TY - JOUR

T1 - Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies

AU - Masnada, Silvia

AU - Hedrich, Ulrike B.S.

AU - Gardella, Elena

AU - Schubert, Julian

AU - Kaiwar, Charu

AU - Klee, Eric W.

AU - Lanpher, Brendan C.

AU - Gavrilova, Ralitza H.

AU - Synofzik, Matthis

AU - Bast, Thomas

AU - Gorman, Kathleen

AU - King, Mary D.

AU - Allen, Nicholas M.

AU - Conroy, Judith

AU - Ben Zeev, Bruria

AU - Tzadok, Michal

AU - Korff, Christian

AU - Dubois, Fanny

AU - Ramsey, Keri

AU - Narayanan, Vinodh

AU - Serratosa, Jose M.

AU - Giraldez, Beatriz G.

AU - Helbig, Ingo

AU - Marsh, Eric

AU - O'Brien, Margaret

AU - Bergqvist, Christina A.

AU - Binelli, Adrian

AU - Porter, Brenda

AU - Zaeyen, Eduardo

AU - Horovitz, Dafne D.

AU - Wolff, Markus

AU - Marjanovic, Dragan

AU - Caglayan, Hande S.

AU - Arslan, Mutluay

AU - Pena, Sergio D.J.

AU - Sisodiya, Sanjay M.

AU - Balestrini, Simona

AU - Syrbe, Steffen

AU - Veggiotti, Pierangelo

AU - Lemke, Johannes R.

AU - Møller, Rikke S.

AU - Lerche, Holger

AU - Rubboli, Guido

PY - 2017/9

Y1 - 2017/9

N2 - Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-micro-electrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.

AB - Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-micro-electrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.

KW - Encephalopathy

KW - Gain-of-function

KW - KCNA2

KW - Loss-of-function

KW - Phenotype-genotype associations

U2 - 10.1093/brain/awx184

DO - 10.1093/brain/awx184

M3 - Journal article

C2 - 29050392

AN - SCOPUS:85031825168

VL - 140

SP - 2337

EP - 2354

JO - Brain

JF - Brain

SN - 0006-8950

IS - 9

ER -