47 patients with FLNA associated periventricular nodular heterotopia

Orphanet Journal of Rare Diseases - Tập 10 - Trang 1-11 - 2015
Max Lange1, Burkhard Kasper2, Axel Bohring3, Frank Rutsch4, Gerhard Kluger5, Sabine Hoffjan6, Stephanie Spranger7, Anne Behnecke8, Andreas Ferbert9, Andreas Hahn10, Barbara Oehl-Jaschkowitz11, Luitgard Graul-Neumann12, Katharina Diepold13, Isolde Schreyer14, Matthias K. Bernhard15, Franziska Mueller16, Ulrike Siebers-Renelt3, Ana Beleza-Meireles17, Goekhan Uyanik18, Sandra Janssens19, Eugen Boltshauser20, Juergen Winkler21, Gerhard Schuierer22, Ute Hehr23
1Department of Neurosurgery, University of Regensburg Medical Center, Regensburg, Germany
2Department of Neurology, Epilepsy Center, University of Erlangen, Medical Center, Erlangen, Germany
3Institute of Human Genetics, University of Muenster, Muenster, Germany
4Department of General Pediatrics, Muenster University Children’s Hospital, Muenster, Germany
5Neuropädiatrie, Schön Klinik Vogtareuth, Vogtareuth, Germany und Paracelsus Medical University, Salzburg/Austria, Salzburg, Austria
6Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany
7Praxis fuer Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany
8Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
9Klinik für Neurologie, Klinikum Kassel and Medical School, Kassel, Germany
10Department of Neuropediatrics, University of Giessen, Giessen, Germany
11Praxis fuer Humangenetik, Homburg, Germany
12Ambulantes Gesundheitszentrum der Charité (Humangenetik), Universitätsmedizin Berlin, Berlin, Germany
13Department of Neuropediatrics, Klinikum Kassel, Kassel, Germany
14Institut für Humangenetik, Uni Jena, Jena, Germany
15Department of Pediatrics, University of Leipzig Medical Center, Leipzig, Germany
16Center for Human Genetics, Regensburg, Germany
17Genetics Clinic, Guy’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom
18Zentrum für Medizinische Genetik, Hanusch-Krankenhaus der Wiener Gebietskrankenkasse, Wien, Austria
19Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium
20Division of Neuropediatrics, University Children’s Hospital Zürich, Zürich, Switzerland
21Division of Molecular Neurology, University Hospital, Friedrich-Alexander-University Erlangen-Nuernberg, Erlangen, Germany
22Department of Neuroradiology, University of Regensburg, Medical Center, Regensburg, Germany
23Department of Human Genetics, University of Regensburg, Medical Center, Regensburg, Germany

Tóm tắt

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. 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. 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. 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.

Tài liệu tham khảo

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Orphanet Journal of Rare Diseases

Tập 10

1-11

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