Rapidly Progressive Atypical Parkinsonism as a Presenting Feature of <scp>ATX‐<i>CACNA1G</i></scp> (<scp>SCA42</scp>)

Parkinsonism can be a prominent clinical manifestation of ATX-ATXN2, ATX-ATXN3, ATX-CACNA1A, ATX-TBP, ATX-STUB1, and ATX-PPP2R2B with mild or absent cerebellar signs1, 2 with some cases resembling multiple system atrophy, progressive supranuclear palsy, or Parkinson's disease. We report a case of severe rapidly progressive atypical parkinsonism poorly responsive to levodopa as the initial and main feature in a patient carrying an CACNA1G variant. A 45-year-old man without a family history of neurological disease began at the age of 41 with postural instability and falls, progressive symmetric bradykinesia with micrographia, upper limb rest, and kinetic tremor, followed by segmental dystonia involving the trunk, right hand, and left leg. He had dream-enactment behavior, constipation, and urinary incontinence, whereas olfaction was normal. At 2 years of symptoms onset, the neurological examination showed symmetrical parkinsonism (MDS-UPDRS-III score of 47), with horizontal slow pursuit and horizontal saccadic eye movements, mild upper gaze limitation with right-eye exotropia without nystagmus. Gait was mainly spastic, with left leg dystonia. However, lower limb strength and deep tendon reflexes were normal, with flexor plantar responses and no spasticity when the tone was examined. There was neither limb nor gait ataxia, and cognition was normal with a Montreal Cognitive Assessment of 26. Even though the response to an acute levodopa challenge was negative (MDS-UPDRS III pretest 47; posttest 44; reduction: 6%), the patient presented a mild improvement of tremor, rigidity, and bradykinesia with 1000 mg levodopa/carbidopa daily. No dyskinesias were present (Video 1). Anti-GAD65 antibodies, 24-h urine copper, and brain MRI were normal. Whole Exome Sequencing revealed a pathogenic heterozygous variant (c.6127C > T, p. (Arg2043)) in the CACNA1G gene. No pathogenic or risk variants for PD were found (Supplementary material 1 in Appendix S1). Genetic testing of relatives was not possible due to a lack of insurance coverage. Disease rapidly progressed and at 4 years of symptoms onset the patient developed severe progressive freezing of gait and severe bradykinesia unresponsive to 1250 mg of daily levodopa (MDS-UPDRS-III score of 63), with severe dysarthria, dysphagia, disproportionate antecollis, camptocormia, pyramidal signs and atypical oromandibular dyskinesia. He became wheelchair-bound (Video 2). A second acute levodopa challenge performed at that time also showed a negative response (MDS-UPDRS III pretest 63; Posttest 53; reduction: 16%) and a subsequent brain MRI was also normal. Imaging of dopaminergic denervation (99mTc-TRODAT-1 SPECT) was not possible due to a lack of insurance coverage. ATX-CACNA1G (SCA-42) is a rare spinocerebellar ataxia, resulting from variants in the CACNA1G gene, codifying T-type calcium channel protein Cav3.1, that is highly expressed in Purkinje neurons and deep cerebellar nuclei.3-6 It is characterized by progressive ataxia, associated with pyramidal signs, tremor and peripheral neuropathy, and more scarcely with chorea and dystonia.3, 5, 7 Cognitive impairment, depression, aggressive behavior and delusions have been described.3, 8, 9 Pathogenic variants in CACNA1G have been also associated to early childhood onset ataxia, with severe intellectual disability, epilepsy, dysmorphism, and microcephaly.6 However, to the best of our knowledge, parkinsonism was not reported previously. This case expands the phenotype of ATX-CACNA1G (SCA-42) by adding rapidly progressive atypical parkinsonism with poor and transient response to levodopa, highlighting the vast clinical heterogeneity of spinocerebellar ataxias.1 We thank the patient and his family for their willingness to participate in this study. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript preparation: A. Writing of the first draft, B. Review and critique. V.A.M.V.: 1A, 1B, 1C, 2A. S.A.C.T.: 1B, 2A, 2B. M.R.: 1A, 1B, 1C, 2A, 2B. M.M.: 1A, 1B, 1C, 2A, 2B. Ethical Compliance Statement: This study was approved by the Institutional Review Board at Fleni and written informed consent was obtained prior to publication. 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: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: V.A.M.V.: Dr. Martínez-Villota is supported by the Movement Disorders Society Visiting Trainee Grant program. S.A.C.T.: Dr. Castillo-Torres is supported by the Edmond J. Safra Foundation Fellowship in Movement Disorders (Class of 2023) and receives funding as Level I National Researcher from Mexico's National Council for Science and Technology (Consejo Nacional de Ciencia y Tecnología, CONACYT). M.R.: Dr. Rossi receives honoraria as neurologist for the from the Movement disorders service at Fleni (Buenos Aires, Argentina). M.M.: Dr. Merello has provided consultancies for St. Jude/Abbott; receives Honoraria from the Movement disorders service at Fleni (Buenos Aires, Argentina), and Glaxo, Abbott. Royalties from Springer, Random House, Cambridge University Press, and Humana Press. Has received grants from Glaxo, Allergan, Mertz, CONICET, and Genzyme. Appendix S1. Supporting information. 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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