Clinical Diagnosis

The diagnosis of X-linked periventricular heterotopia (PH) relies on a combination of clinical features, neuroimaging studies, and family history.

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

• Neuroimaging studies reviewed by an experienced neuroradiologist reveal the following:

  • MRI: bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) in the lateral ventricles beneath an otherwise normal-appearing cortex
    
    Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT.

  • Thinning of the corpus callosum and malformations of the posterior fossa (mild cerebellar hypoplasia, enlarged cysterna magna) in some (see Figure 1) [Poussaint et al 2000]

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

Figure

Figure 1. Anatomic phenotype of PH with FLNA mutation
A. MRI of the head demonstrating characteristic periventricular heterotopia
B. MRI of the head demonstrating thin corpus callosum and hypoplastic cerebellum

Molecular Genetic Testing

Gene. FLNA is the only gene currently known to be associated with X-linked PH [Fox et al 1998].

Other loci. The less-than-100% mutation detection rate by FLNA sequencing suggests that at least one other as-yet-unidentified gene is associated with periventricular heterotopia [Sheen et al 2004a].

Clinical testing

Sequence analysis. No published series have looked at the mutation detection rate using sequence analysis. Parrini et al [2006] determined the mutation detection rate using mutation scanning:

• 93% (8/8 [Parrini et al 2006]; 5/6 [Sheen et al 2001]) for individuals with classic bilateral PH and an X-linked inheritance pattern

• 26% (n=120) for females with classic bilateral PH who were simplex cases (i.e., no family history of PH)

Note: (1) In these two groups, 93% of individuals with a FLNA mutation were female and 7% were male. (2) Overall, Parrini et al [2006] found that the probability of identifying an FLNA mutation in an individual with classic bilateral PH was 49% and the probability of identifying an FLNA mutation in an individual with another phenotype (e.g., polymicrogyria, microcephaly) was 4%.

Deletion/duplication analysis. No deletions or duplications involving FLNA as causative of X-linked periventricular heterotopia have been reported. Because deletion testing of FLNA has only recently become available clinically, data regarding the frequency of exonic, multiexonic, or whole-gene deletions are unknown.

Table 1. Summary of Molecular Genetic Testing Used in X-Linked Periventricular Heterotopia

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Positive Family History 2	Simplex Females 3
FLNA	Sequence analysis	Sequence variants 4	100%	26%	Clinical
	Deletion/ duplication analysis 5	Partial- and whole-gene deletions/ duplications 6	Unknown	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Familial cases with X-linked inheritance pattern (n=8)

3. Females with PH and no known family history of PH (n=120)

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

5. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and array GH may be used.

6. Although this test is available clinically, to date no deletions or duplications of FLNA have been reported as causative of X-linked periventricular heterotopia.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Clinical uses

• Confirmatory diagnostic testing

• Carrier testing

• Prenatal diagnosis

• Preimplantation genetic diagnosis

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The four other phenotypes associated with mutations in FLNA are characterized primarily by skeletal dysplasia and are termed the otopalatodigital spectrum disorders [Robertson et al 2003]. They include:

• Otopalatodigital syndrome type I (OPD1)

• Otopalatodigital syndrome type II (OPD2)

• Frontometaphyseal dysplasia (FMD)

• Melnick-Needles syndrome (MNS)

In males, severity ranges from mild manifestations in OPD1 to more severe presentation in FMD and OPD2; prenatal lethality is most common in males with MNS. Females exhibit variable expressivity. In OPD1, most manifestations are present at birth and females can present with severity similar to affected males, but some have only mild manifestations. In OPD2 and FMD, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia that results in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require assistance with feeding and respiratory support. In FMD, males do not experience progression of skeletal dysplasia but may have joint contractures, scoliosis, and hand and feet malformations. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity.

Periventricular heterotopia is not a finding in these phenotypes, and the FLNA mutations associated with them are felt to be gain of function, whereas those with loss of function likely result in heterotopia formation in the brain. Alternatively, PH may not be 100% penetrant and mutations in this gene may cause either PH, skeletal abnormalities, or possibly both (loss of Flna protein function in mice leads to skeletal phenotypes very similar to those seen in humans with these mutations).

Natural History

X-linked periventricular heterotopia (PH) is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female.

Affected females. The following clinical features have been associated with X-linked PH:

• Seizure disorder

• Psychiatric disorder

• Cardiovascular findings including patent ductus arteriosus, bicuspid aortic valve, vasculopathy and/or coagulopathy leading to stroke, ruptured aneurysm

• Gastric immotility

• Congenital strabismus

• Shortened digits

• Hyperflexible joints [Sheen et al 2005]

• Dyslexia

Seizure disorder. Approximately 88% of individuals diagnosed with X-linked PH 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 heterotopia act as foci for abnormal neuronal activity. Anatomic studies have shown aberrant projections extending from the periventricular heterotopia. Depth electrode recordings have demonstrated epileptogenic discharges from these nodules [Kothare et al 1998]. Thus, the seizure disorder appears to arise from the heterotopia in most individuals.

Psychiatric disorder. Depression has been reported [Maruyama et al 1998]. Additionally, some individuals appear to have mild personality disorders [author, personal observations]. Whether these clinical findings reflect a neuropsychiatric complication of epilepsy remains to be seen.

Cardiovascular findings. Cardiac anomalies including patent ductus arteriosus (PDA) (3/11) and bicuspid aortic valve (1/11) were detected in a cohort of 11 affected individuals. The incidence of these malformations exceeds the general population (PDA = 1 per 1500 live births, bicuspid aortic valve = 1 per 100 births).

Among 11 females with confirmed FLNA mutations, three experienced strokes at early ages. This observation and the findings in affected males suggest a primary vasculopathy with weakened vessel walls and/or a coagulopathy secondary to platelet dysfunction.

Other. Among these same 11 individuals, associated findings 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 patients; therefore, the association with periventricular heterotopia is unknown.

Intelligence appears to be normal to borderline. Although no systematic neuropsychiatric evaluation has been performed on this population, affected individuals generally display no gross cognitive deficits on neurologic examination.

Women with X-linked PH 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 PH) with documented FLNA mutations presented with seizures. One of the males died from sudden rupture of the aorta at age 36 years.

Five other males ranging in age from five days to five months died suddenly and unexpectedly; although their deaths were consistent with sudden cardiovascular or hematologic collapse, the true causes of death were unknown.

A single affected male with a complete loss-of-function mutation also showed overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development.

Two affected dizygotic twin males have been reported, one with early death, the other with intellectual disability but not epilepsy [Gerard-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 PH. 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 mutant allele. Moreover, the affected male's daughter did not inherit the mutant allele, thought to be causal for the male phenotype.

Note: Although three affected brothers with West syndrome/hypsarrhythmia were reported to have an FLNA mutation [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 an FLNA mutation, 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].

One of the mechanisms explaining the phenotype of X-linked PH in females is random X-chromosome inactivation resulting in two populations of neurons: those expressing the mutant allele that presumably reside in the periventricular region as heterotopia and those that express the normal allele and migrate out to the cortical plate [Pilz et al 2002].

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

An FLNA splice mutation has been associated with periventricular nodular heterotopia (PNH), facial dysmorphism, and severe constipation [Hehr et al 2006].

Penetrance

Penetrance is unknown. It is not known what percentage of individuals with FLNA mutations have periventricular heterotopia and it is not known what percentage of individuals with periventricular heterotopia have clinical features.

Nomenclature

There are no terms that were used but that are currently completely out of favor. Frequently used terms are periventricular heterotopia (PVH or PH)f or periventricular nodular heterotopia (PNH or PVNH).

Prevalence

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

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked periventricular heterotopia (PH) the following evaluations are recommended:

• Neuroimaging to establish the diagnosis

• Evaluation by a neurologist

• Evaluation by an epileptologist if seizures are present

• Monitoring of social adjustment with neuropsychiatric evaluation if necessary

• Magnetic resonance angiography (MRA) of the intracranial vessels, carotid arteries, and aorta to address the increased risk for stroke

• Because of the potential risk for aortic aneurysm, a baseline evaluation by a cardiologist and either echocardiogram or cardiac magnetic resonance imaging (MRI), paying particular attention to the ascending aorta

• Evaluation by a hematologist if findings suggest a bleeding diathesis

Treatment of Manifestations

Management of individuals with X-linked PH is directed toward symptomatic treatment.

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

• This includes 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 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.

• Carbamezipine is most often used empirically for treatment, presumably because most affected individuals have focal epilepsy. However, because no significant differences exist between medications for newly diagnosed, presumably localized epilepsy, choices may be made upon the specific attributes of each antiepileptic drug (i.e., risk of teratogenicity of the antiepileptic drug during pregnancy), tolerability, and efficacy.

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

Many individuals with periventricular heterotopia have dyslexia. Therefore, it may be prudent for those with a family history of PH 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 and the risks of seizure medications to fetal development. The prenatal risks associated with seizure medication depend on the type of seizure medication.

Surveillance

Because of the associated increased incidence of aortic or carotid dissection in PH, affected individuals should be monitored by carotid and abdominal ultrasound studies. No clear guidelines exist. However, given that such complications have occurred in early adulthood, it is likely that evaluation should be performed initially in late adolescence and followed up as needed.

An echocardiogram may also be warranted because of reports of valvular abnormalities. No clear guidelines exist. However, as the valvular abnormalities are thought to be congenital, examination in early childhood seems warranted.

Testing of Relatives at Risk

No specific testing is recommended for relatives at risk unless they develop seizures. A brain MRI is recommended for relatives with seizures.

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Other

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

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

X-linked periventricular heterotopia (PH) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• About 50% of females with X-linked PH have inherited the mutation from a parent.

• At least 50% of females with X-linked PH have a de novo mutation.

• Because of variable expression of X-linked PH, 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 mutations, whether symptomatic or asymptomatic, have nodules identifiable by brain imaging.

Sibs of a proband

• The risk to sibs of the proband depends on the genetic status of the proband's mother.

• If the mother has PH and/or an identified FLNA mutation, the risk to a female sib of being affected is 50%.

• If the mother has PH and/or an identified FLNA mutation, the risk to a male sib of inheriting the FLNA mutation is 50%; however, all males with familial FLNA mutations to date have died before birth or soon after birth. Affected males who have survived beyond the neonatal period have been reported; however, the clinical outcome for an affected male is uncertain because of the small number of such cases reported.

• If the mother has no heterotopias 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 periventricular heterotopia and no known family history of PH may have mutations in another unidentified gene that could have a different mode of inheritance. Therefore, the risk to the sibs of a child with PH 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 PH or an identified FLNA mutation is 50%; however, most male conceptuses with PH miscarry or die shortly after birth. Some affected males survive beyond the neonatal period; however, the clinical outcome for an affected male is uncertain as very few cases have been reported.

Offspring of a male proband. Males with X-linked PH do not reproduce.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being affected (depending upon gender, family relationship, and the genetic status of the proband's mother).

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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 are affected, are carriers, or are at risk of being carriers.

Genetic heterogeneity. Because evidence exists for genetic heterogeneity of periventricular heterotopia, women with PH and no known family history of PH should be informed of the possibility that they may have mutations 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies of women who have an identifiable FLNA mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Ultrasound examination. Periventricular 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 such evaluation is not known. Whether periventricular 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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 PH 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 heterotopias.

Normal allelic variants. There are 48 exons in FLNA (reference sequence NM_001110556.1). The normal allelic variants of FLNA are listed in Table 2. Data were retrieved from the NCBI Gene Model site.

Pathologic allelic variants. Pathologic allelic variants in FLNA identified to date have generally been point mutations 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 mutation [Sheen et al 2001].

Thus far, fifteen mutations in FLNA have been reported; see Table 3 (pdf). Three missense mutations and twelve truncation mutations resulting in X-linked PH have been detected in FLNA [Sheen et al 2001, Moro et al 2002]. (For more information, see Table A.) The missense mutation 987G>C (Glu329Asp) was reported recently [Tsuneda et al 2008].

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 is NP_001104026.1).

Abnormal gene product. Twelve of 15 documented mutations are FLNA protein-truncating or -splicing mutations, predicted to result in severe loss of function. The remaining FLNA defects represent amino acid substitutions resulting from missense mutations. The sites of the truncation mutations tend to cluster at the amino terminal of the protein, leaving only a small translated portion of the actin-binding region. The amino acid substitutions, however, are not obviously clustered and exist along the length of the filamin-A protein. Because mutations can occur along the entire length of FLNA, the predilection of truncation mutations for the actin-binding region may merely reflect the incidence of clinical presentations for severe mutations in females. Mild to moderate mutations in FLNA may have fewer clinical phenotypes in females and thus avoid detection. Conversely, in males, severe to moderate defects lead to loss in fetal viability, and only partial-loss-of-function mutations are found [Sheen et al 2001, Moro et al 2002].

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Suggested Reading

1. Lu J, Sheen V. Periventricular heterotopia. Epilepsy Behav. 2005;7:143–9. [PubMed: 15996530]
2. Noebels JL. The inherited epilepsies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill; Chap 230. Available at www.ommbid.com. Accessed 5-31-11.

Revision History

• 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