title: 47 patients with FLNA associated periventricular nodular heterotopia.
abstract: BACKGROUND
  Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established.
  
  
  METHODS
  Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients.
  
  
  RESULTS
  Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age.
  
  
  CONCLUSIONS
  We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.
authors.affiliation: Department of Neurosurgery, University of Regensburg, Medical Center, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany. max.lange@ukr.de.
authors.forename: Max
authors.initials: M
authors.lastname: Lange
authors.affiliation: Department of Neurology, Epilepsy Center, University of Erlangen, Medical Center, Erlangen, Germany. Burkhard.Kasper@uk-erlangen.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kasper
authors.affiliation: Institute of Human Genetics, University of Muenster, Muenster, Germany. abohring@uni-muenster.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Bohring
authors.affiliation: Department of General Pediatrics, Muenster University Children's Hospital, Muenster, Germany. frank.rutsch@ukmuenster.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
authors.affiliation: Neuropädiatrie, Schön Klinik Vogtareuth, Vogtareuth, Germany und Paracelsus Medical University, Salzburg/Austria, Salzburg, Austria. GKluger@Schoen-Kliniken.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kluger
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany. Sabine.Hoffjan@rub.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffjan
authors.affiliation: Praxis fuer Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany. sspranger@aol.com.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Spranger
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany. anne.behnecke@med.uni-heidelberg.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Behnecke
authors.affiliation: Klinik für Neurologie, Klinikum Kassel and Medical School, Kassel, Germany. ferbert@klinikum-kassel.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ferbert
authors.affiliation: Department of Neuropediatrics, University of Giessen, Giessen, Germany. Andreas.Hahn@paediat.med.uni-giessen.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hahn
authors.affiliation: Praxis fuer Humangenetik, Homburg, Saar, Germany. oehl-jaschkowitz@genetik-saar.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Oehl-Jaschkowitz
authors.affiliation: Ambulantes Gesundheitszentrum der Charité (Humangenetik), Universitätsmedizin Berlin, Berlin, Germany. luitgard.graul-neumann@charite.de.
authors.forename: Luitgard
authors.initials: L
authors.lastname: Graul-Neumann
authors.affiliation: Department of Neuropediatrics, Klinikum Kassel, Kassel, Germany. katharina.diepold@klinikum-kassel.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Diepold
authors.affiliation: Institut für Humangenetik, Uni Jena, Jena, Germany. Isolde.schreyer@mti.uni-jena.de.
authors.forename: Isolde
authors.initials: I
authors.lastname: Schreyer
authors.affiliation: Department of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany. matthias.bernhard@medizin.uni-leipzig.de.
authors.forename: Matthias K
authors.initials: MK
authors.lastname: Bernhard
authors.affiliation: Center for Human Genetics, Regensburg, Germany. info@humangenetik-regensburg.de.
authors.forename: Franziska
authors.initials: F
authors.lastname: Mueller
authors.affiliation: Institute of Human Genetics, University of Muenster, Muenster, Germany. Ulrike.Siebers-Renelt@ukmuenster.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Siebers-Renelt
authors.affiliation: Genetics Clinic, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. ana.beleza@gstt.nhs.uk.
authors.forename: Ana
authors.initials: A
authors.lastname: Beleza-Meireles
authors.affiliation: Zentrum für Medizinische Genetik, Hanusch-Krankenhaus der Wiener Gebietskrankenkasse, Wien, Austria. goekhan.uyanik@wgkk.at.
authors.forename: Goekhan
authors.initials: G
authors.lastname: Uyanik
authors.affiliation: Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium. sandra.janssens@ugent.be.
authors.forename: Sandra
authors.initials: S
authors.lastname: Janssens
authors.affiliation: Division of Neuropediatrics, University Children's Hospital Zürich, Zürich, Switzerland. eugen.boltshauser@bluewin.ch.
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.affiliation: Division of Molecular Neurology, University Hospital, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany. Juergen.winkler@uk-erlangen.de.
authors.forename: Juergen
authors.initials: J
authors.lastname: Winkler
authors.affiliation: Department of Neuroradiology, University of Regensburg, Medical Center, Regensburg, Germany. Gerhard.Schuierer@medbo.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schuierer
authors.affiliation: Department of Human Genetics, University of Regensburg, Medical Center, Regensburg, Germany. ute.hehr@ukr.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D064448:Filamins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D054091:Periventricular Nodular Heterotopia / Q000175:diagnosis* / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D064448:Filamins