Journal Identification = EPD Article Identification = 0830 Date: June 8, 2016 Time: 10:40 am Original article Epileptic Disord 2016; 18 (2): 123-36 Epilepsy in KCNH1-related syndromes Mario Mastrangelo 1, Ingrid E. Scheffer 2, Nuria C. Bramswig 3, Lal. D.V. Nair 4, Candace T. Myers 5, Maria Lisa Dentici 6, Georg C. Korenke 7, Kelly Schoch 8, Philippe M. Campeau 9, Susan M. White 10,11, Vandana Shashi 8, Sujay Kansagra 12, Anthonie J. Van Essen 13, Vincenzo Leuzzi 1 1 Pediatric Neurology Division Department of Pediatrics, Child Neurology and Psychiatry, Sapienza-University of Rome, Rome, Italy 2 Florey Institute and University of Melbourne, Austin Health and Royal Children’s Hospital, Melbourne, Australia 3 Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Germany 4 Department of Pediatrics, Saveetha Medical College, Chennai, India 5 Department of Pediatrics, University of Washington, Seattle, WA, USA 6 Bambino Gesù Children Hospital, Rome, Italy 7 Klinik für Neuropädiatrie, Klinikum Oldenburg, Germany 8 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, USA 9 Department of Pediatrics, University of Montreal, Montreal, Canada 10 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Victoria, Australia 11 Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia 12 Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, USA 13 Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands Received December 10, 2015; Accepted April 20, 2016 ABSTRACT – Aim. KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Methods. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Results. Epilepsy was present in 7/9 patients. Both generalized and focal tonic-clonic seizures were observed. Complete seizure control was Correspondence: achieved with pharmacological treatment in 2/7 patients; polytherapy Vincenzo Leuzzi Pediatric Neurology Division, was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. Department of Pediatrics, EEG showed a diffusely slow background in 7/7 patients with epilepsy, Child Neurology and Psychiatry, with variable epileptiform abnormalities. Cerebral folate deficiency and Sapienza-University of Rome, Italy an increase in urinary hypoxanthine and uridine were observed in one <[email protected]> doi:10.1684/epd.2016.0830 patient. Epileptic Disord, Vol. 18, No. 2, June 2016 123 Journal Identification = EPD Article Identification = 0830 Date: June 8, 2016 Time: 10:40 am M. Mastrangelo, et al. Conclusions. Epilepsy is a key phenotypic feature in most individuals with KCNH1-related syndromes, suggesting a direct role of KCNH1 in epilepto- genesis, although the underlying mechanism is not understood. Key words: Zimmermann-Laband syndrome, Temple-Baraitser syn- drome, genetic epilepsy, undefined intellectual disability, KCNH1-related encephalopathy KCNH1 (potassium channel, voltage-gated, subfamily Seizure semiology h, member 1; OMIM-603305) encodes a voltage-gated potassium channel (Kv10.1), with prominent expres- Epilepsy was present in 7/9 patients. Seizure onset sion in the brain, where it is involved in the regulation ranged from birth to eight months in 4/7 patients, of neurotransmitter release and synaptic transmission while in Patients 1, 7 and 9, onset was at 10 years, (Mortensen et al., 2015; Haitin et al., 2013). KCNH1 18 months, and 33 months, respectively. Febrile mutations have been recently demonstrated to have a seizures were observed in Patient 3 only. pathogenic role in two rare disorders: Zimmermann- Focal seizures (including clonic and versive seizures) Laband syndrome (ZLS- OMIM 135500) and Temple occurred in six patients, while generalized seizures Baraitser syndrome (TMBTS- OMIM 611816) (Kortüm (including myoclonic, tonic, clonic, and tonic-clonic) et al., 2015; Simons et al., 2015). These syndromes were reported in six patients (table 2). Photosensitive include dysmorphic facial features, nail hypo/aplasia, absence seizures were observed in Patients 3 and 9. thumb and skeletal anomalies, intellectual disability, Four of seven patients had convulsive status epilepti- and seizures (Bramswig et al., 2015; Kortüm et al., cus (table 2). 2015; Simons et al., 2015). Overlapping clinical pre- sentations have been reported in four cases from a Other clinical features cohort of individuals with uncharacterized intellectual disability (Bramswig et al., 2015). Here, we phenotype All patients had the previously reported pheno- the epilepsy features of patients with KCNH1-related typic hallmarks of KCNH1 disorders (Bramswig et syndromes. al., 2015; Kortüm et al., 2015; Simons et al., 2015). Nail hypo/aplasia was observed in all patients, except Patients and methods Patient 3. Neonatal problems, including neonatal asphyxia, res- The clinical history, including medical history and piratory distress, jaundice, neonatal seizures, and developmental course, seizure semiology, clinical feeding difficulties, were observed in 4/9 patients. examination, antiepileptic drugs treatment, EEG moni- Six of nine patients had hypotonia and 3/8 patients toring, and laboratory and neuroradiological data, was had movement disorders including tremor, choreo- collected for nine cases with KCNH1-related disorders. athetosis, oculo-motor apraxia, and ataxia. Of the eight published cases, five had ZLS and three uncharacterized intellectual disability (Rauch et al., 2012; Castori et al., 2013; Campeau et al., 2014; Bramswig EEG findings et al., 2015; Kortüm et al., 2015; Nair et al., 2015; Simons et al., 2015). A new case of a 12-month-old child with EEG studies showed diffuse background slowing in ZLS was also included. 8/9 patients (table 1). Multifocal epileptiform abnor- malities with prominent fronto-temporal foci were The genetic mutations were identified through whole- observed in 6/7 patients, while occipital foci were exome sequencing (Bramswig et al., 2015; Kortüm et found in 3/7 patients (table 2). A generalized spike-wave al., 2015). It was not possible to detect any of the after photic stimulation was detected in two patients patients’ mutations in their parents by Sanger sequenc- (table 2). As an example, EEG features of Patient 4 are ing (Bramswig et al., 2015; Kortüm et al., 2015). Parental shown in figure 1. mosaicism was similarly excluded (Bramswig et al., 2015; Kortüm et al., 2015). Parental written informed consent was obtained for all subjects. Other diagnostic investigations Results MRI showed non-specific abnormalities in 3/9 patients: ventricular asymmetry, cystic enlargement of the sub- Demographic, electroclinical, and genetic features of arachnoid spaces of the temporal lobes and dilatation nine patients (six female; aged 12 months to 28 years) of cavum vergae, increased extra-axial spaces, and cor- are summarized in table 1. pus callosal hypoplasia (table 1). 124 Epileptic Disord, Vol. 18, No. 2, June 2016 Journal Identification = EPD Article Identification = 0830 Date: June 8, 2016 Time: 10:40 am Epileptic Disord, Vol. 18, No. 2, June 2016 Table 1. Demographic, molecular genetics, and electro-clinical data of the reported series. PATIENTS PATIENT 1 PATIENT 2 PATIENT 3 PATIENT 4 PATIENT 5 PATIENT 6 PATIENT 7 PATIENT 8 PATIENT 9 Clinical Zimmermann- Zimmermann- Zimmermann- Zimmermann- Zimmermann- Zimmermann- Undefined Undefined Undefined diagnosis Laband Laband Laband Laband Laband Laband intellec- intellec- intellec- syndrome syndrome syndrome syndrome syndrome syndrome tual tual tual disability disability disability Reference Patient 1 Patient 2 Patient 4 Patient 5 Patient 6 Unpublished Patient 1 Patient 2 Patient 3 Kortüm et Kortüm et Kortüm et Kortüm et Kortüm et Bramswig Bramswig Bramswig al., 2015 al., 2015 al., 2015 al., 2015 al., 2015 et al., 2015 et al., 2015 et al., 2015 Age and 14 Years, F 28 years, M 14 years, F 10 years, M 8 years, F 12 months, M 15 years, F 5 years, F 5 years, F gender Place of Germany Australia Italy Italy India USA Germany Germany The birth Nether- lands KCNH1 c.1399A>G c.974C>A c.1405G>A c.1054C>G c.1399A>G c.1042G>A c.1070G>A; c.1070G>A; c.1070G>A; gene p.Ile467Val p.Ser325Tyr p.Gly469Arg p.Leu352Val p.Ile467Val p.Gly348Arg p.Arg330Gln p.Arg330Gln p.Arg357Gln mutation c.1066G>C p.Val356Leu Inheritance De novo De novo De novo De novo De novo De novo De novo De novo De novo Gestation Normal Normal Normal Normal Normal Normal Normal Normal Normal and gestation gestation gestation gestation gestation gestation gestation gestation gestation delivery Natural Forceps Caesarean Natural Natural Natural Caesarean Caesarean Caesarean delivery delivery section delivery dystocic delivery section section section because delivery of foetal (meconium Epilepsy in sufferance stained liquor, absent crying, KCNH1 requiring meco- -related syndromes nium suction and stimu- lation) 125 Journal Identification = EPD Article