Natural history of Danon disease

Abstract

Background: Danon disease is a rare but serious cardiac and skeletal myopathy leading to substantial morbidity and early mortality due to arrhythmia and cardiomyopathy. The X-linked nature of inheritance accounts for reported differences in phenotypic severity between men and women. The rarity of Danon disease has limited understanding of the complete phenotype. Clinical estimates of ages of disease onset and survival based on gender have not been published. Methods and Results: We present data on 82 patients with Danon disease from 36 families, the largest series to date. Men were severely affected with cognitive disabilities (100%), hypertrophic cardiomyopathy (88%), and muscle weakness (80%). Men had a high morbidity and were unlikely to reach the age of 25 years without a cardiac transplantation. Women were less severely affected but reported higher than expected levels of cognitive (47%) and skeletal muscle complaints (50%) and manifesting an equal prevalence of dilated cardiomyopathy and hypertrophic cardiomyopathy. Combining our data with that of 63 other Danon disease case reports in the literature, the average ages of first symptom, cardiac transplantation, and death were 12.1, 17.9, and 19.0 years in men and 27.9, 33.7, and 34.6 years in women, respectively. Conclusion: These data more broadly illuminate the Danon disease phenotype and should prove useful to physicians working with and providing genetic counseling to families with Danon disease. Women with Danon disease present with clinical symptoms and events approximately 15 years after men and report a higher proportion of cognitive and skeletal muscle problems than previously recognized. Genet Med 2011:13(6):563-568.

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

“…2010; Boucek et al. 2011). Here, we identified an intragenic deletion in LAMP2 in a female patient with DCM, arrhythmia, and glycogen accumulation noted during cardiac transplant, consistent with Danon disease.…”

Danon Disease: A Rare Systemic Disorder With the Lamp2-Cardiomyopathy

“…Описаны также крупные делеции и дупликации в этом гене. Таким образом, подавляющее большин-ство изменений в LAMP2, приводящих к развитию БД, связано с синтезом укороченного, или делетиро-ванного, протеина [8].…”

Danon Disease Due to a Novel LAMP2 Microduplication

“…The cardinal features of this condition are hypertrophic cardiomyopathy, preexcitation and tachyarrhythmias, and skeletal myopathy, with some affected persons manifesting intellectual disability and/or pigmentary retinopathy. Symptoms in affected males are highly penetrant, progressive, and severe, with mean onset in the preadolescent years; survival beyond 25 years is unlikely without cardiac transplantation (Boucek et al 2011). Although heterozygous females have an attenuated phenotype, potentially fatal cardiac sequelae (preexcitation, arrhythmias, and cardiomyopathy) do occur in a large proportion, and median female survival is approximately 45 years (Boucek et al 2011;Miani et al 2012).…”

“…Symptoms in affected males are highly penetrant, progressive, and severe, with mean onset in the preadolescent years; survival beyond 25 years is unlikely without cardiac transplantation (Boucek et al 2011). Although heterozygous females have an attenuated phenotype, potentially fatal cardiac sequelae (preexcitation, arrhythmias, and cardiomyopathy) do occur in a large proportion, and median female survival is approximately 45 years (Boucek et al 2011;Miani et al 2012). The disease process is characterized pathologically by progressive interstitial fibrosis, muscle fiber hypertrophy, periodic-acid-Schiff-positive sarcoplasmic vacuolation, and myofibrillar disarray (Murakami et al 1995;Sugie et al 2005).…”

“…These proteins permit the targeted import of cytoplasmic proteins (LAMP2-A, LAMP2-B) and RNA (LAMP2-C) into lysosomes for degradation (Cuervo and Dice 1996;Bandyopadhyay et al 2008;Kaushik et al 2011;Demirel et al 2012;Fujiwara et al 2013). The majority of reported Danon disease alleles are private, with nonsense and frameshift mutations predominating (Boucek et al 2011). Recently, nonrecurrent microdeletions and microduplications at the LAMP2 locus have been demonstrated in four unrelated cases (Yang et al 2010;Majer et al 2013).…”