/
/

Danon disease

This is part of Rare diseases.

Diagnosis: Danon disease

Synonyms: Lysosomal-associated membrane protein 2, LAMP2

Innehåll


Date of publication: 2014-10-09
Version: 2.0

ICD 10 code

I43.1

The disease

Danon disease is characterised by heart failure, muscle weakness, and sometimes cognitive impairment in males. The cardiac condition in Danon disease is caused by hypertrophic cardiomyopathy, in which the heart muscle gradually thickens and weakens.

The disease was first described in 1981 by the American neurologist Moris J. Danon and his associates, and belongs to the lysosomal group of diseases. Lysosomes are small cellular subunits present in all cells of the body except for red blood cells, and can be described as the cell’s recycling centre. The role of lysosomes is to deal with and break down different substances. They do this with the help of enzymes, types of protein which contribute to chemical processes without themselves being broken down. This disassembly process frees the component parts of certain substances, and in this way proteins are broken down into amino acids. A re-cycling system is created as, after they have been freed, these components are transported out of the lysosomes and can be used by cells to produce new substances.

All lysosomal diseases share either an impairment of lysosomal function caused by impaired functionality in one of the lysosome’s enzymes, or a deficiency in the transport proteins which carry substances into or out of lysosomes.

Currently, we know of approximately seventy different lysosomal diseases. Some other examples are: aspartylglykosaminuria, cystinosis, Fabry disease, Gaucher disease, GM2 gangliosidosis, Krabbe disease, mannosidosis, metachromatic leukodystrophy, mucopolysaccharidoses I, II, III, IV, VI and VII, Pompe disease and Salla disease. Separate information on these diseases is available in the rare disease database of the Swedish National Board of Health and Welfare.

Occurrence

There is no definite information to indicate how common the disease is. Approximately ten people in Sweden have been diagnosed with Danon disease.

Cause

The cause is a mutation in the LAMP2 gene (lysosomal-associated membrane protein 2). The gene is located on the X chromosome (Xq24) and controls the production of (codes for) the protein constituent in the complex molecule LAMP2, a glycoprotein consisting of sugars and protein. LAMP2 is found in the inner membrane of lysosomes, its function being to protect the membrane from being broken down by enzymes within the lysosomes themselves, and to help transport materials into and out of the lysosomes. An absence of LAMP2 causes an accumulation of glycogen and of mitochondrial debris. (Mitochondria are units in the cell which produce energy). These materials are encapsulated in membranes (vesicles) in different tissues, primarily in cardiac and skeletal musculature. These vesicles are thought to contain pathologically altered lysosomes. The exact mechanism involved in the breaking down of lysosomes is not fully understood. Also associated with Danon disease is damage to the retina of the eye. The reason for this is not yet known.

The accumulation of glycogen in the tissues is similar to what happens in Pompe disease. (See the Swedish National Board of Health and Welfare’s database of rare diseases.) However, in Danon disease, acid maltase enzyme activity is normal.

Heredity

The inheritance pattern of Danon disease is X-linked dominant, which means that the gene causing the disease is located on an X chromosome. A person needs only one copy of the affected X chromosome to develop symptoms and, as men have only one X chromosome, they always develop the disease. They develop it at an earlier age and in a more severe form than women. As women have two X chromosomes and only one of them is affected, they develop symptoms later in life. A woman who carries the mutated gene has a 50 per cent chance of passing it on to her children. Men with the affected gene pass on the disease to all their daughters, while their sons never develop the disease as they inherit only a Y chromosome from their fathers.

Figure: X-linked dominant inheritance via a female carrier with the disease

Figure: X-linked dominant inheritance via a male carrier with the disease

Symptoms

Characteristic symptoms of Danon disease are a combination of heart failure and muscular weakness, frequently accompanied in males by mild cognitive impairment or learning difficulties. As muscular weakness and cognitive disability are initially difficult to identify, the correct diagnosis is often not made until cardiac symptoms present. The nature of symptoms varies between men and women with the disease. Men have more numerous and more severe symptoms, while in women the primary symptom is heart disease, which develops later in life.

Men

Males with the disease usually present with cardiac symptoms during their teens, often between the ages of 15 and 19. Symptoms include irregular pulse, accelerated heartbeat (tachycardia), fainting and breathlessness. There are a few men who do not become ill until their forties. In some cases, the disease is discovered only after sudden cardiac death.

Muscle weakness affects mainly the proximal muscles of the shoulders, pelvis/thighs and neck. Slight weakness may present from early childhood. The weakness is slowly progressive but never becomes severe.

Most males with the disease have learning problems or mild cognitive impairments.

Sight is also commonly affected, mainly in the central field of vision, but this seldom leads to serious visual impairment.

The liver and spleen may become enlarged, although symptoms are not usually serious.

Women

Cardiac symptoms present later in women than in men, usually at between the ages of 30 and 45. Symptoms develop gradually, in the form of slowly progressive heart failure.

Muscle weakness is uncommon in females. Sight may be affected, but usually to a lesser extent than in men. The disease seldom causes developmental or learning difficulties in women.

For most people with Danon disease, the illness leads to early death from heart failure. Without a heart transplant most men die between the ages of 20 and 30, and women at approximately 50.

Diagnosis

In males, typical symptoms of heart failure, muscular weakness and mild cognitive impairment lead to a suspected diagnosis of Danon disease. The diagnosis can be confirmed with the help of a tissue analysis and a DNA analysis. It is common that the disease is suspected in women only after a male in the family has been diagnosed. In families where the diagnosis has been confirmed, it is often discovered that women have the disease although their symptoms are mild, or even absent. For this reason they have not previously been diagnosed correctly.

A 24-hour ECG (electrocardiogram) test is carried out on the heart, as well as ultrasound and MRI (magnetic resonance imaging) examinations. In many cases, irregularities in the electrical impulses of the heart and irregular cardiac rhythms are found. The heart is enlarged and the heart muscle is thickened, especially the wall between the two chambers of the heart (septum), and the wall of the left ventricle. At a later stage the heart becomes weakened and further enlarged (dilated cardiomyopathy).

Blood tests reveal signs of heart failure (elevated proBNP levels) and damage to muscle fibres (elevated CK levels). An EMG (electromyography) may indicate muscle disease.

Tissue samples from either the skeletal or cardiac muscles (muscle biopsy) show an accumulation of glycogen, and fluid-filled blisters in cells (vacuoles). Muscle tissue is also analysed to see if LAMP2 protein is present in muscle fibres. An absence of LAMP2 indicates a definite diagnosis.

The diagnosis can be confirmed by DNA analysis. At the time of diagnosis, the family should be offered genetic counselling. Carrier and prenatal diagnosis, and also pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

As yet there is no cure for Danon disease. Instead, the focus is on alleviating symptoms and providing good-quality care. Treatment is usually carried out in a hospital medical department.

Cardiac function should be regularly monitored both with regard to irregular pulse (arrhythmia) and cardiac insufficiency. An ECG (electrocardiogram) needs to be taken over a longer period to judge the degree of arrhythmia. Medication is given in cases of heart failure. Certain types of arrhythmia can be treated by a procedure where a catheter is threaded through the patient’s blood vessels to reach the heart in order to treat (by freezing or using radio waves) those parts of the heart where the abnormal impulses originate. In other cases a defibrillator, (ICD, implantable cardiac defibrillator) is necessary. This can identify a pathological heart rhythm and restore it to normality by means of electrical impulses. Medication to treat arrhythmia has little effect in Danon disease.

The option of heart transplant should be considered at an early stage, particularly in the case of young men with the disease. The option should also be considered for women, who can develop symptoms of heart failure later in life. As yet, too few people with Danon disease have undergone a heart transplant to be able to judge the results.

Keeping fit is important, but exercise should be frequent rather than strenuous, bearing in mind the presence of heart disease and muscle weakness. Exercise should take place in collaboration with a physiotherapist with a good knowledge of both heart failure and muscle weakness.

Boys with learning difficulties may require habilitation. These measures should be planned on the basis of existing needs and in collaboration with people close to the child. Habilitation teams include professionals with expertise on disabilities and their effects on health, development and everyday life. Help is available within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. Information is also given about support from the local authorities. The whole family should be offered support.

It is possible that adults with the disease will continue to require habilitation programmes. Contact with the specialist clinic should also continue.

Practical advice

It is important to avoid coffee and other drinks with high levels of caffeine (such as energy drinks) which can aggravate cardiac arrhythmia.

National and regional resources in Sweden

Departments of Clinical Genetics at Sweden’s university hospitals collaborate with medical units providing treatment.

Resource personnel

Associate Professor Göran Solders, Neurology Department, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00, email: goran.solders@karolinska.se.

Courses, exchanges of experience, recreation

--

Organizations for the disabled/patient associations etc.

Scandinavian Association for Glycogen Storage Disease, email: postmaster@sagsd.org, www.sagsd.org.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities, Box 6436, Gävlegatan 18 C, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

Courses, exchanges of experience for personnel

--

Research and development

--

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under, “Mer hos oss” in the column on the right-hand side.

Literature

Arad M, Maron BJ, Gorham JM, Johnson WH Jr, Saul JP, Perez-Atayde AR et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005; 352: 362-372.

August DA. Anesthetic implications of Danon disease. Paediatr Anaesth 2009; 10: 1026-1028.

Charron P, Villard E, Sébillon P, Laforet P, Maisonobe T, Duboscq-Bidot L et al. Danon’s disease as a cause of hypertrophic cardiomyopathy: a systematic survey. Heart 2004; 90: 842-846.

Cheng Z, Fang Q. Danon disease: focusing on heart. J Hum Genet 2012; 57: 407-410.

Danon MJ, Oh SJ, DiMauro S, Manaligod JR, Eastwood A, Naidu S et al. Lysosomal glycogen storage disease with normal acid maltase. Neurology 1981; 31: 51-57.

Di Mauro S, Tanji K, Hirano M. LAMP-2 deficiency (Danon disease). Acta Myol 2007; 26: 79-82.

Echaniz-Laguna A, Mohr M, Epailly E, Nishino I, Charron P, Richard P et al. Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease. Muscle Nerve 2006; 33: 393-397.

Kashio N, Usuki F, Akamine T, Nakagawa S, Higuchi I, Nakahara K et al. Cardiomyopathy, mental retardation, and autophagic vacuolar myopathy. Abnormal MRI findings in the head. J Neurol Sci 1991; 105: 1-5.

Konecki DS, Foetisch K, Zimmer KP, Schlotter M, Lichter-Konecki U. An alternatively spliced form of the human lysosome-associated membrane protein-2 gene is expressed in a tissue-specific manner. Biochem Biophys Res Commun 1995; 215: 757-767.

Majer F, Vlaskova H, Krol L, Kalina T, Kubanek M Stolnaya L et al. Danon disease: a focus on processing of the novel LAMP mutation and comments on the beneficial use of peripheral white blood cells in diagnosis of LAMP2 deficiency. Gene 2012; 498: 183-195.

Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009; 301: 1253-1259.

Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 2000; 406: 906-910.

Prall FR, Drack A, Taylor M, Ku L, Olson JL, Gregory D. Ophthalmic manifestations of Danon disease. Ophthalmology 2006; 113: 1010-1013.

Ruivo R, Anne C, Sagné C, Gasnier B. Molecular and cellular basis of lysosomal transmembrane protein dysfunction. Biochim Biophys Acta 2009; 1793: 636-649.

Sabourdy F, Michelakakis H, Anastasakis A, Garcia V, Mavridou I, Nieto M et al. Danon disease: further clinical and molecular heterogeneity. Muscle Nerve 2009; 39: 837-844.

Schorderet DF, Cottet S, Lobrinus JA, Borruat FX, Balmer A, Munier FL. Retinopathy in Danon disease. Arch Ophthalmol 2007; 125: 231-236.

Spinazzi M, Fanin M, Melacini P, Nascimbeni AC, Angelini C. Cardioembolic stroke in Danon disease. Clin Genet 2008; 73: 3883-3890.

van der Kooi AJ, van Langen IM, Aronica E, van Doorn PA, Wokke JH, Brusse E. Extension of the clinical spectrum of Danon disease. Neurology 2008; 70: 1358-1359.

Yang Z, McMahon CJ, Smith LR, Bersola J, Adesina AM, Breinholt JP et al. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation 2005; 112: 1612-1617.

Yanf Z, Vatta M. Danon disease as a cause of autophagic vacuolar myopathy. Congenit Heart Dis 2007; 2: 404-409.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: Danon disease

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Göran Solders, Karolinska University Hospital, Stockholm, Sweden.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2014-10-09
Version: 2.0
Publication date of the Swedish version: 2014-02-27

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.