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(Abst. 3.094), 2014

Authors: Madeline Chadehumbe, Mark Mintz and Richard Boles
Content: Rationale: It is estimated that PNES are diagnosed in about 20% of patients seen at epilepsy centers for intractable seizures. Methods: We report a stigmatized patient with PNES who was later diagnosed with familial hemiplegic migraine (FHM) due to the presence of accompanied focality, dyskinesia and dramatic clinical response to acetazolamide, and a highly-conserved variant in the CACNA1A gene. Results: A 25-year-old Caucasian female presented with a 10-year history of intractable "seizures". She has been evaluated extensively in four large quaternary hospital Epilepsy Monitoring Units with the unified conclusion of PNES for which she was referred to psychiatry for follow up. Despite this conclusion, she continued to have monthly admission through emergency departments for "status epilepticus". Emergency responders, family, and physicians all responded with haste as they all had the semiology of focal epileptic seizures. Her typical episode had an aura of tongue numbness, progressing to tongue twitching with intermittent inability to speak, then followed within five to 60 minutes of focal jerking of the left arm, face and leg, and maintained awareness and without amnesia. Episodes lasted from five minutes up to four days. Non-specific headaches heralded the end of an episode. Multiple drug trials with anti-epileptic medications failed to modify the clinical state. After obtaining an additional opinion, an underlying ion channelopathy was suspected. An 1,100+ targeted NextGen DNA sequencing panel for genes of interest (nucSEEKTM Courtagen Diagnostic Laboratories) revealed a conserved variant in the CACNA1A gene, in which there is a change to alanine in the first of four glutamine resides that are highly conserved throughout vertebrates. This variant is found in 1.0% of European-Americans per 1000Genomes and ESP, and is predicted to be deleterious by SIFT with an equivocal score by PolyPhen2. Pathogenic variants in this gene are associated with a wide range of paroxysmal conditions including FHM and episodic ataxia. On acetazolamide monotherapy, this pateint has since been free of seizure-like episodes, and back in nursing school with the ability to drive. Conclusions: The diagnosis of PNES, particularly when there are atypical presentations, should not be made solely on the lack of electroclinical correlation. Disorders of ion transport ("channelopathies") are increasingly being found to be involved in a wide range of paroxysmal manifestations, including true epilepsy, migraine and movement disorders. Sequence variation in channel genes associated with paroxysmal events generally act as risk factors for disease in a polygenic manner, often with high prevalence rates such as the 1% in the current scenario. Since these conditions are numerous, often have overlapping phenotypes, and there can be disease-related variants in more-than-one gene, massively-parallel gene sequencing assays are the preferred method to identify actionable causes. NextGen assays may be cost effective considering the potential reductions in emergency/urgent care services, additional diagnostic testing, and disability.