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Congestive heart failure in 22 year-old man

A 22-year-old man was addressed to the emergency department because of congestive heart failure. At clinical examination, left and right congestive heart failure was present.
Myocardial Disease


Transcient atrial fibrillation was observed. ECG was performed during sinus rhythm (see Figure1).

ECG was performed during sinus rhythm


Echocardiography exhibited enlarged left ventricle (LVEDD: 61 mm), increased wall thickness (MWTd: 15 mm), depressed systolic dysfunction (LVEF: 25%), enlarged left atrium (LA: 49 mm), mild mitral regurgitation (MR: 2/4) and elevation of systolic pulmonary artery pressure (sPAP: 65 mmHg).

 Echocardiography

The evolution during the first days of medical treatment was simple with heart failure resolution.
Past history of the patient was characterized by a diagnosis of hypertrophic cardiomyopathy at 16 years of age (wall thickness on echocardiography: : IVS 12 mm, LW 16 mm, PW 20 mm) and normal LVEF (65%). The patient also has ophtalmologic problem with choriocapillary atrophy.
Few weeks after hospital discharge, lipothymia occurred and atrio-ventricular block grade 2 was observed, alterning with atrial tachycardia. Pace maker was implanted.
Persistant elevation of CPK was also observed (2-5 fold normal values), without muscular force defect at clinical examination.

Family history was characterised by several relatives with cardiac or non cardiac problems (see pedigree).

 Family history was characterised by several relatives with cardiac or non cardiac problems

What do you think about the diagnosis of this patient ?
Which further investigation would you perform?


Diagnosis, case resolution and treatment

The patient is characterized by the atypical association of hypertrophic cardiomyopathy rapidly evolving towards systolic dysfunction, supraventricular arrhythmia alterning with atrio-ventricular block, hyperCK elevation and visual loss due to choriocapillary atrophy.
The variable association of these clinical features prompted us to considere several possible underlying causes including mitochondrial disease, AMP-kinase gamma-2 disease (PRKAG2 gene), desminopathy, glycogen storage disease (such as Pompe’s disease or Danon’s diasease).

Skeletal muscle biopsy was performed in the patient because of CK elevation. Light microscopy demonstrated some sarcoplasmic clear vacuoles (see the figure below), that were PAS-positive (periodic acid Schiff). Immunohistochemical study indicated the presence of dystrophin on vacuole membranes. In contrast, immunohistochemistry with antibodies against LAMP-2 protein failed to detect any material, demonstrating that LAMP-2 protein was absent in the skeletal muscles of the patients. All these features are typical of Danon’s disease.
Sequencing of the LAMP-2 gene was performed in the patient and led to the identification of a hemizygous 7 pb deletion in exon 1 (173_179del, responsible for a premature stop codon) of the gene. The heterozygous mutation was also present in the mother.

Danon’s disease is an X-linked lysosomal disease, with normal acid maltase, due to a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in cardiac and skeletal muscle cells. The phenotype typically associated with mutations in the LAMP-2 gene is characterized by the triad of cardiomyopathy, skeletal myopathy, and mental retardation. In fact, skeletal myopathy is mild in most cases (85% in the largest studied population), but all male patients had elevated serum CK level, and mild mental retardation is observed in only 70%. In addition, Wolff-Parkinson-White syndrome, or preexcitation, is present in 35%, and ophtalmogic abnormalities with visual loss were reported in several patients. Women are typically less severely affected than males, with later-onset cardiomyopathy.
Mutations of the LAMP-2 gene usually lead to truncated proteins that are lacking the transmembrane domain, and can not function as a structural lysosomal membrane protein. Beyond the structural role of the protein, LAMP-2 may also have aditional role through autophagic vacuoles. 

No specific treatment is currently available. The correct identification of Danon disease is however important, as the pathophysiology, clinical evolution, prognosis, mode of inheritance (X-linked), and therefore genetic counselling, are very different.


Conclusion:

The natural history of Danon’s disease is particularly important to consider as it is characterized in male patients by an early onset and a very poor prognosis. This was the case in our patient with recurrent heart failure. He died at 25 years while waiting for heart transplantation. In the largest population studied so far (20 male subjects with Danon disease), mean age at onset was before 20 years in all cases and all subjects except one died before 30 years. Deaths were related to LV dysfunction and congestive heart failure, or sudden death. This is in contrast with the natural history of HCM, where cardiac death is evaluated to be about 1-2% per year and evolution towards heart failure in only 10%.
The severe cardiac evolution was underlined in another recent study (6 young boys, out of 7, developed cardiac death, aborted sudden death or heart transplantation over a mean follow-up of 8 years). These observations underscore the importance of timely diagnosis and early consideration of heart transplantation.

References


1. Danon MJ, Oh SJ, DiMauro S, et al. Lysosomal glycogen storage disease with normal acid maltase.  Neurology 1981;31:51-57.
2. Nishino I, Fu J, Tanji K, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 2000;406:906-909.
3. Sugie K, Yamamoto A, Murayama K, et al. Clinicopathological features of genetically confirmed Danon disease. Neurology  2002;58:1773-1778.
4. Charron P, Villard E, Sébillon P, et al. Danon’s disease as a cause of Hypertrophic cardiomyopathy: a systematic survey. Heart 2004;90(8):842-6.
5. Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. 2005;352(4):362-72.
6. Echaniz-Laguna A, Mohr M, Epailly E, et al. Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease. Muscle Nerve. 2006;33(3):393-7.
7. Maron BJ, Roberts WC, Arad M, et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA. 2009;301(12):1253-9.

Notes to editor


Presented by Dr Philippe Charron, Centre de référence Maladies cardiaques héréditaires, Hôpital Pitié-Salpêtrière & Université Paris 6, France.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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