Danon Disease

Danon Disease

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Danon Disease is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • GSD IIB
  • Antopol disease
  • glycogen storage cardiomyopathy
  • glycogen storage disease type IIB
  • lysosomal glycogen storage disease without acid maltase deficiency
  • pseudoglycogenosis II
  • vacuolar cardiomyopathy and myopathy, X-linked

Disorder Subdivisions

  • None

General Discussion

Danon disease is a rare genetic disorder characterized by an X-linked dominant inheritance pattern, as a result of which males are more severely affected than females. Among boys, the key features are diseased heart muscle (cardiomyopathy), weakness of the body muscles (skeletal myopathy) and intellectual disability ranging from mild learning problems to overt intellectual disability. In many males, the disease progresses until a heart transplant is required or death occurs in the second to third decade of life. Females are also affected, although usually more mildly, and often onset is delayed until they reach adulthood. However, some females will progress to being considered for cardiac transplantation during their second decade of life, similar to what is observed in males. Other features include heart arrhythmias, which can lead to a need for medications or a pacemaker, and eye disease affecting the retina; the retinal disease does not always affect vision, especially early in the disease. Danon disease is not usually evident at birth unless blood tests are done in a suspected case (i.e. a son born to a mother known to have the disease).

Symptoms

Symptoms of Danon disease vary from case to case and depend on gender. Boys usually show early signs of muscle problems (difficulty sitting or walking) and motor skills may be awkward or delayed. Intellectual disability is usually noticed by parents and/or teachers and can be quite mild. The development of heart disease can lead to further fatigue and shortness of breath. In general, young girls may have no symptoms and will report normal muscle strength and have normal intellect. As females age, symptoms of heart disease can begin to develop. Muscle symptoms are reported by some girls and women but overt findings of frank muscle weakness are usually absent. Visual complaints may also be reported in women and can be an early feature of the disease.



Clinical researchers believe that the skeletal muscle disease preferentially involves the muscles of the back, shoulder, upper legs and the neck muscles. These are the proximal muscles; that is, those closest to the center of the body. Symptoms of weakness in these muscles can include back pain and difficulty raising one's arms over the head, getting out of a chair, or walking up steps. In a young boy, these problems may be suggested by problems meeting motor milestones (sitting, crawling, and walking, running). An experienced neurologist can recognize the extent of muscle disease by performing a physical examination.



The diseased heart muscle (cardiomyopathy) can lead to a thickened, stiff heart (hypertrophic cardiomyopathy) or to an enlarged heart (dilated cardiomyopathy). Hypertrophic cardiomyopathy is more common in males, whereas females are more apt to show features of dilated cardiomyopathy. Sometimes the cardiomyopathy can be the first sign of disease in male children. In both instances, problems with heart function and symptoms of heart failure (shortness of breath, fatigue, fluid gain) can occur. Death from the heart disease seems to occur frequently in males, especially as they reach the second and third decades of life. Heart transplantation has been performed successfully and can greatly improve symptoms and extend life.



The extent of intellectual disability in affected males remains unclear. In the original description of Danon disease, the intellectual disability was classified as a form of mental retardation. However, it is clear that some boys will be more mildly affected. Furthermore, providing education and learning support may help some boys improve their intellectual functioning. In women, intellect appears to be normal, although very little information in the literature addresses this question.



Males with Danon disease typically have abnormalities on certain laboratory tests. The creatine kinase (sometimes referred to as the CPK level) in the blood is often elevated, and is a reflection of ongoing muscle damage. The CPK is usually elevated in males, but can be normal in some females who have Danon disease. Abnormalities in liver function tests are common in males; in some cases these are mistakenly interpreted as a sign of primary liver disease rather than a reflection of skeletal muscle dysfunction. The electrocardiogram (ECG), which measures electrical impulses made by the heart, is often abnormal. Frequently, a conduction abnormality called Wolff-Parkinson-White syndrome or a pre-excitation syndrome will be seen on the ECG. An examination of the retina by an experienced eye doctor (ophthalmologist) will often detect changes in the pigment of the retina. This can be a useful sign in women, as the retinal changes appear to precede other symptoms of the disease in some cases.

Causes

Danon disease is caused by a genetic defect (mutation) in a gene called LAMP2. In many instances the disease is inherited from a parent, typically the mother who is far more apt to remain healthy enough to reach reproductive age than the typically affected male. Without a heart transplant, only a few males may be healthy enough to father their own children. New genetic mutations (sporadic mutations) could also account for the first case in a family, but these have not been widely reported. Affected mothers will pass on the genetic defect to half of their children (both sons and daughters). Affected fathers who are healthy enough to have children will pass on the genetic defect to all of their daughters and none of their sons. This pattern of inheritance is consistent with what occurs in other X-linked genetic conditions.



Since females have two X chromosomes (and males have one), females are somewhat protected from the Danon disease genetic defect. This is explained by the fact that each woman with Danon disease is expected to have one mutated X chromosome (containing a Danon disease mutation) and one normal X chromosome (where the LAMP2 gene is functioning normally). The normal X chromosome protects females and explains, in part, the less severe symptoms and the delay in onset of symptoms until adulthood. However, some women with Danon disease have progressed to the point of needing a heart transplant.



The location of the malfunctioning gene has been traced to gene map locus Xq24. The genetic characteristics of this gene (LAMP2) are transmitted as an X-linked dominant trait.



Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq24" refers to band 24 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.



All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.



X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is turned off. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.



X-linked dominant disorders, like Danon disease, are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive. In the case of Danon disease, males can survive to adulthood, however, their medical problems and the typical need for heart transplantation likely limits their ability to have many children.



The function of the LAMP2 protein (made from the LAMP2 gene) is not well understood. It appears that the LAMP2 protein is important for the function of the cell's lysosomes. Lysosomes, often compared to waste disposal plants, are small structures inside cells that are responsible for breaking down certain molecules and compounds in cells. When the lysosomes do not function properly, cellular products accumulate. One such product that may build-up is glycogen and in some cases the diagnosis of Danon disease is suggested because of excess glycogen seen on a skeletal muscle biopsy. However, it is important to realize that excess glycogen is not always visible on a single muscle biopsy.

Affected Populations

At present, it is thought that Danon disease can affect all ethnic populations. As discussed, males are more severely affected in this X-linked dominant disease.

Standard Therapies

Diagnosis

Because Danon disease is rare and unfamiliar to most physicians, diagnosis is difficult and takes substantial time. The diagnosis is suggested on the basis of a family history compatible with X-linked dominant inheritance and symptoms in affected relatives (cardiomyopathy, skeletal myopathy, intellectual disability, Wolff-Parkinson White, etc.). Skeletal muscle biopsy is probably done in some males in an effort to determine the cause of muscle weakness. If, in the course of examining the biopsy materials, glycogen buildup and/or empty spaces appear in the cells of the muscle tissue (vacuolization), Danon disease must be considered. This also holds true for the analysis of a heart biopsy. A muscle biopsy that yields evidence of glycogen build-up and empty spaces in the muscle cells are key signs and indications that a diagnosis of Danon disease is a high probability.



It is important to recognize that, in early stages of Danon disease, and probably also in women, the muscle biopsy can be non-specific. Thus, a normal or non-specific muscle biopsy does not exclude Danon disease. If other features of Danon disease are present, a non-diagnostic muscle biopsy should not discourage more definitive genetic testing. Patients who appear to have Pompe disease (based on muscle biopsy for instance) but have normal acid maltase activity, should be evaluated for Danon disease. Unexplained hypertrophic cardiomyopathy in males is probably due to Danon disease in some proportion of cases.



Genetic testing of the LAMP2 gene is available in specialized genetics laboratories. Most genetic mutations causing Danon disease predict reduced levels or even absence of the LAMP2 gene product, the LAMP-2 protein. Although the sensitivity of LAMP2 genetic testing is not known at this time, it is the best that is available. Antibodies to the LAMP-2 protein are available and tissue staining (of a muscle biopsy) for the absence of LAMP-2 protein is another potential, but not widely available, diagnostic approach. LAMP-2 antibody testing is likely to be normal in women with Danon disease and if done should be interpreted with caution due to the possibility of a false-negative result.



Treatment

The treatment of Danon disease is directed toward the specific symptoms that are apparent in each individual. It requires a team that should include a primary care physician as well as several specialists, including a cardiologist, neurologist, ophthalmologist, geneticist, genetic counselor, rehabilitation physician, educational specialist, and physical therapist. Currently there is no specific therapy that is known to slow the underlying biological problems caused by LAMP-2 protein deficiency.



Physical therapy can be helpful in maintaining muscle strength and flexibility. Medications for heart disease should be given when indicated by clinical signs and symptoms. The rapid progression of the cardiomyopathy in some males necessitates prompt consideration for heart transplantation. Intellectual disability should be screened for in males and appropriate educational interventions applied as needed. Regular eye examinations, to track the development and progression of retinal disease, should be considered. Biological relatives who are at risk for Danon disease should be evaluated by a physician for early signs of disease. At a minimum, evaluation of such relatives should include a medical history, physical examination (attention to cardiac, neurological, and ocular exams), CPK testing, ECG, and echocardiogram. Genetic consultation and counseling is recommended for all patients and families so that inheritance and reproductive risks are clearly communicated.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Danon disease results from a missing protein, LAMP-2. Other diseases that result from insufficiency or lack of other proteins have been successfully treated with protein replacement therapies. This approach is theoretically possible in Danon disease, but has not been developed to date. There is no evidence or rational to support a high protein diet to treat Danon disease and any protein replacement effort would have to involve the LAMP-2 protein.



A researcher in Colorado, Matthew Taylor, MD, PhD, has developed a registry of Danon disease patients and families to collect information that may advance the understanding of this disease and be helpful in the future development of treatments. He may be contacted at:



Matthew Taylor, MD, PhD

Adult Medical Genetics Program

Colorado Lysosomal Storage Disease Center

12700 East 19th Avenue, F442, Room 8022

Aurora, CO 80045

Email: matthew.taylor@ucdenver.edu

Web site: www.danondisease.org

Phone: 303-724-1400

References

TEXTBOOK

Hirschhorn R, Reuser AJJ. Glycogen Storage Disease Type II: Lysosomal Glycogen Storage Diisease Without a-Glucosidase Deficiency (Danon Disease). In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill Companies; 2001:3410.



JOURNAL ARTICLES

Boucek D, Jirikowic J, Taylor M. Natural history of Danon disease. Genet Med. 2011;13(6):563-8. PMID: 21415759 [PubMed - indexed for MEDLINE]



Stevens-Lapsley JE, Kramer LR, Balter JE, Jirikowic J, Boucek D, Taylor M. Functional performance and muscle strength phenotypes in men and women with Danon disease. Muscle Nerve. 2010;42(6):908-14. PMID: 21104865 [PubMed - indexed for MEDLINE]



Eskelinen EL. Roles of LAMP-1 and LAMP-2 in lysozyme biogenesis and autophagy. Mol Aspects Med. 2006;27:495-502.



Prall FR, Drack A, Taylor M, Ku L, et al. Ophthalmic manifestions of Danon disease. Ophthalmology. 2006;113:1010-13.



Fanin M, Nascimbeni AC, Fulizio L, Spinazzi M, Melacini P, Angelini C. Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease. Am J Pathol. 2006;168:1309-20.



Echaniz-Laguna A, Mohr M, Epailly E, Nishino I, et al. Novel LAMP-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease. Muscle Nerve. 2006;33:393-97.



Yang Z, McMahaon CJ, Smith LR, Bersola J, et al. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation. 2005;112:1612-17.



Balmer C, Ballhausen D, Bosshard NU, Steinmann B, et al. Familial X-linked cardiomyopathy (Danon disease) : diagnostic confirmation by mutation analysis of the LAMP2 gene. Eur J Pediatr. 2005;164:509-14.



Sugie K, Noguchi S, Kozuka Y, Arikawa-Hirasawa E, et al. Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies. J Neuropathol Exp Neurol. 2005;64:513-22.



Charron P, Villard E, Sebillon P, Laforet P, et al. Danon's disease as a cause of hypertrophic cardiomyopathy : a systematic survey. Heart. 2004;90:842-46.



Sugie K, Yamamoto A, Murayama K, Oh SJ, et al. Clinicopathological features of genetically confirmed Danon disease. Neurology. 2002;58 :1773-78.



Nishino I, Fu J, Tanji K, Yamada T, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. 2000;406 :906-10.



INTERNET

Danon disease. Geneva Foundation for Medical Education and Research. www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=1480. Edited September 30, 2011. Accessed February 22, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Danon Disease. Entry No: 300257. Last Edited May 12, 2010. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed February 22, 2012.



Froissart R, Maire I. Danon disease. Orphanet encyclopedia, November 2004 . www.orpha.net/data/patho/GB/uk-Danon.pdf. Accessed February 22, 2012.



Welcome to DanonDisease.org. DanonDisease.org.

www.danondisease.org. Accessed February 22, 2012.

Resources

Association for Glycogen Storage Disease

P.O. Box 896

Durant, IA 52747

USA

Tel: (563)514-4022

Fax: (563)514-4022

Email: info@agsdus.org

Internet: http://www.agsdus.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Adult Medical Genetics Program, University of Colorado

12700 East 19th Avenue

F442, Room 8022

Aurora, CO 80045

Tel: (303)724-1400

Fax: (303)724-0020

Internet: http://www.uch.edu/conditions/genetics/get-care/ and http://www.danondisease.org



Hide & Seek Foundation for Lysosomal Disease Research

6475 East Pacific Coast Highway Suite 466

Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org



DanonDisease.org

12700 East 19th Avenue

F442, Room 8022

Aurora, CO 80045

Tel: (303)724-1400

Fax: (303)724-0858

Email: matthew.taylor@ucdenver.edu

Internet: http://www.danondisease.org



For a Complete Report

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