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

被引：64

作者：

Dilena, Robertino ^{[1
]}

DiFrancesco, Jacopo C. ^{[6
,7
]}

Soldovieri, Maria Virginia ^{[8
]}

Giacobbe, Antonella ^{[2
]}

Ambrosino, Paolo ^{[8
]}

Mosca, Ilaria ^{[8
]}

Galli, Maria Albina ^{[3
]}

Guez, Sophie ^{[4
]}

Fumagalli, Monica ^{[5
]}

Miceli, Francesco ^{[9
]}

Cattaneo, Dario ^{[10
]}

Darra, Francesca ^{[11
]}

Gennaro, Elena ^{[12
]}

Zara, Federico ^{[12
]}

Striano, Pasquale ^{[13
]}

Castellotti, Barbara ^{[14
]}

Gellera, Cinzia ^{[14
]}

Varesio, Costanza ^{[15
]}

Veggiotti, Pierangelo ^{[16
]}

Taglialatela, Maurizio ^{[8
,9
,17
]}

机构：

[1] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Pediat Epileptol & Neurophysiol, I-20122 Milan, Italy

[2] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Infantile Neuropsichiatry, I-20122 Milan, Italy

[3] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Cardiol, I-20122 Milan, Italy

[4] Fdn IRCCS Ca Granda Osped Maggiore Policlin, High Intens Pediat Care, I-20122 Milan, Italy

[5] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Neonatol, I-20122 Milan, Italy

[6] Fdn IRCCS Ist Neurol Carlo Besta, Clin Neurophysiol & Epilepsy Ctr, I-20133 Milan, Italy

[7] Univ Milano Bicocca, Dept Neurol, San Gerardo Hosp, Sch Med & Surg,Milan Ctr Neurosci NeuroMi, I-20900 Monza, Italy

[8] Univ Molise, Dept Med & Hlth Sci, I-86100 Campobasso, Italy

[9] Univ Naples Federico II, Div Pharmacol, Dept Neurosci, I-80131 Naples, Italy

[10] ASST Fatebenefratelli Sacco, Clin Pharmacol Unit, I-20157 Milan, Italy

[11] Univ Verona, Dept Surg Odontostomatol & Maternal Infantile Sci, I-37134 Verona, Italy

[12] EO Osped Galliera, Genet Lab, I-16128 Genoa, Italy

[13] Univ Genoa, G Gaslini Inst, Pediat Neurol & Muscular Dis Unit, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, I-16147 Genoa, Italy

[14] Fdn IRCCS Ist Neurol Carlo Besta, Unit Genet Neurodegenerat & Metab Dis, I-20133 Milan, Italy

[15] C Mondino Natl Neurol Inst, Dept Child Neurol & Psychiat, I-27100 Pavia, Italy

[16] Univ Milan, Childrens Hosp Vittore Buzzi, Dept Biomed & Clin Sci, I-20154 Milan, Italy

[17] Univ Naples Federico II, Dept Neurosci, Via Pansini 5, I-80131 Naples, Italy

来源：

NEUROTHERAPEUTICS | 2018年 / 15卷 / 04期

关键词：

KCNT1; Developmental encephalopathy; Epilepsy of infancy with migrating focal seizures (EIMFS); Quinidine; Therapeutic drug monitoring (TDM); ACTIVATED POTASSIUM CHANNEL; K-NA CHANNELS; ENCEPHALOPATHY; SLO2.2; SENSITIVITY; SPECTRUM;

D O I：

10.1007/s13311-018-0657-9

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

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 16months 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.

引用

页码：1112 / 1126

页数：15

共 44 条

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Does age affect response to quinidine in patients with KCNT1 mutations? Report of three new cases and review of the literature [J].