title: Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus.
abstract: Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior reports have shown that mutations in the filamin A (FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes. Here we report three familial cases of PH with hydrocephalus. One pedigree has a known FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. Another pedigree demonstrated possible linkage to the Xq28 locus including FLNA, although uncharacteristically a male was affected and sequencing of the FLNA gene in this individual revealed no mutation. However, in the third family with an autosomal mode of inheritance, microsatellite analysis ruled out linkage with the FLNA gene. Routine karyotyping and fluorescent in situ hybridization using BAC probes localized to FLNA also showed no evidence of genomic rearrangement. Western blot analysis of one of the affected individuals demonstrated normal expression of the FLNA protein. Lastly, sequencing of greater than 95% of the FLNA gene in an affected member failed to demonstrate a mutation. In conclusion, these findings demonstrate the etiological heterogeneity of PH with hydrocephalus. Furthermore, there likely exists an autosomal PH gene, distinct from the previously described X-linked and autosomal recessive forms. Affected individuals have severe developmental delay and may have radiographic findings of hydrocephalus.
authors.affiliation: Division of Neurogenetics and Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, HIM 816, 4 Blackfan Circle, Boston, MA 02115, USA.
authors.forename: Volney L
authors.initials: VL
authors.lastname: Sheen
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Jean R
authors.initials: JR
authors.lastname: Goodman
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.forename: Adria
authors.initials: A
authors.lastname: Bodell
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Ganesh
authors.forename: Robert
authors.initials: R
authors.lastname: Ravenscroft
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hill
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cherry
authors.forename: Yin Y
authors.initials: YY
authors.lastname: Shugart
authors.forename: James
authors.initials: J
authors.lastname: Barkovich
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects; D015153:Blotting, Western; D001921:Brain / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002828:Choristoma / Q000235:genetics* / Q000473:pathology; D003285:Contractile Proteins / Q000235:genetics; D017029:Epilepsy, Complex Partial / Q000235:genetics; D005260:Female; D064448:Filamins; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics* / Q000473:pathology; D017404:In Situ Hybridization, Fluorescence; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D010375:Pedigree; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000009:adverse effects; D017287:Ventriculoperitoneal Shunt
chemical_list: D000927:Anticonvulsants; D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D014635:Valproic Acid