Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)
- Basil T Darras, MD
Basil T Darras, MD
- Professor of Neurology
- Harvard Medical School
- William J Craigen, MD, PhD
William J Craigen, MD, PhD
- Professor of Molecular and Human Genetics
- Baylor College of Medicine
Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).
There are a number of inborn errors of glycogen metabolism that result from mutations in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.
Glycogen is most abundant in liver and muscle, which are most affected by these disorders. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease.
●The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus".)
●Glycogen serves as the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance and easy fatigability, and progressive weakness.
- Viéitez I, Teijeira S, Miranda S, et al. Gene symbol: LAMP2. Disease: Glycogen storage disease 2b. Hum Genet 2008; 123:113.
- Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 2003; 13:137.
- 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.
- Maron BJ, Roberts WC, Arad M, et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009; 301:1253.
- Di Blasi C, Jarre L, Blasevich F, et al. Danon disease: a novel LAMP2 mutation affecting the pre-mRNA splicing and causing aberrant transcripts and partial protein expression. Neuromuscul Disord 2008; 18:962.
- Bui YK, Renella P, Martinez-Agosto JA, et al. Danon disease with typical early-onset cardiomyopathy in a male: focus on a novel LAMP-2 mutation. Pediatr Transplant 2008; 12:246.
- Regelsberger G, Höftberger R, Pickl WF, et al. Danon disease: case report and detection of new mutation. J Inherit Metab Dis 2009; 32 Suppl 1:S115.
- Yang Z, Funke BH, Cripe LH, et al. LAMP2 microdeletions in patients with Danon disease. Circ Cardiovasc Genet 2010; 3:129.
- Csányi B, Popoiu A, Hategan L, et al. Identification of Two Novel LAMP2 Gene Mutations in Danon Disease. Can J Cardiol 2016; 32:1355.e23.
- Cottinet SL, Bergemer-Fouquet AM, Toutain A, et al. Danon disease: intrafamilial phenotypic variability related to a novel LAMP-2 mutation. J Inherit Metab Dis 2011; 34:515.
- Danon MJ, Oh SJ, DiMauro S, et al. Lysosomal glycogen storage disease with normal acid maltase. Neurology 1981; 31:51.
- Sugie K, Yamamoto A, Murayama K, et al. Clinicopathological features of genetically confirmed Danon disease. Neurology 2002; 58:1773.
- Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med 2005; 352:362.
- Dworzak F, Casazza F, Mora M, et al. Lysosomal glycogen storage with normal acid maltase: a familial study with successful heart transplant. Neuromuscul Disord 1994; 4:243.
- van der Kooi AJ, van Langen IM, Aronica E, et al. Extension of the clinical spectrum of Danon disease. Neurology 2008; 70:1358.
- Boucek D, Jirikowic J, Taylor M. Natural history of Danon disease. Genet Med 2011; 13:563.
- Prall FR, Drack A, Taylor M, et al. Ophthalmic manifestations of Danon disease. Ophthalmology 2006; 113:1010.
- Kim J, Parikh P, Mahboob M, et al. Asymptomatic young man with Danon disease. Tex Heart Inst J 2014; 41:332.
- Sugie K, Yoshizawa H, Onoue K, et al. Early onset of cardiomyopathy and intellectual disability in a girl with Danon disease associated with a de novo novel mutation of the LAMP2 gene. Neuropathology 2016.
- Taylor MR, Ku L, Slavov D, et al. Danon disease presenting with dilated cardiomyopathy and a complex phenotype. J Hum Genet 2007; 52:830.
- Hashida Y, Wada T, Saito T, et al. Early diagnosis of Danon disease: Flow cytometric detection of lysosome-associated membrane protein-2-negative leukocytes. J Cardiol 2015; 66:168.
- Majer F, Vlaskova H, Krol L, et al. Danon disease: a focus on processing of the novel LAMP2 mutation and comments on the beneficial use of peripheral white blood cells in the diagnosis of LAMP2 deficiency. Gene 2012; 498:183.
- Majer F, Pelak O, Kalina T, et al. Mosaic tissue distribution of the tandem duplication of LAMP2 exons 4 and 5 demonstrates the limits of Danon disease cellular and molecular diagnostics. J Inherit Metab Dis 2014; 37:117.