Episodic ataxia type 2 (EA2) is clinically characterized by recurrent attacks of ataxia associated with acetazolamide responsiveness.1 EA2 is caused by mutations in calcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) gene.2 We report an EA2 case with a novel de novo pathogenic CACNA1A mutation, presenting with two different types of episodic attacks.
A 23-year-old female requested an evaluation for recurrent episodes of imbalance. According to her mother, who accompanied her, her illness started at age 15 months with repeating attacks of head nodding that always disappeared after naps (see video). Her physician at that time diagnosed her with a benign paroxysmal tonic upgaze, and he described the presence of nystagmus without any more specific description.. The frequency of the episodes gradually increased from occasional to once a week. When a preschooler, she complained of a sudden sensation of dizziness and ataxia followed by vomiting, which would last up to two hours. The second type of attack became noticeable during her high school years. She experienced recurrent episodes of dysphagia and general weakness, which would last up to two hours. The first type of attack was more common, occurring about 70% of the time. Only rarely did both presentations occur together. A dull headache was sometimes present in both types of attacks. Despite her health problems, she was able to attend school but she always avoided involvement in any sports.
She had no neurological abnormalities, except for horizontal gaze-evoked nystagmus. Electroencephalography, electromyography, and autonomic testing revealed no significant abnormalities. Head magnetic resonance imaging (MRI) obtained at age 13 years displayed no abnormalities (Figure 1a and 1b). MRI performed at age 23 years revealed a slight prominence of the cerebellar sulci (Figure 1c and 1d). Acetazolamide (125mg/day) reduced the severity and number of attacks, especially of ataxia type. Her elder brother and both parents did not show similar symptoms.
Figure 1. Head magnetic resonance imaging (MRI) with T1-weighted image, and DNA sequencing and restriction fragment length polymorphism.
(a, b), age 13 years, no abnormalities; (c, d), age 23 years, slight atrophy of cerebellar vermis; (e, top), CACNA1A p.R1346Stop mutation, patient; (e, bottom), wild-type for C-allele at c.4036 position, sibling.
Genetic sequencing of the 48 exons of CACNA1A and their flanking donor/acceptor sequences detected a nonsense mutation, p.R1346Stop, in the patient, but it was not found in her family members or in 1423 healthy controls. Haplotype analyses confirmed maternal and paternal relationships (Figure 1e).
Most EA2 cases present only with episodic ataxia but some present with attacks of both ataxia and weakness occurring together. Acetazolamide is beneficial for both types of attacks, even in a previously published single case, where attacks of ataxia and weakness occurred independently.3 The response to acetazolamide in our case was better for attacks of ataxia. Therefore, it is possible that there are different mechanisms causing these two phenotypes, perhaps related to the specific mutation.
It is difficult to identify attacks before the child develops full walking and speech skills.4–7 In our case, vertical nystagmus occurring in infancy most likely represented disease onset. A similar phenotype has been observed in another case, but without video documentation.7 Therefore, head nodding and nystagmus may be a useful diagnostic feature in infancy.
Genetic sequencing is an important tool for diagnosis of this disorder. Further studies are warranted to elucidate the underlying pathogenic mechanisms of disease associated with CACNA1A mutations.
Supplementary Material
This video was obtained at age 15 months.
Video Section 1: First part (- 44 seconds). The patient presented with abnormal head movements such as pointing her chin downward with fixating gaze.
Video Section 2: Latter part (- 68 seconds). After taking a nap, she looked normal.
Acknowledgement
CS was partially supported by the American Scandinavian Foundation: Haakon Styri Fund. ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50 NS072187-01S2, Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), and Dystonia Medical Research Foundation.
Footnotes
Financial Disclosure/Conflict of interest concerning the research related to the manuscript:
Nothing to disclose.
Author Roles
Shinsuke Fujioka: retrieved the clinical data and wrote the first draft.
Sruti Rayaprolu: performed genetic tests, reviewed and critiqued the manuscript.
Christina Sundal: reviewed and critiqued the manuscript.
Daniel F. Broderick: performed radiological examinations and reviewed and critiqued the manuscript.
William Tatum: performed clinical examination and reviewed and critiqued the manuscript.
John Shoffner: reviewed and critiqued the manuscript.
Rosa Rademakers: reviewed and critiqued the manuscript.
Neill R. Graff-Radford: provided the blood specimen of controls, and reviewed and critiqued the manuscript.
Owen A. Ross: performed genetic tests, and reviewed and critiqued the manuscript.
Zbigniew K. Wszolek: performed clinical examination of the patient, research organization, and reviewed and critiqued the manuscript.
References
- 1.Baloh RW. Episodic ataxias 1 and 2. Handb Clin Neurol. 2012;103:595–602. doi: 10.1016/B978-0-444-51892-7.00042-5. [DOI] [PubMed] [Google Scholar]
- 2.Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain. 2007;130:2484–2493. doi: 10.1093/brain/awm126. [DOI] [PubMed] [Google Scholar]
- 3.Marti S, Baloh RW, Jen JC, Straumann D, Jung HH. Progressive cerebellar ataxia with variable episodic symptoms--phenotypic diversity of R1668W CACNA1A mutation. Eur Neurol. 2008;60:16–20. doi: 10.1159/000127974. [DOI] [PubMed] [Google Scholar]
- 4.Zafeiriou DI, Lehmann-Horn F, Vargiami E, Teflioudi E, Ververi A, Jurkat-Rott K. Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation. Eur J Paediatr Neurol. 2009;13:191–193. doi: 10.1016/j.ejpn.2008.02.011. [DOI] [PubMed] [Google Scholar]
- 5.Rajakulendran S, Schorge S, Kullmann DM, Hanna MG. Dysfunction of the Ca(V)2.1 calcium channel in cerebellar ataxias. F1000 Biol Rep. 2010;2 doi: 10.3410/B2-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Subramony SH, Schott K, Raike RS, et al. Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. Ann Neurol. 2003;54:725–731. doi: 10.1002/ana.10756. [DOI] [PubMed] [Google Scholar]
- 7.Graves TD, Imbrici P, Kors EE, et al. Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2. Neurobiol Dis. 2008;32:10–15. doi: 10.1016/j.nbd.2008.06.002. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
This video was obtained at age 15 months.
Video Section 1: First part (- 44 seconds). The patient presented with abnormal head movements such as pointing her chin downward with fixating gaze.
Video Section 2: Latter part (- 68 seconds). After taking a nap, she looked normal.