Brain Advance Access published online on May 9, 2006
Brain, doi:10.1093/brain/awl125
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1 Research Institute I.R.C.C.S. Stella Maris Foundation, University of Pisa, Italy
* To whom correspondence should be addressed. 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).
Received January 18, 2006
Revised April 1, 2006
Accepted April 10, 2006
Article
Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations
E. Parrini 1 *,
A. Ramazzotti 1 *,
W. B. Dobyns 2,
D. Mei 1,
F. Moro 1,
P. Veggiotti 3,
C. Marini 1,
E. H. Brilstra 4,
B. Dalla Bernardina 5,
L. Goodwin 6,
A. Bodell 7,
M. C. Jones 8,
M. Nangeroni 9,
S. Palmeri 10,
E. Said 11,
J. W. Sander 12,
P. Striano 13,
Y. Takahashi 14,
L. Van Maldergem 15,
G. Leonardi 16,
M. Wright 17,
C. A. Walsh 18,
and
R. Guerrini 19 *
2 Department of Human Genetics, Neurology and Pediatrics, University of Chicago, IL, USA
3 Child Neuropsychiatry Department, Neurological Institute Casimiro Mondino Foundation I.R.C.C.S., University of Pavia, Italy
4 Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
5 Department of Pediatrics and Child Neuropsychiatry, Verona University Medical School, Torino, Italy
6 Department of Genetics, Nepean Hospital, Penrith, Australia
7 Walsh Laboratory, Harvard Medical School, Boston, MD, USA
8 Children Hospital and Health Centre, San Diego, CA, USA
9 E. Agnelli Hospital, Pinerolo, Torino, Italy
10 Department of Neurological and Behavioural Sciences, University of Siena, Milano, Italy
11 St Luke's Hospital, Gwardamangia, Malta, Japan
12 Department of Clinical and Experimental Epilepsy, Institute of Neurology, London, UK
13 Department of Neurological Sciences, University of Napoli Federico II, Milano, Italy
14 National Epilepsy Centre, Shizuoka Medical Institute of Neurological Disorders, Shizuoka, Japan
15 Human Genetics Centre, Institute of Pathology and Genetics-Loverval, Belgium
16 Unit of Child Neurology and Psychiatry Fatebenefratelli Hospital, Milano, Italy
17 Institute of Human Genetics International Centre for Life, Newcastle-upon-Tyne, UK
18 Division of Neurogenetics and Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MD, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MD, USA
19 Research Institute I.R.C.C.S. Stella Maris Foundation, University of Pisa, Italy; Department of Child Neurology and Psychiatry, University of Pisa, Italy
R. Guerrini, E-mail: renzo.guerrini{at}inpe.unipi.it
Abstract
*These authors contributed equally to this work.
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