Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a boy with an early lethal hypertrophic vacuolar cardiomyopathy of neonatal onset. Abnormal intra- and extralysosomal glycogen storage disease was demonstrated in heart and skeletal muscles. Glycogen content was twice the normal in muscles and over 3-fold the normal in the heart. In this organ, over 50% of the intracellular space was occupied by glycogen and possibly oligosaccharides, as demonstrated by the quantitative morphometric analysis of electron micrographs. The activity of acid alpha-glucosidase was increased in the heart, skeletal muscles, and liver, but was normal in leukocytes. A review of the 11 previously published pedigrees of lysosomal glycogen storage disease with normal in vitro alpha-glucosidase activity allows the delineation of three clinical entities: juvenile and neonatal pseudo-Pompe diseases and partial Pompe disease. Partial Pompe disease, due to the tissue-specific absence of acid alpha-glucosidase, was observed in a single patient. The most common form is the late-onset pseudo-Pompe disease, which is characterized by severe cardiomyopathy and mild myopathy appearing in the second or third decade, prominent arrhythmia with Wolf-Parkinson-White syndrome, and sometimes mental retardation. Patients reported as suffering from Antopol disease probably belong to this group. Dominant inheritance (autosomal or X linked) is likely in most families. The present report appears to be the first one to describe a rapidly fatal neonatal form of lysosomal glycogenosis without acid maltase deficiency. The mode of inheritance of this form is not known. Differential diagosis includes Pompe disease (similar histology) and cardiac phosphorylase b kinase deficiency (similar clinical course). The delineation of neonatal pseudo-Pompe disease makes enzymatic confirmation mandatory in each case suspected of Pompe disease.
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PMID:Nosology of lysosomal glycogen storage diseases without in vitro acid maltase deficiency. Delineation of a neonatal form. 938 33

"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.
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PMID:Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). 1097 94

Danon disease ('lysosomal glycogen storage disease with normal acid maltase') is characterized by a cardiomyopathy, myopathy and variable mental retardation. Mutations in the coding sequence of the lysosomal-associated membrane protein 2 (LAMP-2) were shown to cause a LAMP-2 deficiency in patients with Danon disease. LAMP-2 deficient mice manifest a similar vacuolar cardioskeletal myopathy. In addition to the patient reports LAMP-2 deficiency in mice causes pancreatic, hepatocytic, endothelial and leucocyte vacuolation. LAMP-2 deficient mice represent a valuable animal model of Danon disease. They will further be used to study the exact role of LAMP-2 in autophagy and to analyse the consequences of an impaired autophagic pathway in various tissues.
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PMID:Disease model: LAMP-2 enlightens Danon disease. 1142 88

Danon disease (DD) is a rare lysosomal glycogen storage disease with normal acid maltase activity, which is characterised clinically by cardiomyopathy and myopathy, and a variable degree of mental retardation. The causative gene, LAMP2, has been mapped to chromosome Xq24-q25. LAMP2 encodes a lysosome-associated membrane glycoprotein. We identified a novel LAMP2 mutation of the exon 8 splice acceptor site (IVS7-1G --> A) in an affected male and female, which predicts abnormal splicing. Both affected individuals presented solely with hypertrophic cardiomyopathy. Muscle weakness and mental impairment were absent. Diagnosis of Danon disease was established by muscle biopsy, when the male index patient developed transient severe muscle weakness following heart transplantation. Typical biopsy findings were also found in a heart muscle specimen. Demonstration of the LAMP2 mutation in affected male and female siblings is compatible with X-linked dominant inheritance. Danon disease should be actively looked for in cardiomyopathy patients.
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PMID:Identification of a novel LAMP2 mutation responsible for X-chromosomal dominant Danon disease. 1459 34

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.
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PMID:Asymptomatic hyperCKemia in a case of Danon disease due to a missense mutation in Lamp-2 gene. 1590 87

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.
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PMID:Phenotypic heterogeneity in two unrelated Danon patients associated with the same LAMP-2 gene mutation. 1621 5

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.
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PMID:Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease. 1637 18

Danon disease, an X-linked dominant disorder, results from mutations in the lysosome-associated membrane protein-2 (LAMP2) gene and presents with hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of nine unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified three novel families (including one affected mother) with unreported LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes, and fibroblasts. LAMP-2 protein deficiency was detectable in various tissues, including leukocytes, explaining the multisystem clinical involvement. Skeletal muscle immunopathology showed that mutant protein was not localized in the Golgi complex, vacuolar membranes expressed sarcolemmal-specific proteins, and the degree of muscle fiber vacuolization correlated with clinical muscle involvement. In our female patient, muscle histopathology and LAMP-2 protein analysis was inconclusive, indicating that diagnosis in females requires mutation identification. The random X-chromosome inactivation found in muscle and leukocytes excluded the possibility that selective involvement of some tissues in females is due to skewed X-chromosome inactivation. Therefore, biochemical analysis of leukocytes might be used for screening in male patients, but genetic screening is required in females.
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PMID:Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease. 1656 4

Hypertrophic cardiomyopathies have an estimated prevalence of 1/500. The analysis of the genes coding for the 10 most commonly involved sarcomeric proteins, fails to detect a mutation in about one third of cases. In some of these cases, cardiomyopathy can be attributed to a genetics storage disease with enlarged glycogen vacuolss (PRKAG2 deficiency, Danon disease, Pompe disease) and/or lysosomol vacuoles (Donon disease, Pompe disease, Fabry disease). These diseases all have in common a short PR interval. PRKAG2 deficiency is due to a dominant mutation of the gamma2 subunit of the cardiac AMP kinose. It leads to a storage cardiomyopathy which may be associated with sudden death in 10% of cases, due to ventricular arrhythmia or auriculoventricular blocks. Danon disease is an X-linked dominant inherited disease characterized by cardiomyopathy, squeletal myopathy and mental retardation. Cardiac transplantation is indicated in both affected men and women. In the infantile form of Pompe disease, enzyme replacement therapy with olglucosidase alpha shows efficacy on cardiac failure with a significant regression of ventricular hypertrophy on ECG, echocardiography and radiography
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PMID:[Inherited metabolic cardiomyopathies]. 1754 68

Danon disease, a rare glycogen storage disease, is a dominant X-linked disorder. It is due to mutation in gene for lysosome-associated membrane protein 2 (LAMP 2). The LAMP 2 gene is located on Xq24, and its mutation causes primary deficiency of LAMP 2 and myocyte hypertrophy by accumulations of vacuoles containing glycogen. Danon disease is clinically characterized by the triad of hypertrophic cardiomyopathy (HCM), proximal myopathy and mental retardation. Myopathy and mental retardation can be absent, and cardiomyopathy is usually hypertrophic. This is a case report of the patient with genetically confirmed Danon disease and mixed cardiomyopathy, but without myopathy and mental retardation. ECG showed typical Wolff-Parkinson-White (WPW) pattern while echocardiography demonstrated hypertrophy and dilatation of all cardiac chambers with impaired systolic and diastolic function. Male sex, early onset of symptoms, massive hypertrophy of the myocardium and ventricular preexcitation indicate a genetic basis for HCM. Therapeutic measures, except heart transplantation, do not improve prognosis substantially. Only an accurate diagnosis in patients with unexplained HCM helps in establishing of the appropriate treatment strategies and adequate genetic consultation.
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PMID:[Danon disease: a case report and literature overview]. 1764 61


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