Cognitive development in females with PCDH19 gene-related epilepsy Simona Cappelletti a,1 , Nicola Specchio b, ⁎ ,1 , Romina Moavero c , Alessandra Terracciano d , Marina Trivisano b , Giuseppe Pontrelli e , Simonetta Gentile a , Federico Vigevano b , Raffaella Cusmai b a Unit of Clinical Psychology, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy b Division of Neurology, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy c Systems Medicine Department, Child Neurology Unit, Tor Vergata University of Rome, Italy d Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy e “Amaducci” Neurology Unit, Department of Neuroscience, University of Bari, Bari, Italy abstract article info Article history: Received 8 January 2014 Revised 27 September 2014 Accepted 14 October 2014 Available online 11 December 2014 Keywords: PCDH19 gene Epilepsy Cognitive and behavioral profile Mutations in the PCDH19 gene are now recognized to cause epilepsy in females and are claiming increasing interest in the scientific world. Clinical features and seizure semiology have been described as heterogeneous. Intellectual disability might be present, ranging from mild to severe; behavioral and psychiatric problems are a common feature of the disorder, including aggressiveness, depressed mood, and psychotic traits. The purpose of our study was to describe the cognitive development in 11 girls with a de novo mutation in PCDH19 and early-onset epilepsy. Six patients had average mental development or mild intellectual disability regardless of persistence of seizures in clusters. Five patients presented moderate or severe intellectual disability and autistic features. In younger patients, we found that despite an average developmental quotient, they all presented a delay of expressive language acquisition and lower scores at follow-up testing completed at older ages, underlining that subtle dys- functions might be present. Larger cohort and long-term follow-up might be useful in defining cognitive features and in improving the care of patients with PCDH19. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Protocadherins form a subfamily of calcium-dependent cell–cell adhe- sion molecules in the cadherin superfamily. Protocadherin 19 (PCDH19), which is located at Xq22.1, belongs to the delta-2 protocadherin subclass of the cadherin superfamily [1]. Mutations in the PCDH19 gene are now recognized to cause epilepsy in females and are claiming increasing interest in the scientific world. Protocadherin 19 mutation is an X-linked disorder with an unusual ex- pression pattern since the phenotype is restricted to females; carrier males are apparently unaffected. Clinical features and seizure semiology have been described as het- erogeneous. Seizures have been reported to be in clusters, often precip- itated by fever; they can be focal or generalized, usually polymorphic, so patients may present with tonic–clonic, tonic, absence, myoclonic, and atonic seizures. In the last few years, electroclinical features have been clarified. A recent paper analyzed the main features of epilepsy at its onset, finding a high prevalence of affective symptoms, such as fearful screaming, during the ictal phase [2]. Intellectual disability might be present, ranging from mild to severe; behavioral and psychiatric prob- lems are a common feature of the disorder, including aggressiveness, depressed mood, and psychotic traits [2,3]. Clinical course is usually characterized by persistence of seizures, with clusters decreasing over time, as well as interictal epileptiform abnormalities. A recent review [4] summarized the cognitive and behavioral findings of a total of 110 patients reported up to 2011 (109 females, 1 male). Intellectual disability and behavioral problems occurred in 75.4% and 55.4% of cases, respectively; 44.2% of the patients had been diagnosed with autism spectrum disorders. Cognitive evaluations of girls with PCDH19 mutations are poorly reported. The aim of our study was to describe the cognitive profile in 11 girls with PCDH19-related epilepsy. In the previous reports regarding neuropsychological and psychiatric features in patients with PCDH19, data have been expressed mainly fol- lowing a clinical observation, and standardized assessments are lacking during the follow-up. In our series, all patients have been followed up with standardized cognitive evaluation and have been screened for be- havioral problems; these assessments were conducted for clinical and research purposes. Moreover, in the youngest patients, a neurocognitive Epilepsy & Behavior 42 (2015) 36–40 ⁎ Corresponding author at: Division of Neurology, Bambino Gesù Children's Hospital, IRCCS, P.zza S. Onofrio 4, 00165 Rome, Italy. Tel.: +39 0668592645; fax: +39 0668592463. E-mail address: nicola.specchio@opbg.net (N. Specchio). 1 Both authors equally contributed to this manuscript. http://dx.doi.org/10.1016/j.yebeh.2014.10.019 1525-5050/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh