Lysosome-associated Membrane Protein-2 Deficiency Research Articles

Myocardial Tissue Characterization in Danon Disease.

HomeRadiologyVol. 307, No. 2 PreviousNext Reviews and CommentaryFree AccessImages in RadiologyMyocardial Tissue Characterization in Danon DiseaseFei Chen, Mao Chen Fei Chen, Mao Chen Author AffiliationsFrom the Department of Cardiology, Laboratory of Heart Valve Disease, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, PR China.Address correspondence to M.C. (email: [email protected]).Fei ChenMao Chen Published Online:Jan 17 2023https://doi.org/10.1148/radiol.222333MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In A 14-year-old boy was referred for cardiac MRI, which showed mild left ventricular (LV) wall thickening to 13 mm (Figure, A). No edema signal or late gadolinium enhancement (LGE) was observed (Figure, A, B). Native myocardial T1 was elevated (1331 msec; reference, 1114–1290 msec), but extracellular volume (ECV) fraction (25%) and myocardial T2 (38 msec) were normal (Figure, C–E). LV hypertrophy associated with storage disorders was suspected.Baseline and follow-up cardiac MRI scans in a young boy with Danon disease. (A–E) Cardiac MRI scans at age 14 years show (A) mild left ventricular (LV) hypertrophy (maximum thickness, 13 mm; LV mass index, 93 g/m2) with no edema, (B) late gadolinium enhancement (LGE), (C) abnormal global native T1 value of 1331 msec (reference, 1114–1290 msec), (D) normal global extracellular volume (ECV) fraction of 25% (reference, 21%–33%), and (E) normal global T2 value of 38 msec (reference, 33–44 msec). (F–J) Cardiac MRI scans at age 19 years show (F) extreme LV hypertrophy (maximum thickness, 43 mm; LV mass index, 476 g/m2) with extensive midwall-dominant edema, (G) LGE, and (H-J) increased global tissue characterization metrics ([H] native T1 value [1478 msec], [I] extracellular volume fraction [44%], and [J] T2 value [51 msec]). CE-bSSFP = contrast-enhanced balanced steady-state free precession.Download as PowerPointOpen in Image Viewer At age 19 years, a repeated cardiac MRI showed a marked increase in LV wall thickness to 43 mm (Figure, F). LGE manifested in a nonischemic pattern of midwall-dominant involvement, sparing the basal septum, and with a base-to-apex increasing tendency (Figure, G). Myocardial T1 had increased (1478 msec) since the last examination, as had ECV fraction (44%) (Figure, H, I). T2 imaging showed myocardium edema signals and increased myocardial T2 (51 msec) (Figure, F, J).Genetic testing was indicated and identified a pathogenic mutation in the lysosome-associated membrane protein 2 (LAMP2) gene (c.190_191delGT), suggesting the diagnosis of Danon disease (1). Danon disease, or LAMP2 deficiency (glycogen type 2b storage disease), predominantly affects cardiac and skeletal muscles and also includes neurologic manifestations. It may be underrecognized as a cause of hypertrophic cardiomyopathy in childhood and early adulthood (2,3). Cardiac MRI could reveal cardiomyocyte injury, edema, and fibrosis in the progression of Danon disease, as well as isolated intracellular autophagic vacuoles accumulation during the early stage.Disclosures of conflicts of interest: F.C. No relevant relationships. M.C. No relevant relationships.

LAMP2 deficiency attenuates the neurodegeneration markers induced by HSV-1 infection

Mounting evidence suggests a major role of infectious agents in the pathogenesis of sporadic Alzheimer's disease (AD). Among them, herpes simplex virus type 1 (HSV-1) infection has emerged as a major factor in the etiology of AD. HSV-1 is able to induce some of the main alterations of the disease such as hyperphosphorylation of tau protein and accumulation of amyloid-β peptide. Functional genomic analysis of a cell model of HSV-1 infection and oxidative stress developed in our laboratory revealed lysosomal system to be the main pathway altered, and the lysosome-associated membrane protein 2 (LAMP2) gene one of the most strongly modulated genes. The aim of this work is to study LAMP2 as an AD candidate gene and to investigate its role in the neurodegeneration induced by HSV-1 using a LAMP2 knockdown cell model. LAMP2 deficiency led to a significant reduction of viral DNA replication and formation of infectious particles. In addition, tau hyperphosphorylation and inhibition of Aβ secretion induced by the virus were attenuated by the absence of LAMP2. Finally, genetic association studies revealed LAMP2 genetic variants to be associated with AD risk. In summary, our data indicate that LAMP2 could be a suitable candidate to mediate the AD-like phenotype caused by HSV-1.

Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes.

Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes’ energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.

The ceramide analogue N-(1-hydroxy-3-morpholino-1-phenylpropan-2-yl)decanamide induces large lipid droplet accumulation and highlights the effect of LAMP-2 deficiency on lipid droplet degradation

Excess accumulation of intracellular lipids leads to various diseases. Lipid droplets (LDs) are ubiquitous cellular organelles for lipid storage. LDs are hydrolyzed via cytosolic lipases (lipolysis) and also degraded in lysosomes through autophagy; namely, lipophagy. A recent study has shown the size-dependent selection of LDs by the two major catabolic pathways (lipolysis and lipophagy), and thus experimental systems that can manipulate the size of LDs are now needed. The ceramide analogue N-(1-hydroxy-3-morpholino-1-phenylpropan-2-yl)decanamide (PDMP) affects the structures and functions of lysosomes/late endosomes and the endoplasmic reticulum (ER), and alters cholesterol homeostasis. We previously reported that PDMP induces autophagy via the inhibition of mTORC1. In the present study, we found that PDMP induced the accumulation of LDs, especially that of large LDs, in mouse fibroblast (L cells). Surprisingly, the LD accumulation was relieved by PDMP in L cells deficient in lysosome-associated membrane protein-2 (LAMP-2), which is reportedly important for lipophagy. An electron microscopy analysis demonstrated that the LAMP-2 deficiency caused enlarged autophagosomes/autolysosomes in L cells, which may promote the sequestration and degradation of the PDMP-dependent large LDs. Accordingly, PDMP will be useful to explore the mechanism of LD degradation, by inducing large LDs.

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

Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients. The disease is inherited as an X-linked dominant trait. The primary deficiency of lysosome-associated membrane protein-2 (LAMP-2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives. An early molecular diagnosis is of crucial importance for genetic counselling and for therapeutic interventions: in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.

Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina

The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.

A Nationwide Survey on Danon Disease in Japan.

Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf–Parkinson–White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease.

Secretion of misfolded cytosolic proteins from mammalian cells is independent of chaperone-mediated autophagy

In eukaryotic cells, elimination of misfolded proteins is essential for maintaining protein homeostasis and cell viability. Misfolding-associated protein secretion (MAPS) is a protein quality-control mechanism that exports misfolded cytosolic proteins via a compartment characteristic of late endosomes, but how cytosolic proteins enter this compartment is unclear. Because chaperone-mediated autophagy (CMA) is a known mechanism that imports cytosolic proteins bearing a specific CMA motif to lysosomes for degradation and because late endosomes and lysosomes overlap significantly in mammalian cells, we determined here whether CMA is involved in targeting protein cargoes to the lumen of late endosomes in MAPS. Using HEK293T and COS-7 cells and immunoblotting and -staining and coimmunoprecipitation methods, we show that, unlike CMA, the secretion of misfolded proteins in MAPS does not require cargo unfolding, is inhibited by serum starvation, and is not dependent on the CMA motif in cargo. Intriguingly, knockdown of lysosome-associated membrane protein 2 (LAMP2), which consists of three isoforms, including a variant proposed to form a protein channel on lysosomes for CMA, attenuated MAPS. However, this could not be attributed to the proposed channel function of the LAMP2a isoform because overexpression of a cytosolic MAPS stimulator, DnaJ heat shock protein family (Hsp40) member C5 (DNAJC5), fully rescued the secretion defect associated with LAMP2 deficiency. We conclude that, in MAPS, cargoes use a CMA-independent mechanism to enter a nondegradative prelysosomal compartment.

A Critical Evaluation of Liver Pathology in Humans with Danon Disease and Experimental Correlates in a Rat Model of LAMP-2 Deficiency.

Danon disease is a genetic deficiency in lysosome-associated membrane protein 2 (LAMP-2), a highly glycosylated constituent of the lysosomal membrane and characterized by a cardiomyopathy, skeletal muscle myopathy, and cognitive impairment. Patients, however, often manifest hepatic abnormalities, but liver function has not been well evaluated and the syndrome is relatively uncommon. Hence, we have taken advantage of a rat that has been deleted of LAMP-2 to study the relative role of LAMP-2 on liver function. Interestingly, rats deficient in LAMP-2 develop a striking increase in serum alkaline phosphatase (ALP) and a decrease in bile flow compared with wild-type littermates. Importantly and by ultrastructural analysis, deficient rats manifest dilated canaliculi that lack microvilli with evidence of bile-containing bodies. Moreover, following bile duct ligation, LAMP-2-deficient rats develop rapid and severe evidence of advanced cholestasis, with an increase in serum bilirubin, as early as 6h later. In wild-type control rats, multidrug resistance-associated protein 2 (Mrp2) normally concentrates at the bile canalicular membranes to secrete conjugated bilirubin into bile. However, in LAMP-2y/- rats, Mrp2 was detected in hepatocytes compared with other canalicular proteins including P-glycoproteins, dipeptidyl peptidase IV (CD26), and aminopeptidase (CD13). Our data further suggest that LAMP-2 interacts with the membrane cytoskeletal proteins radixin and F-actin in determining the localization of integral membrane proteins.

Danon disease: a phenotypic expression of LAMP-2 deficiency.

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 fusion with lysosomes; therefore, LAMP-2 deficiency leads to a failure in macroautophagy. There are three LAMP-2 isoforms, LAMP-2A, -2B, and -2C. Clinical features of Danon disease are thought to be mediated by loss of the LAMP-2B isoform which is the major isoform expressed in muscle. It is also known that LAMP-2 plays a role in chaperone-mediated autophagy and RNA- and DNA-targeting autophagy. However, the precise pathophysiological mechanism through which LAMP-2 deficiency causes Danon disease is still not fully understood and its elucidation would promote the development of new therapies.

Morphologic and Clinical Aspects of Danon Disease in a Patient with a Mutation c.137G > A in the LAMP-2 Gene

Danon disease is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). Our study describes a 19-year-old man with isolated hypertrophic cardiomyopathy, in whom we performed DNA analysis and compared results of microscopic analysis of skeletal and cardiac muscles. Sequencing of the LAMP-2 gene revealed a novel point mutation c.137G > A in exon 2, leading to premature stop codon. Ultrastructural analysis of cardiac and skeletal muscles revealed the presence of unusual autophagic vacuoles in both. Although some vacuoles in skeletal muscle reacted strongly with dystrophin, β-sarcoglycan, and laminin, those in cardiomyocytes showed no immunoreactivity. Our immunohistochemical and ultrastructural findings reinforce the claim that in Danon disease the pathomechanism of chaperone-mediated autophagy in cardiomyocytes differs from that in skeletal muscle.

LAMP-2, a novel endocytic receptor on human monocytes derived dendritic cells (MDDC).

Event Abstract Back to Event LAMP-2, a novel endocytic receptor on human monocytes derived dendritic cells (MDDC). Dario Leone1* 1 Medical University Vienna, Clinical Institute of Pathology, Austria LAMP-2, a novel endocytic receptor on human monocytes derived dendritic cells (MDDC). Dario Leone* Renate Kain and Andrew Rees* Clinical Institute of Pathology, Medical University of Wien. Supported by Marie Curie action (Transvir network) Keyword (Human Dendritic Cell, novel endocytic receptor, LAMP-2, uptake, antigen presentation) Lysosome-associated membrane protein-2 (LAMP-2) is a type 2 membrane-protein that is commonly used as lysosome and late endosomal marker and with essential roles in chaperone mediated autophagy and antigen presentation. LAMP-2 is also present on the cell-surface although its role was never studied. We focus on the role of LAMP-2 as a receptor on freshly isolated monocytes and iDCs with possible implication in antigen presentation. LAMP-2 was detected on the surface of immature MDDC both by FACS and confocal microscopy, its expression increased after maturation with IFN-γ LPS. The monoclonal anti-LAMP-2 antibody (H4B4) bound to LAMP-2 on the surface of MDDC and was rapidly and specifically internalized when compared to control antibodies in the presence of Fc blockade. Also the Fab fragment alone is internalized as well. Uptake was absent in MDDC from an individual with genetic LAMP-2 deficiency, Danon-disease. As expected, MDDC LAMP-2 and HLA-DR localized to partially overlapping compartments in iDC but there was no co-localization with HLA-DM. However, confocal microscopy showed that H4B4 transits into a HLA-DM positive compartment 1 hour after ligating LAMP-2 on the cell surface. Co-localization is no longer detectable after 3 hours. Finally, stimulation of immature MDDCs with H4B4 promote activation in the presence of IFN-γ indicated by up-regulation of CD80/CD83. This data suggest that when LAMP-2 is on the membrane acts as a specific receptor for internalization of extracellular molecules. H4B4 mimics natural ligands and after internalization can be found into the MIIC causing as well the maturation of DCs up-regulating CD80/83. Keywords: human dendritic cell, Antigen Presentation, Lysosomes, endocytic receptor, autoan, MHCII compartment Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune receptors and signaling Citation: Leone D (2013). LAMP-2, a novel endocytic receptor on human monocytes derived dendritic cells (MDDC).. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00633 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Dario Leone, Medical University Vienna, Clinical Institute of Pathology, Vienna, 1090, Austria, bleons2.0@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Dario Leone Google Dario Leone Google Scholar Dario Leone PubMed Dario Leone Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A 13‐year‐old girl with proximal weakness and hypertrophic cardiomyopathy with danon disease

Danon disease is caused by deficiency of lysosome-associated membrane protein-2 (LAMP-2). It is characterized clinically by cardiomyopathy, myopathy, and mental retardation in boys. Herein we report a 13-year-old female patient with Danon disease who presented with early-onset skeletal myopathy and cardiomyopathy. She had a de novo novel mutation in the LAMP2 gene, and her muscles showed many autophagic vacuoles with sarcolemmal features and complete absence of LAMP-2 expression. To the best of our knowledge, this girl is one of the earliest-onset manifesting carriers of Danon disease with typical muscle pathology.

G.P.16.10. Danon disease: A novel donor site LAMP2 mutation causing alternative transcripts

Background: LAMP2, the causative gene of Danon disease, is located on chromosome Xq24 and encodes the lysosome-associated membrane protein-2 (LAMP-2). Objectives: To characterize the molecular defect leading to LAMP-2 deficiency, mild myopathy and severe cardiomyopathy in an Italian sporadic case. Patient and methods: The patient had hyperCKemia, hypertrophic cardiomyopathy, no muscle weakness and slight mental impairment. A muscle biopsy showed autophagic vacuoles with sarcolemmal features and glycogen storage.

Danon Disease: An Unusual Presentation of Autism

Danon disease is an X-linked cardioskeletal myopathy, originally reported as "lysosomal glycogen storage disease with normal acid maltase," resulting from a primary deficiency of lysosome-associated membrane protein-2 because of mutations in the lysosome-associated membrane protein-2 gene. Classic clinical features in males include cardiomyopathy (100%, eventually), myopathy (90%), and mental retardation (70%), but mostly of a mild degree. We report on an unusual presentation in a patient with autism, motor delay, and a normal cardiac evaluation. The presence of multiorgan involvement, including elevated liver enzymes, abnormal cranial magnetic resonance imaging, and diffuse hypotonia with swallowing difficulties, prompted a muscle biopsy. A quadriceps muscle biopsy was performed, and the findings were most suspicious for a glycogen storage-type disease. Subsequently, a pathogenic lysosome-associated membrane protein-2 mutation was found. To our knowledge, there are no previous clinical reports of autism in children with Danon disease.

Novel Lamp‐2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease

Lysosome-associated membrane protein-2 deficiency (LAMP-2 deficiency), or Danon disease, is a rare X-linked lysosomal disease characterized by cardiomyopathy, vacuolar myopathy, and mental retardation. Less than 20 families with mutations of the Lamp-2 gene have been reported. We describe a family from Sardinia with eight affected patients (4 females and 4 males) and a novel mutation in exon 2 of the Lamp-2 gene (c.102_103delAG). Females developed isolated cardiomyopathy in adulthood, whereas males presented with cardiomyopathy, myopathy, and mental retardation before the age of 20 years. Cardiomyopathy was lethal in three females in their 40s and in three males before the age 20 years. One patient was successfully treated by heart transplantation with more than 5-year follow-up. This study demonstrates that Danon disease is a frequently fatal condition that is potentially treatable with heart transplantation.

Phenotypic Heterogeneity in Two Unrelated Danon Patients Associated with the SameLAMP‐2Gene Mutation

Danon disease, an X-linked cardioskeletal myopathy caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2), is clinically characterized by cardiomyopathy, myopathy, and variable mental retardation. The pathological hallmark of the disease is the absence of LAMP-2 immunohistochemical staining in muscle. The LAMP-2 gene mutations reported thus far are generally private mutations. We describe two cases of Danon disease with different clinical presentation, in whom we identified the same exon skipping mutation c.928G>A in the LAMP-2 gene. The first patient was affected by an early onset myopathy and hypertrophic cardiomyopathy (HCM) that partially improved with drug treatment. A first muscle biopsy at age 4 months showed markedly increased glycogen, and acid maltase deficiency was ruled out biochemically. A second muscle biopsy, performed at age 3(1/2) years, showed very mild abnormalities. The second child at age 15 years had mild, diffuse muscle weakness and wasting, moderate mental deficiency, and HCM. Two serial biopsies performed at age 8 and 15 years showed similar findings of multiple esterase-positive vacuoles in type I myofibers. In both patients the immunohistochemical study demonstrated the absence of LAMP-2 in skeletal muscle.

Familial X-linked cardiomyopathy (Danon disease): diagnostic confirmation by mutation analysis of the LAMP2gene

A boy presented at age 2.5 years with mild left ventricular hypertrophy and mild myopathy. Hypertrophic cardiomyopathy progressed relentlessly, leading to death at age 16 years shortly before planned heart transplantation. During the course of the disease, his mother developed severe dilated cardiomyopathy and died of its complications at 46 years of age. The combination of myopathy and cardiomyopathy, the biochemical and electron microscopy findings in a muscle biopsy, and the pedigree suggested Danon disease (MIM 300257), an X-linked lysosomal storage disorder caused by deficiency of lysosome-associated membrane protein-2 (LAMP2). The diagnosis was confirmed by the identification of a novel mutation, G138A, in the LAMP2gene, leading to the premature stop codon W46X. Early diagnosis of Danon disease is important for genetic counselling and timely cardiac transplantation, the only effective therapeutic option.

Asymptomatic hyperCKemia in a case of Danon disease due to a missense mutation in Lamp-2 gene

Primary lysosome-associated membrane protein-2 (LAMP-2) deficiency is an X-linked disease, characterized by the clinical triad of cardiomyopathy, vacuolar myopathy and mental retardation, previously known as Danon disease. Mutations of lamp-2 gene have been reported so far in about 20 patients, one of whom was Italian. We describe a new Italian case with persistent hyperCKemia, exercise intolerance and hypertrophic cardiomyopathy but with no muscle weakness or mental impairment. Muscle biopsy revealed a vacuolar myopathy with mild glycogen storage, and immunohistochemical studies detected LAMP-2 deficiency. A new nucleotide substitution (T961C) on exon 8 of lamp-2 gene was identified as responsible for the protein deficiency. This is the first missense mutation so far described. LAMP-2 deficiency should be considered as a cause of recurrent hyperCKemia and hypertrophic cardiomyopathy.

Charcot–Marie–Tooth features and maculopathy in a patient with Danon disease

Danon disease is a rare X-linked disorder caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2).1,2⇓ The pathologic hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal muscle fibers with complete absence of LAMP-2 staining on immunohistochemistry. The characteristic clinical features in male patients include cardiomyopathy in all cases, skeletal myopathy (85%), and mental retardation (70%). Myopathy is usually mild, affecting proximal limb and neck muscles, with moderate muscle atrophy in rare cases.3 We report the case of a patient with mild neuromuscular manifestations mimicking Charcot–Marie–Tooth disease and associated with retinal abnormalities leading to severe visual impairment. A 24-year-old man was followed for a hypertrophic cardiomyopathy diagnosed in childhood during a systematic examination performed because of four cardiac deaths in the family (three uncles died at ages 7, 29, and 34 years, and his maternal grandmother died at age 32 years). Atrial tachycardia and second-degree atrioventricular block subsequently occurred. …