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Brain. 2017 Sep 1;140(9):2337-2354. doi: 10.1093/brain/awx184.

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

Author information

1
Brain and Behaviour Department, University of Pavia, Italy.
2
Department of Child Neurology and Psychiatry, IRCCS C. Mondino National Neurological Institute, Pavia, Italy.
3
Danish Epilepsy Centre, Dianalund, Denmark.
4
Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Germany.
5
Clinical Neurophysiology, Danish Epilepsy Centre, Dianalund, Denmark.
6
Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
7
Center for Individualized Medicine, Mayo Clinic, Scottsdale AZ, USA.
8
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
9
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
10
Departments of Clinical Genomics and Neurology Mayo Clinic, Rochester, MN, USA.
11
Department of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Tübingen, Germany.
12
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
13
Epilepsy Center Kork, Kehl, Germany.
14
Department of Neurology and Clinical Neurophysiology, Children's University Hospital, Temple Street, Dublin, Ireland.
15
Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Ireland.
16
Sackler school of medicine Tel Aviv University, Tel Aviv, Israel.
17
Pediatric Neurology Unit, Sheba Medical Center, Israel.
18
Pediatric Neurology University Hospitals, Geneva, Switzerland.
19
Pediatric Departement, Grenoble CHU, France.
20
Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.
21
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
22
Neurology Laboratory and Epilepsy Unit, Department of Neurology, IIS- Fundación Jiménez Díaz, UAM, Madrid, Spain.
23
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
24
Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, USA.
25
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel Germany.
26
Department of Pediatric Neurology, Elizalde Children's Hospital, Buenos Aires, Argentina.
27
Sociedad Argentina de Neurología Infantil (SANI) / Argentinian Child Neurology Society.
28
Department of Neurology and Neurological Sciences, Stanford University, Palo Alto California, USA.
29
Neuropediatrics Committee of State of Rio De Janeiro, Rio De Janeiro, Brazil.
30
Medical Genetics Department, National Institute for Women, Children and Adolescents Health Fernandes Figueira - Fiocruz, Rio de Janeiro, Brazil.
31
Department of Pediatric Neurology and Developmental Medecine, University Children's Hospital, Tübingen, Germany.
32
Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey.
33
Department of Pediatric Neurology, Gulhane Military Medical School, Ankara, Turkey.
34
GENE - Núcleo de Genética Médica, Belo Horizonte, MG, Brazil.
35
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology and Epilepsy Society, UK.
36
Department of General Paediatrics, Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
37
Department of Women and Child Health, Hospital for Children and Adolescents, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
38
University of Leipzig Hospitals and Clinics, Leipzig, Germany.
39
University of Copenhagen, Copenhagen, Denmark.

Abstract

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-microelectrode 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.

KEYWORDS:

KCNA2; encephalopathy; gain-of-function; loss-of-function; phenotype–genotype associations

PMID:
29050392
DOI:
10.1093/brain/awx184
[Indexed for MEDLINE]

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