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Volney L. Sheen - One of the best experts on this subject based on the ideXlab platform.
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cytoskeletal proteins in cortical development and disease actin associated proteins in Periventricular Heterotopia
Frontiers in Cellular Neuroscience, 2015Co-Authors: Gewei Lian, Volney L. SheenAbstract:The actin cytoskeleton regulates many important cellular processes in the brain, including cell division and proliferation, migration, and cytokinesis and differentiation. These developmental processes can be regulated through actin dependent vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with cellular membranes and proteins. Disruption in the actin cytoskeleton in the brain gives rise to Periventricular Heterotopia (PH), a malformation of cortical development, characterized by abnormal neurons clustered deep in the brain along the lateral ventricles. This disorder can give rise to seizures, dyslexia and psychiatric disturbances. Anatomically, PH is characterized by a smaller brain (impaired proliferation), Heterotopia (impaired initial migration) and disruption along the neuroependymal lining (impaired cell-cell adhesion). Genes causal for PH have also been implicated in actin-dependent processes. The current review provides mechanistic insight into actin cytoskeletal regulation of cortical development in the context of this malformation of cortical development.
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Periventricular Heterotopia: New Insights into Ehlers-Danlos Syndrome
2015Co-Authors: Volney L. Sheen, Christopher A. WalshAbstract:Nature often employs similar mechanisms to complete similar tasks, thus the evolution of homologous proteins across various organ systems to perform similar but slightly different functions. In this respect, disorders attributed to specific genetic mutations,while initially thought to be restricted in function and purpose, may provide broad insight into general cellular and molecular mechanisms of development and maintenance. One such example can be seen in the brain malformation, Periventricular Heterotopia (PH), which is characterized by very specific nodules of neurons that line the lateral ventricles beneath the cerebral cortex. PH is seen as a disorder of neuronal migration and can be caused by mutations in filamin A (FLNA), which encodes an actin-binding protein that regulates the cytoskeleton and cell motility. Recent advances in our understanding of the genetic causes of PH suggest that mutations in this gene, however, are also associated with the connective tissue disorder, Ehlers-Danlos syndrome (EDS), in which affected individuals present with joint and skin hyperextensibility and vascular problems including aortic dissection, excessive bleeding and bruisability.While much still remains unknown regarding the mechanistic role of FLNA in giving rise to PH and EDS, a common cellular an
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overlapping expression of arfgef2 and filamin a in the neuroependymal lining of the lateral ventricles insights into the cause of Periventricular Heterotopia
The Journal of Comparative Neurology, 2006Co-Authors: Grace Tiao, Christopher A. Walsh, Rebecca D Folkerth, Jonathon L Hecht, Volney L. SheenAbstract:Periventricular Heterotopia (PH) is a malformation of cortical development characterized by nodules of neurons, ectopically located along the lateral ventricles of the brain. Mutations in the vesicle transport ADP-ribosylation factor guanine exchange factor 2 gene (ARFGEF2 )o r the actin-binding Filamin A (FLNA) gene cause PH. Previous studies have shown that FLNA expression is developmentally regulated, with strongest expression observed along the ventricular zone (VZ) and to a lesser degree in postmitotic neurons in the cortex. Here we characterize the expression patterns for ARFGEF2 within the central nervous systems of human and mouse in order to better understand their potential roles in causing PH. ARFGEF2 mRNA was widely expressed in all cortical layers, especially in the neural precursors of the ventricular and subventricular zones (SVZ) during development, with persistent but diminished expression in adulthood. ARFGEF2 encodes for the protein brefeldin-inhibited guanine exchange factor 2 (BIG2). BIG2 protein immunoreactivity was most strongly localized to the neural progenitors along the neuroependymal lining of the VZ during development, with decreased expression in adulthood. Furthermore, overlapping BIG2 and FLNA expression was greatest in these same neuroependymal cells of human embryonic brain and was co-expressed in progenitors by Western blot. Finally, transfection of a dominant-negative construct of ARFGEF2 in SHSY5Y neuroblastoma cells partially blocked FLNA transport from the Golgi apparatus to the cell membrane. These results suggest that mutations in ARFGEF2 may impair targeted transport of FLNA to the cell surface within neural progenitors along the neuroependyma and that disruption of these cells could contribute to PH formation. J. Comp. Neurol. 494:476 – 484, 2006. © 2005 Wiley-Liss, Inc. Indexing terms: ARFGEF2; Filamin A; Periventricular Heterotopia
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mutation in filamin a causes Periventricular Heterotopia developmental regression and west syndrome in males
Epilepsia, 2006Co-Authors: Marcelo Rodrigues Masruha, Volney L. Sheen, Luis Otavio Sales Ferreira Caboclo, Henrique Carrete, Iscia L Cendes, Murilo Gimenes Rodrigues, Eliana Garzon, Elza Marcia Targas Yacubian, Americo Ceiki Sakamoto, Megan HarneyAbstract:Summary: Purpose: Familial Periventricular Heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA ,s evere developmental regression, and West syndrome. Methods: The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing. Results: Tw oo fthe siblings are monozygotic twins, and all had West syndrome with hypsarrthymia on EEG. MRI of the brain revealed Periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene. Conclusions: The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause Periventricular Heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits. Ke yW ords: Subependymal Heterotopia— Periventricular Heterotopia—Familial—West syndrome—Male.
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filamin a mutations cause Periventricular Heterotopia with ehlers danlos syndrome
Neurology, 2005Co-Authors: Volney L. Sheen, Elena Parrini, Vijay S Ganesh, Minghui Chen, Timothy R Morgan, Anna C Jansen, R Ravenscroft, T Underwood, James S Wiley, Richard J LeventerAbstract:Objective: To define the clinical, radiologic, and genetic features of Periventricular Heterotopia (PH) with Ehlers-Danlos syndrome (EDS). Methods: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. Results: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain Heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. Conclusion: These results suggest that the Ehlers-Danlos variant of Periventricular Heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.
Ingrid E Scheffer - One of the best experts on this subject based on the ideXlab platform.
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Ectopic Posterior Pituitary Lobe and Periventricular Heterotopia: Cerebral Malformations with the Same Underlying Mechanism?
2015Co-Authors: Anne L Mitchell, Paul Q. Thomas, Margaret Zacharin, Ingrid E SchefferAbstract:with growth hormone deficiency and is part of the spectrum associated with septo-optic dysplasia. Some cases of septo-optic dysplasia are caused by homozygous mutations in the homeobox gene HESX1, whereas heterozygous mutations are associated with milder pheno-types. To date, HESX1 is the only gene associated with ectopic posterior pituitary lobe. We describe an association between ectopic posterior pituitary lobe and Periventricular Heterotopia in four children without classic features of septo-optic dysplasia and suggest possible mecha-nisms on the basis of a review of pituitary embryology and recent molecular genetic advances. METHODS: Among 20 children with ectopic posterior pituitary lobe, four had associated Periventricular Heterotopia. We herein review the clinical and MR imaging findings of these four children. Mutation screening of HESX1 was performed in two. RESULTS: All four children had growth hormone deficiency. None had visual or neurologic disturbances. MR images showed a range of pituitary appearances, with scattered discrete Periventricular Heterotopia in each case. Other abnormalities were limited to small suprasellar lipomas and callosal dysgenesis. A heterozygous HESX1 mutation was present in one case. CONCLUSION: The coexistence of ectopic posterior pituitary lobe and Periventricular hete
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etiological heterogeneity of familial Periventricular Heterotopia and hydrocephalus
Brain & Development, 2004Co-Authors: Volney L. Sheen, Adria Bodell, Robert Sean Hill, Ingrid E Scheffer, Lina Baselvanagaite, Vijay S Ganesh, Jean R Goodman, Robert Ravenscroft, Timothy J Cherry, Yin Yao ShugartAbstract: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.
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ectopic posterior pituitary lobe and Periventricular Heterotopia cerebral malformations with the same underlying mechanism
American Journal of Neuroradiology, 2002Co-Authors: Anne L Mitchell, Paul Q. Thomas, Margaret Zacharin, Ingrid E SchefferAbstract:BACKGROUND AND PURPOSE: Ectopic posterior pituitary lobe often occurs in children with growth hormone deficiency and is part of the spectrum associated with septo-optic dysplasia. Some cases of septo-optic dysplasia are caused by homozygous mutations in the homeobox gene HESX1, whereas heterozygous mutations are associated with milder phenotypes. To date, HESX1 is the only gene associated with ectopic posterior pituitary lobe. We describe an association between ectopic posterior pituitary lobe and Periventricular Heterotopia in four children without classic features of septo-optic dysplasia and suggest possible mechanisms on the basis of a review of pituitary embryology and recent molecular genetic advances. METHODS: Among 20 children with ectopic posterior pituitary lobe, four had associated Periventricular Heterotopia. We herein review the clinical and MR imaging findings of these four children. Mutation screening of HESX1 was performed in two. RESULTS: All four children had growth hormone deficiency. None had visual or neurologic disturbances. MR images showed a range of pituitary appearances, with scattered discrete Periventricular Heterotopia in each case. Other abnormalities were limited to small suprasellar lipomas and callosal dysgenesis. A heterozygous HESX1 mutation was present in one case. CONCLUSION: The coexistence of ectopic posterior pituitary lobe and Periventricular Heterotopia suggests they have a common underlying genetic basis that is due to gene expression at different locations and stages of development. The presence of a heterozygous HESX1 mutation in one case suggests this gene is important in the development of both ectopic posterior pituitary lobe and Periventricular Heterotopia and supports their place in the spectrum of septo-optic dysplasia. Further analysis of HESX1 and other genes in related developmental pathways will elucidate their roles in the development of both malformations.
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mutations in filamin 1 prevent migration of cerebral cortical neurons in human Periventricular Heterotopia
Neuron, 1998Co-Authors: Ingrid E Scheffer, Yaman Z Eksioglu, Donna Graham, Jeremy W Fox, Susan E Hong, Edward D Lamperti, Yuanyi Feng, William B Dobyns, Betsy A HirschAbstract:Abstract Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder Periventricular Heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 ( FLN1 ), which encodes an actin-cross-linking phosphoprotein that transduces ligand–receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.
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Periventricular Heterotopia an x linked dominant epilepsy locus causing aberrant cerebral cortical development
Neuron, 1996Co-Authors: Yaman Z Eksioglu, Ingrid E Scheffer, P Cardenas, J Knoll, Frances Dimario, G Ramsby, Michel J Berg, K Kamuro, Samuel F Berkovic, Geoffrey M. DuykAbstract:Periventricular Heterotopia (PH) involves dramatic malformations of the human cerebral cortex. Here we show that PH is closely linked to markers in distal Xq28 (maximal two-point lod score = 4.77 for F8C at theta = 0; maximal multipoint lod score = 5.37), so that affected females are obligatory mosaics for the mutation; that PH is lethal to at least some affected males; that PH malformations consist of well-differentiated cortical neurons filling the adult subependymal zone; and that individuals with PH are at high risk for epilepsy, though they have no other neurological or external stigmata. The PH gene may represent an important epilepsy susceptibility locus in addition to playing a key role in normal cortical development.
Yin Yao Shugart - One of the best experts on this subject based on the ideXlab platform.
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etiological heterogeneity of familial Periventricular Heterotopia and hydrocephalus
Brain & Development, 2004Co-Authors: Volney L. Sheen, Adria Bodell, Robert Sean Hill, Ingrid E Scheffer, Lina Baselvanagaite, Vijay S Ganesh, Jean R Goodman, Robert Ravenscroft, Timothy J Cherry, Yin Yao ShugartAbstract: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.
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autosomal recessive form of Periventricular Heterotopia
Neurology, 2003Co-Authors: Volney L. Sheen, Adria Bodell, Robert Sean Hill, Meral Topçu, Samuel F Berkovic, Vijay S Ganesh, Timothy J Cherry, D Yalnizoglu, Ilan Blatt, Yin Yao ShugartAbstract:Background: Familial Periventricular Heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant inheritance pattern. Objective: To classify cortical malformation syndromes associated with PH. Methods: Analyses using microsatellite markers directed toward genomic regions of FLNA and to a highly homologous autosomal gene, FLNB, were performed on two pedigrees to evaluate for linkage with either filamin gene. Results: Two consanguineous pedigrees with PH that suggest an autosomal recessive inheritance pattern are reported. MRI of the brain revealed Periventricular nodules of cerebral gray matter intensity, typical for PH. Seizures or developmental delay appeared to be a common presenting feature. Microsatellite analysis suggested no linkage to FLNA or FLNB. Conclusions: Autosomal recessive PH is another syndromic migrational disorder, distinct from X-linked dominant PH. Further classification of these different syndromes will provide an approach for genetic evaluation.
Richard J Leventer - One of the best experts on this subject based on the ideXlab platform.
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A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration
'Elsevier BV', 2018Co-Authors: Adam C. O’neill, Richard J Leventer, Zandra A Jenkins, Tim Morgan, Christina Kyrousi, Johannes Klaus, Edwin P. Kirk, Andrew Fry, Daniela T. Pilz, Micha DrukkerAbstract:Summary: The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation Periventricular nodular Heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development. : O’Neill et al. show that variants in patients with PH are enriched within genes that define basal radial glia transcriptomic signatures and provide mechanistic evidence that a primate-specific isoform of one gene, mutated in a patient with PH, regulates neurogenesis. Keywords: cortical development, evolution, Periventricular Heterotopia, PLEKHG6, MyoGEF, Rho
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Periventricular Heterotopia in 6q terminal deletion syndrome role of the c6orf70 gene
Brain, 2013Co-Authors: Valerio Conti, Aurelie Carabalona, Emilie Pallesipocachard, Elena Parrini, Richard J Leventer, Emmanuelle Buhler, George McgillivrayAbstract:Periventricular nodular Heterotopia is caused by defective neuronal migration that results in heterotopic neuronal nodules lining the lateral ventricles. Mutations in filamin A (FLNA) or ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) cause Periventricular nodular Heterotopia, but most patients with this malformation do not have a known aetiology. Using comparative genomic hybridization, we identified 12 patients with developmental brain abnormalities, variably combining Periventricular nodular Heterotopia, corpus callosum dysgenesis, colpocephaly, cerebellar hypoplasia and polymicrogyria, harbouring a common 1.2 Mb minimal critical deletion in 6q27. These anatomic features were mainly associated with epilepsy, ataxia and cognitive impairment. Using whole exome sequencing in 14 patients with isolated Periventricular nodular Heterotopia but no copy number variants, we identified one patient with Periventricular nodular Heterotopia, developmental delay and epilepsy and a de novo missense mutation in the chromosome 6 open reading frame 70 (C6orf70) gene, mapping in the minimal critical deleted region. Using immunohistochemistry and western blots, we demonstrated that in human cell lines, C6orf70 shows primarily a cytoplasmic vesicular puncta-like distribution and that the mutation affects its stability and subcellular distribution. We also performed in utero silencing of C6orf70 and of Phf10 and Dll1, the two additional genes mapping in the 6q27 minimal critical deleted region that are expressed in human and rodent brain. Silencing of C6orf70 in the developing rat neocortex produced Periventricular nodular Heterotopia that was rescued by concomitant expression of wild-type human C6orf70 protein. Silencing of the contiguous Phf10 or Dll1 genes only produced slightly delayed migration but not Periventricular nodular Heterotopia. The complex brain phenotype observed in the 6q terminal deletion syndrome likely results from the combined haploinsufficiency of contiguous genes mapping to a small 1.2 Mb region. Our data suggest that, of the genes within this minimal critical region, C6orf70 plays a major role in the control of neuronal migration and its haploinsufficiency or mutation causes Periventricular nodular Heterotopia.
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Vascular and connective tissue anomalies associated with X-linked Periventricular Heterotopia due to mutations in Filamin A
European Journal of Human Genetics, 2013Co-Authors: Eyal Reinstein, Richard J Leventer, George Mcgillivray, Sophia Frentz, Tim Morgan, Sixto García-miñaúr, Mitchel Pariani, Anthony Van Der Steen, Michael Pope, Muriel Holder-espinasseAbstract:Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked Periventricular nodular Heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-Periventricular Heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.
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filamin a mutations cause Periventricular Heterotopia with ehlers danlos syndrome
Neurology, 2005Co-Authors: Volney L. Sheen, Elena Parrini, Vijay S Ganesh, Minghui Chen, Timothy R Morgan, Anna C Jansen, R Ravenscroft, T Underwood, James S Wiley, Richard J LeventerAbstract:Objective: To define the clinical, radiologic, and genetic features of Periventricular Heterotopia (PH) with Ehlers-Danlos syndrome (EDS). Methods: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. Results: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain Heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. Conclusion: These results suggest that the Ehlers-Danlos variant of Periventricular Heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.
Vijay S Ganesh - One of the best experts on this subject based on the ideXlab platform.
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filamin a mutations cause Periventricular Heterotopia with ehlers danlos syndrome
Neurology, 2005Co-Authors: Volney L. Sheen, Elena Parrini, Vijay S Ganesh, Minghui Chen, Timothy R Morgan, Anna C Jansen, R Ravenscroft, T Underwood, James S Wiley, Richard J LeventerAbstract:Objective: To define the clinical, radiologic, and genetic features of Periventricular Heterotopia (PH) with Ehlers-Danlos syndrome (EDS). Methods: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. Results: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain Heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. Conclusion: These results suggest that the Ehlers-Danlos variant of Periventricular Heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.
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etiological heterogeneity of familial Periventricular Heterotopia and hydrocephalus
Brain & Development, 2004Co-Authors: Volney L. Sheen, Adria Bodell, Robert Sean Hill, Ingrid E Scheffer, Lina Baselvanagaite, Vijay S Ganesh, Jean R Goodman, Robert Ravenscroft, Timothy J Cherry, Yin Yao ShugartAbstract: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.
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autosomal recessive form of Periventricular Heterotopia
Neurology, 2003Co-Authors: Volney L. Sheen, Adria Bodell, Robert Sean Hill, Meral Topçu, Samuel F Berkovic, Vijay S Ganesh, Timothy J Cherry, D Yalnizoglu, Ilan Blatt, Yin Yao ShugartAbstract:Background: Familial Periventricular Heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant inheritance pattern. Objective: To classify cortical malformation syndromes associated with PH. Methods: Analyses using microsatellite markers directed toward genomic regions of FLNA and to a highly homologous autosomal gene, FLNB, were performed on two pedigrees to evaluate for linkage with either filamin gene. Results: Two consanguineous pedigrees with PH that suggest an autosomal recessive inheritance pattern are reported. MRI of the brain revealed Periventricular nodules of cerebral gray matter intensity, typical for PH. Seizures or developmental delay appeared to be a common presenting feature. Microsatellite analysis suggested no linkage to FLNA or FLNB. Conclusions: Autosomal recessive PH is another syndromic migrational disorder, distinct from X-linked dominant PH. Further classification of these different syndromes will provide an approach for genetic evaluation.