Abstract Bilateral periventricular nodular heterotopia (BPNH) is a neuronal migration disorder that is character- ized by subependymal nodules of gray matter. Recently, a causative gene for BPNH, filamin 1, has been identified, and possible roles of the translated protein in cell migra- tion and blood vessel development have been proposed. We report here the histopathological features of an au- topsy case of BPNH with widespread glomeruloid mi- crovascular anomaly and dysplastic cytoarchitecture in the cerebral cortex, in whom we found a novel exon 11 (Val528Met) filamin 1 mutation. Within the periventricu- lar nodules, well-differentiated pyramidal neurons were randomly oriented. A small proportion of neurons were immunolabeled with antibodies raised against calbindin D-28k, parvalbumin, or calretinin. We used a carbocya- nine dye (DiI) tracing technique to investigate the extent of fiber projections within and outside the nodules. The labeled fibers formed bundles that extended into the sur- rounding white matter. Connections between adjacent nodules were evident. Connections between the nodules and the cerebral cortex were also seen, with a small num- ber of labeled fibers reaching the cortex. In the cerebral cortex, small closely packed vessels ran in a parallel fash- ion throughout all of the layers. Immunohistochemically, the inner rim of individual vessel lumina was labeled by an antibody against factor VIII, and the vessel walls were labeled by antibodies against actin and laminin. Astrocyte processes, labeled with an antibody to glial fibrillary acidic protein, invaded these vascular channels. Ultrastructurally, a network of basal lamina-like materials lined with endothe- lial cells was evident. The cytoarchitecture of the cerebral cortex was disturbed, in that the columnar neuronal ar- rangement was distorted around the malformed vessels. This case appears to represent an example of BPNH manifesting widespread developmental anomalies within the blood ves- sels and the cortical cytoarchitecture in the cerebrum. Keywords Filamin 1 · Migration disorder · Epilepsy · Vascular anomaly · Subependymal heterotopia Introduction Bilateral periventricular nodular heterotopia (BPNH) is a neuronal migration disorder that is characterized by subependymal gray matter nodules. The X-linked domi- nant inheritance pattern for BPNH is one of the most char- acterized syndromes, where the majority of patients with BPNH are female [2, 11, 12, 27, 28, 36, 37] and most males with the underlying gene mutations die during early embryogenesis [11]. A large proportion of patients suffer from seizures that begin in the second or third decade of Akiyoshi Kakita · Shintaro Hayashi · Francesca Moro · Renzo Guerrini · Tsunenori Ozawa · Koji Ono · Shigeki Kameyama · Christopher A. Walsh · Hitoshi Takahashi Bilateral periventricular nodular heterotopia due to filamin 1 gene mutation: widespread glomeruloid microvascular anomaly and dysplastic cytoarchitecture in the cerebral cortex Acta Neuropathol (2002) 104 : 649–657 DOI 10.1007/s00401-002-0594-9 Received: 6 August 2001 / Revised: 12 June 2002 / Accepted: 12 June 2002 / Published online: 23 July 2002 REGULAR PAPER A. Kakita · S. Hayashi · H. Takahashi Department of Pathology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan A. Kakita (✉) Department of Pathological Neuroscience, Resource Branch for Brain Disease Research, Center for Bioresource-based Research, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan e-mail: kakita@bri.niigata-u.ac.jp, Tel.: +81-25-2270673, Fax: +81-25-2270817 F. Moro Neurogenetics Laboratory, DUNPI-IRCCS Fondazione Stella Maris, Via dei Giacinti 2, Pisa, Italy R. Guerrini Neurosciences Unit, Institute of Child Health and Great Ormond Street Hospital for Children, University of College London, The Wolfson Centre, Mecklenburgh Square, London, UK T. Ozawa · K. Ono Department of Neurosurgery, Niigata Chuo Hospital, 1-18 Shinko-chou, Niigata, Japan S. Kameyama Department of Neurosurgery, National Epilepsy Center, Nishi-Niigata Central Hospital, 1 Masago, Niigata, Japan C.A. Walsh Division of Neurogenetics, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Institute of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts, USA © Springer-Verlag 2002