title: Clinical and genetic analysis of a family with two rare reflex epilepsies.
abstract: OBJECTIVE
  To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies.
  
  
  METHODS
  Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status.
  
  
  RESULTS
  The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR. Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings.
  
  
  CONCLUSIONS
  This family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted.
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands; Sapienza University, Pediatrics, Child Neurology, Rome, Italy. Electronic address: d.kasteleijn@umcutrecht.nl.
authors.forename: Dorothée G A
authors.initials: DG
authors.lastname: Kasteleijn-Nolst Trenité
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Volkers
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Strengman
authors.affiliation: St Antonius Hospital Neurology, Nieuwegein, Utrecht, The Netherlands.
authors.forename: Herman M
authors.initials: HM
authors.lastname: Schippers
authors.affiliation: Bronovo Ziekenhuis, Neurology, The Hague, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: Perquin
authors.affiliation: SEIN, Neurology, Heemstede, The Netherlands.
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: de Haan
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Anastasia O
authors.initials: AO
authors.lastname: Gkountidi
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: van't Slot
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Stan F
authors.initials: SF
authors.lastname: van de Graaf
authors.forename: Stan F
authors.initials: SF
authors.lastname: de Graaf
authors.affiliation: University Hospital, Pediatrics, Child Neurology, Nis, Serbia.
authors.forename: Bosanka
authors.initials: B
authors.lastname: Jocic-Jakubi
authors.affiliation: C Poma Hospital, Child Neuropsychiatry, Epilepsy Center, Mantova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Capovilla
authors.affiliation: The Children Hospital Agia Sophia, Neurology, Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Covanis
authors.affiliation: Sapienza University, Pediatrics, Child Neurology, Rome, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Parisi
authors.affiliation: Fondazione Istituto Neurologico Casimiro Mondino, Child Neuropsychiatry, Pavia, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Veggiotti
authors.affiliation: Sapienza University of Rome, Pediatrics and Child Neuropsychiatry, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Brinciotti
authors.affiliation: University of Catania, Pediatrics, Catania, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Incorpora
authors.affiliation: San Filippo Neri, Neurology, Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Piccioli
authors.affiliation: IRCCS, Neuroscience and Neurorehabilitation, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cantonetti
authors.affiliation: Epilepsy Research Institute, Medicine (Neurology), Melbourne, Australia.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Berkovic
authors.affiliation: Epilepsy Research Institute, Medicine (Neurology), Melbourne, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Anja C M
authors.initials: AC
authors.lastname: Sonsma
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Adri J
authors.initials: AJ
authors.lastname: Bader
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: University Utrecht, Biomedical Genetics and Complex Genetics, Utrecht, The Netherlands.
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D020195:Epilepsy, Reflex / Q000235:genetics* / Q000503:physiopathology*; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D010375:Pedigree; D010641:Phenotype; D010775:Photic Stimulation; D000072260:RNA Splicing Factors; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D000072260:RNA Splicing Factors; C486783:SCNM1 protein, human
keywords: Epilepsy; Functional study; Orofacial myoclonus; PPR; Photosensitivity; SCNM1 mutation