一例新生儿甲状旁腺功能减低-感音神经性耳聋-肾发育不良综合征患儿的临床及遗传学分析CSCD

目的分析甲状旁腺功能减低-感音神经性耳聋-肾发育不良(hypoparathyroidism-sensorineural deafness-renal dysplasia, HDR)综合征的临床表型与基因变异特点。方法对1例HDR综合征新生儿进行全基因组拷贝数变异(copy number variation, CNVs)以及外显子组检测, 并分析其临床资料和相关文献。结果患儿为男性, 新生儿期起病, 表现为特殊面容、通贯掌、骶尾部赘生物。血清学检查提示低钙血症、低甲状旁腺激素。听力检测提示双侧感音神经性耳聋。超声检查提示右肾缺如, CNVs检测提示染色体10p15.3-p13(chr10: 105 001_12 815 001)区存在12.71 Mb的缺失, 全外显子测序提示GATA3基因缺失。患儿经补充钙剂及维生素D治疗, 病情有所好转。结论患儿的10p15.3-p13缺失与甲状旁腺功能减退、感音神经性耳聋和右肾缺如等临床表型相关。HDR综合征是罕见的遗传性疾病, 应提高对其的认识, 减少漏诊。     

Ocular albinism with infertility and late‐onset sensorineural hearing loss

Ocular albinism type 1 (OA1) is caused by mutations in the GPR143 gene located at Xp22.2. The manifestations, which are due to hypopigmentation, are confined to the eyes and optic pathway. OA1 associated with late‐onset sensorineural hearing loss was previously reported in a single family and hypothesized to be caused by a contiguous gene deletion syndrome involving GPR143 and the adjacent gene, TBL1X. Here, we report on a family with OA1, infertility, late‐onset sensorineural hearing loss, and a small interstitial Xp microdeletion including the GPR143, TBL1X, and SHROOM2 genes. In addition, we re‐examined a patient previously described with OA1, infertility and a similar Xp deletion with audiologic follow‐up showing a late‐onset sensorineural hearing loss. Our results raise an intriguing question about the possibility for TBL1X (absence) involvement in this type of hearing loss. However, our study cannot claim a causative relationship and more convincing evidence is needed before the hypothesis can be accepted that TBL1X could be involved in late‐onset sensorineural hearing loss and that ocular albinism with late‐onset sensorineural hearing loss can present itself as a contiguous gene deletion/microdeletion syndrome. The finding of infertility in all affected male patients demonstrates that this deletion, including the SHROOM2 gene, may be a potentially causative X‐linked genetic factor of male infertility.     

一个遗传性非综合征型耳聋家系的突变分析

目的分析一个遗传性非综合征型耳聋家系的突变，并探讨缝隙连接蛋白beta2(gap junction protein beta 2，GJB2)基因235delC突变是否会加重线粒体A1555G突变导致的非综合征型耳聋症状。方法对一个母系遗传性非综合征型耳聋核心家系72个成员取外周血提取DNA，经聚合酶链反应扩增后，利用Alw26Ⅰ限制性内切酶酶切及直接测序验证，对其线粒体DNA突变进行研究；利用ApaⅠ限制性内切酶酶切及直接测序验证，筛查核心家系中GJB2基因235delC突变情况，并对GJB2基因235delC和线粒体A1555G突变的关系进行研究。结果在27名母系成员中均发现具有线粒体A1555G突变，呈母系遗传；具有耳聋表型的为21人(77．8％)，家族外显率高；所筛查的包括配偶在内的72名个体中，仅3例具有GJB2基因235delC杂合子突变，且均出现在母系成员中，但3例的耳聋表型却不同。结论线粒体A1555G突变是本家系耳聋遗传易感性的基础，在该家系中GJB2基因的235delC杂合子突变未加重线粒体A1555G突变导致的非综合征型耳聋。     

感音神经性耳聋分子机制的研究进展

感音神经性耳聋主要表现为声波感受障碍引起的听力损失,与耳蜗感觉上皮和螺旋神经元的结构及功能受 损密切相关,但具体的病理机制尚不确切。细胞、分子水平的研究证明细胞凋亡、氧化应激损伤、免疫炎症、代 谢障碍、基因突变可能参与多种因素引起的内耳细胞损伤或死亡,引起听力损失。本文将围绕上述细胞、分子过 程在多种因素引起的感音神经性耳聋内耳细胞损伤和存活中的调控机制进行综述,以帮助研究人员识别关键分子 靶点,为干预、治疗感音神经性耳聋新策略提供参考。     

Confirmation of genetic homogeneity of nonsyndromic low-frequency sensorineural hearing loss by linkage analysis and a DFNA6/14 mutation in a Japanese family

 Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) comprises a group (DFNA1, DFNA6, DFNA14, and DFNA38) of hearing disorders affecting only frequencies below 2000 Hz, and is often associated with tinnitus. An LFSNHL locus has recently been assigned to chromosome 4p16, and mutations in WFS1, the causative gene for Wolfram syndrome, have been found to cause LFSNHL in families with DFNA6, DFNA14, or DFNA38. We performed a genome-wide linkage analysis of a Japanese family in which 20 members were affected with LFSNHL and obtained a maximum LOD score of 5.36 at a recombination fraction of 0.05 (P= 1.00) at the D4S2983 locus on 4p16. Haplotype analysis revealed that the disease locus mapped to between D4S2366 and D4S2983. Mutation analysis revealed a novel missense mutation (K634T) in WFS1. We thus concluded that the LFSNHL in this family was caused by the WFS1 mutation. The mutation observed (K634T) was located in the hydrophobic, extracytoplasmic, juxta-transmembrane region of the WFS1 protein, wolframin, and was hitherto undescribed. This unique mutation site in our patients is likely related to their milder phenotype (lacking tinnitus) compared with those of six previous DFNA6/14 patients with WFS1 mutations. It is likely that a genotype–phenotype correlation is also applicable in the case of DFNA6/14/38. Received: March 28, 2002 / Accepted: April 18, 2002     

Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese

Sixteen Japanese nonsyndromic autosomal dominant sensorineural hearing loss (ADSNHL) families were investigated clinically as well as genetically. Most families showed postlingual hearing loss. Although the severity of their hearing loss varied, most patients showed mild-moderate sensorineural hearing loss of a progressive nature. Mutation analysis was performed for the MYO7A, KCNQ4, and GJB3 genes, which are known to be responsible for autosomal dominant sensorineural hearing loss. The present study reports that a mutation in KCNQ4, a member of a large family of potassium channel genes, was responsible for ADSNHL in one Japanese family. Received: January 16, 2001 / Accepted: March 15, 2001     

Vertebrobasilar angulation and its association with sudden sensorineural hearing loss

The pathogenesis of sudden sensorineural hearing loss (SSNHL) is unclear, though some researchers postulate the major mechanism of onset to be via circulatory disturbance or cochlear inflammation. SSNHL can represent the sole manifestation of anterior inferior cerebellar artery infarction, and patients with a SSNHL may have higher than normal risk of future stoke. According to a vascular remodeling theory, vertebral arteries (VAs) are typically asymmetric with the basilar artery (BA) gradually curving in the opposite direction of the larger VA. Decreased wall shear stress on the inner surface of the curvature (weaker side of the vertebral artery) gives rise to an atherothrombogenic environment. It is hypothesized that angulation of the BA could contribute to the decline of anterior inferior cerebellar artery (AICA) flow or to the development of atheroma formation in the AICA orifice. Vertebrobasilar junction angulation could represent a simple and useful marker of SSNHL caused by a vascular compromise of the cochlea.     

"New" autosomal-dominant infantile sensorineural non-progressive high-frequency hearing loss: report on a Brazilian family

We report on a three-generation Brazilian family with seven patients affected with non-progressive high-frequency sensorineural hearing loss with no associated anomalies first noted in early infancy. To our knowledge this is the first report on this autosomal-dominant condition. Clinical, audiological, and genetic aspects are discussed.     

Management of sudden sensorineural hearing loss - a national survey

The management of Sudden Sensorineural Hearing loss is a controversial issue and there is no universally agreed protocol in its management The aim of this study was to ascertain the referral trends, treatment strategies, and outcome of treatment adopted by the Consultant Otorhinolarygologists in this country. A postal questionnaire was sent to all 32 Consultants in the Republic of Ireland, which achieved 21(65.62%) responses. Patients were referred to 13(61.9%) respondents within two weeks of the onset of symptoms and 3(14.28%) Consultants were referred patients within twenty four hours of the onset of symptoms. All specialists routinely performed full blood count and erythrocyte sedimentation rate, 15(71.42%) routinely assess fasting blood sugar and 5(23.80%) investigate fasting lipids and perform a syphilis screen. MR imaging to outrule vestibular schwanoma is performed by 11(52.38%) respondents. When treated within two weeks of the symptoms 6(28.57%) of the respondents were optimistic about recovery of hearing upon treatment whereas 2(9.52%) considered recovery of useful hearing less likely if treated more than two weeks after onset The triple therapy with oral vasodilators, oral steroids, and Carbogen inhalation was favoured by 9(42.85%). Oral steroid was the sole therapeutic modality by 4(19.04%). The opinion of Consultants was that the referral trend from the primary care physician is appropriate and 20(95.23%). Consultants considered an optimistic outcome if treated within two weeks. The investigations and management protocol for sudden sensorineural hearing loss is not uniform which is consistent with the treatment strategies world wide.     

Kennedy病家系的临床及分子遗传学研究

目的 对Kennedy病家系进行临床表型和雄激素受体(androgen receptor,AR)基因突变分析.方法 收集Kennedy病家系2例患者和6例家系成员,对先证者进行神经系统查体,常规检测神经电生理、肌电图、血清肌酸激酶(creatine kinase,CK).抽取8例样本的外周静脉血,提取基因组DNA,PCR扩增AR基因第1号外显子中的CAG重复片段,PCR产物经1.5％琼脂糖凝胶电泳,男性样本进行DNA直接测序.通过毛细胞电泳片段分析技术明确患者及家系成员AR基因第1外显子CAG序列的重复数.结果 2例患者肌电图均显示感觉、运动神经受累及,血清CK均增高,经AR基因CAG重复序列分析,2例患者(Ⅲ1和Ⅲ3)CAG的重复数分别为58次和54次,并检出了4例女性携带者(Ⅱ1、Ⅱ3、Ⅲ5和Ⅳ1),Ⅱ1携带者CAG的重复数为22/58次,Ⅱ3携带者CAG的重复数为22/54次,Ⅲ5携带者CAG的重复数为24/54次,Ⅳ5携带者CAG的重复数为20/61次,2例表型正常男性成员的CAG的重复数均为24次.结论 CAG重复在本家系中存在不稳定遗传.基因诊断可作为Kennedy病诊断的可靠依据.Kennedy病患者进行AR基因突变检测可帮助家系成员进行遗传咨询,对该病的治疗和预防有重要意义.     

Non-flat audiograms in sensorineural hearing loss and speech perception

OBJECTIVE:

The audibility thresholds for the sound frequency of 137 upward- and downward-sloping audiograms showing sensorineural hearing loss were selected and analyzed in conjunction with speech recognition thresholds obtained from individuals seen at a public otolaryngology clinic to determine which frequencies in slope audiograms best represent speech recognition thresholds.

METHOD:

The linear regression model and mean square error were used to determine the associations between the threshold values.

RESULT:

The mean square error identified larger errors when using thresholds of 500, 1000, and 2000 Hz than when using audibility thresholds of 500, 1000, 2000, and 4000 Hz. The linear regression model showed a higher correlation (91%) between the audiogram thresholds for frequencies of 500, 1000, 2000, and 4000 Hz than for the frequencies of 500, 1000, and 2000 Hz (88%).

CONCLUSION:

Frequencies of 500, 1000, 2000, and 4000 Hz were the most significant in predicting the speech recognition threshold.     

Whole genome analysis in a consanguineous family with early onset Alzheimer's disease

Early-onset Alzheimer's disease (EOAD) is a clinically and genetically heterogeneous condition in which the typical features appear significantly earlier in life (before 65 years). Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in autosomal dominant forms of EOAD. However, in about 50% of Mendelian cases and in most of the sporadic EOAD patients, no mutations have been found. We present clinical characteristics of an Israeli family comprising two affected siblings with EOAD born to neurologically healthy parents who were first cousins (both parents died after 90 years old). Sequence analysis of PSEN1, PSEN2, APP, TAU, PGRN, and PRNP failed to reveal any mutations in the affected siblings. Because the disease in this family is consistent with an autosomal recessive mode of inheritance we identified all homozygous regions identical by descent (IBD) in both siblings, by high-density SNP genotyping. We provide here the first catalog of autozygosity in EOAD and suggest that the regions identified are excellent candidate loci for a recessive genetic lesion causing this disease.     

Cytokine gene polymorphism associations with congenital cytomegalovirus infection and sensorineural hearing loss

Cytomegalovirus (CMV) is the most common viral agent of congenital infections and a leading nongenetic cause of sensorineural hearing loss (SNHL). The host immunologic factors that render a developing foetus prone to intrauterine CMV infection and development of hearing loss are unknown. The aim of this study was to assess the potential associations between the polymorphisms within cytokine and cytokine receptors genes, and the risk of congenital CMV infection, and the hearing outcome. A panel of 11 candidate single nucleotide polymorphisms (SNPs): TNF rs1799964, TNF rs1800629, TNFRSF1A rs4149570, IL1B rs16944, IL1B rs1143634, IL10 rs1800896, IL10RA rs4252279, IL12B rs3212227, CCL2 rs1024611, CCL2 rs13900, CCR5 rs333 was genotyped in 470 infants (72 with confirmed intrauterine CMV infection and 398 uninfected controls), and related to congenital CMV infection, and the outcome. In multivariate analysis, the IL1B rs16944 TT and TNF rs1799964 TC genotypes were significantly associated with intrauterine CMV infection (aOR = 2.32; 95% CI, 1.11–4.89; p = 0.032, and aOR = 2.17, 95% CI, 1.25–3.77; p = 0.007, respectively). Twenty-two out of 72 congenitally infected newborns had confirmed SNHL. Carriers of CT or TT genotype of CCL2 rs13900 had increased risk of hearing loss at birth and at 6 months of age (aOR = 3.59; p = 0.028 and aOR = 4.10; p = 0.039, respectively). This is the first study to report an association between SNPs in IL1B, TNF, and CCL2, and susceptibility to congenital CMV infection (IL1B and TNF) and SNHL (CCL2).