Author + information
- María Villalba-Orero, DVM, PhD,
- Gentzane Sánchez-Elexpuru, MSc,
- Marina López-Olañeta, MLT,
- Oscar Campuzano, PhD,
- Elisabet Bello-Arroyo, MS,
- Pablo García-Pavía, MD, PhD,
- José M. Serratosa, MD, PhD,
- Ramón Brugada, MD, PhD,
- Marina P. Sánchez, PhD and
- Enrique Lara-Pezzi, PhD∗ ()
- ↵∗Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro, 3, 28029 Madrid, Spain
Inherited metabolic storage cardiomyopathies, often clinically misdiagnosed, compose a small, but important, fraction of patients genotyped with clinical suspicion of hypertrophic cardiomyopathy (HCM, ≤1%). Overall, glycogen metabolism disorders affect energy homeostasis, primarily in skeletal muscle, heart, liver, and, less frequently, the central nervous system. These rare diseases are quite variable regarding age of onset, symptoms, morbidity, and mortality. Typical pathologic vacuoles containing glycogen or intermediary metabolites altering cardiac structure and function are usually described in Pompe, Danon, and Fabry diseases as well as in patients with mutations in PRKAG2, the regulatory γ subunit of AMP-activated protein kinase. In affected patients, these multisystem disorders may cause left ventricular hypertrophy that could accompany neuromuscular deficits, liver and/or kidney dysfunction, and abnormalities of the peripheral central nervous system (1,2).
Lafora disease (LD) is a rare neurodegenerative disease (<5/1,000,000) mainly present in Mediterranean countries and consanguineous regions, although its exact prevalence is unknown. It manifests during adolescence with neurological symptoms that eventually lead patients to a vegetative state and premature death. There is no treatment available, apart from antiepileptic drugs and palliative support. LD is caused by mutations in laforin (EPM2A) or malin (EPM2B), which are key regulators of glycogen metabolism. Patients with LD show abnormal glycogen deposits called Lafora bodies, in brain, skeletal muscle, skin, liver, and the heart. The accumulation of Lafora bodies as a result of laforin or malin deficiency has recently led some authors to consider LD as a new member of the family of glycogen storage diseases (3). Although rhythm disturbances and heart failure have been reported in some patients with LD (4), the consequences of laforin or malin loss for cardiac function over time have not been explored.
To address this question, we blindly assessed cardiac function and remodeling in 2 previously described mouse models of LD, lacking either laforin (Epm2a-/-) or malin (Epm2b-/-), which show evident neurological abnormalities beginning at 8 to 10 months of age (5). Experiments were conducted in accordance with the guidelines of the Institutional Animal Welfare Committee. Echocardiography analysis, performed in 2 separate groups of mice at 8 to 10 months of age and at 14 to 16 months of age under light anesthesia, revealed that laforin and malin knockout mice develop cardiac hypertrophy and marked systolic dysfunction by 14 to 16 months of age, as indicated by an increased end-diastolic left ventricular wall thickness and normalized cardiac mass, and a decreased left ventricular ejection fraction (Table 1). Histological assessment showed abundant glycogen aggregates inside the cardiomyocytes, including typical Lafora bodies, and increased cardiomyocytes area in both LD mouse lines. In addition, LD mice showed increased normalized cardiac weight (heart weight to tibial length ratio) and B-type natriuretic peptide expression, confirming the presence of cardiac hypertrophy and dysfunction (Table 1).
These pathological features resemble the inherited metabolic cardiomyopathies of human multisystem glycogen-storage disorders caused by mutations in genes regulating glycogen metabolism. Overall, our results strongly suggest that cardiac studies should be systematically performed in patients with LD, that laforin and malin deficiency should be considered part of the genetic spectrum of metabolic HCM, and that HCM patients with an unknown underlying genetic cause might benefit from genetic screening of laforin and malin genes, especially if neurological symptoms are also present.
Please note: This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2015-65722-R to Dr. Lara-Pezzi and SAF2014-59594-R to Dr. Serratosa), Autonomous Community of Madrid (2010-BMD2321, FIBROTEAM Consortium), European Union’s FP7 (CardioNeT-ITN-289600, CardioNext-ITN-608027), the Spanish Carlos III Institute of Health (CPII14/00027 to Dr. Lara-Pezzi, PI13/00865 to Dr. Sanchez and RD12/0042/066 to Drs. García-Pavía and Lara-Pezzi), and the National Institute of Neurological Disorders And Stroke of the National Institutes of Health (P01NS097197 to Dr. Sánchez). This work was also supported by the Plan Estatal de I+D+I 2013-2016-European Regional Development Fund (FEDER) “A way of making Europe,” Spain. The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Ms. Sánchez-Elexpuru is supported by a fellowship from the Fundacion Conchita Rabago. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Michell M. Kittleson, MD, PhD, served as Guest Editor for this paper. Drs. Villalba-Orero and Sánchez-Elexpuru contributed equally to this work.
- 2017 American College of Cardiology Foundation
- Maron B.J.,
- Maron M.S.,
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