琥珀酸半醛脱氢酶缺乏症不断演变的表型。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Natalia Alexandra Julia-Palacios, Oya Kuseyri Hübschmann, Mireia Olivella, Roser Pons, Gabriella Horvath, Thomas Lücke, Cheuk-Wing Fung, Suet-Na Wong, Elisenda Cortès-Saladelafont, M. Mar Rovira-Remisa, Yılmaz Yıldız, Saadet Mercimek-Andrews, Birgit Assmann, Galina Stevanović, Filippo Manti, Heiko Brennenstuhl, Sabine Jung-Klawitter, Kathrin Jeltsch, H. Serap Sivri, Sven F. Garbade, Àngels García-Cazorla, Thomas Opladen
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引用次数: 0

摘要

这项研究的目的是评估琥珀酸半醛脱氢酶缺乏症(SSADHD)患者在长期随访中不断演变的表型和遗传谱。研究人员对国际神经递质相关疾病工作组(iNTD)患者登记处的 22 名儿童和 9 名成人琥珀酸半醛脱氢酶缺乏症患者的纵向临床和生化数据进行了研究,并对 ALDH5A1 变体进行了硅学分析、致病性评分和分子建模。婴儿期发病的主要初期症状是发育迟缓和肌张力低下。出生年份和特定的初始症状会影响诊断延迟。26 人(中位数 12 岁,年龄范围 1.8-33.4 岁)的临床表型在随访中呈现出多样化的过程:77% 有行为问题,76% 有协调问题,73% 有语言障碍,58% 有癫痫发作,40% 有运动障碍。在共济失调之后,肌张力障碍(19%)、舞蹈症(11%)和运动功能减退(15%)是最常见的运动障碍。在脑成像中,齿状核受累与运动障碍或协调问题同时出现。注意力集中时间短(78.6%)和注意力分散(71.4%)是家长最常提及的行为特征,而冲动、表达愿望或需求有困难以及强迫行为则被认为严重干扰了家庭生活。治疗的主要目的是控制癫痫发作和精神症状。研究发现了四种新的致病变异。硅学评分系统、蛋白质活性和致病性评分显示出高度相关性。即使在同胞中,也未观察到基因型与表型之间的相关性。这项研究展示了疾病表型在病程中的多样化特征,突出了运动障碍,拓宽了人们对SSADHD基因型谱的认识,并强调了硅学方法的可靠应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency

The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency

The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8–33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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