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FLNA-Related Periventricular Nodular Heterotopia

Synonym: X-Linked Periventricular Heterotopia

, MD, MSc and , MD, PhD.

Author Information

Initial Posting: ; Last Update: September 17, 2015.


Clinical characteristics.

FLNA-related periventricular nodular heterotopia (PVNH), a neuronal migration disorder, is characterized by the presence of uncalcified nodules of neurons ectopically situated along the surface of the lateral ventricles. Affected individuals are predominantly heterozygous females; males most often show early lethality. Affected females present with seizures at an average age of 14-15 years; intelligence ranges from normal to borderline. The risk for cardiovascular disease, stroke, and other vascular/coagulation problems appears to be increased.


The diagnosis of FLNA-related PVNH is established by the identification of:

  • Characteristic head MRI findings; and
  • Heterozygous pathogenic variants in FLNA in females or hemizygous pathogenic variants in FLNA in males.


Treatment of manifestations: Treatment of epilepsy generally follows principles for a seizure disorder caused by a known structural brain abnormality. Antiepileptic drugs are typically selected based on specific attributes (e.g., teratogenic risk during pregnancy, tolerability, and efficacy). Because of the risk for aortic or carotid dissection, it may also be wise to ensure good blood pressure control. Standard treatment for aortic or carotid dissection, congenital heart disease, and valvular disease.

Surveillance: Echocardiogram and cardiac MRI may be used to screen for FLNA-associated cardiovascular problems. Special attention should be paid to the presence of congenital heart disease, valvular abnormalities, and also dilatation of the ascending aorta.

Evaluation of relatives at risk: Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

Pregnancy management: The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus. There are currently no guidelines regarding the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy.

Genetic counseling.

FLNA-related PVNH is inherited in an X-linked manner. The condition is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. About 50% of affected females inherit the pathogenic variant from their mother and at least 50% have a de novo pathogenic variant. For women with FLNA-related PVNH, the risk of passing the pathogenic variant to each child is 50%. Because of the high rate of prenatal lethality in males, most sons born to women with FLNA-related PVNH are unaffected. Prenatal diagnosis by molecular genetic testing is possible if the pathogenic variant has been identified in an affected relative. Periventricular nodules may be visualized by imaging as early as 24 weeks' gestation; however, the sensitivity of imaging for the prenatal detection of PVNH is not known.


Suggestive Findings

FLNA-related periventricular nodular heterotopia (PVNH) should be suspected in an individual with the following clinical features, neuroimaging studies, and family history.

Clinical findings. No clinical findings are diagnostic. Affected individuals typically have seizures and normal intellect.

Neuroimaging studies reviewed by an experienced neuroradiologist reveal the following:

  • On MRI, bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) lining the lateral ventricles beneath an otherwise normal-appearing cortex; occasionally, mild abnormalities of cerebral cortical gyri
    Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT imaging.
  • Thinning of the corpus callosum and malformations of the posterior fossa (mild cerebellar hypoplasia, enlarged cisterna magna) in some (see Figure 1)
Figure 1. . Anatomic phenotype of PVNH in an individual with a heterozygous pathogenic variant in FLNA A.

Figure 1.

Anatomic phenotype of PVNH in an individual with a heterozygous pathogenic variant in FLNA A. MRI of the head demonstrating characteristic periventricular nodular heterotopia B. MRI of the head demonstrating thin corpus callosum and hypoplastic cerebellum (more...)

Family history consistent with X-linked inheritance with male lethality is strongly suggestive.

Establishing the Diagnosis

Female proband. The diagnosis of FLNA-related PVNH is established in a female proband by the identification of characteristic head MRI findings and a heterozygous pathogenic variant in FLNA by molecular genetic testing (see Table 1).

Male proband. Affected males typically show male lethality; however the diagnosis of FLNA-related PVNH is established in a male proband by the identification of characteristic head MRI findings and a hemizygous pathogenic variant in FLNA by molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing or use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of FLNA is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multi-gene panel that includes FLNA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost.

Table 1.

Molecular Genetic Testing Used in FLNA-Related Periventricular Nodular Heterotopia

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
FLNASequence analysis 3, 493% 5, 6
Gene-targeted deletion / duplication analysis 73/33 8

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.


93% (8/8 [Parrini et al 2006] and 5/6 [Sheen et al 2001]) for individuals with classic bilateral PVNH and an X-linked inheritance pattern. 93% of individuals with a FLNA pathogenic variant were female and 7% were male.


Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Of 33 individuals with PVNH and a family history of X-linked inheritance who were not found to have an FLNA pathogenic variant by sequence analysis, genomic rearrangements were identified in three [Clapham et al 2012].

Clinical Characteristics

Clinical Description

FLNA-related periventricular nodular heterotopia (PVNH) is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female.

The following clinical features have been associated with FLNA-related PVNH:

  • Seizure disorder
  • Cardiovascular findings including patent ductus arteriosus; dilatation and rupture of the thoracic aorta; atrial and ventricular septal defects; valvular dystrophy; and vasculopathy and/or coagulopathy leading to stroke
  • Congenital strabismus
  • Shortened digits
  • Hyperflexible joints [Sheen et al 2005]
  • Dyslexia

Seizure disorder. Approximately 88% of individuals diagnosed with FLNA-related PVNH present with a seizure disorder [Guerrini & Carrozzo 2001]. Age of onset may be within the first years of life, but more typically individuals present during childhood. The severity of the seizure disorder may range from mild (with rare frequency and remission without need of antiepileptic drugs) to intractable seizures.

No correlation exists between the extent and severity of the nodular heterotopia seen radiographically and the clinical manifestations. The ectopic heterotopias act as foci for abnormal neuronal activity. Anatomic studies have shown aberrant projections extending from the periventricular heterotopias. Depth electrode recordings have demonstrated epileptogenic discharges from these nodules [Kothare et al 1998]. Thus, the seizure disorder appears to arise from the heterotopias in most individuals.

Cardiovascular findings. Over the last decade there have been reports of several serious cardiovascular anomalies in individuals with FLNA-related PVNH. The most important abnormality is thoracic aortic dilatation or aneurysm formation that may lead to sudden aortic rupture or dissection [Feng & Walsh 2004].

In a study examining cardiovascular lesions in a cohort of individuals with PVNH, five of the six individuals with heterozygous (female) or hemizygous (male) pathogenic variants in FLNA had one or more cardiac anomaly. Lesions included patent ductus arteriosus, thoracic aortic aneurysm, atrial septal defect, ventricular septal defect, and dysplasia of the mitral and aortic valves [de Wit et al 2011] (see Molecular Genetic Pathogenesis).

A study of a family in which five males had FLNA-related PVNH found that four of the five boys had one or more cardiovascular diagnoses (PDA in 2, ASD in 1, dysplastic mitral valve in 2), demonstrating that not all males with FLNA-related PVNH die during the perinatal period [Oegema et al 2013].

Some individuals with FLNA-related PVNH display connective tissue and vascular anomalies also seen in classic Ehlers-Danlos syndrome [Sheen et al 2005]. In a recent review of the vascular and connective tissue anomalies associated with pathogenic variants in FLNA, ten of the eleven affected individuals showed one or more congenital cardiac or vascular anomalies. In this particular study, thoracic aortic aneurysm emerged as the most frequent lesion – a significant finding given its potential lethality [Reinstein et al 2013]. Such anomalies include joint hypermobility, aortic dilation and other vascular anomalies, and nodular brain heterotopias. Increasingly, the Ehlers-Danlos variant of PVNH is considered to fall within the spectrum of X-linked PVNH caused by pathogenic variants in FLNA [Reinstein et al 2013].

Pulmonary findings. There are several case reports of individuals with FLNA-related PVNH who have pulmonary disease. Several reported individuals(both male and female) had cardiorespiratory failure before age one year. The severity of the poorly defined respiratory disease, resembling bronchopulmonary dysplasia, has led to lung transplantation in several of these young children [Masurel-Paulet et al 2011, Clapham et al 2012, Lord et al 2014].

Other. Other associated clinical findings in individuals with FLNA-related PVNH included gastric immotility (1/11), strabismus (2/11), and shortened digits (1/11).

Note: Immune compromise with recurrent infection was reported in two of the individuals in the initial report, but immune compromise has not been seen in any other affected individual; therefore, the association with PVNH is unknown.

Intelligence is normal to borderline. Formal cognitive testing of 12 affected individuals with FLNA pathogenic variants demonstrated an average IQ of 95, but also a strikingly high number of affected people with dyslexia [Chang et al 2005, Chang et al 2007].

Women with FLNA-related PVNH may have an increased incidence of pregnancy loss as a result of spontaneous abortion of affected male pregnancies.

Affected males. Two simplex males (affected males with no family history of PVNH) with documented hemizygous FLNA pathogenic variants presented with seizures. One of the males died from sudden rupture of the aorta at age 36 years [Sheen et al 2001].

Five other males ranging in age from five days to five months died suddenly and unexpectedly; while their deaths were consistent with sudden cardiovascular or hematologic collapse, the actual causes of death were unknown [Parrini et al 2004, Parrini et al 2006].

A single affected male with a hemizygous complete loss-of-function variant in FLNA also showed overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development [Huttenlocher et al 1994].

Two affected dizygotic twin males have been reported, one with early death, the other with intellectual disability but not epilepsy [Gérard-Blanluet et al 2006].

Mosaicism. Somatic mosaicism for an A>G substitution at the intron 11 acceptor splice site was reported by Parrini et al [2004] in a male with bilateral PVNH. Sequence analysis and denaturing high-performance liquid chromatography of genomic DNA on a pool of hair roots, single hair roots, and white blood cells revealed that only 42% and 69% of the samples for hair and blood, respectively, had the pathogenic variant. Moreover, the affected male's daughter did not inherit the pathogenic variant, thought to be causal for the male phenotype. Other somatic pathogenic variants were recently reported [Jamuar et al 2014].

Note: Although three affected brothers with West syndrome/hypsarrhythmia were initially reported to have a hemizygous FLNA pathogenic variant [Masruha et al 2006] this reported sequence variant has subsequently been thought to be a rare polymorphism [Robertson 2006].

Genotype-Phenotype Correlations

All individuals known to have a heterozygous (female) or hemizygous (male) FLNA pathogenic variant, including those who are asymptomatic, have heterotopia identifiable by brain MRI or CT [Fox et al 1998, Poussaint et al 2000, Sheen et al 2001, Moro et al 2002].

While more studies correlating genotype and phenotype are needed, pathogenic truncation variants tend to cluster near the N-terminal and presumably lead to severe loss of function and a more severe phenotype (male lethality). Pathogenic missense variants are found throughout the extent of FLNA and some appear to have milder phenotypes, as males with these pathogenic variants can survive to term. Presumably, these milder pathogenic variants lead to a partially functional protein [Sheen et al 2001].

A hemizygous pathogenic FLNA splice variant has been associated with PVNH, facial dysmorphism, and severe constipation [Hehr et al 2006].


Penetrance is unknown. All individuals with known deleterious loss-of-function FLNA variants have shown periventricular nodular heterotopia.


Frequently used terms are periventricular heterotopia (PVH or PH) or periventricular nodular heterotopia (PNH or PVNH).


The prevalence of PVNH is difficult to assess because individuals with the mild phenotype may never seek medical evaluation.

Differential Diagnosis

The frequent occurrence of familial or nonfamilial periventricular nodular heterotopia (PVNH) in males and females with no documented FLNA pathogenic variant suggests that it is a heterogeneous disorder.

Of 120 females with classic bilateral PVNH who were simplex cases (i.e., no family history of PVNH), 31 (26%) had an identifiable heterozygous pathogenic variant in FLNA. Overall, Parrini et al [2006] found that the probability of identifying an FLNA pathogenic variant in an individual with classic bilateral PVNH was 49% and the probability of identifying an FLNA pathogenic variant in an individual with another phenotype (e.g., polymicrogyria, microcephaly) was 4%.

Periventricular nodular heterotopia also occurs in the following syndromes (whether each of these represents a truly distinct disorder or FLNA-related PVNH plus a concurrent condition remains to be determined):

Laminar heterotopia occurring in deep white matter and band-like heterotopia occurring between the cortex and ventricular surface are seen in X-linked subcortical band heterotopia.

PVNH may be misdiagnosed initially as tuberous sclerosis complex; however, MRI findings distinguish the two disorders.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FLNA-related periventricular nodular heterotopia (PVNH) the following evaluations are recommended:

  • Evaluation by a neurologist
  • Evaluation by an epileptologist if seizures are present
  • Magnetic resonance angiography (MRA) of the intracranial vessels, carotid arteries, and aorta to address the increased risk for stroke
  • Echocardiogram or cardiac magnetic resonance imaging (MRA) to evaluate for valvular dysplasia, congenital cardiac anomalies, or aortic and vascular disease. Because of the potential risk for congenital cardiovascular anomalies and/or aortic aneurysm, a baseline evaluation by a cardiologist may be prudent.
  • Evaluation by a hematologist if findings suggest a bleeding diathesis
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management of individuals with FLNA-related PVNH is directed toward symptomatic treatment.

Treatment of epilepsy generally follows basic principles for a seizure disorder caused by a known structural brain abnormality, including:

  • 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 electrical brain dysfunction that may be present in individuals with epilepsy.
    • Repeat imaging may be necessary only in the setting of new neurologic findings on examination.
  • Treatment with antiepileptic agents. Choice of antiepileptics is generally made empirically based on the clinical features of the seizure disorder. However, because no significant differences exist between medications for newly diagnosed, presumably localized epilepsy, choices may be made on the specific attributes of each antiepileptic drug (i.e., risk of teratogenicity of the antiepileptic drug during pregnancy), tolerability, and efficacy.

Because of the risk for aortic or carotid dissection, it may also be wise to ensure good blood pressure control.

Treatment of aortic/carotid dissection, congenital heart disease, and valvular disease is the same as in the general population.

Many individuals with periventricular nodular heterotopia have dyslexia. Therefore, it may be prudent for those with a family history of PVNH to have children tested for dyslexia at an early age.

Prevention of Secondary Complications

The secondary complications are those associated with prolonged seizure medication usage.


Because of the associated increased incidence of aortic or carotid dissection in PVNH, affected individuals should be screened by echocardiogram and cardiac MRI. There is insufficient data at present to provide definitive guidelines. However, given that such complications have occurred in early adulthood, it is reasonable to perform evaluation initially in late adolescence, with follow up as needed. Cardiology evaluation of those who have connective tissue findings and classic PVNH would be prudent.

Evaluation of Relatives at Risk

Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, head MRI can be used to clarify the disease status of at-risk relatives.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Ideally, women should seek information prior to conception regarding risks to the fetus associated with taking an anti-seizure medication during pregnancy so that changes in the anti-seizure medication regimen (if needed) can be made prior to conception. If not done prior to conception, discussion of the risks and benefits of anti-seizure medication use during pregnancy should occur as soon as the pregnancy is recognized. The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus.

Currently no guidelines exist on the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy in women with PVNH. See Marfan Syndrome and Ehlers-Danlos Syndrome, Classic Type for possible pregnancy management recommendations.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


Surgical resection has been attempted but has not proven beneficial [Li et al 1997].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

FLNA-related periventricular nodular heterotopia (PVNH) is inherited in an X-linked manner.

Risk to Family Members

Parents of a female proband

  • About 50% of females with FLNA-related PVNH have inherited the FLNA pathogenic variant from a parent.
  • If there is only one family member affected with FLNA-related PVNH (i.e., a simplex case), a parent may have the pathogenic variant or the affected child may have a de novo FLNA pathogenic variant. At least 50% of females with FLNA-related PVNH have a de novo pathogenic variant
  • In a family with more than one affected individual, a parent of an affected child has the pathogenic variant. Note: If a parent has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in the parent’s leukocyte DNA, the parent has germline mosaicism.
  • Because of variable expression of FLNA-related PVNH, brain MRI should be considered for either parent of a proband if the parent has a history of seizures or learning disabilities. Because very few affected males have been identified, it is unlikely that the father is affected. All individuals with FLNA pathogenic variants, whether symptomatic or asymptomatic, have nodules identifiable by brain imaging.

Parents of a male proband

  • The father of an affected male will not have the disease nor will he be a carrier of the FLNA pathogenic variant.
  • If the FLNA pathogenic variant has been identified in the proband, it is appropriate to offer molecular genetic testing to the mother.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • If the mother (or, in rare cases, the father) has PVNH and/or an identified FLNA pathogenic variant, the risk to a female sib of being affected is 50%.
  • If the mother of the proband has PVNH and/or an identified FLNA pathogenic variant, the risk to a male sib of inheriting the FLNA pathogenic variant is 50%; males with familial FLNA pathogenic variants tend to die before birth or soon after birth. Affected males who have survived beyond the neonatal period have been reported; the clinical outcome for an affected male is uncertain because of the small number of such cases reported.
  • If the mother has no heterotopia identified by brain imaging, the recurrence risk for future pregnancies is low. Germline mosaicism has not been reported, although this possibility cannot be completely excluded. It is also possible that a child with PVNH and no known family history of the disorder has pathogenic variants in another unidentified gene that could have a different mode of inheritance. Therefore, the risk to the sibs of a child with PVNH and no known family history is low but greater than that found in the general population.

Offspring of a female proband

  • The risk to the offspring of females with MRI or CT findings of PVNH or an identified FLNA pathogenic variant is 50%; however, most male conceptuses with PVNH miscarry or die shortly after birth.
  • Some affected males survive beyond the neonatal period; the clinical outcome for an affected male is uncertain as very few cases have been reported.

Offspring of a male proband

  • In rare cases, males with FLNA pathogenic variants survive to adulthood and father children.
  • All male offspring of males with FLNA pathogenic variants will be healthy noncarriers, whereas all female offspring will be heterozygous for the FLNA pathogenic variant and hence affected.

Other family members of a proband. The proband's maternal aunts may be at risk of having inherited the FLNA pathogenic variant and the aunts’ offspring, depending on their gender, may be at risk of having inherited the pathogenic variant and being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have an FLNA pathogenic variant.

Genetic heterogeneity. Because evidence for genetic heterogeneity of PVNH exists, women with PVNH and no known family history of the disorder should be informed of the possibility that they may have pathogenic variants in a different as-yet-unidentified gene and may be at a low risk of having affected offspring because of possible autosomal recessive inheritance.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the FLNA pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk are possible options.

Ultrasound examination. Fetal ultrasound is relatively insensitive at detecting PVNH until later in pregnancy. Periventricular nodular heterotopias may be detected by fetal ultrasound examination or MRI as early as 24 weeks' gestation. Fetal MRI is performed at some centers using ultrafast MRI so that sedation is not required to reduce fetal movement. The sensitivity of prenatal imaging for the detection of PVNH is not known. Whether periventricular nodular heterotopias may be detected even earlier in gestation by imaging studies is not known.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

FLNA-Related Periventricular Nodular Heterotopia: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for FLNA-Related Periventricular Nodular Heterotopia (View All in OMIM)


Molecular Genetic Pathogenesis

The filamin class of actin-binding proteins is known to regulate cell stability, protrusion, and motility across various biologic systems [Ott et al 1998, Leonardi et al 2000, Stahlhut & van Deurs 2000]. Filamin-deficient melanocytes fail to undergo locomotion in response to factors that elicit migration in the same filamin-expressing cells. They exhibit prolonged circumferential blebbing, abnormal phagocytosis, and impaired volume regulation, perhaps secondary to abnormal regulation of sodium channel activity. Findings suggest that FLNA may have an influence similar to that of integrins, which have been implicated in cell adhesion and neuronal migration [Meyer et al 1997, Loo et al 1998, Dulabon et al 2000] on neuroblast migration during cortical development within the central nervous system. Recent studies suggest that genes in which mutation causes PVNH are involved in vesicle trafficking, necessary for delivery of proteins involved in cell adhesion [Ferland et al 2009]. Disruption of this process likely results in the formation of periventricular nodular heterotopias.

Gene structure. FLNA comprises 48 exons (reference sequence NM_001110556.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic variants in FLNA identified to date have generally been single nucelotide variants or deletions with presumed loss of function. Each family or individual representing a simplex case (i.e., a single occurrence in a family) has had a unique pathogenic variant [Sheen et al 2001].

Normal gene product. Filamin-A encodes a large (280-kd) cytoplasmic actin-binding phosphoprotein that links membrane receptors to the actin cytoskeleton and represents a potentially crucial link between signal transduction and the cytoskeleton. The protein consists of an actin-binding domain at the amino terminus, 23 repeats that resemble Ig-like domains and form a rod-like structure interrupted by two hinge regions, and a truncated C-terminal repeat that undergoes dimerization and binding to membrane receptors. The reference sequence of the protein isoform encoded by the transcript variant NM_001110556.1 is NP_001104026.1.

Abnormal gene product. More than 40 documented pathogenic variants in FLNA are protein-truncating or -splicing variants, predicted to result in severe loss of function [Walsh & Engle 2010]. Over a dozen missense FLNA variants are associated with PVNH, whereas another dozen or more missense variants are associated with other FLNA-related disorders. Truncation variants occur throughout the length of the protein. Many, though not all, PVNH-associated missense variants occur in the N-terminal actin-binding domain of FNH. Mild to moderate variants, either missense or truncations near the C-terminus, may have milder clinical phenotypes in females and thus avoid detection. Conversely, in males, severe to moderate defects lead to loss of fetal viability, and only partial-loss-of-function variants are found in surviving males [Sheen et al 2001, Moro et al 2002].

Mouse model. An Flna knockout mouse model demonstrates abnormal embryologic development of the heart and vasculature, including congenital abnormalities of the left-ventricular outflow tract, the atria, the ventricles, and the great vessels of the heart. The vasculature of these Flna knockout mice also demonstrated coarse, dilated, and abnormally branching blood vessels. Furthermore, the blood vessels had abnormal adherens junctions or abnormal cell-to-cell contact [Feng et al 2006].


Literature Cited

  1. Aalberts JJ, van Tintelen JP, Oomen T, Bergman JE, Halley DJ, Jongbloed JD, Suurmeijer AJ, van den Berg MP. Screening of TGFBR1, TGFBR2, and FLNA in familial mitral valve prolapse. Am J Med Genet A. 2014;164A:113–9. [PubMed: 24243761]
  2. Bernstein JA, Bernstein D, Hehr U, Hudgins L. Familial cardiac valvulopathy due to filamin A mutation. Am J Med Genet A. 2011;155A:2236–41. [PubMed: 21815255]
  3. Cardoso C, Boys A, Parrini E, Mignon-Ravix C, McMahon JM, Khantane S, Bertini E, Pallesi E, Missirian C, Zuffardi O, Novara F, Villard L, Giglio S, Chabrol B, Slater HR, Moncla A, Scheffer IE, Guerrini R. Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion. Neurology. 2009;72:784–92. [PubMed: 19073947]
  4. Chang BS, Katzir T, Liu T, Corriveau K, Barzillai M, Apse KA, Bodell A, Hackney D, Alsop D, Wong ST, Walsh CA. A structural basis for reading fluency: white matter defects in a genetic brain malformation. Neurology. 2007;69:2146–54. [PubMed: 18056578]
  5. Chang BS, Ly J, Appignani B, Bodell A, Apse KA, Ravenscroft RS, Sheen VL, Doherty MJ, Hackney DB, O'Connor M, Galaburda AM, Walsh CA. Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia. Neurology. 2005;64:799–803. [PubMed: 15753412]
  6. Clapham KR, Yu TW, Ganesh VS, Barry B, Chan Y, Mei D, Parrini E, Funalot B, Dupuis L, Nezarati MM, du Souich C, van Karnebeek C, Guerrini R, Walsh CA. FLNA genomic rearrangements cause periventricular nodular heterotopia. Neurology. 2012;78:269–78. [PMC free article: PMC3280053] [PubMed: 22238415]
  7. de Wit MC, de Coo IF, Halley DJ, Lequin MH, Mancini GM. Movement disorder and neuronal migration disorder due to ARFGEF2 mutation. Neurogenetics. 2009;10:333–6. [PMC free article: PMC2758209] [PubMed: 19384555]
  8. de Wit MC, de Coo IF, Lequin MH, Halley DJ, Roos-Hesselink JW, Mancini GM. Combined cardiological and neurological abnormalities due to filamin A gene mutation. Clin Res Cardiol. 2011;100:45–50. [PMC free article: PMC3022162] [PubMed: 20730588]
  9. Dobyns WB, Guerrini R, Czapansky-Beilman DK, Pierpont ME, Breningstall G, Yock DH Jr, Bonanni P, Truwit CL. Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: a new X-linked mental retardation syndrome. Neurology. 1997;49:1042–7. [PubMed: 9339687]
  10. Dulabon L, Olson EC, Taglienti MG, Eisenhuth S, McGrath B, Walsh CA, Kreidberg JA, Anton ES. Reelin binds alpha3beta1 integrin and inhibits neuronal migration. Neuron. 2000;27:33–44. [PubMed: 10939329]
  11. Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, Kwiatkowski DJ, Walsh CA, Filamin A. FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci U S A. 2006;103:19836–41. [PMC free article: PMC1702530] [PubMed: 17172441]
  12. Feng Y, Walsh CA. The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol. 2004;6:1034–8. [PubMed: 15516996]
  13. Ferland RJ, Batiz LF, Neal J, Lian G, Bundock E, Lu J, Hsiao YC, Diamond R, Mei D, Banham AH, Brown PJ, Vanderburg CR, Joseph J, Hecht JL, Folkerth R, Guerrini R, Walsh CA, Rodriguez EM, Sheen VL. Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia. Hum Mol Genet. 2009;18:497–516. [PMC free article: PMC2722192] [PubMed: 18996916]
  14. Fox JW, Lamperti ED, Ekşioğlu YZ, Hong SE, Feng Y, Graham DA, Scheffer IE, Dobyns WB, Hirsch BA, Radtke RA, Berkovic SF, Huttenlocher PR, Walsh CA. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron. 1998;21:1315–25. [PubMed: 9883725]
  15. Gérard-Blanluet M, Sheen V, Machinis K, Neal J, Apse K, Danan C, Sinico M, Brugières P, Mage K, Ratsimbazafy L, Elbez A, Janaud JC, Amselem S, Walsh C, Encha-Razavi F. Bilateral periventricular heterotopias in an X-linked dominant transmission in a family with two affected males. Am J Med Genet A. 2006;140:1041–6. [PubMed: 16596669]
  16. Guerrini R, Carrozzo R. Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing. Seizure. 2001;10:532–43. [PubMed: 11749114]
  17. Guerrini R, Dobyns WB. Bilateral periventricular nodular heterotopia with mental retardation and frontonasal malformation. Neurology. 1998;51:499–503. [PubMed: 9710025]
  18. Hehr U, Hehr A, Uyanik G, Phelan E, Winkler J, Reardon W. A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. J Med Genet. 2006;43:541–4. [PMC free article: PMC2564542] [PubMed: 16299064]
  19. Huttenlocher PR, Taravath S, Mojtahedi S. Periventricular heterotopia and epilepsy. Neurology. 1994;44:51–5. [PubMed: 8290091]
  20. Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, Servattalab S, Mehta BK, Topcu M, Amrom D, Andermann E, Dan B, Parrini E, Guerrini R, Scheffer IE, Berkovic SF, Leventer RJ, Shen Y, Wu BL, Barkovich AJ, Sahin M, Chang BS, Bamshad M, Nickerson DA, Shendure J, Poduri A, Yu TW, Walsh CA. Somatic mutations in cerebral cortical malformations. N Engl J Med. 2014;371:733–43. [PMC free article: PMC4274952] [PubMed: 25140959]
  21. Kothare SV, VanLandingham K, Armon C, Luther JS, Friedman A, Radtke RA. Seizure onset from periventricular nodular heterotopias: depth-electrode study. Neurology. 1998;51:1723–7. [PubMed: 9855532]
  22. Leonardi A, Ellinger-Ziegelbauer H, Franzoso G, Brown K, Siebenlist U. Physical and functional interaction of filamin (actin-binding protein-280) and tumor necrosis factor receptor-associated factor 2. J Biol Chem. 2000;275:271–8. [PubMed: 10617615]
  23. Li LM, Dubeau F, Andermann F, Fish DR, Watson C, Cascino GD, Berkovic SF, Moran N, Duncan JS, Olivier A, Leblanc R, Harkness W. Periventricular nodular heterotopia and intractable temporal lobe epilepsy: poor outcome after temporal lobe resection. Ann Neurol. 1997;41:662–8. [PubMed: 9153529]
  24. Loo DT, Kanner SB, Aruffo A. Filamin binds to the cytoplasmic domain of the beta1-integrin. Identification of amino acids responsible for this interaction. J Biol Chem. 1998;273:23304–12. [PubMed: 9722563]
  25. Lord A, Shapiro AJ, Saint-Martin C, Claveau M, Melançon S, Wintermark P. Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns. Respir Care. 2014;59:e171–7. [PubMed: 25053830]
  26. Masruha MR, Caboclo LO, Carrete H Jr, Cendes IL, Rodrigues MG, Garzon E, Yacubian EM, Sakamoto AC, Sheen V, Harney M, Neal J, Hill RS, Bodell A, Walsh C, Vilanova LC. Mutation in filamin A causes periventricular heterotopia, developmental regression, and West syndrome in males. Epilepsia. 2006;47:211–4. [PubMed: 16417552]
  27. Masurel-Paulet A, Haan E, Thompson EM, Goizet C, Thauvin-Robinet C, Tai A, Kennedy D, Smith G, Khong TY, Solé G, Guerineau E, Coupry I, Huet F, Robertson S, Faivre L. Lung disease associated with periventricular nodular heterotopia and an FLNA mutation. Eur J Med Genet. 2011;54:25–8. [PubMed: 20888935]
  28. Meyer SC, Zuerbig S, Cunningham CC, Hartwig JH, Bissell T, Gardner K, Fox JE. Identification of the region in actin-binding protein that binds to the cytoplasmic domain of glycoprotein IBalpha. J Biol Chem. 1997;272:2914–9. [PubMed: 9006936]
  29. 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;58:916–21. [PubMed: 11914408]
  30. Moro F, Pisano T, Bernardina BD, Polli R, Murgia A, Zoccante L, Darra F, Battaglia A, Pramparo T, Zuffardi O, Guerrini R. Periventricular heterotopia in fragile X syndrome. Neurology. 2006;67:713–5. [PubMed: 16924033]
  31. Neal J, Apse K, Sahin M, Walsh CA, Sheen VL. Deletion of chromosome 1p36 is associated with periventricular nodular heterotopia. Am J Med Genet A. 2006;140:1692–5. [PubMed: 16835933]
  32. Oegema R, Hulst JM, Theuns-Valks SD, van Unen LM, Schot R, Mancini GM, Schipper ME, de Wit MC, Sibbles BJ, de Coo IF, Nanninga V, Hofstra RM, Halley DJ, Brooks AS. Novel no-stop FLNA mutation causes multi-organ involvement in males. Am J Med Genet A. 2013;161A:2376–84. [PubMed: 23873601]
  33. Ott I, Fischer EG, Miyagi Y, Mueller BM, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol. 1998;140:1241–53. [PMC free article: PMC2132689] [PubMed: 9490735]
  34. Parrini E, Mei D, Wright M, Dorn T, Guerrini R. Mosaic mutations of the FLN1 gene cause a mild phenotype in patients with periventricular heterotopia. Neurogenetics. 2004;5:191–6. [PubMed: 15459826]
  35. 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;129:1892–906. [PubMed: 16684786]
  36. Poussaint TY, Fox JW, Dobyns WB, Radtke R, Scheffer IE, Berkovic SF, Barnes PD, Huttenlocher PR, Walsh CA. Periventricular nodular heterotopia in patients with filamin-1 gene mutations: neuroimaging findings. Pediatr Radiol. 2000;30:748–55. [PubMed: 11100490]
  37. Reinstein E, Frentz S, Morgan T, García-Miñaúr S, Leventer RJ, McGillivray G, Pariani M, van der Steen A, Pope M, Holder-Espinasse M, Scott R, Thompson EM, Robertson T, Coppin B, Siegel R, Bret Zurita M, Rodríguez JI, Morales C, Rodrigues Y, Arcas J, Saggar A, Horton M, Zackai E, Graham JM, Rimoin DL, Robertson SP. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. Eur J Hum Genet. 2013;21:494–502. [PMC free article: PMC3641385] [PubMed: 23032111]
  38. Robertson SP, Twigg SR, Sutherland-Smith AJ, Biancalana V, Gorlin RJ, Horn D, Kenwrick SJ, Kim CA, Morava E, Newbury-Ecob R, Orstavik KH, Quarrell OW, Schwartz CE, Shears DJ, Suri M, Kendrick-Jones J, Wilkie AO., OPD-spectrum Disorders Clinical Collaborative Group. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet. 2003;33:487–91. [PubMed: 12612583]
  39. Robertson SP. Filamin a, periventricular nodular heterotopia, and West syndrome. Epilepsia. 2006;47:1082. [PubMed: 16822260]
  40. 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;10:1775–83. [PubMed: 11532987]
  41. Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, Grant PE, Shugart YY, Imitola J, Khoury SJ, Guerrini R, Walsh CA. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004;36:69–76. [PubMed: 14647276]
  42. 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;64:254–62. [PubMed: 15668422]
  43. Sheen VL, Topçu M, Berkovic S, Yalnizoglu D, Blatt I, Bodell A, Hill RS, Ganesh VS, Cherry TJ, Shugart YY, Walsh CA. Autosomal recessive form of periventricular heterotopia. Neurology. 2003a;60:1108–12. [PubMed: 12682315]
  44. Sheen VL, Wheless JW, Bodell A, Braverman E, Cotter PD, Rauen KA, Glenn O, Weisiger K, Packman S, Walsh CA, Sherr EH. Periventricular heterotopia associated with chromosome 5p anomalies. Neurology. 2003b;60:1033–6. [PubMed: 12654978]
  45. Stahlhut M, van Deurs B. Identification of filamin as a novel ligand for caveolin-1: evidence for the organization of caveolin-1-associated membrane domains by the actin cytoskeleton. Mol Biol Cell. 2000;11:325–37. [PMC free article: PMC14777] [PubMed: 10637311]
  46. Walsh CA, Engle EC. Allelic diversity in human developmental neurogenetics: insights into biology and disease. Neuron. 2010;68:245–53. [PMC free article: PMC3010396] [PubMed: 20955932]

Suggested Reading

  1. Lu J, Sheen V. Periventricular heterotopia. Epilepsy Behav. 2005;7:143–9. [PubMed: 15996530]
  2. Noebels JL. The inherited epilepsies. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 230. New York, NY: McGraw-Hill. Available online.

Chapter Notes

Author History

Adria Bodell, MS, CGC; Beth Israel Deaconess Medical Center (2007-2015)
Ming Hui Chen, MD, MSc (2015-present)
Volney L Sheen, MD, PhD; Harvard Medical School (2007-2015)
Christopher A Walsh, MD, PhD (2007-present)

Revision History

  • 17 September 2015 (me) Comprehensive update posted to live Web site
  • 11/10/2014 (cw/mhc) Revision: cardiovascular added, other modifications made
  • 4 June 2009 (cd/cw) Revision: deletion/duplication analysis available; mutation added; Differential Diagnosis edited
  • 10 April 2007 (me) Comprehensive update posted to live Web site
  • 4 August 2004 (me) Comprehensive update posted to live Web site
  • 21 January 2004 (cd) Revision: testing
  • 17 October 2003 (cw) Revision: Genetically Related Disorders
  • 8 October 2002 (me) Review posted to live Web site
  • 29 April 2002 (cw) Original submission
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