Abstract
We report a 52-year-old woman presenting with autosomal dominant progressive cerebellar ataxia and familial hemiplegic migraine type 1 whose genetic evaluation, negative for spinocerebellar ataxia (SCA) types 1, 2, 3, and 6, revealed instead a heterozygous pathogenic missense mutation in CACNA1A (NM_001127221:c.1748G > A:p.Arg583Gln). A systematic literature review showed that Arg583Gln is associated predominantly with progressive ataxia combined with episodic disorders (overwhelmingly hemiplegic migraine) whereas Thr666Met, the other most common CACNA1A missense mutation, with a combination of progressive ataxia and episodic disorders in half the cases and episodic disorders only in the other half. While uncertainties remain in the genotype-phenotype correlation of all CACNA1A mutations, the accumulated evidence suggests that that the co-occurrence of hemiplegic migraine and autosomal dominant progressive cerebellar ataxia should guide the clinician to test for CACNA1A missense mutation rather than CAG expansions or truncating mutations.
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The dataset used and analyzed for this study is available from the corresponding author upon request.
Funding
This study was funded by The Parkinson’s Patient Diagnostic Genetic Assistance Fund at the University of Cincinnati located in Cincinnati, OH, USA.
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Kevin R. Duque, Luca Marisili, Andrea Sturchio, Abhimanyu Mahajan, Aristide Merola, Alberto J. Espay, and Marcelo A. Kauffman. The first draft of the manuscript was written by Kevin R. Duque and Luca Marsili. All authors read and approved the final manuscript.
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The authors declare that they have no conflict of interest related to the research covered in this article. Aristide Merola is supported by NIH (KL2 TR001426) and has received speaker honoraria from CSL Behring, Cynapsus Therapeutics, Lundbeck, AbbVie, and Abbott. He has received grant support from Lundbeck and Abbott. Alberto J. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for AbbVie, Neuroderm, Neurocrine, Amneal, Adamas, Acadia, Acorda, InTrance, Sunovion, Lundbeck, and US WorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from US WorldMeds, Acadia, and Sunovion. Marcelo A. Kauffman is an employee of the CONICET and has received grant support from the Ministry of Science and Technology of Argentina and the Ministry of Health of Buenos Aires.
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The clinical assessment and genetic testing on the patient were part of the study #2017-5985 approved by the Human Research Ethics committee of the University of Cincinnati. The procedures used in this study adhere to the tenets of the 1964 Declaration of Helsinki.
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Electronic Supplementary Material
Supplementary File 1.
List of the examined articles describing individuals harboring the CACNA1A missense mutations Arg583Gln and Thr666Met. (DOCX 26 kb)
Supplementary Table S1.
Table summarizing the major gait parameters in our patient. (DOCX 40.2 kb)
Video 1.
Neurologic examination of the patient showing scanning speech, hypermetric saccades in horizontal pursuit and wide-based gait. (MP4 1654 kb)
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Duque, K.R., Marsili, L., Sturchio, A. et al. Progressive Ataxia with Hemiplegic Migraines: a Phenotype of CACNA1A Missense Mutations, Not CAG Repeat Expansions. Cerebellum 20, 134–139 (2021). https://doi.org/10.1007/s12311-020-01185-9
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DOI: https://doi.org/10.1007/s12311-020-01185-9