Early‐Onset Isolated Dystonia Associated with <scp>COL6A3</scp> Mutation Responsive to Deep Brain Stimulation

Dystonia is a neurological movement disorder characterized by involuntary, sustained, or intermittent muscle contractions, leading to abnormal movements or postures. Isolated dystonia, a specific form, manifests primarily as dystonia without involvement of other neurological or systemic issues, potentially caused by genetic factors or unknown etiology.1 Recently, biallelic mutations in the COL6A3 gene have been revealed to cause the recessively inherited early-onset isolated dystonia, also known as DYT27—an autosomal recessive neurological disorder characterized by the onset of segmental isolated dystonia within the first 20 years of life, primarily affecting the craniocervical region and upper limbs.2, 3 Treatments for DYT27 are mostly oral medications and botulinum toxin injections, with poor efficacy. This letter describes a 17-year-old male who developed involuntary twisting movements of the right upper limb at age 10, followed by leftward spinal curvature and involuntary head tilt at 13, and subsequently retrocollis and worsening dystonic posturing of the right upper limb at 16. Disease progression led to right upper extremity motor impairment with loss of writing and eating ability necessitating conversion to left hand usage. The patient's retrocollis symptoms were alleviated during sleep, but exacerbated by anxiety and fatigue. Initial treatment with oral clonazepam (0.5 mg, twice daily) and baclofen (5 mg, three times daily) was ineffective, and botulinum toxin therapy was not administered. Concurrent with worsening dystonia, the patient exhibited mood and social disturbances. Physical examination revealed involuntary twisting movements of the right upper limb, intermittent large-amplitude retrocollis, and leftward head and neck tilt. However, speech and swallowing were unaffected. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) total score was 31 (Supplemental Table S1 and Video 1). Genetic testing of blood identified a heterozygous nucleotide variant c.9130G > A (p.V3044I) in the COL6A3 gene, indicating a change from G to A at the codon encoding amino acid 3044, leading to a valine (V) to isoleucine (I) substitution. The accurate genomic coordinates and transcript information are NM_004369.4 Exon41, chr2:238243368. Furthermore, the patient's parents did not exhibit similar clinical manifestations, and the clinical exome sequencing results of the family members revealed that the parents did not carry the COL6A3 mutation. Due to poor medication response, bilateral GPi-DBS was performed under general anesthesia after obtaining informed consent. Bilateral electrodes (model L302; PINS, Beijing, China) were accurately implanted in the GPi. Postoperative CT scans showed no complications, and fusion with preoperative MRI confirmed accurate electrode placement (Fig. 1). The generator was activated in monopolar mode on postoperative day 4, with bilateral parameters adjusted to 3.0 V, 130 Hz, and 60 μs pulse width by the third postoperative week. By this time, the patient exhibited preliminary yet significant improvement in motor symptoms, notably a marked reduction in involuntary retrocollis frequency and amplitude. At the 10-month follow-up, the patient exhibited sustained and significant improvement in the frequency and amplitude of involuntary retrocollis movements, regaining the ability to use the right hand for eating. The total BFMDRS score was 5, representing an 83.87% improvement compared to the preoperative assessment. Additionally, anxiety, depression, and quality of life were markedly alleviated (Supplemental Table S1 and Video 2). Previous studies have confirmed isolated dystonia-causing mutations in TOR1A, THAP1, GNAL, ANO3, PRKRA, KMT2B, and HPCA genes.4 Recently, COL6A3, encoding the α-3 chain of type VI collagen involved in synaptogenesis and synaptic network stability,5 has been identified as a pathogenic factor for early-onset isolated dystonia.2, 6 COL6A3 mutations are associated with Bethlem myopathy 1, Ullrich congenital muscular dystrophy 1, and Dystonia 27.2, 7 Previous studies suggest considering COL6A3 biallelic mutations in children or adolescents with isolated dystonia originating from the upper limbs, neck, or jaw region,8 consistent with this case's age of onset and symptom characteristics. Zech et al2 found that isolated dystonia patients exhibited at least one pathogenic mutation in COL6A3 exon 41, and functional validation using zebrafish models suggested that exon 41 disruption could potentially cause the phenotypic specificity observed. In this case, the patient harbored a heterozygous c.9130G > A (p.V3044I) variant in the exon 41 region of the COL6A3 gene, while the parents did not carry this gene mutation and were unaffected. Therefore, we hypothesize that this genetic variant is a de novo mutation, not inherited within the family, but rather occurring as a new mutation during the patient's individual development. More comprehensive, multidimensional research and validation are still needed to definitively establish the pathogenic role of the COL6A3 c.9130G >A (p.V3044I) heterozygous variant in isolated dystonia. As genetic testing becomes more accessible, identifying the underlying etiology is crucial for guiding therapeutic decisions, particularly in medication-refractory dystonia cases. This case highlights the importance of preoperative genetic screening for dystonia patients being considered for DBS surgery, as establishing a definitive genetic diagnosis aids prognostic counseling and facilitates selecting optimal therapeutic targets tailored to the specific dystonia subtype. For isolated dystonia patients with poor response to oral medications or botulinum toxin, DBS is increasingly considered a safe and effective treatment modality,9 with clinical benefits potentially mediated through neural network modulation.10 The patient's significant and sustained motor improvement demonstrated the therapeutic value of GPi-DBS for isolated dystonia. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. J.Y.: 1A, 1B, 1C, 2A, 2B, 3A X.H: 1A, 1B, 1C, 2A, 3A C.Q.: 1A, 1B, 2C,3B Y.L.: 1A, 1B, 2C,3B L.Z.: 1A, 1B, 2C,3B B.L.:1A,3B W.D.:1A,3B J.S.:3B L.C.:3B X.W.:3B J.Y.: 1A, 1B, 1C, 2A, 2B, 2C, 3B W.Z.: 1A, 1B, 1C, 2A, 2B, 2C, 3B The authors thank the patient and his family for contributing to this study and the members of the Functional Neurosurgery Department at Nanjing Brain Hospital for their exceptional collaboration managing this case. Ethical Compliance Statement: The parents of index patient gave their informed consent prior to their participation in the study. The study was approved by the ethics committee of Nanjing Brain Hospital Affiliated to Nanjing Medical University. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: This study was supported by the Special Funds of the Jiangsu Provincial Key Research and Development Projects (Nos. BE2022049 and BE2022049-1), Nanjing Health Science and Technology Development Special Fund Project (No. ZKX20031), Special Funds of the Jiangsu Provincial Key Research and Development Projects (grant No. BE2019612), and Jiangsu Provincial Cadre Health Research Projects (grant No. BJ17006). The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. Data available on request due to privacy/ethical restrictions. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. TABLE S1. Clinical scores of patients at different time points before and after DBS surgery. Abbreviation: BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; HAMA, Hamilton Anxiety Scale; HAMD, Hamilton Depression Rating Scale; MMSE, Mini-mental State Examination; MoCA, Montreal Cognitive Assessment; SF-36, 36-item Short Form Health Survey. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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