Cataplexy in Patients Harboring the KCNMA1 p.N999S Mutation Jennifer Heim, MD,1,* Anusha Vemuri, MD,2 Sara Lewis, PhD,1,3 Brandon Guida, PhD,1,3 Matthew Troester, DO,4 Sotirios Keros, MD PhD,5 Andrea Meredith, PhD,6 and Michael C. Kruer, MD1,3

KCNMA1 codes for the pore-forming alpha-subunit of the voltage- and calcium-sensitive potassium channel (BK channel). BK channel dysfunction has previously been implicated in paroxysmal dyskinesia.1–3 We describe 3 unrelated patients with cataplexy, all sharing the same KCNMA1 gene mutation identified by whole exome sequencing (KCNMA1 [NM_002247.3] c.2984 A > G [p.N999S]), previously described as conferring a gain of function and reported in patients with paroxysmal dyskinesia and developmental delay phenotype.1–4 Parents do not harbor the mutation and are asymptomatic. Patient 1 has an additional variant in the KCNMA1 gene (c.3382 C > T [p.Arg1128Trp]) predicted to be benign.4 Patient 1 is a 4-year-old female with cataplexy (Video S1), hypotonia, and global developmental delay, conceived via sperm donor (neither KCNMA1 variant is maternally inherited, father’s genotype is unknown). MRI brain was normal. No signs of narcolepsy were evident and CSF hypocretin-1 was normal (425.5 pg/mL). Clonazepam, amitriptyline, and levetiracetam were ineffective. Initiation of acetazolamide and docosahexaenoic-acid subjectively reduced cataplexy and the acetazolamide’s efficacy was supported by an n = 1 trial (Fig. 1). A reduction in the frequency of cataplexy was associated with parallel neurodevelopmental progress. Patient 2 is a 6-year-old female with cataplexy (Video S2), global developmental delay, and absence seizures. Diagnostic evaluation for narcolepsy and Niemann-Pick C were all unrevealing. Absence seizures began at age 6 years. She has about 12 cataplexy events daily, as well as dozens of absence seizures daily. She has not tried any medication at the time of this submission. Patient 3 is a 12-year-old male with cataplexy (Video S3), intellectual disability, autism spectrum disorder, speech and

FIG 1. (A) number of episodes recorded manually daily by caregivers of patient 1 during acetazolamide dosage increases (+), decreases (−), and washout (Ø). (B) Decreased number of episodes with acetazolamide treatment. Number of days indicated/dosage. *P < 0.05 Mann–Whitney test.


Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, Arizona, USA; 2Pathology Department, University of Chicago Medical Center, Chicago, Illinois, USA; 3Departments of Child Health, Neurology, Genetics, Cellular & Molecular Medicine, University of Arizona College of Medicine Phoenix, Phoenix, Arizona, USA; 4Pediatric Epilepsy & Sleep Medicine Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, Arizona, USA; 5New York Presbyterian Hospital, Weill Cornell Medical Center, New York, New York City, USA; 6University of Maryland School of Medicine, Baltimore, Maryland, USA *Correspondence to: Jennifer Heim, MD, Barrow Neurological Institute at Phoenix Children’s Hospital, 1919 E Thomas Rd, Phoenix, AZ 85016, USA; E-mail: [email protected] Keywords: acetazolamide, KCNMA1, pediatric movement disorder, cataplexy, PNKD3. Received 11 March 2020; revised 4 May 2020; accepted 25 May 2020. Published online 21 August 2020 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.13024

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(7): 861–862. doi: 10.1002/mdc3.13024 © 2020 International Parkinson and Movement Disorder Society




motor dyspraxia. He experienced up to 60 episodes daily, although frequency has slowly improved over time. His cataplexy has not responded to levetiracetam, carbamazepine, valproic acid, vitamin B complex, cannabidiol, docosahexaenoicacid, 5-HIAA, or pimozide. Cataplexy began in infancy in all 3 patients, with strong emotions and illness as identified triggers, but most events lack identifiable triggers. Although events mimic seizures, video EEG captured cataplexy in each patient, without any discernible change in background. Cataplexy was stereotyped between patients, characterized by behavioral arrest, and a slow lean to the ground, with loss of axial tone and dystonic extremity posturing, lasting seconds to a few minutes, occurring multiple times daily. Eyes typically remain open with the ability to maintain eye contact, suggesting retained consciousness. Repetitive mouth gaping is a common feature. Patients recovered quickly from cataplexy. BK potassium channel dysfunction should be considered as a potential cause in patients with cataplexy. Our experience with patient 1 suggests that a trial of acetazolamide, a known treatment for certain paroxysmal dyskinesias, is helpful in controlling cataplexy. Interestingly, acetazolamide has been suggested to potentiate BK channel activity,5 while biophysical analysis of the N999S mutation shows a gain-of-function.4 This paradox may be explained by non-BK effects of acetazolamide,4 cell-typespecific effects, or other unknown factors.

Acknowledgments We gratefully acknowledge the participation of all the index families in our studies; without their support, this work would not have been possible. This study was supported in part by NIH NINDS 1R01NS106298 (MCK), NHLBI R01-HL102758 and NIGMS T32-GM008181 (ALM), and S&R Foundation Ryuji Ueno Award (ALM).

Disclosures Ethical Compliance Statement: This study was approved by the Phoenix Children’s Hospital IRB, reference number 15-080. Informed consent to publish case reports and videos was obtained from all participants’ parents/legal guardians (signed consent documents for individual participants available upon request). 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: The authors report no relevant conflicts of interest. Jennifer Heim, Matthew Troester, and Michael C. Kruer are employed by Phoenix Children’s Hospital. Sotirios Keros has been employed by Sanford Children’s Hospital in the last 12 months. Michael C. Kruer has received grant funding from the NIH (NIH NINDS 1R01NS106298). Andrea Meredith has received funding from National Heart, Lung, and Blood Institute (NHLBI) R01-HL102758 and Training Program in Integrative Membrane Biology National Institute of General Medical Sciences (NIGMS) T32-GM008181. Financial Disclosures for the Previous 12 Months: The authors report no relevant conflicts of interest.

References 1. Du W, Bautista JF, Yang H, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 2005;37:733–738. 2. Zhang ZB, Tian MQ, Gao K, Jiang YW, Wu Y. De novo KCNMA1 mutations in children with early-onset paroxysmal dyskinesia and developmental delay. Mov Disord 2015;30(9):1290–1292. 3. Li X, Poschmann S, Chen Q, et al. De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity. Eur J Hum Genet 2018;26(2):220–229. 4. Moldenhauer HJ, Matychak KK, Meredith AL. Comparative gain-offunction effects of the KCNMA1-N999S mutation on human BK channel properties. J Neurophysiol 2020;123(2):560–570. 5. Tricarico D, Barbieri M, Mele A, Carbonara G, Camerino DC. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J 2004;18(6):760–761.

Supporting Information Supporting information may be found in the online version of this article. Video S1 Patient 1: 4-year-old female having a typical drop attack during an office visit. Note gradual loss of tone, mouth movements, and curled fingers, followed by rapid return to baseline. Video S2 Patient 2: this video demonstrates drop attacks in the same patient at different ages. The first portion of the video was taken at age 13 months, the second portion at age 6 years, and represent the patient’s typical, stereotyped drop attacks, followed by rapid return to baseline. Video S3 Patient 3: 13-year-old male having 2 typical drop attacks. These videos were captured toward the end of the events. Note arm and neck dystonia, unresponsiveness, followed by rapid return to baseline.

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(7): 861–862. doi: 10.1002/mdc3.13024

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LETTERS: NEW OBSERVATIONS CLINICAL PRACTICE Cataplexy in Patients Harboring the KCNMA1 p.N999S Mutation Jennifer Heim, MD,1,* Anusha Vemuri, MD,2 Sa...
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