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Letter to the editor
CLCN2-Related Leukoencephalopathy Presenting as Isolated Paroxysmal Non-Kinesigenic Dyskinesia: Clinical, Imaging, and Genetic Correlations -
Subhajit Roy
, Ravindranadh Chowdary Mundlamuri
, Seena Vengalil, Pritam Raja, Nalini Atchayaram, Ravi Yadav -
Journal of Movement Disorders 2026;19(2):221-224.
DOI: https://doi.org/10.14802/jmd.25268
Published online: December 1, 2025
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
- Corresponding author: Ravindranadh Chowdary Mundlamuri, DM Department of Neurology, National Institute of Mental Health and Neurosciences, Hosur Road, Bengaluru-560029, Karnataka, India / Tel: +91-08026995107, 5140 / E-mail: mundlamuri.ravi@yahoo.com
• Received: October 5, 2025 • Revised: November 9, 2025 • Accepted: December 1, 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,
Leukoencephalopathies are a diverse group of white matter disorders, often genetically mediated, with variable clinical presentations. Among these, chloride voltage-gated channel 2 (CLCN2)-related leukoencephalopathy is a rare autosomal recessive condition caused by biallelic mutations in the CLCN2 gene, which encodes the voltage-gated chloride channel ClC-2 [1]. These channels are integral to chloride homeostasis across neuronal and glial membranes. Loss-of-function mutations result in intracellular chloride accumulation, osmotic dysregulation, and vacuolation of myelinated white matter [2].
Clinically, the classic triad of CLCN2-related leukoencephalopathy includes mild cerebellar ataxia, visual disturbances from optic nerve involvement, and characteristic magnetic resonance imaging (MRI) changes [1]. However, the phenotypic spectrum has been expanded to include epilepsy, cognitive impairment, and, in rare cases, movement disorders [3-6]. While paroxysmal kinesigenic dyskinesia (PKD) has occasionally been reported, paroxysmal nonkinesigenic dyskinesia (PNKD) as an isolated presentation remains undocumented.
We present an adult man with a genetically confirmed homozygous CLCN2 mutation who presented solely with PNKD and showed a remarkable response to carbamazepine, underscoring the importance of recognizing atypical phenotypes and suspecting genetic leukoencephalopathies in adult patients with unexplained dyskinesia and characteristic imaging, especially in those with consanguineous backgrounds.
A 37-year-old man, born of a consanguineous marriage, presented with a 3-year history of episodic, involuntary twisting movements involving both hands and feet. The episodes were spontaneous, lasted 2–3 minutes, occurred 2–3 times weekly, and were not precipitated by sudden movements, stress, or exertion. There was no associated loss of consciousness. There was no history of cognitive decline, visual impairment, tremor, or imbalance. Notably, while the patient had no personal history of seizures, his two siblings reportedly had well-controlled epilepsy (Supplementary Figure 1).
General physical and neurological examinations between episodes were normal. A very brief home-recorded video captured almost at the end of one such episode (Supplementary Video 1) demonstrated residual dyskinetic movements without any apparent trigger and with spontaneous resolution. Considering the temporal profile, absence of identifiable triggers, and spontaneous remission, the phenomenology and clinical context were considered to be PNKD. The patient was started on 200 mg of carbamazepine per day, which was subsequently increased to 900 mg per day. Following dose optimization, the attack frequency was reduced to one episode every 5–6 months.
MRI of the brain revealed symmetric bilateral T2-fluid-attenuated inversion recovery (FLAIR) hyperintensities in the posterior limb of the internal capsule, cerebral peduncles, and middle cerebellar peduncles, without atrophy or contrast enhancement (Figure 1).
Routine blood investigations, nerve conduction studies (NCSs), abdominal ultrasonography, electrocardiogram, and two-dimensional echo were normal. Other workups for dyskinetic movements, including evaluations for Wilson’s disease (serum copper, ceruloplasmin, and 24-h urinary copper levels), were normal. Electroencephalography was normal. Ophthalmologic examination, including visual acuity and fundoscopy, was unremarkable.
Genetic testing using a leukodystrophy gene panel revealed a homozygous frameshift deletion in CLCN2 gene, (ENST00000265593.9): Exon 15 c.1542_1543del (p.Ser516HisfsTer38) (Supplementary Figure 2). The variant was classified as pathogenic (American College of Medical Genetics criteria: PVS1, PM2, PP3) and consistent with autosomal recessive inheritance. This mutation aligns with the phenotype of leukoencephalopathy with ataxia (OMIM #615651). The patient continues to do well on follow-up, with sustained symptom control.
CLCN2-related leukoencephalopathy is a rare, autosomal recessive white matter disorder attributed to pathogenic variants in the CLCN2 gene, which encodes the voltage-gated chloride channel ClC-2 [1,2]. These channels are expressed widely in the brain, testis, and other tissues and play a critical role in maintaining ionic homeostasis by mediating chloride efflux. Their dysfunction results in intracellular chloride accumulation, osmotic imbalance, and myelin vacuolation, predominantly affecting the posterior internal capsules, cerebral peduncles, and cerebellar white matter [1].
Clinically, the disease presents with a broad phenotypic spectrum. While early literature described a classic triad of cerebellar ataxia, optic atrophy, and distinctive white matter imaging, later reports identified seizures, cognitive impairment, and variable pyramidal signs as additional features [1,3]. Notably, despite striking MRI findings, several individuals may remain minimally symptomatic, contributing to underdiagnosis or misclassification [3-5].
Although movement disorders have been increasingly associated with CLCN2 mutations, they remain uncommon. Most documented cases involve PKD or dystonia in conjunction with other neurological findings [2,4,6]. In contrast, PNKD has not previously been reported as an isolated manifestation of CLCN2-related leukoencephalopathy, particularly in the Indian population. Unlike PKD, PNKD occurs spontaneously without precipitating triggers such as sudden movement, which was evident in our patient.
The MRI findings in our patient were crucial for suggesting underlying leukodystrophy and prompted further genetic analysis. Symmetrical T2-FLAIR hyperintensities in the posterior limb of the internal capsule, cerebral peduncles, and cerebellar peduncles are characteristic of CLCN2-related pathology and should alert clinicians to this possibility [4,5]. The topological substrates of paroxysmal dyskinesias provide additional perspectives related to their occurrence in patients with CLCN2-related leukoencephalopathies. Involvement of subcortical white matter tracts, particularly the posterior limb of the internal capsule, has been implicated in secondary forms of paroxysmal dystonia or nonkinesigenic dyskinesia. Uca and Altaş7 described a patient with multiple sclerosis in whom a demyelinating plaque within the posterior internal capsule produced PNKD of the contralateral limbs. Such lesions likely disturb the thalamocortical and cerebellothalamocortical loops, leading to transient loss of inhibitory control and episodic motor network disinhibition. In our patient, MRI demonstrated symmetric T2-FLAIR hyperintensities involving the internal capsules and cerebellar peduncles, regions integral to these motor pathways. This anatomic pattern provides a plausible substrate for secondary paroxysmal dyskinesia, suggesting that focal or diffuse white matter dysfunction in CLCN2-related disease can manifest with transient dyskinetic phenomena.
Carbamazepine, a sodium channel blocker, has demonstrated efficacy in managing paroxysmal dyskinesias, including PKD and other channelopathies [4,8]. Although CLCN2-related leukoencephalopathy arises from defective chloride channel function, the improvement in symptoms observed with carbamazepine administration in our patient is best interpreted as an indirect, network-level modulation rather than a disease-specific effect. Carbamazepine exerts its primary action through use-dependent blockade of voltage-gated sodium channels, thereby reducing repetitive neuronal firing and stabilizing membrane excitability [9]. Disturbed chloride conductance in patients with CLCN2 mutations can alter neuronal resting potentials and weaken GABAergic inhibition, creating a state of secondary hyperexcitability within motor pathways. By limiting excessive depolarization and synaptic transmission, sodium channel blockade may restore the excitatory–inhibitory balance in these circuits, leading to the suppression of paroxysmal dyskinesia. Similar symptomatic benefits have been reported in patients with secondary PNKD due to structural or metabolic etiologies. Montilla- Uzcátegui et al. [10] described a patient with Fahr syndrome who exhibited marked improvement in PNKD with low-dose carbamazepine, underscoring its potential to stabilize hyperexcitable neuronal networks irrespective of the primary molecular defect. Accordingly, the response in our case most plausibly reflects symptomatic network stabilization rather than direct correction of chloride channel dysfunction.
This case is unique in multiple respects. First, to the best of our knowledge, this is the first reported case of CLCN2-related leukoencephalopathy presenting as isolated PNKD without other classic features, such as optic atrophy, tremors, or ataxia. Second, the distinctive MRI findings provided vital information that prompted us to suspect leukodystrophy and pursue targeted genetic testing, ultimately confirming the diagnosis. Third, the identified homozygous c.1542_1543del (p.Ser516HisfsTer38) variant in Exon 15 of the CLCN2 gene with respect to the PNKD context has not previously been reported, thereby expanding the mutational spectrum of this condition. Finally, the clinical improvement with carbamazepine administration suggests that certain paroxysmal dyskinesias in the context of leukodystrophy may represent treatable channelopathies, with implications for early recognition and intervention.
This case highlights the importance of maintaining a high index of suspicion for genetic leukoencephalopathies in adult patients with unexplained dyskinesia and characteristic imaging, especially in those with consanguineous backgrounds.
CLCN2-related leukoencephalopathy is a clinically heterogeneous disorder with evolving phenotypic boundaries. This case represents a rare and possibly first report of PNKD as the sole manifestation of a homozygous CLCN2 mutation, expanding the known clinical spectrum. Diagnostic recognition was enabled by MRI clues and confirmed through genetic analysis. The remarkable response to carbamazepine offers therapeutic insight and highlights the need to consider CLCN2 mutations in patients with atypical adult-onset dyskinesias with leukodystrophy imaging.
Supplementary Materials
The Data Supplement is available with this article at https://doi.org/10.14802/jmd.25268.
Supplementary Figure 1.
Pedigree chart of the affected individual (born out of consanguineous parentage). AAO, age at onset; AOD, age of death.
Supplementary Figure 2.
Schematic diagram depicting the effect of the mutation resulting into mutant truncated protein.
Video 1.
Video shows involuntary choreiform dyskinetic movement involving the both upper limb and shoulder (very brief video, recorded almost at the end of the event).
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Ethics Statement
Written informed consent was obtained from the patient/caregiver for this publication.
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Conflicts of Interest
The authors have no financial conflicts of interest.
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Funding Statement
None
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Acknowledgments
None
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Author Contributions
Conceptualization: Subhajit Roy, Ravindranadh Chowdary Mundlamuri. Data curation: Subhajit Roy, Ravindranadh Chowdary Mundlamuri. Formal analysis: Subhajit Roy, Ravindranadh Chowdary Mundlamuri. Investigation: Ravindranadh Chowdary Mundlamuri. Methodology: Subhajit Roy, Ravindranadh Chowdary Mundlamuri. Project administration: Ravindranadh Chowdary Mundlamuri. Supervision: Ravi Yadav, Nalini Atchayaram. Validation: Seena Vengalil, Pritam Raja. Visualization: Ravindranadh Chowdary Mundlamuri. Writing—original draft: Subhajit Roy. Writing—review & editing: all authors.
Notes
Figure 1.
Brain magnetic resonance imaging findings. A-F: Axial T2-weighted images show hyperintensity (arrows) in bilateral posterior limb of internal capsule, cerebral peduncles, and superior and middle cerebellar peduncles. G-I: T1-weighted (G), susceptibility-weighted imaging (H), and postcontrast T1-weighted (I) sequences are unremarkable, indicating no excessive mineralization/blooming and no contrast enhancement.
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XML DownloadCLCN2-Related Leukoencephalopathy Presenting as Isolated Paroxysmal Non-Kinesigenic Dyskinesia: Clinical, Imaging, and Genetic Correlations
Figure 1. Brain magnetic resonance imaging findings. A-F: Axial T2-weighted images show hyperintensity (arrows) in bilateral posterior limb of internal capsule, cerebral peduncles, and superior and middle cerebellar peduncles. G-I: T1-weighted (G), susceptibility-weighted imaging (H), and postcontrast T1-weighted (I) sequences are unremarkable, indicating no excessive mineralization/blooming and no contrast enhancement.
Figure 1.
CLCN2-Related Leukoencephalopathy Presenting as Isolated Paroxysmal Non-Kinesigenic Dyskinesia: Clinical, Imaging, and Genetic Correlations
