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Danon disease(GSD2B, FORMERLY)

MedGen UID:
209235
Concept ID:
C0878677
Disease or Syndrome
Synonyms: Antopol disease; Glycogen storage cardiomyopathy; Glycogen storage disease limited to the heart; Glycogen storage disease type 2b (formerly); Glycogen Storage Disease Type IIb; GSD IIb; GSD2B (formerly); LYSOSOMAL GLYCOGEN STORAGE DISEASE WITHOUT ACID MALTASE DEFICIENCY; Lysosomal glycogen storage disease without acid maltase deficiency (formerly); Pseudoglycogenosis 2; PSEUDOGLYCOGENOSIS II; Vacuolar cardiomyopathy and myopathy X-linked
SNOMED CT: Danon disease (419097006); Glycogenosis due to LAMP-2 deficiency (419097006); Lysosomal glycogen storage disease with normal acid maltase activity (419097006); Glycogen storage disease due to LAMP-2 deficiency (419097006); Glycogen storage disease due to lysosomal associated membrane protein 2 deficiency (419097006)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): LAMP2 (Xq24)
 
Monarch Initiative: MONDO:0010281
OMIM®: 300257
Orphanet: ORPHA34587

Disease characteristics

Excerpted from the GeneReview: Danon Disease
Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Males are typically more severely affected than females. Males usually present with childhood onset concentric hypertrophic cardiomyopathy that is progressive and often requires heart transplantation. Rarely, hypertrophic cardiomyopathy can evolve to resemble dilated cardiomyopathy. Most affected males also have cardiac conduction abnormalities. Skeletal muscle weakness may lead to delayed acquisition of motor milestones. Learning disability and intellectual disability, most often in the mild range, are common. Additionally, affected males can develop retinopathy with subsequent visual impairment. The clinical features in females are broader and more variable. Females are more likely to have dilated cardiomyopathy, with a smaller proportion requiring heart transplantation compared to affected males. Cardiac conduction abnormalities, skeletal muscle weakness, mild cognitive impairment, and pigmentary retinopathy are variably seen in affected females. [from GeneReviews]
Authors:
Matthew RG Taylor  |  Eric D Adler   view full author information

Additional descriptions

From OMIM
Danon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease; 232300) with 'normal acid maltase' or alpha-glucosidase (GAA; 606800) (Danon et al., 1981). However, Nishino et al. (2000) stated that Danon disease is not a glycogen storage disease because glycogen is not always increased. Sugie et al. (2005) classified Danon disease as a form of autophagic vacuolar myopathy, characterized by intracytoplasmic autophagic vacuoles with sarcolemmal features. The characteristic vacuole is believed to be an autolysosome surrounded by secondarily-generated membranes containing sarcolemmal proteins, basal lamina, and acetylcholinesterase activity. X-linked myopathy with excessive autophagy (XMEA; 310440) is a distinct disorder with similar pathologic features.  http://www.omim.org/entry/300257
From MedlinePlus Genetics
Danon disease is a condition characterized by weakening of the heart muscle (cardiomyopathy); weakening of the muscles used for movement, called skeletal muscles (myopathy); and intellectual disabilities. People with Danon disease may develop the condition at different ages. Signs and symptoms of this condition appear about 15 years earlier in individuals with a Y chromosome (typical for males) than in individuals with two X chromosomes (typical for females). People with a Y chromosome first experience health problems in childhood or adolescence; without treatment, these individuals typically live into early adulthood. People with two X chromosomes start experiencing health problems in early adulthood and typically survive into mid-adulthood without treatment.

Cardiomyopathy is the most common symptom of Danon disease, and it occurs in all people with a Y chromosome and in most people with two X chromosomes. Beginning in childhood, most affected individuals with a Y chromosome develop hypertrophic cardiomyopathy, which is a thickening of the heart muscle that may make it harder for the heart to pump blood. Others with Danon disease may have dilated cardiomyopathy, which is a condition that weakens and enlarges the heart, preventing it from pumping blood efficiently. About half of people with Danon disease who have two X chromosomes have hypertrophic cardiomyopathy, and the other half have dilated cardiomyopathy. Rarely, individuals with hypertrophic cardiomyopathy later develop dilated cardiomyopathy. Either type of cardiomyopathy can lead to heart failure and premature death.

Individuals with Danon disease can have other heart-related signs and symptoms, including a sensation of fluttering or pounding in the chest (palpitations), an abnormal heartbeat (arrhythmia), or chest pain. Many affected individuals have abnormalities of the electrical signals that control the heartbeat (conduction abnormalities). Affected individuals often have a specific conduction abnormality known as cardiac preexcitation. The type of cardiac preexcitation most often seen in people with Danon disease is called the Wolff-Parkinson-White syndrome pattern.

Skeletal myopathy occurs in most people with Danon disease who have one Y chromosome and in some affected individuals with two X chromosomes. The weakness typically occurs in the muscles of the shoulders, neck, and upper thighs. Many individuals with Danon disease who have one Y chromosome have elevated levels of an enzyme called creatine kinase in their blood, which often indicates muscle disease.

Most people with Danon disease who have one Y chromosome have mild intellectual disabilities, but this is much less common in affected individuals with two X chromosomes.

There can be other signs and symptoms of the condition in addition to the three characteristic features. Several affected individuals have had gastrointestinal disease, breathing problems, or visual abnormalities.  https://medlineplus.gov/genetics/condition/danon-disease

Clinical features

From HPO
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Atrioventricular block
MedGen UID:
13956
Concept ID:
C0004245
Disease or Syndrome
Delayed or lack of conduction of atrial depolarizations through the atrioventricular node to the ventricles.
Primary dilated cardiomyopathy
MedGen UID:
2880
Concept ID:
C0007193
Disease or Syndrome
Familial dilated cardiomyopathy is a genetic form of heart disease. It occurs when heart (cardiac) muscle becomes thin and weakened in at least one chamber of the heart, causing the open area of the chamber to become enlarged (dilated). As a result, the heart is unable to pump blood as efficiently as usual. To compensate, the heart attempts to increase the amount of blood being pumped through the heart, leading to further thinning and weakening of the cardiac muscle. Over time, this condition results in heart failure.\n\nIt usually takes many years for symptoms of familial dilated cardiomyopathy to cause health problems. They typically begin in mid-adulthood, but can occur at any time from infancy to late adulthood. Signs and symptoms of familial dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath (dyspnea), extreme tiredness (fatigue), fainting episodes (syncope), and swelling of the legs and feet. In some cases, the first sign of the disorder is sudden cardiac death. The severity of the condition varies among affected individuals, even in members of the same family.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
Increased size of the heart, clinically defined as an increased transverse diameter of the cardiac silhouette that is greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio) on a posterior-anterior projection of a chest radiograph or a computed tomography.
Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Syncope
MedGen UID:
21443
Concept ID:
C0039070
Sign or Symptom
Syncope is a syndrome in which loss of consciousness is of relatively sudden onset, temporary (usually less than 1 to 2 minutes), self-terminating, and of usually rapid recovery. Syncope leads to a generalized weakness of muscles with loss of postural tone, inability to stand upright, and loss of consciousness. Once the patient is in a horizontal position, blood flow to the brain is no longer hindered by gravitation and consciousness is regained. Unconsciousness usually lasts for seconds to minutes. Headache and drowsiness (which usually follow seizures) do not follow a syncopal attack. Syncope results from a sudden impairment of brain metabolism usually due to a reduction in cerebral blood flow.
Ventricular tachycardia
MedGen UID:
12068
Concept ID:
C0042514
Finding
A tachycardia originating in the ventricles characterized by rapid heart rate (over 100 beats per minute) and broad QRS complexes (over 120 ms).
Wolff-Parkinson-White pattern
MedGen UID:
12162
Concept ID:
C0043202
Disease or Syndrome
Wolff-Parkinson-White syndrome is a condition characterized by abnormal electrical pathways in the heart that cause a disruption of the heart's normal rhythm (arrhythmia).\n\nThe heartbeat is controlled by electrical signals that move through the heart in a highly coordinated way. A specialized cluster of cells called the atrioventricular node conducts electrical impulses from the heart's upper chambers (the atria) to the lower chambers (the ventricles). Impulses move through the atrioventricular node during each heartbeat, stimulating the ventricles to contract slightly later than the atria.\n\nPeople with Wolff-Parkinson-White syndrome are born with an extra connection in the heart, called an accessory pathway, that allows electrical signals to bypass the atrioventricular node and move from the atria to the ventricles faster than usual. The accessory pathway may also transmit electrical impulses abnormally from the ventricles back to the atria. This extra connection can disrupt the coordinated movement of electrical signals through the heart, leading to an abnormally fast heartbeat (tachycardia) and other changes in heart rhythm. Resulting symptoms include dizziness, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, and fainting (syncope). In rare cases, arrhythmias associated with Wolff-Parkinson-White syndrome can lead to cardiac arrest and sudden death. The most common arrhythmia associated with Wolff-Parkinson-White syndrome is called paroxysmal supraventricular tachycardia.\n\nComplications of Wolff-Parkinson-White syndrome can occur at any age, although some individuals born with an accessory pathway in the heart never experience any health problems associated with the condition.\n\nWolff-Parkinson-White syndrome often occurs with other structural abnormalities of the heart or underlying heart disease. The most common heart defect associated with the condition is Ebstein anomaly, which affects the valve that allows blood to flow from the right atrium to the right ventricle (the tricuspid valve). Additionally, the heart rhythm problems associated with Wolff-Parkinson-White syndrome can be a component of several other genetic syndromes, including hypokalemic periodic paralysis (a condition that causes episodes of extreme muscle weakness), Pompe disease (a disorder characterized by the storage of excess glycogen), Danon disease (a condition that weakens the heart and skeletal muscles and causes intellectual disability), and tuberous sclerosis complex (a condition that results in the growth of noncancerous tumors in many parts of the body).
Atrial arrhythmia
MedGen UID:
39317
Concept ID:
C0085611
Pathologic Function
A type of supraventricular tachycardia in which the atria are the principal site of electrophysiologic disturbance.
Myocardial fibrosis
MedGen UID:
56239
Concept ID:
C0151654
Pathologic Function
Myocardial fibrosis is characterized by dysregulated collagen turnover (increased synthesis predominates over unchanged or decreased degradation) and excessive diffuse collagen accumulation in the interstitial and perivascular spaces as well as by phenotypically transformed fibroblasts, termed myofibroblasts.
Second degree atrioventricular block
MedGen UID:
75546
Concept ID:
C0264906
Disease or Syndrome
An intermittent atrioventricular block with failure of some atrial impulses to conduct to the ventricles, i.e., some but not all atrial impulses are conducted through the atrioventricular node and trigger ventricular contraction.
Increased QRS voltage
MedGen UID:
909971
Concept ID:
C1112650
Finding
Elevation of the voltage (height) of the QRS complex. There are several criteria in use, but the most common is the Sokolov-Lyon criterion (S wave depth in V1 + tallest R wave height in V5-V6 greater than 35 mm).
Myocardial necrosis
MedGen UID:
254841
Concept ID:
C1442837
Disease or Syndrome
Irreversible damage to heart tissue (myocardium) due to lack of oxygen after a heart attack (myocardial infarction).
Severely reduced left ventricular ejection fraction
MedGen UID:
868396
Concept ID:
C4022790
Finding
A large reduction in the fraction of blood pumped from the left ventricle with each cardiac cycle. The normal range in adults is at over 50 percent, and a severe reduction is defined as less than 30 percent.
Hypokinesia
MedGen UID:
39223
Concept ID:
C0086439
Finding
Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Exercise-induced muscle cramps
MedGen UID:
383715
Concept ID:
C1855578
Finding
Sudden and involuntary contractions of one or more muscles brought on by physical exertion.
EMG: myopathic abnormalities
MedGen UID:
867362
Concept ID:
C4021726
Pathologic Function
The presence of abnormal electromyographic patterns indicative of myopathy, such as small-short polyphasic motor unit potentials.
Lower limb amyotrophy
MedGen UID:
870475
Concept ID:
C4024921
Finding
Muscular atrophy affecting the lower limb.
Skeletal muscle autophagosome accumulation
MedGen UID:
1814214
Concept ID:
C5676640
Finding
Abnormal accumulation of autophagosomes in skeletal muscle tissue.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Danon disease in Orphanet.

Professional guidelines

PubMed

Hong KN, Eshraghian EA, Arad M, Argirò A, Brambatti M, Bui Q, Caspi O, de Frutos F, Greenberg B, Ho CY, Kaski JP, Olivotto I, Taylor MRG, Yesso A, Garcia-Pavia P, Adler ED
J Am Coll Cardiol 2023 Oct 17;82(16):1628-1647. doi: 10.1016/j.jacc.2023.08.014. PMID: 37821174
Ranganath PG, Tower-Rader A
Curr Cardiol Rep 2021 Jun 3;23(7):87. doi: 10.1007/s11886-021-01518-y. PMID: 34081227
D'souza RS, Levandowski C, Slavov D, Graw SL, Allen LA, Adler E, Mestroni L, Taylor MR
Circ Heart Fail 2014 Sep;7(5):843-9. doi: 10.1161/CIRCHEARTFAILURE.114.001105. PMID: 25228319Free PMC Article

Recent clinical studies

Therapy

Yadin D, Guetta T, Petrover Z, Alcalai R, Seidman J, Seidman CE, Ofek E, Kornowski R, Hochhauser E, Arad M
Biochem Pharmacol 2023 Sep;215:115735. Epub 2023 Aug 10 doi: 10.1016/j.bcp.2023.115735. PMID: 37572991
Zhai Y, Miao J, Peng Y, Wang Y, Dong J, Zhao X
Trends Cardiovasc Med 2023 Feb;33(2):81-89. Epub 2021 Nov 2 doi: 10.1016/j.tcm.2021.10.012. PMID: 34737089
Staikou C, Stamelos M, Stavroulakis E
Anaesthesiol Intensive Ther 2019;51(2):133-146. doi: 10.5114/ait.2019.86278. PMID: 31268275
Thakur R, Afzal A, Carey SA, Bass K, Felius J, Roberts WC, Hall SA
Rev Cardiovasc Med 2018 Jun 30;19(2):69-71. doi: 10.31083/j.rcm.2018.02.903. PMID: 31032605
Tanidir C, Tanidir IC, Tuzcu V
Cardiol Young 2015 Oct;25(7):1418-20. Epub 2014 Nov 17 doi: 10.1017/S1047951114002303. PMID: 25400066

Prognosis

Fadl SA, Revels JW, Rezai Gharai L, Hanneman K, Dana F, Proffitt EK, Grizzard JD
Radiographics 2022 May-Jun;42(3):625-643. Epub 2022 Mar 11 doi: 10.1148/rg.210147. PMID: 35275782
Darden D, Hsu JC, Tzou WS, von Alvensleben JC, Brooks M, Hoffmayer KS, Brambatti M, Sauer WH, Feld GK, Adler E
Heart Rhythm 2021 Jul;18(7):1194-1202. Epub 2021 Mar 16 doi: 10.1016/j.hrthm.2021.03.024. PMID: 33737230
Cenacchi G, Papa V, Pegoraro V, Marozzo R, Fanin M, Angelini C
Neuropathol Appl Neurobiol 2020 Jun;46(4):303-322. Epub 2019 Nov 25 doi: 10.1111/nan.12587. PMID: 31698507
Di Nora C, Miani D, D'Elia AV, Poli S, Iascone M, Nucifora G, Finato N, Sponga S, Proclemer A, Livi U
Eur J Med Genet 2020 Feb;63(2):103645. Epub 2019 Apr 5 doi: 10.1016/j.ejmg.2019.04.002. PMID: 30959184
Nelson BC, Hashem SI, Adler ED
Curr Cardiol Rep 2017 Mar;19(3):26. doi: 10.1007/s11886-017-0829-y. PMID: 28251514

Clinical prediction guides

Argiro A, Bui Q, Hong KN, Ammirati E, Olivotto I, Adler E
JACC Heart Fail 2024 Feb;12(2):248-260. Epub 2023 Oct 7 doi: 10.1016/j.jchf.2023.09.015. PMID: 37966402
Lotan D, Salazar-Mendiguchía J, Mogensen J, Rathore F, Anastasakis A, Kaski J, Garcia-Pavia P, Olivotto I, Charron P, Biagini E, Baban A, Limongelli G, Ashram W, Wasserstrum Y, Galvin J, Zorio E, Iacovoni A, Monserrat L, Spirito P, Iascone M, Arad M; Cooperating Investigators‡
Circ Genom Precis Med 2020 Dec;13(6):e003117. Epub 2020 Nov 5 doi: 10.1161/CIRCGEN.120.003117. PMID: 33151750
He J, Xu J, Chen L, Ji K, Fan X, Zhao S, Lu M
Clin Radiol 2020 Sep;75(9):712.e1-712.e11. Epub 2020 Jun 1 doi: 10.1016/j.crad.2020.04.012. PMID: 32499120
Nair V, Belanger EC, Veinot JP
Cardiovasc Pathol 2019 Mar-Apr;39:12-24. Epub 2018 Dec 1 doi: 10.1016/j.carpath.2018.11.002. PMID: 30594732
Nelson BC, Hashem SI, Adler ED
Curr Cardiol Rep 2017 Mar;19(3):26. doi: 10.1007/s11886-017-0829-y. PMID: 28251514

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