Elsevier

Epilepsy & Behavior

Volume 7, Issue 2, September 2005, Pages 143-149
Epilepsy & Behavior

Review
Periventricular heterotopia

https://doi.org/10.1016/j.yebeh.2005.05.001Get rights and content

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.

Section snippets

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

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

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

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].

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

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

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

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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