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HOME > J Mov Disord > Volume 18(2); 2025 > Article
Letter to the editor
A Chinese Child With Dystonia Linked to the EIF2AK2 Missense Variant: A Case Report
Lifang Dai1,2*orcid, Changhong Ren1,2*orcid, Shenghan Guan4*orcid, Xiaojuan Tian1,2orcid, Hui Xiong1,2corresp_iconorcid, Changhong Ding1,2,3corresp_iconorcid
Journal of Movement Disorders 2025;18(2):190-192.
DOI: https://doi.org/10.14802/jmd.24215
Published online: February 20, 2025

1Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China

2Laboratory for Clinical Medicine, Capital Medical University, Beijing, China

3Department of Neurology, Baoding Children’s Hospital, Baoding, China

4Capital Medical University, Beijing, China

Corresponding author: Changhong Ding, MD Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56 Nanlishi Road, Xicheng District, Beijing 100045, China / Tel: +86-010-59616356 / Fax: +86-010-59616356 / E-mail: chding2018@126.com
Corresponding author: Hui Xiong, MD, PhD Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56 Nanlishi Road, Xicheng District, Beijing 100045, China / Tel: +86-010-59616356 / Fax: +86-010-59616356 / E-mail: xh_bjbj@163.com
*These authors contributed equally to this work.
• Received: October 20, 2024   • Revised: December 4, 2024   • Accepted: February 19, 2025

Copyright © 2025 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,
The eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) regulates the cytoprotective integrated stress response (ISR), which is crucial for cellular adaptation to stress conditions. EIF2AK2 is activated by various stimuli, such as double-stranded RNA (commonly during viral infections), oxidative stress, endoplasmic reticulum stress, cytokines, and growth factors [1]. Variants within the EIF2AK2 gene were initially linked to leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome in 2020 and then later associated with EIF2AK2-related dystonia (dystonia 33) in 2021 [2,3]. We report a Chinese boy with EIF2AK2-related dystonia who responded well to levodopa treatment at Beijing Children’s Hospital [4].
The proband was the second-born child of a healthy mother. His parents were nonconsanguineous, and he was delivered at term after an uneventful pregnancy. Although he reached developmental milestones before the onset of the disease, he had mild dysarthria and was unable to speak clearly. His father developed dystonia of the right arm at age 6 years, followed by dystonia of the left arm, neck, and trunk 6 months later, with no further progression since then. The patient’s oldest brother is healthy.
The patient developed characteristic features of a movement disorder, including tremors of the bilateral arms and legs, at age 3 years and 1 month. At age 6 years and 5 months, his right foot everted and he developed scoliosis as a result of dystonia. His parents did not take him to the hospital until his dystonia progressed to the muscles of the left limb, bilateral arms, trunk, and neck, which is characteristic of isolated generalized dystonia without diurnal fluctuations, after COVID-19 infection at age 7 years and 11 months. His dystonia progressed, and he experienced pain in the lower limbs and trunk without sweating or cognitive regression. He could not walk independently and became wheelchair-bound at age 8 years. His brain MRI, immunological (antinuclear antibodies, double-stranded DNA, and extractable nuclear antigen), and metabolism (ammonia, lactic acid, and homocysteine) results were normal. Owing to severe dystonia and pain, 2 mg/kg/day oral levodopa was started at age 8 years. His symptoms improved after 5 days of treatment. He could walk independently. After 1 month of levodopa treatment, 0.05 mg/kg/day benzhexol hydrochloride was added to address his tremors, resulting in significant tremor relief. After 4 months of medication treatment, the dosage of oral levodopa was increased to 10 mg/kg/day. His dystonia markedly improved thereafter, and his speech at age 8 years and 5 months was clearer than before. From age 10 years to the last follow-up, he was still able to walk independently despite slight postural abnormalities; however, his dystonia worsened during a respiratory infection but did not affect his ability to walk independently. The dosage of levodopa was not reduced but instead increased for dystonia flare-ups. The Burke-Fahn-Marsden Dystonia Rating Scale Motor (BFMDRS-M) and disability (BFMDRS-D) assessments revealed notable improvements after levodopa treatment, as evidenced by score improvements of 90% and 74%, respectively (Table 1). The patient’s father also took 0.05 mg/kg/day levodopa, which had a mild benefit.
The symptoms of dystonia worsened after fever in this child. Ion channel diseases, such as sodium/potassium-transporting ATPase subunit alpha-3 isoform 3-related disorders, and immune diseases, such as anti-N-methyl-D-aspartate receptor encephalitis, should be considered in further examinations. According to his family history, inherited dystonia should be considered first. Whole-exome sequencing was conducted on DNA samples extracted from the proband and his family members. Sanger sequencing was employed to validate the likely pathogenic variations. An inherited heterozygous missense variant at c.388 G>A (p.G130R) of EIF2AK2 was detected in the proband, which was inherited from his father (Figure 1). The variant was classified according to the American College of Medical Genetics and Genomics classification as pathogenic.
Among EIF2AK2-related dystonia cases, the p.G130R variant is particularly prevalent [5]. To date, the same p.G130R variant in EIF2AK2 has been found in 13 patients from 5 families harboring dystonia. Prior studies revealed that of five EIF2AK2-related dystonia patients who were treated with levodopa, only one benefitted marginally; the other patients experienced no relief of dystonia [3,5,6]. Our patient, harboring the EIF2AK2 p.G130R variant, is the first Chinese individual to experience symptoms that were aggravated by infection, especially COVID-19 infection, and exhibit remarkable improvement with levodopa treatment. The resolution of this patient’s symptoms may also be due to his recovery from COVID-19 infection, even though the worsening of his symptoms due to COVID-19 was more prominent than that due to other respiratory pathogens. Our findings broaden the clinical spectrum of EIF2AK2.

Ethics Statement

Written informed consent was obtained from the patient’s parents. This study was approved by the Ethics Committee of Beijing Children’s Hospital (approval no. 2019-k-219).

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study received support from the National Natural Science Foundation of China (No. 82171393), Natural Science Foundation of Capital Medical University (PYZ23150), and Beijing Vlove Charity Foundation.

Acknowledgments

We are grateful to the family members for their cooperation and permission to publish this case.

Author Contributions

Conceptualization: Changhong Ding. Data curation: Lifang Dai, Changhong Ren. Formal analysis: Shenghan Guan. Funding acquisition: Hui Xiong, Lifang Dai. Investigation: Changhong Ding. Methodology: Lifang Dai, Xiaojuan Tian. Project administration: Changhong Ding, Hui Xiong. Resources: Lifang Dai. Software: Changhong Ren. Supervision: Hui Xiong. Validation: Changhong Ding. Visualization: Lifang Dai. Writing—original draft: Lifang Dai. Writing—review & editing: Changhong Ding, Hui Xiong.

Figure 1.
Family pedigree. The proband is depicted by the arrow. Sequencing chromatograms demonstrated that the heterozygous missense variant at c.388 G>A (p.G130R) of EIF2AK2 was identified in the proband inherited from his father (the red arrow indicates the A/G hybrid peak in the proband and the father, and only the A peak is shown in the mother and brother, and the G peak is not shown). EIF2AK2, eukaryotic translation initiation factor 2 alpha kinase 2.
jmd-24215f1.jpg
Table 1.
The changes in the BFMDRS-M and BFMDRS-D scores of patient’s dystonia before and after medication therapy
Duration of oral levodopa BFMDRS-M
BFMDRS-D
Eyes Mouth Speech and swallowing Neck Right arm Left arm Trunk Right leg Left leg Total (120) Speech Wrighting Feeding Eating Hygiene Dressing Walking Total (30)
Severe symptoms before treatment 0 0 1 8 16 6 16 16 12 75 1 4 0 0 4 4 6 19
5 days 0 0 1 4.5 9 4 9 12 6 45.5 1 3 0 0 3 3 3 13
1 month 0 0 1 4 6 4 6 4 2 27 1 3 0 0 2 2 2 10
2 months 0 0 1 0.5 4 2 2 1 1 11.5 1 2 0 0 2 2 2 9
4 months to 23 months 0 0 1 0 2 1 1 1 1 7 1 1 0 0 1 1 1 5

BFMDRS-M, Burke-Fahn-Marsden Dystonia Rating Scale Motor; BFMDRS-D, Burke-Fahn-Marsden Dystonia Rating Scale disability.

  • 1. Silva AM, Whitmore M, Xu Z, Jiang Z, Li X, Williams BR. Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. J Biol Chem 2004;279:37670–37676.ArticlePubMed
  • 2. Mao D, Reuter CM, Ruzhnikov MRZ, Beck AE, Farrow EG, Emrick LT, et al. De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation. Am J Hum Genet 2020;106:570–583.ArticlePubMedPMC
  • 3. Kuipers DJS, Mandemakers W, Lu CS, Olgiati S, Breedveld GJ, Fevga C, et al. EIF2AK2 missense variants associated with early onset generalized dystonia. Ann Neurol 2021;89:485–497.PubMed
  • 4. Wang X, Zeng Y, Tian J, Xu H, Song F, Guo Y, et al. A brief introduction to the FUTang Updating medical REcords (FUTURE) database. Pediatr Investig 2021;5:247–248.ArticlePubMedPMCPDF
  • 5. Magrinelli F, Moualek D, Tazir M, Pacha LA, Verghese A, Bhatia KP, et al. Heterozygous EIF2AK2 variant causes adolescence-onset generalized dystonia partially responsive to DBS. Mov Disord Clin Pract 2021;9:268–271.PubMedPMC
  • 6. Waller SE, Morales-Briceño H, Williams L, Mohammad SS, Fellner A, Kumar KR, et al. Possible EIF2AK2-associated stress-related neurological decompensation with combined dystonia and striatal lesions. Mov Disord Clin Pract 2021;9:240–244.PubMedPMC

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      A Chinese Child With Dystonia Linked to the EIF2AK2 Missense Variant: A Case Report
      Image
      Figure 1. Family pedigree. The proband is depicted by the arrow. Sequencing chromatograms demonstrated that the heterozygous missense variant at c.388 G>A (p.G130R) of EIF2AK2 was identified in the proband inherited from his father (the red arrow indicates the A/G hybrid peak in the proband and the father, and only the A peak is shown in the mother and brother, and the G peak is not shown). EIF2AK2, eukaryotic translation initiation factor 2 alpha kinase 2.
      A Chinese Child With Dystonia Linked to the EIF2AK2 Missense Variant: A Case Report
      Duration of oral levodopa BFMDRS-M
      BFMDRS-D
      Eyes Mouth Speech and swallowing Neck Right arm Left arm Trunk Right leg Left leg Total (120) Speech Wrighting Feeding Eating Hygiene Dressing Walking Total (30)
      Severe symptoms before treatment 0 0 1 8 16 6 16 16 12 75 1 4 0 0 4 4 6 19
      5 days 0 0 1 4.5 9 4 9 12 6 45.5 1 3 0 0 3 3 3 13
      1 month 0 0 1 4 6 4 6 4 2 27 1 3 0 0 2 2 2 10
      2 months 0 0 1 0.5 4 2 2 1 1 11.5 1 2 0 0 2 2 2 9
      4 months to 23 months 0 0 1 0 2 1 1 1 1 7 1 1 0 0 1 1 1 5
      Table 1. The changes in the BFMDRS-M and BFMDRS-D scores of patient’s dystonia before and after medication therapy

      BFMDRS-M, Burke-Fahn-Marsden Dystonia Rating Scale Motor; BFMDRS-D, Burke-Fahn-Marsden Dystonia Rating Scale disability.


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