Brain Advance Access originally published online on May 9, 2006
Brain 2006 129(7):1892-1906; doi:10.1093/brain/awl125
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Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations
1 Research Institute I.R.C.C.S. Stella Maris Foundation, University of Pisa Italy 2 Department of Child Neurology and Psychiatry, University of Pisa Italy 3 Child Neuropsychiatry Department, Neurological Institute Casimiro Mondino Foundation I.R.C.C.S., University of Pavia Italy 4 Department of Pediatrics and Child Neuropsychiatry, Verona University Medical School Italy 5 E. Agnelli Hospital Pinerolo, Torino, Italy 6 Department of Neurological and Behavioural Sciences, University of Siena Italy 7 Department of Neurological Sciences, University of Napoli Federico II Italy 8 Unit of Child Neurology and Psychiatry Fatebenefratelli Hospital Milano, Italy 9 Walsh Laboratory, Harvard Medical School Boston, MD, USA 10 Division of Neurogenetics and Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MD, USA 11 Program in Biological and Biomedical Sciences, Harvard Medical School Boston, MD, USA 12 Department of Human Genetics, Neurology and Pediatrics, University of Chicago IL, USA 13 Children Hospital and Health Centre, San Diego CA, USA 14 Department of Clinical and Experimental Epilepsy, Institute of Neurology London, UK 15 Institute of Human Genetics International Centre for Life, Newcastle-upon-Tyne UK 16 Department of Medical Genetics, University Medical Center Utrecht, The Netherlands 17 Department of Genetics, Nepean Hospital Penrith, Australia 18 St Luke's Hospital Gwardamangia, Malta, Japan 19 National Epilepsy Centre, Shizuoka Medical Institute of Neurological Disorders Shizuoka, Japan 20 Human Genetics Centre, Institute of Pathology and Genetics-Loverval Belgium
Correspondence to: Prof. Renzo Guerrini, Division of Child Neurology and Psychiatry I.R.C.C.S. Stella Maris Foundation, University of Pisa-via dei Giacinti, 2-56018 Calambrone, Pisa, Italy E-mail: renzo.guerrini{at}inpe.unipi.it
Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers–Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).
Key Words: periventricular heterotopia; filamin A; FLNA; mutation; genetic counselling
Abbreviations: CH, calponin homology; DHPLC, denaturing high performance liquid chromatography; EDS, Ehlers–Danlos syndrome; NMD, nonsense-mediated mRNA decay; OPD, otopalatodigital; PH, periventricular heterotopia; PMG, polymicrogyria; PNH, periventricular nodular heterotopia; RT–PCR, reverse transcription–polymerase chain reaction
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Received January 18, 2006. Revised April 1, 2006. Accepted April 10, 2006.
*These authors contributed equally to this work.
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