1/47. Maternally inherited cardiomyopathy: clinical and molecular characterization of a large kindred harboring the A4300G point mutation in mitochondrial deoxyribonucleic acid.OBJECTIVES: The purpose of this study was to describe the clinical and molecular features of a large family with maternally inherited cardiomyopathy (MICM). BACKGROUND: Recently, several mitochondrial deoxyribonucleic acid (mtDNA) point mutations have been associated with MICM. However, the distinctive clinical and morphologic features of MICM are not fully appreciated. This is partially due to the small size of the reported pedigrees, often lacking detailed clinical and laboratory information. methods: Clinical and genetic analysis of the family was carried out. RESULTS: echocardiography showed mostly symmetrical hypertrophic cardiomyopathy in 10 family members. The illness had an unfavorable course. Progressive heart failure occurred in three subjects, who eventually died; one individual underwent heart transplantation. Electrocardiographic or echocardiographic signs of cardiac hypertrophy in the absence of significant clinical complaints were observed in five subjects. neurologic examination was normal. The mutation was detected in blood from all available subjects. Abundance of mutated molecules ranged between 13% and 100% of total mtDNA genomes. The severity of the disease could not be foreseen by the proportion of mutation in blood. CONCLUSIONS: This report contributes a better description of the clinical aspects of MICM and provides important clues to distinguish it from hypertrophic cardiomyopathy. We suggest that mtDNA mutations, particularly in the transfer ribonucleic acid for isoleucin, should be systematically searched in patients with MICM. The identification of an underlying maternally inherited mitochondrial dna defect in familial cases of cardiomyopathy may considerably influence the management and genetic counseling of affected patients.- - - - - - - - - - ranking = 1keywords = cardiac (Clic here for more details about this article) |
2/47. Scintigraphic evidence for a specific long-chain fatty acid transporting system deficit and the genetic background in a patient with hypertrophic cardiomyopathy.The mechanism of cardiac uptake of long-chain free fatty acids has not been fully determined. We encountered a hypertrophic cardiomyopathy patient who showed a lack of cardiac uptake of 2 different types of long-chain fatty acid analogues on the scintigraphic images. Flow cytometric analysis revealed no platelet or monocyte CD36 molecule expression (type I CD36 deficiency) and his CD36 gene showed homozygous mutation for 478C to T substitution, leading to an abnormal CD36 amino acid sequence. These findings strongly suggest that a specific transporting system rather than a simple diffusion is commonly involved in the cardiac uptake of long-chain free fatty acids in humans, and that the CD36 protein is the most likely candidate for the specific transporter and to explain scintigraphic defects on fatty acid imaging.- - - - - - - - - - ranking = 3keywords = cardiac (Clic here for more details about this article) |
3/47. A case of Lafora's disease associated with cardiac arrhythmia.Progressive myoclonic epilepsies are rare, genetically transmitted diseases characterized by epileptic seizures, myoclonus, and progressive neurologic deterioration. Unverricht-Lundborg disease, Lafora's disease, neuronal ceroid lipofuscinosis, mitochondrial disorders, and sialidosis are included in this group. Lafora's disease is a progressive disorder of the central nervous system with onset in the late first or second decade of life and is inherited in an autosomal-recessive pattern. The first clinical manifestation is generalized tonic-clonic seizures, myoclonus, or both, usually seen between the ages of 11 and 18 years. The other clinical manifestations are progressive dementia and limb ataxia. diagnosis is based on showing the typical inclusions in the brain, liver, skin, or muscle tissue specimens. The case of a 6-year-old male patient, who was admitted with the clinical findings of third-degree atrioventricular block and dementia and eventually diagnosed with Lafora's disease, is presented.- - - - - - - - - - ranking = 4keywords = cardiac (Clic here for more details about this article) |
4/47. Identification of a novel mutation in the ryanodine receptor gene (RYR1) in a malignant hyperthermia Italian family.malignant hyperthermia (MH) is an inherited autosomal dominant pharmacogenetic disorder and is one of the main causes of death subsequent to anaesthesia. Around 50% of affected families are linked to the ryanodine receptor (RYR1) gene. To date, 19 mutations have been identified in the coding region of this gene and appear to be associated with the MH-susceptible phenotype. Here we report the identification by two independent methods of a novel mutation associated with the MH-susceptible phenotype in the RYR1 gene: the 6488G-->C transversion, resulting in the replacement of the Arg2163 with a proline residue.- - - - - - - - - - ranking = 0.13736912341879keywords = death (Clic here for more details about this article) |
5/47. Recurrent umbilical cord torsion leading to fetal death in 3 subsequent pregnancies: a case report and review of the literature.During a span of 3.5 years, a 30-year-old, gravida 9, para 3 woman experienced 3 pregnancies complicated by umbilical cord torsion and constriction. In each case, the complication resulted in acute vascular compromise and intrauterine fetal demise. Gross examination disclosed cord constriction and torsion at the fetal end of the cord in each instance. Histologic sections from the cord torsion sites demonstrated fibrosis and deficiencies in Wharton's jelly in each case. Cytogenetic studies prepared using fetal villous tissue demonstrated normal karyotypes in fetal cells from the first 2 pregnancies (46,XX and 46,XY, respectively). The karyotype from the third pregnancy showed a 46,XX,del(X)(q24) mutation in 3 of 15 cultured cells, while 12 of 15 cells possessed a normal 46,XX karyotype. This cytogenetic abnormality was not believed to represent the cause of fetal demise in this case. To our knowledge, this is the first report of umbilical cord torsion in 3 pregnancies within one family. The familial clustering observed in this report suggests that a genetic predisposition for umbilical cord torsion may exist in some cases.- - - - - - - - - - ranking = 0.54947649367518keywords = death (Clic here for more details about this article) |
6/47. Molecular autopsy of sudden unexplained death in the young.Sudden unexplained death (SUD) claims over 4,000 persons between the age of 1 and 22 each year in the united states. Nearly half of all pediatric SUD cases have a normal structural autopsy evaluation and are dismissed without a diagnosis. With the discovery of the genetic basis for potentially fatal arrhythmias associated with the inherited long qt syndrome (LQTS), postmortem molecular diagnosis of this disorder is possible. The authors describe the results of a molecular autopsy performed on a 17-year-old boy found dead in bed. A novel clinical test involving an epinephrine challenge in the decedent's mother implicated a potential defect in the phase 3 potassium current encoded by the gene KVLQT1. Exon-specific amplification by polymerase chain reaction and direct dna sequencing of KVLQT1 revealed a 5-base pair deletion in the genetic material recovered from the decedent's paraffin-embedded heart tissue. The ability to perform molecular autopsies on archived necropsy material undoubtedly will transform the forensic evaluation of SUD. The combination of catecholamine provocation testing in survivors and a postmortem LQTS gene analysis may unmask families with "concealed" LQTS and establish the cause and manner of death in SUDS.- - - - - - - - - - ranking = 1.3023799234161keywords = death, sudden (Clic here for more details about this article) |
7/47. Familial amyloidotic polyneuropathy (ATTR Val30Met) with widespread cerebral amyloid angiopathy and lethal cerebral hemorrhage.We report an autopsy case of familial amyloidotic polyneuropathy (FAP) with cerebral hemorrhage. A 38-year-old woman with a typical FAP pedigree started developing severe diarrhea and sensori-motor polyneuropathy at the age of 28 years; autonomic nervous system, heart and renal dysfunction manifested themselves in the following years. Genetic analysis revealed a single amino acid substitution at codon 30 of transthyretin (ATTR Val30Met). Ten years after her initial symptoms, the patient died of a sudden convulsive attack and respiratory failure. autopsy revealed lethal cerebral hemorrhages and uremic lungs. Histochemical and immunohistochemical analyses revealed TTR-derived amyloid protein in every tissue examined, particularly in glomeruli and peripheral vessels. Severe meningo-cerebrovascular amyloidosis was also detected. Because uremia causes oxidative damage to the vascular system and amyloid formation is closely associated with oxidative stress, it is possible that uremic endothelial damage facilitated an unusual cerebral amyloid deposition. In typical FAP (ATTR Val30Met), cerebral amyloid angiopathy does not usually have clinical manifestations. However, cerebral amyloid angiopathy should be considered to explain FAP symptoms when some risk factors such as uremic vascular damage are accompanying features.- - - - - - - - - - ranking = 0.11954129572582keywords = sudden (Clic here for more details about this article) |
8/47. A novel mutation in glial fibrillary acidic protein gene in a patient with alexander disease.alexander disease is a rare, progressive, leukoencephalopathy whose hallmark is the widespread accumulation of Rosenthal fibers. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death before adulthood. Definitive diagnosis of alexander disease has required biopsy or autopsy to demonstrate the presence of Rosenthal fibers. However, missense mutations in the coding region of the glial fibrillary acidic protein (GFAP) gene have recently been associated with a high percentage of pathologically proven cases. Here we report that a 10-year-old Japanese patient who showed clinical signs of alexander disease is heterozygous for a C to T transition in which predicts a novel A244V amino acid substitution in the conserved 2A alpha-helix domain of GFAP. The nucleotide change was not found in 65 normal individuals (130 alleles). These results provide further support for a causative role for GFAP mutations in alexander disease, and suggest dna sequencing as an alternative diagnostic to biopsy.- - - - - - - - - - ranking = 0.13736912341879keywords = death (Clic here for more details about this article) |
9/47. Evidence for a single nucleotide polymorphism in the kcnq1 potassium channel that underlies susceptibility to life-threatening arrhythmias.INTRODUCTION: Congenital long qt syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. methods AND RESULTS: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in approximately 11% of the Japanese population. This 1727G>A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in approximately 30% reduction in the slow delayed rectifier K current I(Ks) without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. CONCLUSION: We demonstrate that a common polymorphism in the kcnq1 potassium channel could be a molecular basis for mild I(Ks) dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.- - - - - - - - - - ranking = 1keywords = cardiac (Clic here for more details about this article) |
10/47. Familial left ventricular hypertrabeculation in two blind brothers.So far, left ventricular hypertrabeculation (LVHT) has been described to occur only sporadically. In a 49-year-old man with Leber's hereditary optic neuropathy (LHON) due to the primary LHON mutation G3460A, arterial hypertension was reported since 2000 and palpitations since 1995. ECG revealed wolff-parkinson-white syndrome. Transthoracic echocardiography and cardiac MRI showed myocardial thickening and LVHT. pindolol markedly improved the cardiac abnormalities. Surprisingly, LVHT was also found in the 50-year-old brother of the index patient who also had LHON and also carried the G3460A mtDNA mutation. This brother also had wolff-parkinson-white syndrome and myocardial thickening, but without hypertension. It is concluded that LVHT, previously described to occur only sporadically, may be hereditary in single cases.- - - - - - - - - - ranking = 2keywords = cardiac (Clic here for more details about this article) |
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