Format

Send to

Choose Destination
Neurotherapeutics. 2018 Oct;15(4):1112-1126. doi: 10.1007/s13311-018-0657-9.

Early Treatment with Quinidine in 2 Patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) Due to Gain-of-Function KCNT1 Mutations: Functional Studies, Clinical Responses, and Critical Issues for Personalized Therapy.

Author information

1
Pediatric Epileptology and Neurophysiology (RD), Infantile Neuropsichiatry (AG), Cardiology (MAG), High Intensity Pediatric Care (SG), Neonatology (MF), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122, Milan, Italy.
2
Clinical Neurophysiology and Epilepsy Center, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133, Milan, Italy.
3
Department of Neurology, San Gerardo Hospital, School of Medicine and Surgery, Milan Center for Neuroscience (NeuroMi), University of Milano-Bicocca, 20900, Monza, Italy.
4
Department of Medicine and Health Science, University of Molise, 86100, Campobasso, Italy.
5
Division of Pharmacology, Department of Neuroscience, University of Naples "Federico II", 80131, Naples, Italy.
6
Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco, 20157, Milan, Italy.
7
Department of Surgical, Odontostomatological, and Maternal-Infantile Sciences, University of Verona, 37134, Verona, Italy.
8
Laboratory of Genetics, E.O. Ospedali Galliera, 16128, Genoa, Italy.
9
Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, "G. Gaslini" Institute, 16147, Genoa, Italy.
10
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133, Milan, Italy.
11
Department of Child Neurology and Psychiatry, "C. Mondino" National Neurological Institute, 27100, Pavia, Italy.
12
Department of Biomedical and Clinical Sciences, Children's Hospital Vittore Buzzi, University of Milan, and Pediatric Neurology, 20154, Milan, Italy.
13
Department of Medicine and Health Science, University of Molise, 86100, Campobasso, Italy. mtaglial@unina.it.
14
Division of Pharmacology, Department of Neuroscience, University of Naples "Federico II", 80131, Naples, Italy. mtaglial@unina.it.
15
Department of Neuroscience, University of Naples "Federico II", Via Pansini 5, 80131, Naples, Italy. mtaglial@unina.it.

Abstract

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare early-onset developmental epileptic encephalopathy resistant to anti-epileptic drugs. The most common cause for EIMFS is a gain-of-function mutation in the KCNT1 potassium channel gene, and treatment with the KCNT1 blocker quinidine has been suggested as a rational approach for seizure control in EIMFS patients. However, variable results on the clinical efficacy of quinidine have been reported. In the present study, we provide a detailed description of the clinical, genetic, in vitro, and in vivo electrophysiological profile and pharmacological responses to quinidine of 2 EIMFS unrelated patients with a heterozygous de novo KCNT1 mutation: c.2849G>A (p.R950Q) in patient 1 and c.2677G>A (p.E893K) in patient 2. When expressed heterologously in CHO cells, KCNT1 channels carrying each variant showed gain-of-function effects, and were more effectively blocked by quinidine when compared to wild-type KCNT1 channels. On the basis of these in vitro results, add-on quinidine treatment was started at 3 and 16 months of age in patients 1 and 2, respectively. The results obtained reveal that quinidine significantly reduced seizure burden (by about 90%) and improved quality of life in both patients, but failed to normalize developmental milestones, which persisted as severely delayed. Based on the present experience, early quinidine intervention associated with heart monitoring and control of blood levels is among the critical factors for therapy effectiveness in EIMFS patients with KCNT1 gain-of-function mutations. Multicenter studies are needed to establish a consensus protocol for patient recruitment, quinidine treatment modalities, and outcome evaluation, to optimize clinical efficacy and reduce risks as well as variability associated to quinidine use in such severe developmental encephalopathy.

KEYWORDS:

Developmental encephalopathy; Epilepsy of infancy with migrating focal seizures (EIMFS); KCNT1; Quinidine; Therapeutic drug monitoring (TDM)

PMID:
30112700
PMCID:
PMC6277296
[Available on 2019-10-14]
DOI:
10.1007/s13311-018-0657-9
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center