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中华妇幼临床医学杂志(电子版)

Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition) ›› 2024, Vol. 20 ›› Issue (03): 331 -338. doi: 10.3877/cma.j.issn.1673-5250.2024.03.012

Original Article

ATP1A3-related disorders: a family report and literature review

Zhiqiang Sheng1,†(), Yanran Yuan1   

  1. 1. Department of Pediatric Rehabilitation, Jining No.1 People′s Hospital, Jining 272011, Shandong Province, China
  • Received:2024-03-14 Revised:2024-05-01 Published:2024-06-01
  • Corresponding author: Zhiqiang Sheng
  • Supported by:
    TCM Science and Technology Project of Shandong Province(2019-0742)
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Objective

To investigate clinical manifestations and pathogenic gene variations of ATP1A3-related disorders.

Methods

A Child with an ATP1A3-related disorders who visited the Department of Pediatric Rehabilitation, Jining No.1 People′s Hospital on January 28, 2023 was selected into this study. Whole exome sequencing (WES) was carried out for the child and his family members, followed by validation using sanger sequencing. Retrieved literature of study on clinical characteristics and pathogenic gene variations of ATP1A3-related disorders were summarized based on domestic and foreign databases. This study was approved by the Medical Ethics Committee of Jining No.1 People′s Hospital (Approve No.2022-094).

Results

①This child is a 4-year-old boy with clinical features including left-sided hemiplegia of the upper and lower limbs, weakness in the distal muscles of the left lower limb, dystonia in the left limb, and weakness in the left knee tendon reflex. Brain MRI showed abnormal signals in the right parietal lobe, suspected to be an enlarged perivascular space, with no obvious abnormalities found on magnetic resonance angiography (MRA). This boy′s sister showed initial symptoms at the age of 4, which the left limb were not flexible, and the condition was getting worse. She had systemic involvement and quadriplegia by the age of 10. Sanger sequencing confirmed that both the affected child and his sister had harbored a heterozygous c. 2401G>T (p.Asp801Tyr) variant of the ATP1A3 gene, while neither of their parents and younger sister had carried the same variant.Based on the guide lines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2_verystrong+ PM1+ PM2_supporting+ PP2+ PP3). ② Literature search results were as follow. According to the search strategy of this study, a total of 39 articles met the inclusion criteria of this study, involving 97 patients with ATP1A3-related disorders, onset age of 1 day to 59 years, of which 79.4%(77/97) were infancy. Hemiplegia in 45.4% (44/97) patients, dystonia in 37.1% (36/97) patients, and seizures in 22.7%(22/97) patients. There were 51 types of mutations in the ATP1A3 gene, and the vast majority (94/97) were missense variants.

Conclusions

ATP1A3-related disorders mostly occur in infants and young children. The clinical manifestations of ATP1A3-related disorders are mainly hemiplegia, dystonia and seizures. ATP1A3 gene variants are mainly missense variants, and possibly gonadal chimerism.

Key words: Genetics, medical, ATP1A3 gene, ATP1A3-related disorders, Gonadal mosaicism, Genetic varian, Child
图1 先证者(男性，4岁3个月龄)的颅脑影像学图像(图1A：MRI T1加权像；图1B：MRA图像未见明显异常)注：MRA为磁共振脑血管成像。先证者为ATP1A3基因突变相关疾病患儿
图2 先证者(男性，4岁3个月龄)的家系系谱图注：Ⅰ表示第1代，Ⅱ表示子代。□表示正常男性；○表示正常女性；■和●分别表示男、女患者；表示先证者。虽然其胞姐为家族第1个发病者，但是由于未被确诊，所以本研究仅确定其为该病患者。先证者为ATP1A3基因突变相关疾病患儿
图3 先证者(男性，4岁3个月龄)及其父母、胞姐、妹ATP1A3基因Sanger测序结果[图3A：先证者携带ATP1A3突变基因c.2401G>T(p.Asp801Tyr)杂合变异；图3B：先证者父亲为ATP1A3基因野生型；图3C：先证者母亲为ATP1A3基因野生型；图3D：先证者胞姐携带ATP1A3突变基因c.2401G>T(p.Asp801Tyr)杂合变异；图3E：先证者胞妹为ATP1A3基因野生型]注：先证者为ATP1A3基因突变相关疾病患儿
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