Novel mutations in a Chinese family with two patients with succinic semialdehyde dehydrogenase deficiency

Abstract

Background: A considerable proportion of pediatric disease burden is mainly caused by inborn errors of metabolism. Succinic semi-aldehyde dehydrogenase (SSADH) deficiency is an unusual disorder of the gamma-aminobutyric acid metabolism. Till date, very few cases have been reported in China.

Case presentation: Trio-WES was used to characterize the ALDH5A1 gene in two children of a Chinese family, who presented with seizures, psychomotor delay, development regression, borderline cognition, hypotonia, and harbored the compound heterozygotes NM_001080.3: c.1321G > A (p. Gly441Arg) and c.727_735del (p. Leu243_Ser245del). The former has been reported earlier (rs1041467895), whereas the latter is novel. Amino acid coding at highly conserved amino acid residues was observed to be altered by both mutations. This structural impairment influenced the enzyme structure as indicated by the in silico protein modeling. Cerebral magnetic resonance imaging of the proband and her brother showed excessive gap in the cerebrum and abnormal signals in the bilateral frontal lobe, bilateral basal ganglia, and cerebral foot. Elevated levels of Gamma-hydroxybutyric aciduria were found in their patients on urine organic acid analysis.

Conclusion: Our findings contribute to the current knowledge of missense and deletion mutations associated with SSADH deficiency.

Chinese abstract

背景：相当一部分儿科疾病负担主要是由先天代谢缺陷引起的。琥珀酸半醛脱氢酶（SSADH）缺乏症是一种罕见的γ-氨基丁酸代谢紊乱。到目前为止, 中国报告的病例很少。

病例介绍：Trio-WES被用来表征一个中国家庭的两名儿童的ALDH5A1基因, 孩子表现为癫痫发作、精神运动迟缓、发育倒退、边缘认知、肌张力下降, 并带有复合杂合子NM_001080.3：c.1321G>A（p.Gly441Arg）和c.727_735del（p.Leu243_Ser245del）。前者已有报道（rs1041467895）, 而后者是新型的。观察到在高度保守的氨基酸残基上编码的氨基酸被这两个突变改变。如计算机蛋白模型所示, 这种结构缺陷影响了酶的结构。先证者及其哥哥的脑磁共振成像显示大脑间隙过大, 双侧额叶、双侧基底神经节区和大脑足部信号异常。尿液有机酸分析发现患者γ-羟丁酸水平升高。

结论：我们的发现有助于目前对与SSADH缺乏症相关的错义突变和缺失突变的认识。

Keywords:

• SSADH deficiency
• ALDH5A1 gene
• whole exome sequencing
• novel mutation

Acknowledgments

We would like to thank the staff of the department of Genetics and Endocrinology for the patient’s data.

Disclosure statement

The authors declare that they have no competing interests.

Ethic statement

This study was approved by the Institutional Review Board of Guangzhou Women and Children’s Medical Center. (No.2016061601)

Informed consent

Informed consent of this study was obtained from the patients’ parents and her family.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No. 81671119) and the Major Medical Collaboration and Innovation Program of Guangzhou Science Technology and Innovation Commission (No. 201604020020). This study was partially supported by the fund from Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center (NO: YIP-2019-003).