Periventricular heterotopia: Phenotypic heterogeneity and correlation with Filamin A mutations

Research Institute, I.R.C.C.S, Stella Maris Foundation, University of Pisa, Italy.
Brain (Impact Factor: 9.2). 08/2006; 129(Pt 7):1892-906. DOI: 10.1093/brain/awl125
Source: PubMed


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).

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    • "DNA sequencing revealed both sisters to be heterozygous for a c.2002C > T transition in exon 13 of the FLNA gene resulting in a p.Gln668Ter mutation. This nonsense mutation has previously been reported as a FLNA disease-causing mutation in a patient with PNH [5]. Analysis of lymphocyte extracted DNA from the mother and father did not reveal the FLNA exon 13 mutation. "
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    ABSTRACT: Background X-linked periventricular nodular heterotopia is a disorder of neuronal migration resulting from mutations in the filamin A gene. This is an X-linked dominant condition where most affected patients are female and present with seizures. Extra–cerebral features such as cardiac abnormalities and thrombocytopenia have also been documented. Loss of function mutations in filamin A are predicted to result in prenatal lethality in males. Somatic mosaicism and mutations that lead to partial loss of function of the protein are hypothesized to explain viability of males reported in the literature. We report the first case of germline mosaicism involving a loss of function mutation in filamin A in a family where brain MRI, clinical exam, and mutation analysis is normal in both biological parents. Case presentation The index patient, a 39 year old female with normal development, had her first seizure at 24 years with no evidence of any precipitating factors. Brain MRI shows bilateral periventricular nodular heterotopia. She has thrombocytopenia and an echocardiogram at age 32 years revealed a mildly dilated aortic root and ascending aorta with mild aortic regurgitation. The second patient, the 36 year old younger sister of the index case, is currently healthy with no evidence of seizures or cardiac abnormalities. Her brain MRI is consistent with bilateral periventricular nodular heterotopia. The mother is healthy at 57 years of age with a normal brain MRI. The father is healthy at 59 years of age with a normal brain MRI. DNA sequencing of lymphocyte extracted DNA from the two sisters shows a c.2002C > T transition in exon 13 of filamin A resulting in a p.Gln668Ter mutation. This nonsense mutation was not detected in peripheral blood lymphocytes from the unaffected parents. Conclusion This report provides evidence for germline mosaicism in filamin A-associated periventricular nodular heterotopia. This case must now be considered when providing genetic counseling to families where a proband presents as an isolated case and parental investigations are unremarkable.
    BMC Neurology 06/2014; 14(1):125. DOI:10.1186/1471-2377-14-125 · 2.04 Impact Factor
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    • "PH represents a heterogeneous group of migrational disorders, characterized by nodules that are composed of neurons positioned ectopically along the lateral ventricular walls; they also behave as epileptogenic foci [22]. Prior studies have demonstrated an X-linked form of PH caused by mutations in the filamin A gene [23,24]. Mutations in other proteins, like ARFGEF2, CHS1, FAT4, coding for proteins involved in neuronal migration also lead to PH [23-25]. "
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    ABSTRACT: I was honored to be awarded the Casey Holter Essay Prize in 2013 by the Society for Research into Hydrocephalus and Spina Bifida. The purpose of the prize is to encourage original thinking in a way to improve the care of individuals with spina bifida and hydrocephalus. Having kept this purpose in mind, I have chosen the title: Neural stem cells, are they the hope of a better life for patients with fetal-onset hydrocephalus? The aim is to review and discuss some of the most recent and relevant findings regarding mechanisms leading to both hydrocephalus and abnormal neuro/gliogenesis. By looking at these outcome studies, it is hoped that we will recognize the potential use of neural stem cells in the treatment of hydrocephalus, and so prevent the disease or diminish/repair the associated brain damage.
    Fluids and Barriers of the CNS 03/2014; 11(1):7. DOI:10.1186/2045-8118-11-7
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    • "X-linked PNH is mainly confined to females, indicating that FLNA null mutations in males are predominantly associated with prenatal death. In addition, PNH patients can co-present abnormal cerebral migration with other brain, skeletal, or visceral abnormalities [30-35], while higher chance of FLNA mutation has been implicated as the causes for these cases. Furthermore, clustered missense mutations in FLNA have been identified in a diverse spectrum of congenital malformations in humans [19,36], including otopalatodigital syndrome (OPD), frontometaphyseal dysplasia (FMD) and Melnick–Needles syndrome (MNS). "
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    ABSTRACT: Filamin-A (FLNA), also called actin-binding protein 280 (ABP-280), was originally identified as a non-muscle actin binding protein, which organizes filamentous actin into orthogonal networks and stress fibers. Filamin-A also anchors various transmembrane proteins to the actin cytoskeleton and provides a scaffold for a wide range of cytoplasmic and nuclear signaling proteins. Intriguingly, several studies have revealed that filamin-A associates with multiple non-cytoskeletal proteins of diverse function and is involved in several unrelated pathways. Mutations and aberrant expression of filamin-A have been reported in human genetic diseases and several types of cancer. In this review, we discuss the implications of filamin-A in cancer progression, including metastasis and DNA damage response.
    Cell and Bioscience 02/2013; 3(1):7. DOI:10.1186/2045-3701-3-7 · 3.63 Impact Factor
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