Danon disease: a phenotypic expression of LAMP-2 deficiency

Abstract Danon disease is an X-linked disorder clinically characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Cardiomyopathy is a severe and life-threatening problem, for which cardiac transplantation is the only therapeutic option. The most striking finding in muscle biopsy samples is small basophilic granules scattered in myofibers, which are in fact small autophagic vacuoles surrounded by membranes with sarcolemmal features characterized by the recruitment of sarcolemmal proteins and acetylcholine esterase and by the presence of basal lamina on its luminal side. The mechanism underlying the formation of these autophagic vacuoles with unique sarcolemmal features (AVSF) still remains a mystery and its origin is unknown. In heart, cardiomyocytes show dramatically increased vacuolation and degenerative features, including myofibrillar disruption and lipofuscin accumulation. In brain, pale granular neurons and neurons with lipofuscin-like granules may be seen. Danon disease is caused by loss-of-function mutations in the LAMP2 gene, which encodes lysosome-associated membrane protein 2 (LAMP-2), a single-spanned transmembrane protein localized in the limiting membranes of lysosomes and late endosomes. Most mutations lead to splicing defects or protein truncation, resulting in a loss of transmembrane and/or cytoplasmic domains, leading to LAMP-2 protein deficiency. LAMP-2 is required for the maturation of autophagosomes by fus...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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ConclusionThese findings will aid in diagnosing DD patients carrying thisLAMP2 mutation that presents with a HCM phenotype. Furthermore, this study illustrates the importance of utilizing a molecular diagnostic approach in HCM patients and is the first study to report aLAMP2 p.G93R mutation associated with mild DD and identify that XCI serves a protective role in DD etiology.
Source: Molecular Genetics & Genomic Medicine - Category: Genetics & Stem Cells Authors: Tags: ORIGINAL ARTICLE Source Type: research
Authors: Guo S, Zhou L, Wang R, Lv Z, Xu H, Han B, Korantzopoulos P, Hu F, Liu T Abstract The present study reports on a family with two members affected by Danon disease but having different phenotypes. The clinical manifestations of Danon disease include cardiomyopathy, skeletal myopathy and different degrees of intellectual disability that varies greatly among patients. The present case study reports on two siblings, an older sister and a younger brother, with Danon disease from an affected pedigree, presenting with distinctly different phenotypes. The sister was diagnosed with dilated cardiomyopathy at the age ...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
We report the case of an adult male patient with dilated-phase hypertrophic cardiomyopathy secondary to Danon disease, who received an LVAD as a bridge to transplantation.
Source: Journal of Cardiology Cases - Category: Cardiology Source Type: research
This study was carried out in accordance with the recommendations of “the UAB Institutional Review Board for Human Use (IRB)” with written informed consent from all subjects. The protocol was approved by the “The UAB Institutional Review Board for Human Use (IRB).” This study was carried out in accordance with the recommendations of “UAB IACUC committee.” The protocol was approved by the “UAB IACUC.” All subjects gave written informed consent in accordance with the Declaration of Helsinki. Author Contributions SW, AvH, and BRK were involved in patient recruitment, examinati...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
We report on long term follow up (14.7 years, IQ range 9-21 years) of 4 patients, transplanted for Danon disease cardiomyopathy, showing two LAMP-2 gene variants, the novel c.815T > C and the previously reported c.294G > A. We have also analysed previous published paper on this topic comparing available data from different follow up. Being a skeletal and cardiac muscle disease, with systemic effects, long term results about HTx are indispensable to justify any treatments in this subset of patients. PMID: 30959184 [PubMed - as supplied by publisher]
Source: European Journal of Medical Genetics - Category: Genetics & Stem Cells Authors: Tags: Eur J Med Genet Source Type: research
AbstractRASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identifiedLZTR1, PPP1CB andMRAS as new causative genes in RASopathies. However, information on the phenotypes ofLZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants ofLZTR1, PPP1CB, andMRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 pat...
Source: Human Genetics - Category: Genetics & Stem Cells Source Type: research
ConclusionsThe clinical characteristics of DD differ substantially from traditional descriptions: age at presentation of DD is older, the disease is not multisystemic in women, and pre-excitation is infrequent.ResumenIntroducción y objetivosLa enfermedad de Danon (ED) es una enfermedad producida por mutaciones en el gen LAMP2. Se la considera una enfermedad multisistémica caracterizada por miocardiopatía hipertrófica con preexcitación e hipertrofia extrema, discapacidad intelectual, miopatía, presentación infantil y peor pronóstico en varones. Hay pocas series que per...
Source: Revista Espanola de Cardiologia - Category: Cardiology Source Type: research
A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy, Published online: 10 May 2018; doi:10.1038/s41431-018-0136-0A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy
Source: European Journal of Human Genetics - Category: Genetics & Stem Cells Authors: Source Type: research
In conclusion, HF in HCM is associated with diverse and complex pathophysiology, but a substantially more favorable prognosis than conventional non–HCM HF, and highly amenable to effective treatment options in the vast majority of patients. Graphical abstract
Source: JACC: Heart Failure - Category: Cardiology Source Type: research
Conclusion MTO1 deficiency is lethal in some but not all cases, and a genotype-phenotype relation is suggested. Aside from lactic acidosis and cardiomyopathy, developmental delay and other phenotypic features affecting multiple organ systems are often present in these patients, suggesting a broader spectrum than hitherto reported. The diagnosis should be suspected on clinical features and the presence of markers of mitochondrial dysfunction in body fluids, especially low residual complex I, III and IV activity in muscle. Molecular confirmation is required and targeted genomic testing may be the most efficient approach. Alt...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
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