Objective: To describe a homogeneous subtype of periventricular nodular heterotopia (PNH) as part of a newly defined malformation complex. Methods: Observational study including review of brain MRI and clinical findings of a cohort of 50 patients with PNH in the temporo-occipital horns and trigones, mutation analysis of the FLNA gene, and anatomopathologic study of a fetal brain. Results: There were 28 females and 22 males. All were sporadic with the exception of an affected mother and son. Epilepsy occurred in 62%, cerebellar signs in 56%, cognitive impairment in 56%, and autism in 12%. Seventy percent were referred within the 3rd year of life. Imaging revealed a normal cerebral cortex in 76% and abnormal cortical folding in 24%. In all patients the hippocampi were under-rotated and in 10% they merged with the heterotopia. Cerebellar dysgenesis was observed in 84% and a hypoplastic corpus callosum in 60%. There was no gender bias or uneven gender distribution of clinical and anatomic severity. No mutations of FLNA occurred in 33 individuals examined. Heterotopia in the fetal brain revealed cytoarchitectonic characteristics similar to those associated with FLNA mutations; cortical pathology was not typical of polymicrogyria. Cerebellar involvement was more severe and the hippocampi appeared simple and under-rotated. Conclusions: This series delineates a malformation complex in which PNH in the trigones and occipito-temporal horns is associated with hippocampal, corpus callosum, and cerebellar dysgenesis. This subtype of PNH is distinct from classic PNH caused by FLNA mutations.
Bibliographical noteFunding Information:
T. Pisano reports no disclosures. A.J. Barkovich receives research support from NIH/NINDS and NIH/NIBIB. R. Leventer and W. Squier report no disclosures. I. Scheffer has received honoraria from GlaxoSmithKline, UCB, Biocodex, Athena Diagnostics, Janssen-Cilag, and Eli Lilly. She has pending patents entitled: Therapeutic compound: patent number: 61/010176; countries of patent: patent types: application year: 2008. She has received research support from the National Health and Medical Research Council of Australia: Health Research Council of New Zealand, NIH University of Melbourne, Austin Health Medical Research Foundation, Brockhoff Foundation, Perpetual Charitable Trustees, ANZ Trustees, Child Health Research Foundation, and Shepherd Foundation. E. Parrini and S. Blaser report no disclosures. C. Marini has received research support from Sixth Framework Thematic Priority Life sciences, Genomics and Biotechnology for Health, the Italian Ministry of Health and Education, and the Mariani Foundation. S. Robertson and G. Tortorella report no disclosures. F. Rosenow has received Scientific Advisory Boards from UCB, GSK, Pfizer, Eisai, and received honoraria from UCB. G. McGillivray has received honoraria from Roche and works as geneticist at Victorian Clinical Genetics Service. E. Andermann has received honoraria from UCB and has received research support from Sunovion Pharma, UCB, Santhera Pharma, and NINDS/NIH. F. Andermann reports no disclosures relevant to the manuscript. S. Berkovic was in the Scientific Advisory Boards: UCB SV2A. He has received honoraria from UCB. He is one of the inventors listed on a patent held by Bionomics Inc on diagnostic testing of using the SCN1A gene. He receives research support from UCB, Novartis, Sanofi Aventis, National Health, and Medical Research Council of Australia. W. Dobyns receives research support from NIH. R. Guerrini has received honoraria from Biocodex, UCB, Eisai Inc, ValueBox, and EMA (European Medicine Agency). He receives research support from the Italian Ministry of Health, the European Community Sixth Framework Thematic Priority Life Sciences, Genomics and Biotechnology for Health, the Italian Ministry of Education, University and Research, the Tuscany Region, the Telethon Foundation, and the Mariani Foundation. Go to Neurology.org for full disclosures.