LAMP2 – Danon disease

Danon disease is an X‐linked dominant lysosomal glycogen storage disorder caused by loss‐of‐function variants in LAMP2, encoding a lysosome‐associated membrane glycoprotein critical for autophagy. Affected individuals present predominantly with hypertrophic cardiomyopathy, skeletal myopathy, and variable intellectual disability, often accompanied by Wolff‐Parkinson‐White syndrome and exercise intolerance. Diagnosis relies on clinical suspicion, histopathology showing autophagic vacuolar myopathy, and identification of pathogenic LAMP2 variants.

1 Clinical Validity

Multiple independent cohorts and families have demonstrated a definitive association between LAMP2 and Danon disease. In an unselected pediatric hypertrophic cardiomyopathy (HCM) cohort, 2/50 probands harbored LAMP2 nonsense mutations (4%) (PMID:16144992). Nine unrelated patients with HCM and vacuolar myopathy carried null LAMP2 alleles (PMID:16565504), and targeted sequencing of 64 pediatric HCM cases identified 4 LAMP2‐mutated probands (6%) (PMID:27460667). Segregation of pathogenic variants was observed in at least 9 additional affected relatives across these studies. Gene–disease association is Definitive based on robust replication, multi‐family segregation, and concordant functional data.

2 Genetic Evidence

Danon disease follows X‐linked dominant inheritance. Pathogenic variants include nonsense, frameshift, splice‐site, microdeletions, and multi‐exon duplications. Segregation has been confirmed in multiple pedigrees, including male hemizygotes and heterozygous female carriers. Case reports describe de novo and familial mutations such as c.138G>A (p.Trp46Ter) segregating with cardiomyopathy in a boy and his mother (PMID:15889279). Recurrent variants include a splice acceptor mutation c.929‐1G>A and a founder missense c.877C>T (p.Cys293Ter) in diverse populations. Affected individuals frequently exhibit hypertrophic cardiomyopathy (HP:0001639), skeletal myopathy (HP:0003756), and intellectual disability (HP:0001249).

3 Functional / Experimental Evidence

LAMP2 deficiency disrupts autophagosome–lysosome fusion, causing glycogen and vacuole accumulation in cardiac and skeletal muscle. In Lamp2 knockout mice, cardiomyopathy with ventricular arrhythmias and autophagy failure recapitulates human disease (PMID:25637286). Patient‐derived iPSC‐cardiomyocytes exhibit histological and functional autophagy failure that is ameliorated by DNA methylation inhibitors, demonstrating allele reactivation and rescue of autophagic flux (PMID:27678261). Immunohistochemistry and flow cytometry confirm absent LAMP2 protein in muscle and leukocytes of male and mosaic female carriers.

4 Conflicting Evidence

A mild Danon phenotype has been reported for splice‐site mutation c.65‐2A>G due to tissue‐specific rescue of full‐length LAMP2 transcript, illustrating phenotypic variability without refuting the overall gene–disease link (PMID:26748608).

5 Integration & Clinical Utility

Genetic screening for LAMP2 should be included in cardiomyopathy panels, especially in young patients with HCM, WPW syndrome, or muscle symptoms. Early molecular diagnosis enables timely consideration of cardiac transplantation and family counseling. Flow cytometric detection of LAMP2‐negative leukocytes offers a rapid carrier screening tool in males and mosaic females.

Key Take‐home: Definitive evidence supports LAMP2 testing in hypertrophic cardiomyopathy and related presentations to optimize diagnosis, management, and familial risk assessment.

References

• Circulation • 2005 • Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. PMID:16144992
• The American journal of pathology • 2006 • Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease. PMID:16565504
• European journal of pediatrics • 2005 • Familial X-linked cardiomyopathy (Danon disease): diagnostic confirmation by mutation analysis of the LAMP2 gene. PMID:15889279
• The American journal of cardiology • 2016 • Identification of LAMP2 Mutations in Early-Onset Danon Disease With Hypertrophic Cardiomyopathy by Targeted Next-Generation Sequencing. PMID:27460667
• Acta Neuropathologica Communications • 2015 • LAMP-2 deficiency leads to hippocampal dysfunction but normal clearance of neuronal substrates of chaperone-mediated autophagy in a mouse model for Danon disease. PMID:25637286
• Circulation • 2016 • Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor. PMID:27678261
• Clinical Genetics • 2016 • The c.65-2A>G splice site mutation is associated with a mild phenotype in Danon disease due to the transcription of normal LAMP2 mRNA. PMID:26748608

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