DiagnosisClinical DiagnosisThe 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. FigureFigure 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 TestingGene. 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. Data regarding the frequency of exonic, multiexonic, or whole-gene deletions of FLNA are unknown.Table 1. Summary of Molecular Genetic Testing Used in X-Linked Periventricular HeterotopiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ¹ Test AvailabilityPositive Family History ² Simplex Females ³ FLNASequence analysisSequence variants ^{4100% 26% Clinical Deletion/ duplication analysis 5Partial- and whole-gene deletions/ duplications 6UnknownUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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. 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 Genetically Related (Allelic) DisordersThe 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 HistoryX-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 CorrelationsAll 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].

Differential DiagnosisThe frequent occurrence of familial or nonfamilial periventricular heterotopia in males and females with no documented FLNA mutation suggests that PH is a heterogeneous disorder.Other syndromes in which periventricular heterotopia occurs:Nonfamilial periventricular heterotopia caused by perinatal insult or chromosomal rearrangement Autosomal recessive periventricular heterotopia. Several families with PH consistent with autosomal recessive inheritance have been reported. Mutations in ARFGEF2 on chromosome 20 have been identified in two Turkish families with autosomal recessive PH with microcephaly [Sheen et al 2003a, Sheen et al 2004b]. Autosomal dominant forms of PH (chromosome 5p15, 1p36, 7q11) [Sheen et al 2003b, Ferland et al 2006, Neal et al 2006] Bilateral periventricular nodular heterotopia (BPNH)/frontonasal malformations [Guerrini & Dobyns 1998] Periventricular heterotopia (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 PH Bilateral anterior PH with fronto-perisylvian polymicrogyria [Parrini et al 2006] Bilateral PH involving temporo-occipital and trigones with hippocampal malformation, and subclassified into polymicrogyria or cerebellar hypoplasia or hydrocephalus [Parrini et al 2006] Periventricular heterotopia, intellectual disability, and epilepsy associated with 5q14.3-q15 deletion [Cardoso et al 2009] Movement disorder and neuronal migration disorder caused by ARFGEF2 mutation [de Wit et al 2009]Whether each of these represents a truly distinct disorder or an X-linked FLNA mutation 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 occur in X-linked subcortical band heterotopia.PH is often misdiagnosed initially as tuberous sclerosis complex; however, MRI findings distinguish between the two disorders.

ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsManagement 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 ComplicationsThe 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. SurveillanceBecause 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.Evaluation of Relatives at RiskNo specific testing is recommended for relatives at risk unless they develop seizures. A brain MRI is recommended for relatives with seizures.Therapies Under InvestigationSearch 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.OtherSurgical resection has been attempted but has not proven beneficial [Li et al 1997].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Periventricular Heterotopia, X-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFLNAXq28Filamin-AFLNA @ LOVDFLNAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Periventricular Heterotopia, X-Linked (View All in OMIM) View in own window 300017FILAMIN A; FLNA 300049HETEROTOPIA, PERIVENTRICULAR, X-LINKED DOMINANTMolecular Genetic PathogenesisThe 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. Table 2. Normal Allelic Variants of FLNAView in own windowNucleotide ChangeProtein ResidueCodon PositionAmino Acid PositionC>TPro>Pro3221T>CVal>Ala2320T>CPhe>Leu1370T>CVal>Ala2552G>APro>Pro31631T>CAla>Ala31950G>CVal>Val32206G>ALys>Lys32559G>AAla>Thr31764T>CSer>Ser1256Pathologic 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].