Periventricular heterotopia

Epilepsy & Behavior 7 (2005) 143–149 www.elsevier.com/locate/yebeh

Review

Periventricular heterotopia Jie Lu, Volney Sheen * Division of Neurogenetics and Howard Hughes Medical Institute, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA Received 4 May 2005; accepted 4 May 2005 Available online 29 June 2005

Abstract Periventricular heterotopia (PH) is clinically diagnosed on the basis of the radiographic characteristics of heterotopic nodules composed of disorganized neurons along the lateral ventricles of the brain. Epilepsy is the main presenting symptom of patients with PH. Behaviorally, patients generally are of normal intelligence, although there have been associated findings of learning disabilities, namely, dyslexia. Two genes responsible for PH have been identified: FilaminA, which encodes for the protein filamin A, and ARFGEF2, which encodes for the vesical transport-regulating protein ARFGEF2. The much more common X-linked dominant form of this disorder is due to filamin A, affects females, and is typically lethal in males. A much rarer autosomal recessive form due to ARFGEF2 mutations leads to microcephaly and developmental delay in addition to PH. Cell motility, adhesion defects, and weakening along the neuroepithelial lining may result from defects in these genes during cortical development and contribute to PH, but the mechanisms are not clear yet. Treatment of PH is largely symptomatic, following basic principles for epilepsy management and genetic counseling. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Epilepsy; Periventricular heterotopia; Neuronal migration disorder; Cortical development; ARFGEF2; Filamin A

1. Introduction: Normal cortical development and periventricular heterotopia Normal development of the cerebral cortex progresses along a highly defined spatial and temporal sequence of events. Neural progenitors undergo an expansive proliferation, generating the large numbers of neurons that ultimately comprise the cerebral cortex. These postmitotic neurons must migrate from the ventricular zone into the cortical plate and arrest at their appropriate position in the different layers that define the cortex. Lastly, the neurons undergo differentiation into specific neuronal cell types, extend local and long-distance projections, and establish functional connectivity [1]. Disruption of the normal temporal and spatial stages of cortical development has been thought to contribute *

Corresponding author. E-mail address: [email protected] (V. Sheen).

1525-5050/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2005.05.001

to the characteristic features seen in various cortical malformation syndromes. For example, altered neuronal proliferation within the ventricular zone can give rise to a small brain (microcephaly). Impaired departure of neurons from the ventricular zone may subsequently contribute to the formation of neuronal nodules along the lateral ventricles (periventricular heterotopia). Disorders of neuronal migration and motility lead to highly disorganized cortical layers and loss in the normal folds of the brain, resulting in a smooth brain (lissencephaly). Finally, a failure in neuronal arrest, where neurons migrate beyond the external brain barrier, produces a smooth brain as well as small nodules on the surface of the brain (cobblestone lissencephaly) [2]. Periventricular nodular heterotopia (PH, Fig. 1) is characterized by ectopic neuronal nodules, positioned along the lateral ventricles. PH can be caused by genetic mutations (e.g., FilaminA, ARFGEF2) [3,4], or extrinsic factors (e.g., irradiation [5], infection [6], injury [7]). The

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Fig. 1. Anatomical phenotype of PH with FLNA mutation. (A) MRI scan of the head demonstrating characteristic periventricular heterotopia. (B) MRI scan of the head demonstrating thin corpus callosum and hypoplastic cerebellum.

restriction of these nodules to the ventricular zone would suggest that the causative genes or the external insults involved in this disorder affect primarily only a small subpopulation of neurons along the ventricle. Moreover, the overlying cortex often appears normal, and the nodules are composed of highly differentiated neurons of varying types that have the ability to project and receive extensive processes and elaborate dense synaptic terminals [8]. These observations indicate not only a spatial restriction of this pathological process but likely a temporal one as well, since neuronal migration and differentiation are largely preserved. In this review, we discuss the recent progress on PH with respect to the causative genetic mutations, molecular mechanisms, and current thoughts on clinical and radiographic presentation as well as treatment in patients with PH.

2. Genetics of PH Two genes are already known to cause PH: filaminA (FLNA) and adenosine diphosphate-ribosylation factor guanine exchange factor 2 (ARFGEF2). The clinical diagnosis of these inherited forms of PH is dependent on the mode of inheritance. The X-linked dominant form of PH is caused by mutations in FLNA, whereas the autosomal recessive form of PH and microcephaly is caused by mutations in ARFGEF2. Other syndromes associated with PH have been described, clearly suggesting that this disorder is heterogeneous. 2.1. FilaminA and PH PH due to FLNA is inherited in an X chromosomelinked dominant fashion. Heterozygous females carrying one normal and one mutated copy of this gene develop the PH phenotype. Affected hemizygous males who carry only a mutated copy of this gene typically show early lethality.

The location and type of FLNA mutations, detected in the human disorder, can provide some indication of the severity of the phenotype. Both point mutations and deletions (truncation mutations) in FLNA have been observed in individuals with PH, although most familial forms of PH have demonstrated truncation mutations [9]. The sites of the truncation mutations tend to cluster at the amino terminus, leaving only a small translated portion of the protein. These more severe mutations lead to male lethality likely from vascular compromise rather than a neurological cause, as cases of perinatal death in these males show profound bleeding. Furthermore, no clear correlation exists between the number of heterotopic nodules seen along the ventricles and the severity of the various mutations. The missense mutations are not obviously clustered and exist along the length of the protein. Because mutations can occur along the entire length of the FLNA gene, the predilection of truncation mutations for the amino terminus may merely reflect the incidence of clinical presentations for more severe mutations in females. Mild-to-moderate mutations in both males and females may avoid detection, as the only overt clinical presentation may be seizures. Conversely, in males, moderate-to-severe defects lead to loss in fetal viability, and only partial-loss-of-function mutations are found[9–13]. 2.2. ARFGEF2 and PH PH due to ARFGEF2 is inherited in an autosomal recessive fashion on chromosome 20. Heterozygous parents have no clinical phenotype, whereas homozygous offspring carrying mutations in both alleles develop heterotopic nodules, microcephaly, and severe developmental delay. In the two pedigrees described so far, both missense and truncation mutations of the ARFGEF2 gene were found [4]. The nucleotide change in one family predicted the substitution in a conserved amino acid, whereas the second family had a single-base-pair deletion and predicted premature termination in translation of the protein. Both mutations could change the structure of the protein, impairing GEF function and leading to the severe abnormal phenotypes. 2.3. Additional genetic syndromes and PH Although greater than 80% of affected pedigrees have a detectable FLNA mutation, only 20% of the individual sporadic cases have FLNA mutation, indicating that PH is a heterogeneous disorder. PH has been associated with duplications of the distal region of chromosome 5p [14], where affected subjects present with complex partial seizures. The radiographic findings demonstrate a noncontiguous periventricular heterotopia as well as subcortical heterotopia or focal gliosis. PH with agenesis

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of corpus callusum and ocular colobomas is associated with a balanced translocation involving chromosomes 2p24 and 9q32 and disruption of two zinc finger-encoding proteins, ASXL2 and KIAA1803 [15]. PH and polymicrogyria have been reported following a balanced reciprocal translocation t(1;6)(p12;p12.2), interrupting the mannosidase a, class 1A, and glutathione S-transferase A2 genes [16]. Finally, three familial cases of PH with hydrocephalus have been described [17]. All three families have hydrocephalus, bilateral nodular PH, and seizures. One family has a known FLNA mutation. The second family showed linkage to the Xq28 region including the FLNA locus, though no mutation was detected. Both genetic and molecular studies, however, on the third pedigree clearly excluded FLNA as a causal gene, further reiterating the etiological heterogeneity of PH.

3. Mechanisms underlying PH Although the genetic associations in PH between FLNA and ARFGEF2 mutations are clearly established, the functions of these proteins in cortical development and other organ systems are little explored and not well understood. In fact, other human diseases besides PH have been associated with FLNA mutations. Disorders in bone development such as frontometaphyseal dysplasia, Melnick–Needles syndrome, and oto-palato-digital syndrome have been attributed to mutations in this gene and none of the affected individuals with these syndromes have periventricular nodular heterotopia. These observed phenotypes have been attributed to gain-offunction mutations [18]. Similarly, the ARFGEF2 gene has only recently been identified and implicated in vesicle and membrane trafficking from the Golgi apparatus, with no clearly established role in the central nervous system. 3.1. FilaminA and PH Located on the X chromosome, FLNA encodes a large (280 kDa) cytoplasmic actin-binding phosphoprotein that links membrane receptors to the actin cytoskeleton. The protein consists of an actin-binding domain at the amino terminus, 23 repeats that resemble Ig-like domains and form a rodlike structure interrupted by two hinge regions, and a C-terminal repeat that undergoes homodimerization (and heterodimerization with FLNB) and serves as a binding site for membrane-associated proteins. More than 30 interactors have been shown to bind the FLNA receptor binding region at the C terminus, suggesting that this protein may serve to modulate and transduce various signals onto the cytoskeleton, which is required for maintaining the shape and locomotion of many cell types [19]. FLNA protein is develop-

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mentally regulated in brain, with highest expression in fetal periods and lower levels at postnatal ages. The protein also localizes to various cell types in the central nervous system including the neuroependyma along the ventricular zone, the endothelial cells lining the blood vessels, and in early postmitotic neurons of cortical plates, suggesting a crucial function for this protein in cortical development [3]. Previous studies have implicated filamin in cell motility, suggesting that PH may result primarily from a cell autonomous impairment in migration (motility). FLNA-deficient melanocytes fail to undergo locomotion in response to factors that elicit migration in the same FLNA- expressing cells. They exhibit prolonged circumferential blebbing, abnormal phagocytosis, and impaired volume regulation [20]. A direct mechanism can be drawn with the association of FLNA and integrins, which have been implicated in cell adhesion and neuronal migration [21–24]. As increased FLNA binding to bintegrin restricts integrin-dependent cell migration [24], loss of this adhesion could potentially disrupt neuronal motility by disrupting attachment and migration on radial glial fibers [23]. Overexpression of a FLNA- interacting protein (FILIP) in ventricular zone progenitors has also been shown to cause FLNA degradation and prevent migration from the ventricular zone [25]. Finally, FLNA interacts with two extracellular matrix adhesion-associated proteins, Mig2 and migfilin. Together, they appear to modulate actin assembly and cell shape, such that disruption in cell shape could impair neuronal migration [26]. Non-cell-autonomous processes could contribute to the formation of PH. Hemizygous males harboring the FLNA mutation die from a severe vasculopathy, whereas heterozygous females often develop dilation of the aorta and patent ductus arteriosus. An autopsy case of a patient with bilateral PH due to a FLNA mutation showed widespread glomeruloid microvascular anomalies and dysplastic cytoarchitecture in the cerebral cortex [12]. Cerebrovascular accidents have also been noted with greater frequency in the FLNA mutation population [3] such that small vessel strokes from the glomeruloid vasculopathy could compromise the brain tissue and lead to heterotopia. 3.2. ARFGEF2 and PH Located on chromosome 20, ARFGEF2 encodes for the protein brefeldin-inhibited GEF2 (BIG2), a 1785amino-acid protein with a conserved SEC7 domain that serves in the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) for the G-protein-dependent ADP ribosylation proteins (ARPs). The ARPs are implicated in intracellular membrane and vesicular trafficking through the trans-Golgi network and appear to be regulated by the BIG proteins [27,28]. Expression

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of BIG-2 mRNA gradually increases from E11 to E17 during the period of cortical neurogenesis in mice, with high levels of expression found in the cortical and diencephalic ventricular zones. BIG-2 immunoreactivity is very prominent along the neuroependymal lining of the ventricular zone and is restricted intracellularly to the Golgi apparatus in mouse neuroepithelial cells. These observations support a developmental role for ARFGEF2 in cortical development. BIG2 likely regulates the vesicle trafficking of some key proteins, possibly adhesion molecules, which are required for the departure of neuronal precursors from the ventricular zone [4]. Dominant-negative inhibition of BIG2 induces redistribution of vesicle coat proteins AP-1 and GGA1 and membrane tubulation of the trans-Golgi network [29]. Inhibition of BIG-2 also impairs transport of the adhesion molecules b-catenin and E-cadherin from the Golgi to the cell surface and causes retraction of axonal and dendritic growth cones in vitro [30,31]. Impairments in neurite extension and adhesion could potentially lead to PH in an analogous fashion by causing retraction of the leading process of migratory neurons. The actual motility of the neurons, however, may be preserved, as the majority of neurons appear to reach their appropriate positions in the cortex. 3.3. Potential shared mechanisms More recent observations suggest that PH may not entirely represent a problem in cell motility. Males with PH due to a FLNA mutation have a grossly normal-appearing cerebral cortex, suggesting that neurons expressing the mutated form of the FLNA protein are largely able to migrate into the cortical plate [13]. Furthermore, the heterotopic nodules contain GABAergic neurons, suggesting interneurons are able to migrate relatively long distances from the ganglionic eminence along the ventricular zone into the cortex [12]. Thus, X inactivation alone, where neurons with the activated X allele containing the normal FLNA gene migrate into the cortex and neurons with activated X allele containing the mutated FLNA gene fail to migrate and give rise to PH, cannot explain the human phenotype. The virtually identical characteristic of bilateral nodular heterotopia in PH suggests that the causative genes may share a final common mechanistic pathway. Both FLNA and ARFGEF2 are most highly expressed along the ependymal lining of the ventricular zone. Furthermore, the neuroepithelial lining is disrupted in the human brain with PH (personal observations). Finally, both genes have been implicated in cell adhesion [26,30,31]. Thus defects in adhesion along the neuroependyma may weaken the ventricular lining and allow proliferative cells to break through this structural barrier and give rise to heterotopia. Alternatively, disruption in the neuroepithelium may alter radial glial endfeet and

impair the initial attachment of migratory neurons prior to their migration into the cortex.

4. Clinical aspects of PH X-linked PH due to FLNA mutations is observed mainly in females, who present with seizures or psychiatric disorders, but otherwise have generally normal to borderline normal intelligence. In contrast, the autosomal recessive PH due to ARFGEF2 mutations is associated with epilepsy, microcephaly, and severe developmental delay [2]. 4.1. Epilepsy and PH Most cases of PH, from either genetic mutations or other causes, present with epilepsy. The type of seizures is variable, and the severity may range from mild (with rare frequency and remission without need for antiepileptic drugs) to intractable. Age of onset may be within the first years of life, but more typically individuals present during adolescence. Furthermore, no correlation exists between the extent and severity of the nodular heterotopia due to FLNA mutations as seen radiographically and the clinical manifestations. Finally, epileptogenic discharges have been recorded by depth electrodes, suggesting that seizure activity may originate from within the heterotopic nodules [32]. The heterotopic nodules also extend connections to other nodules or the overlying cerebral cortex [32–35], providing a potential extranodular network for epileptogenesis. While mechanisms underlying epileptogenesis in PH are not yet known because of limited studies on patient samples and animal models, some analogous observations can be gained from studies on focal cortical dysplasia, including subcortical heterotopia. Neurons within these nodular neuronal heterotopia are mainly calbindin immunoreactive, suggesting a failure of GABAergic interneurons to migrate into the cortex [34]. Messenger RNA expression of GABA receptor subunits is also reduced [36], while the expression of several glutamate receptor subunits is enhanced [37,38]. Thus, epilepsy can be viewed as a final common electrophysiological pathway for a variety of these malformations in the cortex where an imbalance between excitatory and inhibitory tone leads to seizure onset [39]. 4.2. Dyslexia and PH While most patients with PH are reported to have normal intelligence, a recent association of the cortical malformation with dyslexia has been suggested [40]. Intelligence and reading ability were higher or better in those subjects whose heterotopic nodules were restricted in anatomic distribution as compared with

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those subjects whose heterotopia were diffusely present along the lateral ventricles. The reading disability has been associated with acquired white matter dysfunction [41,42] and cortical gray matter anomalies [43,44], presumably leading to a disruption of intracortical circuitry. Similar impairments in neural processing likely result from the periventricular nodules, although the direct mechanisms need further exploration. 4.3. Cardiovascular and hematologic complications in PH Mutations in FLNA have been associated with both heart and blood disorders [3]. Within a compilation of 11 females with confirmed FLNA mutations, the incidence of cardiac anomalies, including patent ductus arteriosus (3/11) and bicuspid aortic valve (1/11), appeared to exceed the incidence of these malformations in the general population. Furthermore, three of these affected individuals suffered strokes at early ages. Of two known males with PH who survived into adulthood, one died from a ruptured aortic aneurysm. Five additional males with PH and harboring mutations in the gene have been reported, and they died suddenly and unexpectedly in the first weeks of life (5 days to 5 months). Although the true causes of death were unknown, the presentation was felt to be consistent with sudden cardiovascular or hematologic collapse. Finally, a single affected male born carrying a complete loss of function FLNA mutation showed overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development. These observations suggest a primary vasculopathy with weakened vessel walls and/or a coagulopathy secondary to platelet dysfunction. 4.4. Ehlers–Danlos syndrome and PH Recent studies have linked the connective tissue disorder Ehlers–Danlos syndrome (EDS) with X-linked dominant PH due to FLNA mutations [10,45,46]. Genetic analyses have shown that some cases of PH share features consistent with EDS, including joint hypermobility, increased skin extensibility, and the development of aortic dilation in early adulthood. Most cases, however, have no identifiable FLNA mutation, suggesting that unique noncoding alleles of FLNA or other genes are involved. While the exact relationship between the disruption in connective tissue in EDS and the impaired neuronal migration in PH is not apparent, disruption in cell adhesion may represent a common mechanism. EDS is generally caused by defects in collagen that alter the crosslinkage and adhesion of collagen fibrils in the extracellular matrix. In X-linked PH, FLNA mediates cell matrix adhesions through migfilin and b-integrins [24,26]. Hence impaired cell adhesion may both contribute to the strength/elasticity loss in connective tissue leading to EDS, and prevent

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postmitotic neurons from migrating from the ventricular zone to the cortex leading to PH.

5. Radiographic aspects of PH Although the characteristic radiographic finding of periventricular nodular heterotopia is indistinguishable for the various PH syndromes, brain imaging by MRI or CT can provide other distinguishing features that separate mutations in ARFGEF2 from those in FLNA. MRI studies of individuals with known FLNA mutations typically show bilateral near-contiguous periventricular nodular heterotopia with associated features of thinning of the corpus callosum and malformations of the posterior fossa (mild cerebellar hypoplasia, enlarged cisterna magna) [3]. In contrast, ARFGEF2 mutations result in PH with microcephaly, slightly enlarged ventricles, and delayed myelination suggested by white matter changes [4]. That said, while imaging alone is diagnostic of a PH syndrome, it is not confirmatory for FLNA or ARFGEF2 mutations, which require genotyping or exonic sequencing for absolute identification of cause.

6. Treatment approaches to PH No formal guidelines exist for the treatment of PH. However, once diagnosis is established by radiographic imaging of the brain, further intervention is based on symptomatic presentation and prophylactic management. The treatment of epilepsy generally follows the basic principles for a seizure disorder caused by a known structural brain abnormality. This approach includes acquiring a detailed initial history and evaluation to confirm the suspicion of a seizure disorder. Testing may include an electroencephalogram (EEG) to define the location and severity of the interictal activity. Most seizures are partially or entirely controlled on antiepileptic medication [47]. Carbamazepine is often used empirically for treatment, given the focality of the seizure disorder. However, because no significant differences exist between medications for newly diagnosed, presumably localized epilepsy, choices may be made on the basis of the specific attributes of each antiepileptic drug (i.e., risk of teratogenicity of the antiepileptic drug during pregnancy, tolerability, and efficacy). Few patients have undergone surgical resection of the heterotopia and the outcomes have been variable to poor [33,35,48]. Recognition of the various conditions associated with PH may assist in additional management. Neuropsychiatric issues may require the enlistment of a therapist, while neurocognitive testing may be beneficial to exclude any significant learning disabilities. Screening of the aorta and neck and intracranial vessels by magnetic reso-

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nance angiography may be prudent given the increased risks of stroke risk and aortic rupture during early adulthood. Screening of the heart by echocardiogram may prove beneficial given the association with cardiac defects. Finally, genetic counseling should be offered for preconception planning.

7. Conclusion PH is a heterogeneous disorder characterized by nodules of neurons ectopically positioned along the lateral ventricle. The X-linked dominant form of PH is caused by mutations in the actin-binding protein filamin A and the autosomal recessive form of PH is due to mutations in the guanine-exchange factor ARFGEF2. Disruption in neuronal adhesion and motility, as well as weakening along the neuroepithelial lining, may cause this malformation during cortical development. Seizures are the most common presenting feature.

Acknowledgment V.L.S. is supported by a grant from the NIMH (1KO8MH/NS63886) and the Milton fund. V.L.S. is a Charles A. Dana fellow and Beckman Young Investor.

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