Letter to the Editor Photosensitive epilepsy and long QT: expanding Timothy syndrome phenotype Timothy syndrome (TS) is an autosomal dominant disorder caused by mutations of CACNA1C gene, encoding the CaV 1.2 L-type channel gene (Gillis et al., 2012). Clinical phenotype includes pro- longed-QT, hands and feet syndactyly, facial dysmorphisms, con- genital heart defects, intellectual disability, seizures and autism spectrum disorder (Napolitano et al., 2006). We report a child affected by TS and epilepsy, diagnosed with a novel CACNA1C gene mutation. The child was born at term after uneventful pregnancy to healthy non-consanguineous parents. He presented with bilateral, complete cutaneous syndactyly of the last three hand fingers and congenital talipes equinovarus. During development, the child showed mild hypotonia and joint laxity, clumsiness, intention tremor, dyspraxia, autistic spec- trum disorder, and dysmorphic features (brittle, curly hair, a round face with relatively large eyes and small nose and mouth, a thin upper lip, down slanting palpebral fissures, and anteverted nares). At the age of 2 years, he started to suffer absences with eyelid myoclonia. Electroencephalogram (EEG) (age 3) showed multifocal and sometimes diffuse spike-polyspike and waves, electro-clinical pattern of absence with eyelid myoclonia, and photoparoxysmal response (PPR). Valproic acid failed to control seizures, which dis- appeared at the age of 4 years after initiation of ethosuximide and clonazepam therapy. At the age of 7 years, he began to present episodes character- ized by sudden loss of consciousness, apnea, cyanosis and hypoto- nia, lasting 1–5 min, followed by hypotonia and somnolence. Each episode had a trigger (loud, frightening noises, or other frightening stimuli). Valproic acid was resumed suspecting epilepsy relapse. Diagnostic workup included: TORCH serology, abdominal and cardiac ultrasounds, brain magnetic resonance imaging (MRI: age 4 and 10 years), electrocardiogram (EKG: age 6 years), molecular tests (array-CGH; PTPN11, SHOC2, GJA1, CUL4B, CACNA1C exons 8 and 8A sequencing), with normal results in all tests. At the age of 12 years, while awake, after a sudden noise, the child had a cardiac arrest due to ventricular fibrillation, requiring three rounds of electric defibrillation. The child was intubated, transferred to our pediatric ICU and underwent hypothermia (for 36 h). Upon arrival, long QT syndrome (LQTS, 760 ms) was diag- nosed (L.L.) based on EKG findings (Fig. 1A. Re-evaluation of previ- ous EKGs by a pediatric cardiologist (L.L.) confirmed the presence of LQTS (550 ms) already in early childhood. The child received beta-blockers and mexiletine and finally underwent implantation of a cardioverter defibrillator. In the months following cardiac arrest, the child progressively improved up to complete recovery. EEG showed normal back- ground activity and persistence of PPR. At the last follow-up (age 15 years), the patient, under valproic acid, presented rare photo-induced seizures; the EEG showed nor- mal background activity and a photomyogenic response (Fig. 1B). The cardiac pacemaker was well functioning, no arrhythmic events had been registered since its implantation. Sequencing of the entire coding region of the CACNA1C gene revealed a de novo heterozygous missense mutation in exon 9 of the gene c.1220A > G p.(Glu407Gly) (nomenclature is identical for both CACNA1C reference sequences NM_000719.6 and NM_001167625.1) (Fig. S1A–B, Supplementary Material). The mutation is not reported in variant databases (ExAC, dbSNP, 1000 genomes) and affects a highly conserved amino acid (Fig. S1C, Supplementary Material). No mutations were detected in other genes associated with LQTS (ANK2, CALM1, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1). The unusual association between epilepsy and TS in our patient suggests a possible phenotype-genotype correlation. Generally, seizures are uncommon in TS patients and usually symptomatic of cerebral damage (Gillis et al., 2012; Napolitano et al., 2006). Conversely, our patient experienced seizures without a history of acute cardiac events and with a normal cerebral MRI. At onset, our patient’s electroclinical pattern was consistent with generalized epilepsy of childhood (eyelid myoclonia with absences). Differently from the classical presentation of this epi- lepsy (Poleon and Szaflarski, 2017), he had an early onset and a poor response to valproic acid. Moreover, he presented photosen- sitivity since the first EEG. Some years after epilepsy onset, he pre- sented also photoinduced seizures, inconstantly associated with PPR in EEGs. PPR appears typically between 5 and 15 years in various epilep- sies (Poleon and Szaflarski, 2017). Its appearance before 5 years of age could occur in Dravet syndrome, epileptic encephalopathies, neurodegenerative disorders, and benign idiopathic epilepsies (Binelli et al., 2015). Among children with early PPR appearance, about 30% suffer from a static disorder with a known or suspected genetic origin (Binelli et al, 2015), and genes encoding ion channels could be implicated (Poleon and Szaflarski, 2017). In our patient a direct link between CACNA1C mutation and epi- lepsy is likely; mutations in voltage-gated calcium channels (VGCCs) genes have been linked to different types of epilepsy (Rajakulendran and Hanna, 2016). Our patient’s p.Glu407Gly mutation is de novo, its minor allele frequency is less than 1:100,000, and it affects a highly conserved residue, adjacent to the two recurrent mutations causing either classical or atypical TS. All CACNA1C mutations manifesting as TS phenotype affect resi- dues that are clustered near the end of several transmembrane alpha helixes that surround the lumen of the channel on the intra- cellular side of the protein (Fig. S1D–E, Supplementary Material). Both the classical p.Gly406Arg exon 8 and the p.Glu407Gly are pre- dicted to increase by +1 unit the net charge of this protein region, https://doi.org/10.1016/j.clinph.2019.09.003 1388-2457/Ó 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved. Clinical Neurophysiology 130 (2019) 2134–2136 Contents lists available at ScienceDirect Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph