients with DD had normal CMR. In males, LVH
was typically concentric (3 in 4 males with LVH) with
normal systolic function (left ventricular ejection
fraction [LVEF] 61  5%). Females (n ¼ 7, LVEF 49 
20%) presented with asymmetrical LVH (5 in 6 with
LVH), right ventricular hypertrophy (in 4, 100% of
females with isolated LVH) and 2 different pheno-
types: HCM (4 females) or DCM phenotype (2 fe-
males). Eleven patients with DD had gadolinium-
based contrast administered. Of these, 3 showed no
LGE. All remaining patients (n ¼ 8, 73%) had various
LGE patterns and distributions but LGE was always
sparing the mid-septum (in 100% of LGE patients).
Extensive LGE consistently sparing the mid-septum
may represent a specific sign of DD cardiomyopathy
(Figure 1B).
JACC: CARDIOVASCULAR IMAGING, VOL. -, NO. -, 2020
- 2020:-–-
These findings define a crucial role of CMR imaging
in DD. The proposed sex-related phenotypes and LGE
sign may aid the difficult identification of LAMP-2
cardiomyopathy.
Marzia Rigolli, MD, DPhil*
Andrew M. Kahn, MD, PhD
Michela Brambatti, MD
Francisco J. Contijoch, PhD
Eric D. Adler, MD
*University of California, San Diego
Altman Clinical and Translational Research Institute
9500 Gilman Dr, MC 0990
La Jolla, California 92093-0990
E-mail: mrigolli@ucsd.edu
https://doi.org/10.1016/j.jcmg.2020.08.011
Please note: Drs. Rigolli and Contijoch are supported by the University of Cali-
fornia, San Diego, California and the National Institutes of Health HL145817
research funds. Drs. Kahn, Brambatti, and Adler received funding from Rocket
Pharmaceuticals. Dr. Adler receives funding from the California Institute of
Regenerative Medicine. Dr. Adler has an equity interest in Rocket Pharmaceu-
ticals. Drs. Kahn and Brambatti received research funding from Rocket Phar-
maceuticals. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and
animal welfare regulations of the authors’ institutions and Food and Drug
Administration guidelines, including patient consent where appropriate. For
more information, visit the JACC: Cardiovascular Imaging author instructions
page.
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