47 patients with FLNA associated periventricular nodular heterotopia

Orphanet Journal of Rare Diseases

Ute Hehr⁷  Gerhard Schuierer⁶  Juergen Winkler^1,17  Eugen Boltshauser^2,22  Sandra Janssens⁸  Goekhan Uyanik⁵  Ana Beleza-Meireles^1,12  Ulrike Siebers-Renelt^2,23  Franziska Mueller²  Matthias K. Bernhard^1,19  Isolde Schreyer^1,16  Katharina Diepold¹  Luitgard Graul-Neumann⁹  Barbara Oehl-Jaschkowitz^2,20  Andreas Hahn^2,21  Andreas Ferbert⁴  Anne Behnecke^1,18  Stephanie Spranger^1,14  Sabine Hoffjan^1,11  Gerhard Kluger³  Frank Rutsch^1,10  Axel Bohring^2,23  Burkhard Kasper^1,13  Max Lange^1,15 

[1] Department of Neuropediatrics, Klinikum Kassel, Kassel, Germany;Center for Human Genetics, Regensburg, Germany;Neuropädiatrie, Schön Klinik Vogtareuth, Vogtareuth, Germany und Paracelsus Medical University, Salzburg/Austria, Salzburg, Austria;Klinik für Neurologie, Klinikum Kassel and Medical School, Kassel, Germany;Zentrum für Medizinische Genetik, Hanusch-Krankenhaus der Wiener Gebietskrankenkasse, Wien, Austria;Department of Neuroradiology, University of Regensburg, Medical Center, Regensburg, Germany;Department of Human Genetics, University of Regensburg, Medical Center, Regensburg, Germany;Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium;Ambulantes Gesundheitszentrum der Charité (Humangenetik), Universitätsmedizin Berlin, Berlin, Germany;Department of General Pediatrics, Muenster University Children’s Hospital, Muenster, Germany;Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany;Genetics Clinic, Guy’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom;Department of Neurology, Epilepsy Center, University of Erlangen, Medical Center, Erlangen, Germany;Praxis fuer Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany;Department of Neurosurgery, University of Regensburg, Medical Center, Franz-Josef-Strauss-Allee 11, Regensburg, 93053, Germany;Institut für Humangenetik, Uni Jena, Jena, Germany;Division of Molecular Neurology, University Hospital, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany;Institute of Human Genetics, Heidelberg University, Heidelberg, Germany;Department of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany;Praxis fuer Humangenetik, Homburg, Saar, Germany;Department of Neuropediatrics, University of Giessen, Giessen, Germany;Division of Neuropediatrics, University Children’s Hospital Zürich, Zürich, Switzerland;Institute of Human Genetics, University of Muenster, Muenster, Germany

关键词: Phenotype;    Seizures;    Score;    Imaging;    Filamin A;    Periventricular nodular heterotopia;   

Others  :  1228798
DOI  :  10.1186/s13023-015-0331-9

 received in 2015-06-24, accepted in 2015-08-27,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Lange et al.

【 图 表 】

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