5′-Cytosine DNA-methyltransferase mRNA levels in hereditary colon carcinoma

 DNA methylation plays an important part in the regulation of gene expression. Alterations in DNA methylation in tumours have been reported and have been used to generate hypotheses about mutagenesis and silencing of tumour suppressor genes. However, the underlying mechanism is still poorly understood, and conflicting data on the levels of overexpression of 5′-cytosine DNA methyltransferase in sporadic colon carcinoma have been published. We used a competitive RT-PCR assay for quantification of mRNA of 5′-cytosine DNA methyltransferase in colon biopsies obtained from patients with hereditary colon carcinoma syndromes and compared the results with those obtained in a control group. No significant difference was found between the flat mucosa of FAP patients and the mucosa of the control group. In FAP and HNPCC patients, the 5′-cytosine DNA methyltransferase mRNA levels of adenomas were significantly higher (P<0.05) than of flat mucosa in the same group, but both showed great variability from patient to patient. Our findings suggest that the mRNA levels of methyltransferase cannot be used as predictive marker for screening in families affected by hereditary colon carcinoma. Received: 20 July 1998 / Accepted: 21 September 1998     

Morphologic evaluation of the liver in hereditary angioedema patients on long-term treatment with androgen derivatives

17 alpha-Alkylated androgens are highly effective in preventing attacks in HAE patients. These drugs, however, seem to be implicated in the development of cholestatic jaundice, peliosis hepatis, and liver tumors. In order to assess the risk-benefit balance of the long-term therapy with androgen derivatives, a follow-up investigation was performed in 13 HAE patients. The results of this study indicate that long-term treatment (15 to 47 mo) with low doses of danazol or stanozolol does not induce significant hepatic damage detectable by laboratory tests or liver biopsy. However, the limited number of patients, although in a rather long period of observation, still suggests a careful control and the use of minimal effective doses.     

Genomic instability occurs in colorectal carcinomas but not in adenomas

Genomic instability, as demonstrated by the presence of additional alleles at short tandemly repeated (STR) loci, has recently been observed in colorectal tumours from individuals with hereditary non-polyposis colorectal cancer (HNPCC), and in some sporadic tumours. These neoplasms have been called replication error positive (RER⁺). In this study, we confirm the presence of genomic instability in a proportion of unselected colorectal carcinomas but find no evidence of instability in adenomas. We further report replication errors in a tetranucleotide sequence, and in STRs within two tumour suppressor genes. 108 colorectal adenocarcinomas and 46 adenomas were analysed for the presence of variant bands at 4–15 microsatellite markers. Seven (6.5%) of carcinomas were RER⁺, four of which originated from the proximal colon. Analysis of the adenomas and of matched adenoma-carcinoma and carcinoma-metastatic samples from four patients suggests that the replication errors may occur during the development of carcinomas but are rare in adenomas. © 1993 Wiley-Liss, Inc.     

Hereditary uroporphyrinogen-decarboxylase deficiency predisposing porphyria cutanea tarda (chronic hepatic porphyria) in females after oral contraceptive medication

Summary Porphyria cutanea tarda (PCT) was diagnosed in 27 women aged 23–48 years (mean, 35 years) who had been under oral-hormonal-contraceptive medication for 1–18 years, in 3 women under substitutional estrogen treatment in the menopause, and in 2 men aged 65 and 76 years after estrogen treatment of prostatic carcinoma. In all patients, total urinary porphyrin excretion was elevated, with an average uro-and heptacarboxyporphyrin predominance of 88%, thus proving PCT. On the patients, 84% showed a significant decrease of erythrocyte uroporphyrinogen-decarboxylase (UD; EC 4.1.1.37) activity to 50% of control levels suggesting a hereditary predisposition for the development of a chronic hepatic porphyria. Estrogens and alcohol are capable of reducing hepatic UD activity. Women with hereditary red cell UD deficiency may be regarded as predisposed to PCT when under estrogen intake, especially in combination with the potentiating influence of alcohol and chronic liver disease. Normal erythrocyte UD values in patients with additive alcohol consumption may implicate a stronger inhibitory effect for alcohol on UD, suggesting a merely toxic form of chronic hepatic porphyria.     

Leber遗传性视神经病变24例临床分析

回顾分析了 2 4例 ( 4 8眼 )Leber遗传性视神经病变的临床特征。患者年龄从 1 2岁到 44岁 ,平均 ( 2 0 3± 7 2 )岁 ,男性占 83%。发病典型者多为 1眼无痛性视力下降。视力下降程度从眼前手动到 1 2 ,其中 40眼 ( 83% )≤ 0 1。视野缺损主要为中心暗点或旁中心暗点 ,色觉障碍严重。本组部分病例发病早期有特征性眼底改变 ,包括视盘明显充血 ,视盘周围小血管扩张迂曲 ,神经纤维层水肿。眼底荧光血管造影视盘及盘缘血管无荧光素渗漏。     

Altered gating and conductance of Na+ channels in hyperkalemic periodic paralysis

Electrophysiological studies on muscle fibres from patients with hyperkalemic periodic paralysis with myotonia have shown that the episodes of weakness are caused by a sustained depolarization of the sarcolemma to potentials between -40 and -60 mV. In muscle fibre segments from three such patients this sustained depolarization was caused by noninactivating Na⁺ channels with reduced single-channel conductance blocked by TTX and procainamide. As the chloride conductance was normal, myotonia may be best explained with the abnormal reopenings of the Na⁺ channels. The recently described genetic linkage between hyperkalemic periodic paralysis with myotonia and the gene coding for the TTX-sensitive Na⁺ channel suggests an altered primary structure of this channel causing its abnormal function.     

全外显子组测序和目标序列靶向捕获测序在遗传性视网膜变性基因诊断中的差异

目的:对比外显子组测序(whole exome sequencing,WES)和目标序列靶向捕获测序检测中国遗传性视网膜变性(inherited retinal dystrophies,IRDs)患者致病基因变异的差异。方法:收集182例IRDs家系,所有先证者均接受系统的眼科检查和必要的全身检查,采集患者及家属血样并提取基因组DNA。按照就诊的时间顺序将患者平均分为两组,一组91例接受WES,另一组91例应用本课题组设计并定制的“遗传性眼病基因诊断芯片” (hereditary eye disease enrichment panel,HEDEP)进行IRDs致病基因外显子区域靶向捕获测序。对候选致病基因用Sanger测序进行验证,并对家系成员进行共分离分析,使用多重连接依赖的探针扩增技术对拷贝数变异进行验证,针对二代测序捕获效率低的区域如RPGR ORF15区,应用Sanger 测序补充检测。根据美国医学遗传学与基因组学学会和分子病理学协会(American College of Medical Genetics and Genomics and the Association for Molecular Pathology,ACMG/AMP)制定的《ACMG/AMP基因变异分类标准与指南》将检测到的所有基因变异进行分类,本文只包含“致病的”、“可能致病的”的基因变异,不包含“意义不明确的”、“可能良性的”和“良性的”基因变异。结果:应用HEDEP确诊的家系共51例,阳性率为56.04%(51/91);应用WES确诊的家系共30例,阳性率为33.00%(30/91);总阳性率44.51%(81/182)。平均测序深度以及测序覆盖度方面,HEDEP优于WES,此外HEDEP具有检测拷贝数变异潜力。本研究共检测到29个IRDs基因的致病突变,最常见的致病基因为USH2A、ABCA4和RPGR,基因突变频率分别为11.54%(21/182)、6.59%(12/182)、3.85%(7/182);共发现43个新的致病突变,并检测到6例家系携带RPGR ORF15区的突变。结论:针对临床确诊的IRDs病例,HEDEP较WES能获得更高的基因诊断阳性率和更精确的诊断结果,可作为IRDs基因诊断的首选方法,WES可作为其他基因诊断方法的补充手段。同时,本研究丰富了IRDs致病基因的突变频谱,为将来IRDs基因诊断、遗传咨询和基因治疗奠定了基础。     

遗传性无综合征耳聋一家系畸变产物耳声发射测试

目的　探索遗传性进行性无综合征耳聋患者的听功能改变特点。方法　一个常染色体显性遗传进行性无综合征耳聋家系 5 2名成员及听力正常组 15名 ,进行了纯音测试及畸变产物耳声发射 (distortionproductotoacousticemissions,DPOAE)测试。结果　无综合征耳聋家系中 34名成员纯音测试为感音神经性聋 ,其中纯音听阈均值 (puretoneaverage ,PTA)≥ 40dB的 15例 (2 9耳 )DPOAE反应缺失 ,PTA≤ 35dB伴高频下降的 12例 (2 3耳 )DPOAE高频或高、中频振幅下降或缺失 ;2 1名 (42耳 )纯音听阈正常成员中 ,有 12例 (15耳 )DPOAE高频或高、中频振幅下降或缺失。结论　DPOAE能鉴别出耳蜗亚临床的病理改变 ,对该病的早期诊断 ,遗传咨询有指导意义。     

Clinicopathological features of hereditary breast cancer

The possible role of germline mutations ofBRCA1 andBRCA2 as causative agents of familial breast cancer was assessed. Their possible involvement in the carcinogenesis of hereditary breast cancer was investigated using 63 clinically suspect families. Twenty-one lineages (33.3%) had mutations in one of the twoBRCA genes. This relatively low incidence suggested that germline mutations in unknown genes are involved in the carcinogenesis of hereditary breast cancer in the Japanese population. However, the clinicopathological features characteristic of hereditary breast cancer, such as early disease onset, a high incidence of bilateral breast cancer, and a high incidence of multiple primary carcinomas in other organs were confirmed in the present study.