Abstract：
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.
摘要：
该研究的目的是评估长期随访中琥珀酸半醛脱氢酶缺乏症（SSADHD）患者的表型和遗传谱。通过计算机模拟分析研究了来自国际神经递质相关疾病工作组（iNTD）患者注册的22名儿童和9名成人SSADHD患者的纵向临床和生化数据。ALDH5A1变异体的致病性评分和分子建模。主要的初始症状，在婴儿期发病，是发育迟缓和张力低下。出生年份和特定的初始症状会影响诊断延迟。26例患者的临床表型（中位数为12年，范围1.8-33.4年)在后续行动中表现出多样化的过程：77%的行为问题，76%的协调问题，73%的言语障碍,58%的癫痫发作和40%的运动障碍。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。观察到齿状核参与脑成像以及运动障碍或协调问题。注意力持续时间短(78.6%)和注意力分散(71.4%)是父母提到的最常见的行为特征，沟通愿望或需求和强迫行为的问题被认为是对家庭生活的强烈干扰。治疗主要是为了控制癫痫发作和精神症状。确定了四种新的致病变异。在计算机评分系统中，蛋白质活性和致病性评分显示出高度的相关性。未观察到基因型/表型相关性，即使是兄弟姐妹。本研究呈现疾病表型在病程中的多样化特征,突出运动障碍，拓宽了SSADHD基因型谱的知识，并强调了计算机方法的可靠应用。
