Huntington's Disease‐like Syndrome as a Rare Presentation of <scp> <i>CACNA1A</i> </scp> ‐Related DisorderPetros Boumis, Constantin Potagas, Christos Koros et al.|Movement Disorders Clinical Practice|2025 Huntington's disease (HD)-like syndromes or HD phenocopies account for around 1% of suspected HD cases and lack pathogenic CAG expansions in HTT.1, 2 Although the majority of HD-like patients remain without a molecular diagnosis, recent studies employing next generation sequencing (NGS) have broadened the genetic spectrum associated with this phenotype, identifying on very rare occasions causative variants in a diverse group of genes, including CACNA1A.3-5 CACNA1A variants are typically associated with familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2) or spinocerebellar ataxia 6. CACNA1A encodes the a1 subunit of the Cav2.1 calcium channel, especially abundant in Purkinje cells. Although recent studies have expanded the phenotypic spectrum of CACNA1A-related disorders, an HD-like presentation is not a widely-recognized feature of CACNA1A-related disease.6-8 We presently report a patient with a typical HD-like presentation, who eventually developed episodic and progressive ataxia, and carried a heterozygous causative variant in CACNA1A. We present a 65-year-old woman, with a 15-year history of generalized choreiform movements and a family history of similar involuntary movements in her mother. There was no other significant past medical history nor history of alcohol abuse. She was first hospitalized for her movement disorder aged 56 and underwent extensive investigations to rule out secondary causes of chorea, including antiphospholipid antibodies and limbic encephalitis panels, that were unremarkable. Genetic testing for HD came back negative. She was discharged with a diagnosis of generalized chorea of unknown cause on haloperidol drops at a dose of 1 mg three times daily, which led to partial symptomatic improvement. On examination aged 61, a generalized choreiform and dystonic movement disorder was observed (Video 1). There was mild unilateral cogwheel rigidity, mild difficulty in tandem gait and mildly affected postural reflexes. She had a unified HD rating scale motor score of 20, which is considered a relatively mild score (range 0–124, higher scores indicating more severe impairment). Cognitive testing revealed mild impairment in attention, verbal fluency and visuospatial function with a Montreal cognitive assessment (MoCA) score of 19/30. Further repeat-expansion genetic testing for C9ORF72-related disorder, SCA17 and SCA1,2,3,6,7 was negative.9 At the age of 65, she was hospitalized for the recent emergence of episodes of dizziness, severe unsteadiness and dysarthria of 4–5 hours duration, with a frequency of 1–2 per month. She was on haloperidol, trihexyphenidyl and clonazepam. On examination, the generalized choreiform and dystonic movement disorder was still present (Video 2). There was also mildly ataxic gait with moderate difficulty on tandem walking, mild dysarthria, broken pursuit, mild dysmetria with mild intention tremor, particularly on the left, and mild dysdiadochokinesis (Video 3). Her cognitive assessment revealed mild deterioration (MoCA, 14/30). Repeat imaging, EEG, and extensive blood and CSF tests were unremarkable. More specifically, there was no evidence of caudate atrophy or ischemic changes on brain MRI. During hospitalization, she developed an episode of severe gait ataxia, severe limb dysmetria and exacerbation of cerebellar dysarthria, which lasted 3–4 hours (Video 4). Caffeine consumption was reported on the same morning. The patient retrospectively associated some of the past ataxic episodes with caffeine intake or severe emotional stress. Following discharge, genetic testing with whole exome sequencing revealed a novel heterozygous, likely-pathogenic, nonsense variant in CACNA1A (NM_001127222.2): c.5505G>A, p.(Trp1835Ter), expected to lead to a premature termination codon. Accordingly, a diagnosis of EA2 presenting as a HD phenocopy was reached. Genetic counseling was offered and a trial of acetazolamide recommended. HD-like syndromes are defined by the presence of a movement disorder compatible with HD (typically choreiform, but also relatively pure dystonic or akinetic-rigid); one or more of: family history compatible with autosomal dominant inheritance, behavioral/psychiatric symptoms or cognitive deterioration; and negative molecular testing for HD.2 Our patient, at presentation, fulfilled the definition of an HD-like syndrome. Subsequently, with the emergence of the episodic nature of ataxic symptoms, the diagnostic possibility of a channelopathy was raised, leading eventually to the identification of a CACNA1A causative variant.10 Despite the expanding phenotypic spectrum of CACNA1A-related disorders, including, beyond EA2 and FHM, epilepsy, progressive ataxia, developmental delay, autism spectrum disorder, psychiatric manifestations and even early-onset paroxysmal dystonia, an HD-like presentation is not a widely-recognized feature of CACNA1A-related disease.6-8 In fact, only two cases of HD-like syndrome with CACNA1A variants have been reported, both from a French HD phenocopy cohort.4 These cases had a typical HD-like presentation, one subsequently developing a mild cerebellar syndrome and the other pure dysarthria. Neither developed features of episodic ataxia. The presently identified CACNA1A variant, which would not have been picked up on standard SCA6 repeat expansion testing in CACNA1A, is a novel nonsense variant, expected to act through a loss-of-function (LoF) mechanism. LoF variants are thought to be often associated with EA2, so the emergence of episodic ataxia in our patient is consistent with the type of variant identified.7 Interestingly, the CACNA1A variants carried by the previously reported patients with HD-like syndrome were missense variants, usually associated with gain-of-function, and did not lead to episodic ataxia. The authors postulated that CACNA1A variants might cause an HD phenotype because of a possible interaction with junctophilin 3 in the nanoenvironment of the Cav2 channel shown using a proteomic approach, given that CTG repeat-expansions in junctophilin 3 cause HD-like 2.4 In conclusion, the present case expands the phenotypic spectrum of CACNA1A-related disorders and the genotypic spectrum of HD-like syndromes and illustrates how the use of NGS in daily clinical practice can identify a growing number of genes that may rarely be associated with unusual neurological phenotypes. (1) Research project: A. Conception, B. Organization, C. Execution. (2) Clinical methodology: A. Design, B. Execution, C. Review and Critique. (3) Genetic analysis: A. Design, B. Execution, C. Review and Critique. (4) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; P.B.: 2B, 4A; C.P.: 2A, 2B, 2C, 4B; C.K.: 2A, 2B, 2C, 4B; VC: 2A, 2B, 2C, 4B; N.R.: 2B, 4B; C.Kon.: 2B, 2C, 4B; S.A.: 1C, 2B, 4B; C.Ka.: 1B, 3B, 3C, 4B; E.L.: 1B, 1C, 3B, 3C, 4B; N.T.: 1A, 3A, 4B; E.A.: 2A, 2B, 2C, 4B; L.S.: 1A, 1B, 4B; S.P.: 2A, 2B, 2C, 4B; G.K.: 1B, 3A, 3C, 4B; G.Kou.: 1B, 2A, 2B, 2C, 3A, 3C, 4A. The 1st Department of Neurology at Eginition Hospital is a Center of ERN-RND. The publication of this article in OA mode was financially supported by HEAL-Link. Ethical Compliance Statement: The study conformed to the Declaration of Helsinki. Written informed consent was obtained from the patient for the performance of genetic studies and participation in the study. Special consent was given for the inclusion of the videos in which the patient may be identified. We confirm that all co-authors 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 Conflict of Interest: This work was supported by the National Network for Research of Neurodegenerative Diseases on the basis of Medical Precision (Grant 2018 E01300001), funded by the General Secretariat of Research and Innovation (GSRI), Greece. The authors declare that there are no conflicts of interest relevant to this work. Financial disclosures for the previous 12 months: CK has received funding from the Michael J. Fox Foundation for his participation in the Parkinson's Progression Markers Initiative (PPMI) study. CKon has received travel grants from Genesis Pharma. LS has received the following grants: PPMI2 (supported by the Michael J. Fox Foundation), “BRAIN PRECISION” (funded by the General Secretariat of Research and Innovation), “Longitudinal evaluation of a cohort of asymptomatic SNCA mutation carriers to investigate early events in PD pathobiology” (funded by the Michael J. Fox Foundation), “Targeting the Autophagy Lysosome Pathway in Human MSA” (funded by the MSA Trust, Collaborator), and “CMA as a Means to Counteract alpha-Synuclein Pathology in Non-Human Primates” (funded by the Michael J. Fox Foundation, Collaborator); has served on Advisory Boards for Abbvie, Innovis Pharma and ITF Hellas; has received honoraria from ITF Hellas, Innovis Pharma and Abbvie; has participated in clinical trials as site PI, funded by Roche, AB Science, Immunovant and Sanofi. GKar has received research grants from Pfizer. GKou has received research grants from Genesis Pharma and advisory board remuneration, honoraria or travel grants from Genesis Pharma, Bristol-Myers-Squibb and AstraZeneka. The authors declared that there are no additional disclosures to report. 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.