Stepwise Developmental Regression Associated With Novel CACNA1A Mutation Andrea A. Guerin, MD*, Annette Feigenbaum, MD*, Elizabeth J. Donner, MD † , and Grace Yoon, MD* † Mutations in CACNA1A were previously described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. We report on an 11-year-old girl with episodes of seizures, ataxia, head- ache, a decreased level of consciousness, and motor regression, with a background of mental retardation and mild cerebellar atrophy. Sequence analysis of the CACNA1A gene revealed a de novo Ile712Val sequence variant, which was not reported previously. Ó 2008 by Elsevier Inc. All rights reserved. Guerin AA, Feigenbaum A, Donner EJ, Yoon G. Stepwise developmental regression associated with novel CACNA1A mutation. Pediatr Neurol 2008;39:363-364. Introduction Mutations in CACNA1A, which encodes the pore-form- ing a 1A subunit of neuronal P/Q type calcium channels, were previously described in familial hemiplegic mi- graine, episodic ataxia type 2, and spinocerebellar ataxia type 6. In familial hemiplegic migraine, CACNA1A mis- sense mutations were described in all families with ataxia [1]. In contrast, episodic ataxia type 2 is characterized by episodes of cerebellar ataxia, migraine, and interictal nystagmus, and is caused by nonsense mutations of CACNA1A. Spinocerebellar ataxia type 6 is autosomal- dominant, is caused by expansion of CAG repeats within the CACNA1A gene, and is usually characterized by adult- onset ataxia [2]. Case Report We report on an 11-year-old girl with episodes of seizures, ataxia, head- ache, a decreased level of consciousness, and motor regression, with a back- ground of mental retardation and mild cerebellar atrophy. Her prenatal and delivery history were normal. Early motor milestones were appropriate un- til age 15 months, when she presented with status epilepticus, myoclonic seizures, ataxia, and a decreased level of consciousness. She subsequently lost the ability to speak. Subsequent seizures were accompanied by devel- opmental regression. Over the years, the patient experienced stepwise de- cline, characterized by unexplained coma, hemiplegia, and slow recovery. These episodes occurred over months, and she never fully recovered to baseline functional status with each attack. She had inter-episode nystag- mus. The exacerbation of her signs always entailed severe developmental regression, and she is now wheelchair-bound and completely dependent for all activities of daily living. Serial magnetic resonance images demonstrated progressive bilateral mesiotemporal sclerosis, and mild atrophy of the cerebellar vermis and ce- rebral hemispheres. Visual and brainstem auditory-evoked potentials pro- duced normal results. Somatosensory-evoked potentials revealed delayed cortical responses bilaterally. Extensive metabolic investigations were negative. Given the combination of mixed movement disorder with hemiplegia, superimposed on a background of episodic coma and regression, the possibility of a channelopathy was explored. Sequence analysis of the CACNA1A gene revealed a de novo Ile712Val sequence variant, which was not reported previously. This variant was not found in either parent, and the family history was noncontributory. Previous studies described the successful use of acetazolamide in the treatment of episodic ataxia type 2 and familial hemiplegic migraine [3], and we placed our patient on a trial of acetazolamide therapy. The Interna- tional Cooperative Ataxia Rating Scale [4] was used to document motor function at baseline and after 3 months of acetazolamide at a dose of 125 mg twice daily. A baseline 24-hour electroencephalogram revealed right frontotemporal seizures. At the 3-month follow-up visit, she exhibited decreased tremor in both the upper and lower extremities. Her parents reported that she had in- creased stability sitting upright, and had begun to vocalize simple sounds. During the examination, she was able to lift her left leg against gravity, which she was previously unable to do. According to the Inter- national Cooperative Ataxia Rating Scale, she demonstrated marked improvement in the ability to perform the knee-tibia test and the heel-to- knee test, as well as a decrease in saccadic eye movements and dysmetria of the saccade. A follow-up electroencephalogram revealed disorganized background activity with diffuse attenuation over the right hemisphere, but there were no epileptiform discharges or other electrical evidence From the *Division of Clinical and Metabolic Genetics, and † Division of Neurology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada. Communications should be addressed to: Dr. Yoon; Division of Neurology and Division of Clinical and Metabolic Genetics; Department of Pediatrics, Hospital for Sick Children; University of Toronto; 555 University Ave.; Toronto, Ontario M5G 1X8, Canada. E-mail: grace.yoon@utoronto.ca Received May 21, 2008; accepted July 28, 2008. Ó 2008 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2008.07.030  0887-8994/08/$—see front matter Guerin et al: Novel Mutation in CACNA1A 363