Fabry病在中国汉族肥厚型心肌病人群的患病率(英文)

目的:研究中国汉族肥厚型心肌病人群中α-Galactosidase A突变的患病率及其临床表现。方法:对439名肥厚型心肌病患者及156名健康对照GLA基因进行全外显子测序,及基因型及临床表型进行关联分析。结果:确定了2个致病性突变,包括1个错义突变E66Q和1个剪接位点的突变c.547+1GC。2个突变在156名健康人群未发现,在1000人基因组计划中未报道。确定中国汉族肥厚型心肌病人群中α-Galactosidase A突变0.45%的患病率。结论:Fabry病在中国汉族肥厚型心肌病人群中α-Galactosidase A突变的患病率较低。基因检测有助于Fabry病与肥厚型心肌病的鉴别诊断。     

Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are caused by mutations in 14 and 15 different disease genes, respectively, in a part of the patients and the disease genes for cardiomyopathy overlap in part with that for limb-girdle muscular dystrophy (LGMD). In this study, we examined an LGMD gene encoding caveolin-3 (CAV3) for mutation in the patients with HCM or DCM. A Thr63Ser mutation was identified in a sibling case of HCM. Because the mutation was found at the residue that is involved in the LGMD-causing mutations, we investigate the functional change due to the Thr63Ser mutation as compared with the LGMD mutations by examining the distribution of GFP-tagged CAV3 proteins. It was observed that the Thr63Ser mutation reduced the cell surface expression of caveolin-3, albeit the change was mild as compared with the LGMD mutations. These observations suggest that HCM is a clinical spectrum of CAV3 mutations.     

Mutation analysis of the natriuretic peptide precursor B (NPPB) gene in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetically heterogenous disease caused by mutations in genes that primarily encode sarcomeric proteins. No mutation is identified in up to 40% of HCM patients, suggesting other causative genes exist. Natriuretic peptide precursor B (NPPB; also known as "BNP") is a cardiac hormone involved in body fluid homeostasis and cardiac myocyte growth. NPPB concentrations are markedly increased in patients with ventricular hypertrophy, and it is therefore possible mutations in the NPPB gene could cause HCM. METHODS: Genomic DNA was extracted from peripheral blood in 238 consecutive probands with HCM. The coding regions and intron/exon boundaries in the NPPB gene were amplified by PCR, and products were screened for sequence variants using high-performance liquid chromatography, followed by direct DNA sequencing. RESULTS: Four sequence variants in the NPPB gene were identified in 9 of the 238 probands screened. Two of the variants were intronic, one was a synonymous variant at codon 79, and the final variant resulted in an amino acid substitution from arginine to histidine at codon 47 (Arg47His). The Arg47His variant was identified in a control population consisting of 204 chromosomes at an allelic frequency of 0.5%, and is therefore unlikely to cause disease. CONCLUSION: No disease causing mutations were identified in the NPPB gene in this cohort, indicating that mutations in this gene are unlikely to be responsible for HCM.     

Mitochondrial Haplogroups Modify the Risk of Developing Hypertrophic Cardiomyopathy in a Danish Population

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes coding for proteins involved in sarcomere function. The disease is associated with mitochondrial dysfunction. Evolutionarily developed variation in mitochondrial DNA (mtDNA), defining mtDNA haplogroups and haplogroup clusters, is associated with functional differences in mitochondrial function and susceptibility to various diseases, including ischemic cardiomyopathy. We hypothesized that mtDNA haplogroups, in particular H, J and K, might modify disease susceptibility to HCM. Mitochondrial DNA, isolated from blood, was sequenced and haplogroups identified in 91 probands with HCM. The association with HCM was ascertained using two Danish control populations. Haplogroup H was more prevalent in HCM patients, 60% versus 46% (p = 0.006) and 41% (p = 0.003), in the two control populations. Haplogroup J was less prevalent, 3% vs. 12.4% (p = 0.017) and 9.1%, (p = 0.06). Likewise, the UK haplogroup cluster was less prevalent in HCM, 11% vs. 22.1% (p = 0.02) and 22.8% (p = 0.04). These results indicate that haplogroup H constitutes a susceptibility factor and that haplogroup J and haplogroup cluster UK are protective factors in the development of HCM. Thus, constitutive differences in mitochondrial function may influence the occurrence and clinical presentation of HCM. This could explain some of the phenotypic variability in HCM. The fact that haplogroup H and J are also modifying factors in ischemic cardiomyopathy suggests that mtDNA haplotypes may be of significance in determining whether a physiological hypertrophy develops into myopathy. mtDNA haplotypes may have the potential of becoming significant biomarkers in cardiomyopathy.     

Genetic variation screening of TNNT2 gene in a cohort of patients with hypertrophic and dilated cardiomyopathy

Mutations in troponin T (TNNT2) gene represent the important part of currently identified disease-causing mutations in hypertrophic (HCM) and dilated (DCM) cardiomyopathy. The aim of this study was to analyze TNNT2 gene exons in patients with HCM and DCM diagnosis to improve diagnostic and genetic consultancy in affected families. All 15 exons and their flanking regions of the TNNT2 gene were analyzed by DNA sequence analysis in 174 patients with HCM and DCM diagnosis. We identified genetic variations in TNNT2 exon regions in 56 patients and genetic variations in TNNT2 intron regions in 164 patients. Two patients were found to carry unique mutations in the TNNT2 gene. Limited genetic screening analysis is not suitable for routine testing of disease-causing mutations in patients with HCM and DCM as only individual mutation-positive cases may be identified. Therefore, this approach cannot be recommended for daily clinical practice even though, due to financial constraints, it currently represents the only available strategy in a majority of cardio-centers.     

Detection of a large duplication mutation in the myosin-binding protein C3 gene in a case of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance caused by mutations in genes coding for sarcomeric and/or regulatory proteins expressed in cardiomyocytes. In a small cohort of HCM patients (n = 8), we searched for mutations in the two most common genes responsible for HCM and found four missense mutations in the MYH7 gene encoding cardiac β-myosin heavy chain (R204H, M493V, R719W, and R870H) and three mutations in the myosin-binding protein C3 gene (MYBPC3) including one missense (A848V) and two frameshift mutations (c.3713delTG and c.702ins26bp). The c.702ins26bp insertion resulted from the duplication of a 26-bp fragment in a 54-year-old female HCM patient presenting with clinical signs of heart failure due to diastolic dysfunction. Although such large duplications (> 10 bp) in the MYBPC3 gene are very rare and have been identified only in 4 families reported so far, the identical duplication mutation was found earlier in a Dutch patient, demonstrating that it may constitute a hitherto unknown founder mutation in central European populations. This observation underscores the significance of insertions into the coding sequence of the MYBPC3 gene for the development and pathogenesis of HCM.     

No Fabry Disease in Patients Presenting with Isolated Small Fiber Neuropathy

Objective

Screening for Fabry disease in patients with small fiber neuropathy has been suggested, especially since Fabry disease is potentially treatable. However, the diagnostic yield of testing for Fabry disease in isolated small fiber neuropathy patients has never been systematically investigated. Our aim is to determine the presence of Fabry disease in patients with small fiber neuropathy.

Methods

Patients referred to our institute, who met the criteria for isolated small fiber neuropathy were tested for Fabry disease by measurement of alpha-Galactosidase A activity in blood, lysosomal globotriaosylsphingosine in urine and analysis on possible GLA gene mutations.

Results

725 patients diagnosed with small fiber neuropathy were screened for Fabry disease. No skin abnormalities were seen except for redness of the hands or feet in 30.9% of the patients. Alfa-Galactosidase A activity was tested in all 725 patients and showed diminished activity in eight patients. Lysosomal globotriaosylsphingosine was examined in 509 patients and was normal in all tested individuals. Screening of GLA for mutations was performed for 440 patients, including those with diminished α-Galactosidase A activity. Thirteen patients showed a GLA gene variant. One likely pathogenic variant was found in a female patient. The diagnosis Fabry disease could not be confirmed over time in this patient. Eventually none of the patients were diagnosed with Fabry disease.

Conclusions

In patients with isolated small fiber neuropathy, and no other signs compatible with Fabry disease, the diagnostic yield of testing for Fabry disease is extremely low. Testing for Fabry disease should be considered only in cases with additional characteristics, such as childhood onset, cardiovascular disease, renal failure, or typical skin lesions.     

Hypertrophic cardiomyopathy family with double-heterozygous mutations; does disease severity suggest doubleheterozygosity?

Background. With the improvement in genetic testing over time, double-heterozygous mutations are more often found by coincidence in families with hypertrophic cardiomyopathy (HCM). Double heterozygosity can be a cause of the wellknown clinical diversity within HCM families. Methods and results. We describe a family in which members carry either a single mutation or are double heterozygous for mutations in myosin heavy chain gene (MYH7) and cysteine and glycine-rich protein 3 (CSRP3). The described family emphasises the idea of a more severe clinical phenotype with double-heterozygous mutations. It also highlights the importance of cardiological screening where NT-proBNP may serve as an added diagnostic tool. Conclusion. With a more severe inexplicable phenotype of HCM within a family, one should consider the possibility of double-heterozygous mutations. This implies that in such families, even when one disease-causing mutation is found, all the family members still have an implication for cardiological screening parallel to extended genetic screening. (Neth Heart J 2009;17:458–63.)     

Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formation

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most common hereditary cardiac conditions. Both are frequent causes of sudden death and are often associated with an adverse disease course. Alpha-cardiac actin is one of the disease genes where different missense mutations have been found to cause either HCM or DCM. We have tested the hypothesis that the protein-folding pathway plays a role in disease development for two actin variants associated with DCM and six associated with HCM. Based on a cell-free coupled translation assay the actin variants could be graded by their tendency to associate with the chaperonin TCP-1 ring complex/chaperonin containing TCP-1 (TRiC/CCT) as well as their propensity to acquire their native conformation. Some variant proteins are completely stalled in a complex with TRiC and fail to fold into mature globular actin and some appear to fold as efficiently as the wild-type protein. A fraction of the translated polypeptide became ubiquitinated and detergent insoluble. Variant actin proteins overexpressed in mammalian cell lines fail to incorporate into actin filaments in a manner correlating with the degree of misfolding observed in the cell-free assay; ranging from incorporation comparable to wild-type actin to little or no incorporation. We propose that effects of mutations on folding and fiber assembly may play a role in the molecular disease mechanism.     

A new assay for functional screening of BRCA2 linker region mutations identifies variants that alter chemoresistance to cisplatin

Variants of unknown significance (VUS) complicate the assignment of risk to new DNA sequence variants found in at-risk populations. This study focused on the poorly studied linker region of the cancer-associated BRCA2 protein encoded by exons twelve through fourteen of BRCA2. To develop a new method to characterize VUS in this region of BRCA2, we first chose to study 4 reported VUS occurring on evolutionarily conserved residues within the linker region. To determine if these VUS represent neutral changes or if they impact the function of the BRCA2 protein, we stably transfected expression plasmids encoding wild-type or each mutant peptide into T47D breast cancer cells, which are wild-type for BRCA2. Four mutant peptide expressing cell lines and a wild-type linker region expressing cell line next were studied by challenging transfected cell lines with the DNA crosslinking compound cisplatin (10 μM) for 5 days. Expression of the wild-type linker region and certain mutant linker peptides (N2452D and I2285V) decreased apoptosis (as demonstrated by cell death detection assay) in transfected cell lines, indicating that the linker region peptide directly or indirectly affects the DNA damage repair pathway. By determining the cell survival and assaying the apoptotic index of treated cell lines, one could potentially use this screen to determine that a particular VUS has a functional impact on BRCA2 function, and hence is of functional significance. We conclude that this method is useful for screening the effect of linker region VUS on BRCA2 function, and to identify mutations for further testing. We also conclude that mutations in the linker region may have heretofore unappreciated roles in BRCA2 function.     

A mutation in the β-myosin rod associated with hypertrophic cardiomyopathy has an unexpected molecular phenotype

Hypertrophic cardiomyopathy (HCM) is a common, autosomal dominant disorder primarily characterized by left ventricular hypertrophy and is the leading cause of sudden cardiac death in youth. HCM is caused by mutations in several sarcomeric proteins, with mutations in MYH7, encoding β-MyHC, being the most common. While many mutations in the globular head region of the protein have been reported and studied, analysis of HCM-causing mutations in the β-MyHC rod domain has not yet been reported. To address this question, we performed an array of biochemical and biophysical assays to determine how the HCM-causing E1356K mutation affects the structure, stability, and function of the β-MyHC rod. Surprisingly, the E1356K mutation appears to thermodynamically destabilize the protein, rather than alter the charge profile know to be essential for muscle filament assembly. This thermodynamic instability appears to be responsible for the decreased ability of the protein to form filaments and may be responsible for the HCM phenotype seen in patients.     

Familial screening and genetic counselling in hypertrophic cardiomyopathy: the Rotterdam experience

Hypertrophic cardiomyopathy (HCM) is a disease characterised by unexplained left ventricular hypertrophy (LVH) (i.e. LVH in the absence of another cardiac or systemic disease that could produce a similar degree of hypertrophy), electrical instability and sudden death (SD). Germline mutations in genes encoding for sarcomere proteins are found in more than half of the cases of unexplained LVH. The autosomal dominant inherited forms of HCM are characterised by incomplete penetrance and variability in clinical and echocardiographic features, prognosis and therapeutic modalities. The identification of the genetic defect in one of the HCM genes allows accurate presymptomatic detection of mutation carriers in a family. Cardiac evaluation of at-risk relatives enables early diagnosis and identification of those patients at high risk for SD, which can be the first manifestation of the disease in asymptomatic persons. In this article we present our experience with genetic testing and cardiac screening in our HCM population and give an overview of the current literature available on this subject. (Neth Heart J 2007;15:184-9.)     

Delayed AICD therapy and cardiac arrest resulting from undersensing of ventricular fibrillation in a subject with hypertrophic cardiomyopathy–A case report

Defibrillation testing is no longer routinely performed after automatic implantable cardioverter-defibrillator (AICD) implantation. However, certain subjects undergoing AICD implantation may be at higher risk of undersensing of ventricular arrhythmias resulting in potentially fatal outcomes. We present the case of a 30-year-old woman with hypertrophic cardiomyopathy (HCM; ‘asymmetric septal hypertophy’ morphologic variant) and prophylactic AICD who experienced an out of hospital cardiac arrest. AICD interrogation revealed undersensing as a result of intermittent high amplitude electrograms during an episode of ventricular fibrillation (VF). The subject underwent replacement and repositioning of the AICD lead along with pulse generator replacement (that utilized a different VF sensing algorithm) with appropriate sensing of VF and successful defibrillation testing. The presence of intermittent high amplitude electrograms during episodes of VF in AICDs using the AGC function should be recognized as a situation that may necessitate interventions to prevent undersensing and consequent delay in therapy.     

心肌肌钙蛋白T基因突变在心肌病发病机制中的研究进展

肥厚型和扩张型心肌病中,基因缺陷分别占发病的50％和35％,其病理生理机制,主要包括肌小节蛋白基因突变引起的收缩力产生缺陷,细胞骨架蛋白基因突变引起的收缩力传递缺陷等。心肌肌钙蛋白T将肌钙蛋白C和肌钙蛋白I连接到肌动蛋白和原肌球蛋白上,在心肌细胞收缩和舒张过程中发挥重要作用。在肥厚型和扩张型心肌病中发现了多种心肌肌钙蛋白T的基因突变,围绕心肌肌钙蛋白T的研究有助于阐明心肌病的发病机制。本文总结了心肌肌钙蛋白T基因突变在心肌病发病机制中的研究情况。     

Utility of genetic screening in hypertrophic cardiomyopathy: prevalence and significance of novel and double (homozygous and heterozygous) beta-myosin mutations

Genetic screening of the beta-myosin heavy chain gene (MYH7) was evaluated in 100 consecutive unrelated patients with hypertrophic cardiomyopathy (HCM) and 200 normal unrelated subjects. Seventeen beta-myosin mutations were identified in 19 patients. Notably, 13, or 76%, were novel. Mutations were detected in both alleles in two patients: homozygous for Lys207Gln in one, and heterozygous for Pro211 Leu and Arg663His in another. No mutation was detected in the controls. MYH7-associated HCM was associated with more marked left atrial enlargement and syncope than non-MYH7-related HCM. Our findings indicate that: (1) screening methods should allow identification of novel mutations; and (2) more than one sarcomeric mutation may be present in a patient more commonly than is appreciated. Further studies are necessary to ascertain the clinical consequences of the novel and compound gene abnormalities, and to determine whether correlating functional domain to phenotype provides more useful information about the clinical significance of the molecular defects.     

ENerGetIcs in hypertrophic cardiomyopathy: traNslation between MRI, PET and cardiac myofilament function (ENGINE study)

Introduction

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant heart disease mostly due to mutations in genes encoding sarcomeric proteins. HCM is characterised by asymmetric hypertrophy of the left ventricle (LV) in the absence of another cardiac or systemic disease. At present it lacks specific treatment to prevent or reverse cardiac dysfunction and hypertrophy in mutation carriers and HCM patients. Previous studies have indicated that sarcomere mutations increase energetic costs of cardiac contraction and cause myocardial dysfunction and hypertrophy. By using a translational approach, we aim to determine to what extent disturbances of myocardial energy metabolism underlie disease progression in HCM.

Methods

Hypertrophic obstructive cardiomyopathy (HOCM) patients and aortic valve stenosis (AVS) patients will undergo a positron emission tomography (PET) with acetate and cardiovascular magnetic resonance imaging (CMR) with tissue tagging before and 4 months after myectomy surgery or aortic valve replacement + septal biopsy. Myectomy tissue or septal biopsy will be used to determine efficiency of sarcomere contraction in-vitro, and results will be compared with in-vivo cardiac performance. Healthy subjects and non-hypertrophic HCM mutation carriers will serve as a control group.

Endpoints

Our study will reveal whether perturbations in cardiac energetics deteriorate during disease progression in HCM and whether these changes are attributed to cardiac remodelling or the presence of a sarcomere mutation per se. In-vitro studies in hypertrophied cardiac muscle from HOCM and AVS patients will establish whether sarcomere mutations increase ATP consumption of sarcomeres in human myocardium. Our follow-up imaging study in HOCM and AVS patients will reveal whether impaired cardiac energetics are restored by cardiac surgery.     

The enhancement of Raf-1 kinase activity by knockdown of Spry2 is associated with high sensitivity to paclitaxel in v-Ha-ras-transformed NIH 3T3 fibroblasts

The aim of the current study was to determine the frequency of mutations in the beta-myosin heavy chain gene (MYH7) in a cohort of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and their families, and to investigate correlations between genotype and phenotype. About 130 consecutive patients diagnosed with HCM or DCM (69 with HCM and 61 with DCM) attending the cardiology clinic of Post Graduate Institute of Medical Education and Research were screened for mutations in the MYH7 gene. The control group for genetic studies consisted of 100 healthy subjects. We report 14 mutations in 6 probands (5 probands in HCM and 1 proband in DCM) and their family members. Out of these 6 mutations, 3 are new and are being reported for the first time. One known mutation (p.Gly716Arg) was found to be "de novo" which resulted in severe asymmetric septal hypertrophy (31 mm) and resulted in the sudden cardiac death (SCD) of the proband at the age of 21 years. Further, a DCM causing novel mutation p.Gly377Ser was identified which resulted in the milder phenotype. The present study shows that there is genetic and phenotypic heterogeneity of cardiomyopathies in Indian population. Further, the location and type of mutation in a given sarcomeric gene determines the severity and phenotypic plasticity in cardiomyopathies.     

Evaluation of ultrasound lung comets by hand-held echocardiography

Background

Most patients with hypertrophic cardiomyopathy (HCM) have asymmetric septal hypertrophy and among them, 25% present dynamic subaortic obstruction. Apical HCM is unusual and mid-ventricular HCM is the most infrequent presentation, but both variants may be associated to an apical aneurysm. An even more rare presentation is the coexistece mid-ventricular and apical HCM. This case is a combination of obstructive HCM with mid-ventricular HCM and an apical aneurysm, which to date, has not been reported in the literature.

Case presentation

The patient is a 49 year-old lady who presents a combination of septal asymmetric hypertrophic cardiomyopathy (HCM) and midventricular HCM, a subaortic gradient of 65 mm Hg and a midventricular gradient of 20 mm Hg, plus an apical aneurysm. Her clinical presentation was an acute myocardial infarction in June 2005. One month after hospital discharge, the electrocardiogram (ECG) showed a right bundle branch block (RBBB) with no Q waves or ST segment elevation. Coronary angiography revealed normal coronary arteries, left ventricular hypertrophy and an apical aneurysm.

Conclusion

This case is a rare example of an asymptomatic patient with subaortic and mid-ventricular hypertrophic cardiomyopathy, who presents a myocardial infarction and normal coronary arteries, and during the course of her disease develops an apical aneurysm.     

Phospholamban Gene Mutations Are Not Associated with Hypertrophic Cardiomyopathy in a Northern Greek Population

Hypertrophic cardiomyopathy (HCM) is a genetically transmitted cardiac disease characterized by unexplained myocardial hypertrophy and diverse clinical spectrum. Currently, more than 250 HCM-related mutations in 10 genes encoding contractile sarcomeric proteins have been identified. Phospholamban (PLN) is a modest modulator of intracellular Ca2+ homeostasis and may be a candidate gene responsible for cardiomyopathy. In this study 53 consecutive patients with HCM, coming from Northern Greece, were screened for mutations of PLN gene. The patients were evaluated by clinical history, physical examination, electrocardiogram and echocardiography. All PCR products were analyzed for mutation by both restriction analysis and sequencing. The systematic mutation screening did not reveal any mutation in exons 1 and 2 or in the promoter region of phospholamban gene. Additionally, no polymorphisms were detected in all patients. Therefore, PLN gene mutations were not found to be associated with HCM in a Northern Greece population.     

Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy

About 10% of cases of hypertrophic cardiomyopathy (HCM) evolve into dilated cardiomyopathy (DCM) with unknown causes. We studied 11 unrelated patients (pts) with HCM who progressed to DCM (group A) and 11 who showed "typical" HCM (group B). Mutational analysis of the beta-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), and cardiac troponin T (TNNT2) genes demonstrated eight mutations affecting MYH7 or MYBPC3 gene, five of which were new mutations. In group A-pts, the first new mutation occurred in the myosin head-rod junction and the second occurred in the light chain-binding site. The third new mutation leads to a MYBPC3 lacking titin and myosin binding sites. In group B, two pts with severe HCM carried two homozygous MYBPC3 mutations and one with moderate hypertrophy was a compound heterozygous for MYBPC3 gene. We identified five unreported mutations, potentially "malignant" defects as for the associated phenotypes, but no specific mutations of HCM/DCM.