s of the 52nd Workshop for Pediatric Research Frankfurt, Germany. 27-28 October 2016 Published: 10 May 2017 A1 First report of a lethal infantile autosomal recessive ITGB6V438M disorder correlating with impaired integrin αVβ6 receptor dimerization in intestinal epithelia Rhea van den Bruck, Patrick P Weil, Thomas Ziegenhals, Philipp Schreiner, Stefan Juranek, Daniel Gödde, Silvia Vogel, Frauke Schuster, Valerie Orth, Johannes Dörner, Daniel Pembaur, Meike Röper, Stefan Störkel, Hubert Zirngibl, Stefan Wirth, Andreas CW Jenke, Jan Postberg Department of Paediatrics, HELIOS Medical Centre Wuppertal, Centre for Clinical and Translational Research (CCTR), Witten/Herdecke University Hospital, Centre for Biomedical Education and Research (ZBAF), Wuppertal, Germany; Chair of Biochemistry, Theodor-BoveriInstitute at the Biocenter, University of Würzburg, Würzburg, Germany; Molecular Pathology Department, HELIOS Medical Centre Wuppertal, Witten/Herdecke University Hospital, Wuppertal, Germany; Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, HELIOS Medical Centre Wuppertal, Witten/Herdecke University Hospital, Wuppertal, Germany; Department of Surgery II, HELIOS Medical Centre Wuppertal, Witten/Herdecke University Hospital, Wuppertal, Germany Correspondence: Jan Postberg Molecular and Cellular Pediatrics 2017, 4(Suppl 1):A1 Rhea van den Bruck and Patrick P Weil are joint first authors Background A male dizygotic twin was delivered at a gestational age of 36 weeks in the Children’s Hospital of the Helios Medical Centre Wuppertal, Witten/Herdecke University Hospital. Contrary to his brother the boy presented dystrophic at birth (1.715 g birth weight; 150 g below 3rd percentile) and developed adverse gastrointestinal conditions within the first 2 months of life. These included chronic mucosal inflammation and oedematous lamina propria in the intestine, which contributed to intractable diarrhoea. At an age of 7 months the infant eventually died of enteral haemorrhages and liver failure. Further anamnesis revealed several similar fatalities in the familial clan with reportedly frequent parental consanguinity. Intractable chronic diarrhoea in infancy are heterogeneous disorders challenging for diagnostics and therapy. Despite extensive diagnostic approaches the etiology of many cases remains elusive. Investigating putatively underlying genetic disorders might clarify many cases. Results To contribute to the diagnosis we performed whole exome sequencing of the affected infant as well as his twin brother and parents. We identified a suspicious nonsynonymous single nucleotide polymorphism (SNP) in the integrin beta-6 gene (ITGB6G1312A) entailing a V438M substitution. This SNP is very rare in the G1000 cohort and predicted being potentially harmful. The allelic distribution in the genotyped family members fit well with an autosomal recessive inheritance scheme. We performed computational biological and molecular biological analyses on the αVβ6 integrin receptor function suggesting that © The Author(s). 2017 Open Access This article International License (http://creativecommons.o reproduction in any medium, provided you giv the Creative Commons license, and indicate if the integrin αVβ6 dimerization could be impaired, potentially causing a loss of αVβ6 function in wound healing and epithelial tissue integrity. Conclusions Our study provides a starting point for elucidating integrin αVβ6 function and for understanding a pathomechanistical relevance of ITGB6V438M. Consent for publication The authors have written informed consent from the patients’ guardian/parent. A2 Development of neuropsychological functions in patients with glutaric aciduria type I Nikolas Boy, Jana Heringer, Gisela Haege, Esther M. Glahn, Georg F. Hoffmann, Sven F. Garbade, Peter Burgard, Stefan Kölker Centre for Child and Adolescent Medicine, Department of General Pediatrics, Division of Neuropaediatrics and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany Molecular and Cellular Pediatrics 2017, 4(Suppl 1):A2 Background Glutaric aciduria type I (GA-I) is an inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase (GCDH). Metabolic treatment according to current guideline recommendations has significantly improved neurological outcome. However, cognitive functions have not yet been studied in detail. Methods In a cross-sectional design, 30 patients detected by newborn screening (n = 13), high-risk screening (n = 3) or targeted metabolic testing (n = 14) were studied for simple reaction time (SRT), continuous performance (CP), visual working memory (VWM), visual-motor coordination (Tracking) and visual search (VS). Dystonia (n = 13 patients) was categorized using the Barry-Albright-Dystonia Scale (BADS). Patients were compared with 196 healthy controls. Developmental functions of cognitive performances were analysed using a negative exponential function model. Results BADS scores correlated with speed tests but not with tests measuring stability or higher cognitive functions without time constraints. Developmental functions of GA-I patients significantly differed from controls for SRT and VS but not for VWM and showed obvious trends for CP and Tracking. Dystonic patients were slower in SRT and CP but reached their asymptote of performance similar to asymptomatic patients and controls in all tests. Asymptomatic patients did not differ from controls, except showing significantly better results in Tracking and a trend for slower reactions in visual search. Data across all age groups of patients and controls fitted well to a model of negative exponential development. is distributed under the terms of the Creative Commons Attribution 4.0 rg/licenses/by/4.0/), which permits unrestricted use, distribution, and e appropriate credit to the original author(s) and the source, provide a link to

中文翻译：

---

第 52 届儿科研究研讨会摘要

德国法兰克福第 52 届儿科研究研讨会。2016 年 10 月 27-28 日 发表时间：2017 年 5 月 10 日 A1 与肠上皮整合素 αVβ6 受体二聚化受损相关的致命婴儿常染色体隐性遗传 ITGB6V438M 疾病的首次报告 Rhea van den Bruck、Patrick P Weil、Thomas Ziegenhals、Philipp Steraner Gödde、Silvia Vogel、Frauke Schuster、Valerie Orth、Johannes Dörner、Daniel Pembaur、Meike Röper、Stefan Störkel、Hubert Zirngibl、Stefan Wirth、Andreas CW Jenke、Jan Postberg 儿科、HELIOS 医疗中心伍珀塔尔、临床和转化研究中心(CCTR)，Witten/Herdecke 大学医院，生物医学教育和研究中心 (ZBAF)，德国伍珀塔尔；维尔茨堡大学生物中心 Theodor-BoveriInstitute 生物化学主席，德国维尔茨堡；分子病理科，HELIOS 医学中心伍珀塔尔，威滕/赫德克大学医院，伍珀塔尔，德国；整形、重建、美容和手外科，HELIOS 医疗中心伍珀塔尔，威滕/赫德克大学医院，伍珀塔尔，德国；外科 II，HELIOS 医疗中心伍珀塔尔，威滕/赫德克大学医院，伍珀塔尔，德国通讯：Jan Postberg Molecular and Cellular Pediatrics 2017, 4(Suppl 1):A1 Rhea van den Bruck 和 Patrick P Weil 是共同第一作者 背景 A异卵双胞胎男性在 36 周时在赫利俄斯医学中心伍珀塔尔、威滕/赫德克大学医院的儿童医院分娩。与他的兄弟相反，这个男孩在出生时就出现营养不良（出生体重 1.715 克；150 克低于第 3 个百分位数）并在出生后的前 2 个月内出现胃肠道不良状况。这些包括慢性粘膜炎症和肠道固有层水肿，导致顽固性腹泻。在 7 个月大时，婴儿最终死于肠出血和肝功能衰竭。进一步的病史揭示了家族中有几起类似的死亡事件，据报道，父母经常有血缘关系。婴儿期顽固性慢性腹泻是对诊断和治疗具有挑战性的异质性疾病。尽管有广泛的诊断方法，但许多病例的病因仍然难以捉摸。调查假定的潜在遗传疾病可能会澄清许多情况。结果 为了有助于诊断，我们对受影响的婴儿及其双胞胎兄弟和父母进行了全外显子组测序。我们在整合素 beta-6 基因 (ITGB6G1312A) 中发现了一个可疑的非同义单核苷酸多态性 (SNP)，它需要一个 V438M 替换。这种 SNP 在 G1000 队列中非常罕见，预计可能有害。基因分型的家庭成员中的等位基因分布与常染色体隐性遗传方案非常吻合。我们对 αVβ6 整联蛋白受体功能进行了计算生物学和分子生物学分析，表明 © The Author(s)。2017 开放获取本文国际许可（http://creativecommons.o 在任何媒体中复制，前提是您提供知识共享许可，并指出整合素 αVβ6 二聚化是否可能受到损害，可能导致伤口愈合和上皮组织完整性中 αVβ6 功能的丧失。结论我们的研究为阐明整合素 αVβ6 功能和理解 ITGB6V438M 的病理机制相关性提供了一个起点。出版同意书作者已获得患者监护人/父母的书面知情同意书。A2 I 型戊二酸尿症患者神经心理功能的发展 Nikolas Boy、Jana Heringer、Gisela Haege、Esther M. Glahn、Georg F. Hoffmann、Sven F. Garbade、Peter Burgard、Stefan Kölker 儿童和青少年医学中心，系普通儿科，神经儿科和代谢医学部，海德堡大学医院，Im Neuenheimer Feld 430，D-69120 海德堡，德国分子和细胞儿科 2017，4（增刊 1）：A2 背景 戊二酸尿症 I 型 (GA-I) 是一种由戊二酰辅酶 A 脱氢酶 (GCDH) 缺乏引起的遗传性代谢疾病。根据当前指南推荐的代谢治疗显着改善了神经学结果。然而，尚未对认知功能进行详细研究。方法 在横断面设计中，对通过新生儿筛查（n = 13）、高危筛查（n = 3）或靶向代谢检测（n = 14）检测到的 30 名患者进行了简单反应时间（SRT）、持续表现研究(CP)、视觉工作记忆 (VWM)、视觉运动协调 (Tracking) 和视觉搜索 (VS)。肌张力障碍（n = 13 名患者）使用巴里-奥尔布赖特-肌张力障碍量表 (BADS) 进行分类。患者与 196 名健康对照者进行了比较。使用负指数函数模型分析认知表现的发展功能。结果 BADS 分数与速度测试相关，但与测量稳定性或无时间限制的更高认知功能的测试无关。GA-I 患者的发育功能与 SRT 和 VS 对照组有显着差异，但 VWM 无差异，并且在 CP 和 Tracking 方面显示出明显的趋势。肌张力障碍患者在 SRT 和 CP 中较慢，但在所有测试中都达到了与无症状患者和对照组相似的渐近线。无症状患者与对照组没有区别，除了在跟踪中显示出明显更好的结果以及在视觉搜索中反应较慢的趋势。所有年龄组的患者和对照的数据都非常适合负指数发展模型。