Flna-Related Periventricular Nodular Heterotopia

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2021-01-18
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Summary

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.

Diagnosis/testing.

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.

Management.

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.

Diagnosis

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.

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

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 multigene 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 multigene 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 are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in FLNA-Related Periventricular Nodular Heterotopia

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

See Table A. Genes and Databases for chromosome locus and protein.

2.

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

3.

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.

4.

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.

5.

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.

6.

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

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.

8.

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 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

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

Nomenclature

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

Prevalence

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):

  • Nonfamilial PVNH caused by perinatal insult or chromosomal rearrangement
  • Autosomal recessive PVNH (OMIM 608097). Several families with PVNH consistent with autosomal recessive inheritance have been reported. Biallelic pathogenic variants in ARFGEF2 on chromosome 20 have been identified in two Turkish families with autosomal recessive PVNH with microcephaly [Sheen et al 2003a, Sheen et al 2004] and in a female with a movement disorder, neuronal migration disorder, and acquired microcephaly [de Wit et al 2009].
  • Autosomal dominant forms of PVNH (OMIM 608098) (chromosome 5p15, 1p36, 7q11) [Sheen et al 2003b, Neal et al 2006, Ferland et al 2009]
  • Bilateral periventricular nodular heterotopia (BPNH)/frontonasal malformations (OMIM 300049) [Guerrini & Dobyns 1998]
  • PVNH (unilateral/bilateral and isolated) in two boys with fragile X syndrome [Moro et al 2006]
  • BPNH with micronodules
  • BPNH with ambiguous genitalia
  • BPNH with microcephaly
  • BPNH/intellectual disability/syndactyly [Dobyns et al 1997]
  • BPNH/nephrosis syndrome
  • BPNH/short gut syndrome
  • Unilateral PVNH
  • Bilateral anterior PVNH with fronto-perisylvian polymicrogyria [Parrini et al 2006]
  • Bilateral PVNH involving temporo-occipital and trigones with hippocampal malformation, and subclassified into polymicrogyria or cerebellar hypoplasia or hydrocephalus [Parrini et al 2006]
  • Periventricular nodular heterotopia, intellectual disability, and epilepsy associated with 5q14.3-q15 deletion (OMIM 612881) [Cardoso et al 2009]

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.

Management

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.

Surveillance

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 ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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].