Skip Navigation
Genetics Home Reference: your guide to understanding genetic conditions
http://ghr.nlm.nih.gov/     A service of the U.S. National Library of Medicine®

Periventricular heterotopia

Reviewed November 2007

What is periventricular heterotopia?

Periventricular heterotopia is a condition in which nerve cells (neurons) do not migrate properly during the early development of the fetal brain, from about the 6th week to the 24th week of pregnancy. Heterotopia means "out of place." In normal brain development, neurons form in the periventricular region, located around fluid-filled cavities (ventricles) near the center of the brain. The neurons then migrate outward to form the exterior of the brain (cerebral cortex) in six onion-like layers. In periventricular heterotopia, some neurons fail to migrate to their proper position and form clumps around the ventricles.

Periventricular heterotopia usually becomes evident when seizures first appear, often during the teenage years. The nodules around the ventricles are then typically discovered when magnetic resonance imaging (MRI) studies are done. Affected individuals usually have normal intelligence, although some have mild intellectual disability. Difficulty with reading and spelling (dyslexia) has been reported in some people with periventricular heterotopia.

Less commonly, individuals with periventricular heterotopia may have more severe brain malformations, small head size (microcephaly), developmental delays, recurrent infections, blood vessel abnormalities, or other problems. Periventricular heterotopia may also occur in association with other conditions such as Ehlers-Danlos syndrome, which results in extremely flexible joints, skin that stretches easily, and fragile blood vessels.

How common is periventricular heterotopia?

Periventricular heterotopia is a rare condition. Its incidence is unknown.

What are the genetic changes related to periventricular heterotopia?

Periventricular heterotopia is related to chromosome 5.

Mutations in the ARFGEF2 and FLNA genes cause periventricular heterotopia.

In most cases, periventricular heterotopia is caused by mutations in the FLNA gene. This gene provides instructions for producing the protein filamin A, which helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. Certain mutations in the FLNA gene result in an impaired FLNA protein that cannot perform this function, disrupting the normal migration patterns of neurons during brain development.

Periventricular heterotopia can also be caused by mutations in the ARFGEF2 gene. This gene provides instructions for making a protein that is involved in the movement (trafficking) of small sac-like structures (vesicles) within the cell. Vesicle trafficking is important in controlling the migration of neurons during the development of the brain. Mutations in the ARFGEF2 gene may disrupt this function, which could result in the abnormal neuronal migration seen in periventricular heterotopia.

Researchers believe that mutations in the FLNA or ARFGEF2 genes may also result in weakening of the attachments (adhesion) between cells that form the lining of the ventricles. A weakened ventricular lining could allow some neurons to form clumps around the ventricles while others migrate normally to the exterior of the brain, as seen in periventricular heterotopia.

In a few cases, periventricular heterotopia has been associated with abnormalities in chromosome 5. In each case, the affected individual had extra genetic material caused by an abnormal duplication of part of this chromosome. It is not known how this duplicated genetic material results in the signs and symptoms of periventricular heterotopia.

Related Chromosome(s)

Changes involving this chromosome are associated with periventricular heterotopia.

  • chromosome 5

Related Gene(s)

Changes in these genes are associated with periventricular heterotopia.

  • ARFGEF2
  • FLNA

Can periventricular heterotopia be inherited?

Periventricular heterotopia can have different inheritance patterns. When this condition is caused by mutations in the FLNA gene, it is inherited in an X-linked dominant pattern.

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In X-linked periventricular heterotopia, males experience much more severe symptoms of the disorder than females, and in most cases die before birth.

In about 50 percent of cases of X-linked periventricular heterotopia, an affected person inherits the mutation from a mother who is also affected. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

Periventricular heterotopia caused by mutations in the ARFGEF2 gene is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Individuals with periventricular heterotopia in whom ARFGEF2 gene mutations have been identified have a severe form of the disorder, including microcephaly, severe developmental delay, and seizures beginning in infancy. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of periventricular heterotopia?

These resources address the diagnosis or management of periventricular heterotopia and may include treatment providers.

  • Gene Review: X-Linked Periventricular Heterotopia (http://www.ncbi.nlm.nih.gov/books/NBK1213)
  • Genetic Testing Registry: Heterotopia, periventricular, associated with chromosome 5p anomalies (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1842562)
  • Genetic Testing Registry: Heterotopia, periventricular, autosomal recessive (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1842563)
  • Genetic Testing Registry: Heterotopia, periventricular, Ehlers-Danlos variant (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1845235)
  • Genetic Testing Registry: X-linked periventricular heterotopia (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1848213)

You might also find information on the diagnosis or management of periventricular heterotopia in Educational resources (http://www.ghr.nlm.nih.gov/condition/periventricular-heterotopia/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/periventricular-heterotopia/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about periventricular heterotopia?

You may find the following resources about periventricular heterotopia helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for periventricular heterotopia?

  • familial nodular heterotopia
  • periventricular nodular heterotopia

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about periventricular heterotopia?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding periventricular heterotopia?

autosomal ; autosomal recessive ; cell ; cerebral cortex ; chromosome ; cytoskeleton ; developmental delay ; disability ; duplication ; familial ; gene ; imaging ; incidence ; inheritance ; inherited ; magnetic resonance imaging ; microcephaly ; mutation ; neuronal migration ; protein ; recessive ; sex chromosomes ; syndrome ; teenage ; vesicle ; X-linked dominant

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res. 2006 Aug;173(2):322-33. Epub 2006 May 25. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16724181?dopt=Abstract)
  • OMIM: HETEROTOPIA, PERIVENTRICULAR, ASSOCIATED WITH CHROMOSOME 5p ANOMALIES (http://omim.org/entry/608098)
  • OMIM: HETEROTOPIA, PERIVENTRICULAR, EHLERS-DANLOS VARIANT (http://omim.org/entry/300537)
  • OMIM: HETEROTOPIA, PERIVENTRICULAR, X-LINKED DOMINANT (http://omim.org/entry/300049)
  • Lian G, Sheen V. Cerebral developmental disorders. Curr Opin Pediatr. 2006 Dec;18(6):614-20. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17099359?dopt=Abstract)
  • LoTurco JJ, Bai J. The multipolar stage and disruptions in neuronal migration. Trends Neurosci. 2006 Jul;29(7):407-13. Epub 2006 May 19. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16713637?dopt=Abstract)
  • Lu J, Tiao G, Folkerth R, Hecht J, Walsh C, Sheen V. Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles: insights into the cause of periventricular heterotopia. J Comp Neurol. 2006 Jan 20;494(3):476-84. (http://www.ncbi.nlm.nih.gov/pubmed/16320251?dopt=Abstract)
  • Moro F, Carrozzo R, Veggiotti P, Tortorella G, Toniolo D, Volzone A, Guerrini R. Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene. Neurology. 2002 Mar 26;58(6):916-21. (http://www.ncbi.nlm.nih.gov/pubmed/11914408?dopt=Abstract)
  • Parrini E, Ramazzotti A, Dobyns WB, Mei D, Moro F, Veggiotti P, Marini C, Brilstra EH, Dalla Bernardina B, Goodwin L, Bodell A, Jones MC, Nangeroni M, Palmeri S, Said E, Sander JW, Striano P, Takahashi Y, Van Maldergem L, Leonardi G, Wright M, Walsh CA, Guerrini R. Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Brain. 2006 Jul;129(Pt 7):1892-906. Epub 2006 May 9. (http://www.ncbi.nlm.nih.gov/pubmed/16684786?dopt=Abstract)
  • OMIM: PERIVENTRICULAR HETEROTOPIA WITH MICROCEPHALY, AUTOSOMAL RECESSIVE (http://omim.org/entry/608097)
  • Sheen VL, Basel-Vanagaite L, Goodman JR, Scheffer IE, Bodell A, Ganesh VS, Ravenscroft R, Hill RS, Cherry TJ, Shugart YY, Barkovich J, Straussberg R, Walsh CA. Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus. Brain Dev. 2004 Aug;26(5):326-34. (http://www.ncbi.nlm.nih.gov/pubmed/15165674?dopt=Abstract)
  • Sheen VL, Dixon PH, Fox JW, Hong SE, Kinton L, Sisodiya SM, Duncan JS, Dubeau F, Scheffer IE, Schachter SC, Wilner A, Henchy R, Crino P, Kamuro K, DiMario F, Berg M, Kuzniecky R, Cole AJ, Bromfield E, Biber M, Schomer D, Wheless J, Silver K, Mochida GH, Berkovic SF, Andermann F, Andermann E, Dobyns WB, Wood NW, Walsh CA. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet. 2001 Aug 15;10(17):1775-83. (http://www.ncbi.nlm.nih.gov/pubmed/11532987?dopt=Abstract)
  • Sheen VL, Jansen A, Chen MH, Parrini E, Morgan T, Ravenscroft R, Ganesh V, Underwood T, Wiley J, Leventer R, Vaid RR, Ruiz DE, Hutchins GM, Menasha J, Willner J, Geng Y, Gripp KW, Nicholson L, Berry-Kravis E, Bodell A, Apse K, Hill RS, Dubeau F, Andermann F, Barkovich J, Andermann E, Shugart YY, Thomas P, Viri M, Veggiotti P, Robertson S, Guerrini R, Walsh CA. Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. Neurology. 2005 Jan 25;64(2):254-62. (http://www.ncbi.nlm.nih.gov/pubmed/15668422?dopt=Abstract)
  • Sheen VL, Walsh CA. Periventricular heterotopia: new insights into Ehlers-Danlos syndrome. Clin Med Res. 2005 Nov;3(4):229-33. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16303888?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: November 2007
Published: October 20, 2014