A family with Danon disease caused by a splice site mutation in LAMP2 that generates a truncated protein

Abstract

Background Danon disease is an X‐linked dominant hereditary condition caused by mutations in the gene encoding lysosomal‐associated membrane protein 2 ( LAMP 2), leading to failure of lysosome binding to autophagosomes, accumulation of glycogen in the heart, and abnormal cardiac function. Methods We describe identification of a mutation in LAMP 2 , c.741+1G>T, in a family with Danon disease by whole exome sequencing. Results Pathology examination of patient skeletal muscle biopsy showed myogenic damage and autophagic vacuoles with sarcolemmal features ( AVSF ). Numerous autophagic vacuoles accumulated in muscle cells were detected by electron microscopy, indicating abnormal autophagy function. Conclusion The mutation did not result in loss of mRNA exons; rather, a 6‐nucleotide (two‐codon) insertion, where the latter was a stop codon, leading to early termination of LAMP 2 protein translation. The resulting truncated protein lacks an important transmembrane domain, which will impair lysosome/autophagosome fusion, damage autophagy function, and result in the clinical manifestations of Danon disease.

Review: Danon disease: Review of natural history and recent advances

“…Elevated serum troponin T levels were found during the acute cardiac phase , especially in severely affected patients with rapidly fatal outcomes , similar to what occurs in ischemic heart disease.…”

“…Heart block was present in 35–50% of cases, requiring pacemaker implantation. Atrial fibrillation, flutter and life‐threatening ventricular arrhythmias (VA) were frequent (60% of patients), and a possible cause of syncope and sudden death . In such patients, preventive treatment including cardioversion, radiofrequency ablation of the accessory pathway , resynchronization pacemaker implantation and ICD implantation are indicated.…”

“…Many patients had hepatomegaly (36% of cases) , overt hepatopathy or increased liver enzyme levels from childhood .…”

“…The structures called ‘autophagic vacuoles with sarcolemmal features (AVSF)’ or type 2 vacuoles are due to an accumulation of autophagosomes and lysosomes, and were found scattered in the cytoplasm , suggesting they are synthesized de novo from the lysosomal membrane rather than being sarcolemma‐derived . The presence of AVSF is highly suggestive of LSD and may lead to the diagnosis of DD .…”

Danon disease: a case report and literature review

“…Echocardiography always shows typical concentric left ventricular (LV) hypertrophy [ 19 ] with preserved ejection fraction (EF) [ 20 ] in the early stage of DD, but progressed toward dilated pattern later. Serum troponin-T (TnT) levels are elevated in the acute cardiac phase [ 21 ], especially those with rapidly fatal outcome [ 22 ]. Cardiac Magnetic resonance imaging (MRI) can be used to differentiate DD from non-ischemic cardiomyopathy [ 23 ], analyze HCM patterns [ 24 ], and monitor fibrosis progression, which is essential to identify implantable cardioverter defibrillator (ICD) implantation or HTx [ 25 ].…”