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Bilateral periventricular nodular heterotopia in France: frequency of mutations in FLNA, phenotypic heterogeneity and spectrum of mutations G Solé, I Coupry, C Rooryck, et al. J Neurol Neurosurg Psychiatry 2009 80: 1394-1398
doi: 10.1136/jnnp.2008.162263
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Short report
Bilateral periventricular nodular heterotopia in France: frequency of mutations in FLNA, phenotypic heterogeneity and spectrum of mutations G Sole´,1,2 I Coupry,1 C Rooryck,1,3 E Gue´rineau,1 F Martins,1 S Deve´s,3 C Hubert,1 N Souakri,1 O Boute,4 C Marchal,2 L Faivre,5 E Landre´,6 S Debruxelles,2 A DieuxCoeslier,4 C Boulay,7 S Chassagnon,8 V Michel,2 M-C Routon,9 A Toutain,10 N Philip,11 D Lacombe,1,3 L Villard,12 B Arveiler,1,3 C Goizet1,2,3 c Additional tables are published online only at http:// jnnp.bmj.com/content/vol80/ issue12 1 Universite´ Victor Segalen Bordeaux 2, Laboratoire de Ge´ne´tique Humaine, Bordeaux, France; 2 CHU Bordeaux, Fe´de´ration des Neurosciences Cliniques, Hoˆpital Pellegrin, Bordeaux, France; 3 CHU Bordeaux, Service de Ge´ne´tique Me´dicale, Hoˆpital PellegrinEnfants, Bordeaux, France; 4 CHU Lille, Service de Ge´ne´tique Clinique, Hoˆpital Jeanne de Flandre, Lille, France; 5 CHU Dijon, Centre de Ge´ne´tique, Hoˆpital d’Enfants, Dijon, France; 6 CHU Cochin Port-Royal, Centre de Neurochirurgie, Hoˆpital Sainte-Anne, Paris, France; 7 CH Mulhouse, Service de Neurologie et d’Explorations Fonctionnelles du Syste`me Nerveux et Neuro-musculaire, Mulhouse, France; 8 CHU Strasbourg, De´partement de Neurologie, Strasbourg, France; 9 CHG d’Orsay, Service de Pe´diatrie et de Ne´onatologie, Orsay, France; 10 CHU Tours, Service de Ge´ne´tique Me´dicale, Hoˆpital Bretonneau, Tours, France; 11 APHM Marseille, De´partement de Ge´ne´tique Me´dicale, Hoˆpital TimoneEnfants, Marseille, France; 12 INSERM U910, Faculte´ de Me´decine de La Timone, Marseille, France
Correspondence to: Dr C Goizet, Laboratoire de Ge´ne´tique Humaine, Universite´ Victor Segalen Bordeaux 2, 146 rue Le´o Saignat, 33076 Bordeaux cedex, France;
[email protected] GS and IC contributed equally to this work. Received 30 September 2008 Revised 26 November 2008 Accepted 9 December 2008
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ABSTRACT Bilateral periventricular nodular heterotopia (BPNH) is the most common form of periventricular heterotopia. Mutations in FLNA, encoding filamin A, are responsible for the X linked dominant form of BPNH (FLNA-BPNH). Recently, atypical phenotypes including BPNH with Ehlers–Danlos syndrome (BPNH-EDS) have been recognised. A total of 44 FLNA mutations have so far been reported in this phenotype. Most of these mutations lead to a truncated protein, but few missense mutations have also been described. Here, the results of a mutation screening conducted in a series of 32 BPNH patients with the identification of 12 novel point mutations in 15 patients are reported. Nine mutations were truncating, while three were missense. Three additional patients with BPNH-EDS and a mutation in FLNA are described. No phenotype–genotype correlations could be established, but these clinical data sustain the importance of cardiovascular monitoring in FLNA-BPNH patients.
Periventricular heterotopia (PH) is one of a clinically and genetically heterogeneous group of neuronal migration disorders.1–3 Most patients with PH have seizures which vary considerably in severity and age at onset.4 5 PH can be laminar or nodular (PNH). The latter is characterised by nodules of neurons in inappropriate locations adjacent to the walls of the lateral ventricles.6 PNH can be either uni- or bilateral, and isolated or associated with other cerebral malformations, including cerebellar hypoplasia, mega cisterna magna, corpus callosum agenesia, microcephaly, hydrocephaly and polymicrogyria.3 Bilateral PNH (BPNH) is the most common form of PH and is predominantly observed in women. Mutations in the FLNA gene (MIM+300017), encoding filamin A, are responsible for the X linked dominant form of BPNH (XL-BPNH or FLNABPNH) (MIM# 300049) which accounts for 80– 100% of familial BPNH, about 20–30% of sporadic BPNH in females and less than 10% of sporadic BPNH in males.3 7–9 FLNA-BPNH patients usually have normal intelligence and mild to moderate hypoplasia of the cerebellar vermis.3 A great majority have well-controlled or episodic seizures.3 Extracerebral features, such as abnormal cardiac valves, patent ductus arteriosus, dilatation of vasalva sinuses, a propensity for premature stroke, coagulopathy, thrombocytopenia, small joint
hyperextensibility and gut dysmobility, are observed with variable frequency.3 7 9 Filamin A is a cytoskeletal protein that crosslinks actin by an N-terminal actin-binding domain (ABD) comprising two calponin homology domains (CH1 and CH2) and contains 24 immunoglobulin-like repeats interrupted by two hinge regions.10–12 Homodimerisation is mediated by repeat 24 nearest to the C-terminal. So far, 44 FLNA point mutations have been reported in association with PNH. Most patients have a classical BPNH phenotype, but more recently uncommon phenotypes have been described in BPNH with Ehlers–Danlos syndrome (EDS) (MIM# 300537) (n = 8), BPNH with frontometaphyseal dysplasia (FMD) (n = 1), BPNH with severe constipation (n = 1) and unilateral PNH (n = 2).3 8 9 13–18 Here, we present the results of a clinical and molecular analysis of a large series of BPNH patients, showing the wide spectrum of phenotypes caused by FLNA mutations.
MATERIAL AND METHODS We studied 32 patients from 29 different families, mostly of French origin, with BPNH diagnosed by brain MRI. The patients and their available relatives gave written informed consent in accordance with French law before collection of blood samples. The 47 FLNA coding exons (exon 2 to exon 48) and their intron–exon boundaries (Genbank, NT_011726) were amplified and analysed by DHPLC on an automated Wave Nucleic Acid Fragment Analysis System 2100A (Transgenomic, Elancourt, France). Amplification products with abnormal DHPLC elution profiles were reamplified and sequenced on both strands. Exon 2 was directly sequenced. PCR products were sequenced on an ABI3130XL automatic sequencer (Applera). Sequences were analysed with Seq Scape Software (Applera). Seventy-five unrelated French Caucasian female healthy subjects were screened to evaluate the frequency of missense mutations which were systematically tested for modifications of splicing consensus sequences at Splice Site Prediction by Neural Network. Multiple alignments of FLNA paralogues and orthologues in various species were performed using the ClustalW software.
J Neurol Neurosurg Psychiatry 2009;80:1394–1398. doi:10.1136/jnnp.2008.162263
J Neurol Neurosurg Psychiatry 2009;80:1394–1398. doi:10.1136/jnnp.2008.162263
NA
+
+ 50
2
2 N
2 2 2 2 2 2
2
+ 27
+
2 N
2 2 ? ? 2 2
2
2 + 2 2
2
+ 2 + +
2
2 2 2 2
2 2 2 2
2
2 2 2 2 2 2
2 N
+ C
2 2 2 2 2 2
+
+ 19
2
+ 4
2
2 2 2
39 F
4
2 2 + 2
2
2 2 2 ? 2 2
2 N
+
+ ?
2
2 2 2
45 F
5
2 2 2 +
2 2 2 2
2
+ + 2 2 +
2
+ 2 + + + AA
+ + + 2 2 2
2 2 2 2 2 ?
+
+ 15
2 N
NA
2 NA
+
+ 2 +
43 F
8
+ N
2 N
2
+ 18
NA
2 2 2
+ + 2
+
3 M
7
29 F
6
+ 2 2 +
2
+ 2 + + 2 AA
2 N
NA
2 NA
2
+ + +
15 F
9
2 2 2 2
2
2 2 ? 2 2 2
+ H
2
+ 1
NA
2 2 2
4 F
10
2 2 2 +
2
2 2 ? ? 2 PDA
2 N
2
+ 2
NA
2 2 2
4 F
11
2 2 2 2
2
2 2 2 ? 2 2
2 N
2
+ 17
NA
2 2 2
11 F
12
2 2 2 2
2
2 2 ? 2 2 2
+ N
2
+ 1
NA
2 2 2
10 F
13
2 + 2 +
2
2 2 ? ? 2 2
2 N
2
+ 15
2
2 2 2
32 F
14
2 + + +
2
AI 2 + 2 2 +
2 2 2 2 2 2
+ C,P
+
+ 1
2
2 2 2
41 F
16
+ + 2 + 2 AA
2 N
2
+ 16
2
+ 2 2
35 F
15
2 2 + 2
2
2 2 2 2 2 2
2 C,P
NA
2 NA
2
2 2 2
24 F
17
2 2 2 2
NA
2 + NA NA NA 2
2 NA
NA
2 NA
NA
2 2 2
fe M
18
2 2 2 2
2
2 2 2 2 2 2
+ N
+
+ ?
NA
2 2 2
20 M
19
+ 2 2 2
2
2 2 2 2 2 2
+ N
2
+ 2
NA
2 2 2
5 M
20
2 2 2 +
2
2 2 2 2 2 2
2 N
NA
2 NA
2
+ + 2
32 F
21
+ 2 2 +
+
2 2 2 2 2 VSD
2 N
2
+ 4
NA
+ + 2
5 F
22
2 2 2 2
2
2 2 2 2 2 2
+ N
NA
2 NA
NA
2 + 2
6 F
23
2 2 2 +
2
2 + 2 2 2 2
2 N
2
+ 2
NA
2 + +
3 F
24
2 2 2 +
+
2 2 2 ? 2 2
2 N
NA
2 NA
NA
2 + 2
4 F
25
2 2 2 2
2
2 2 2 2 2 2
+ N
NA
2 NA
NA
2 2 2
12 M
26
2 2 2 2
2
2 2 ? ? 2 2
2 N
?
+ 1
2
2 2 2
43 F
27
2 2 2 2
2
2 2 ? ? 2 2
2 N
+
+ 11
2
2 2 2
32 F
28
2 2 2 +
2
2 2 2 2 2 2
2 N
+
+ 12
2
2 2 2
26 F
29
2 2 2 2
2
2 2 2 2 2 2
2 N
+
+ ?
2
2 2 2
26 F
30
+ 2 2 +
2
2 2 ? 2 2 2
+ N
+
+ 14
2
2 2 2
41 F
31
2 2 2 +
2
2 2 2 2 2 2
2 N
2
+ 48
2
+ + +
48 F
32
Occipital encephalocele was present in patients 4 and 30, occipitocerebellar encephalocele in patient 16, posterior thinning of the corpus callosum in patient 29 and ventricular dilatation in patient 16. Bold text denotes mutated patients. 2, absent; ?, no data; +, present; AA, aortic aneurysm; AI, aortic insufficiency; C, cerebellar signs; F, female; Fe, fetus; H, axial hypotonia; M, male; N, normal; NA, not applicable; P, pyramidal signs (brisk reflexes and/or extensor palmar reflexes and/or dysarthria); PDA, persistent ductus arteriosus; VSD, ventricular septal defect; WMH, white-matter hyperintensities.
Respiratory problems Brain MRI features Mega cisterna magna Cerebellar hypoplasia WMH FLNA mutation
2 2 2
2 2 2
2 2 2
12 F
52 F
35 F
3
Age (years) Sex Familial history BPNH Epilepsy Spontaneous miscarriages Clinical features Spontaneous miscarriage Seizures Age at onset of seizures (years) Pharmacoresistant seizures Cognitive delay/MR Neurological examination Ehlers–Danlos syndrome Dysmorphism Ankle dislocation Joint hyperlaxity Skin hyperextensivity Cardiovascular anomalies
2
1
Cases
Clinical and brain MRI features of the 32 bilateral periventricular nodular heterotopia (BPNH) patients included in this study
Features
Table 1
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Short report
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Short report
Figure 1 Schematic representation of the FLNA protein and distribution of the 12 mutations identified in this study. The mutations identified in sporadic patients are noted above the protein, and the mutations identified in familial patients are noted below. The asterisks indicate the mutation on the electrophoregrams. Pedigrees are provided for each of the familial patients. Black symbols represent patients with bilateral periventricular nodular heterotopia shown on the brain MRI. The hatched symbol represents the patient with aortic dissection who did not undergo a brain MRI. Transversal brain images are provided for most patients showing bulging of the heterotopic nodules into the walls of lateral ventricles. Sagittal images are provided for patient 16 showing ventricles dilatation and occipitocerebellar encephalocele, and for patient 15 showing mega cisterna magna. ABD, actin-binding domain.
X inactivation analysis was performed in all female patients with an identified FLNA mutation.19 20 The Fisher exact t test was used for statistical analysis because of the small size of the population studied.
RESULTS Twenty-five unrelated sporadic patients and seven patients issued from four different kindreds were studied. All patients had diffuse and symmetrical BPNH on brain MRI. There were 27 females but only five males, one of which was a fetus from a medically interrupted pregnancy. The severity of the disease was highly variable (table 1). Blood cell counts were not performed.
Identification of mutations in FLNA We identified 12 novel pathogenic mutations in 15 French women (fig 1). Nine mutations (67%) were expected to produce a truncated protein (supplementary table 2), including an 1396
intronic splice mutation (c.1828+2T.G) affecting the donor site of intron 12 that decreased the in silico predicted splicing score from 0.99 to 0. In addition, three missense mutations (p.Ile119Asn, p.Val122Gly, p.Ser123Tyr) were observed, all affecting highly conserved amino acids in the CH1 domain of the ABD (supplementary table 2). These three mutations were not found in 150 control X chromosomes from healthy women. None of them modified the predicted score of splicing. Mutations were found in all seven familial cases (table 1). Cosegregation was confirmed in three of the four families, including p.Val122Gly in patients 8 and 9 (fig 1). In the fourth family (patient 15), paternal transmission of the p.Ile119Asn mutation was suspected (fig 1), but molecular confirmation could not be obtained. The father of patient 15 had BPNH with mega cisterna magna and severe supra-aortic dilatation. His cognitive performance was normal. The supra-aortic dilatation was repaired surgically at age 41. He died at age 57 during a second attempt at repair. J Neurol Neurosurg Psychiatry 2009;80:1394–1398. doi:10.1136/jnnp.2008.162263
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Short report The mutations (including p.Ser123Tyr) occurred de novo in sporadic patients 2, 11, 25 and 29, for whom available parents’ DNA was sequenced.
X inactivation studies All 15 mutated patients underwent analysis for the skewing of X inactivation. Two were homozygous at the AR locus and hence uninformative. Six patients had skewed X inactivation (>70/30), which was extreme (>85/15) in two women with truncating mutations (supplementary table 2).
Phenotype–genotype correlations The main clinical and MRI features of the 32 patients, whether or not they had FLNA mutations, are shown in supplementary table 3. A positive familial history of PNH, epilepsy and miscarriages, as well as the presence of cardiac anomalies and megacisterna magna, were significantly more frequent in the patients with a mutation in FLNA. However, we failed to establish correlations in these patients between the type and location of the mutation, or the presence of skewed X inactivation, and the severity of the disease.
DISCUSSION We have investigated 32 patients with BPNH, either isolated or associated with variable features (table 1), and found a FLNA mutation in 15 of them (47%), including all seven familial cases (100%). Our 15 FLNA-BPNH patients, all female, were similar in some respects to those previously reported (table 1). These include the high frequency of seizures (n = 12), posterior fossa anomalies (n = 8), cardiovascular anomalies (aortic aneurysms (AA), patent ductus arteriosus, ventricular septal defect and valvular dystrophy (VD)) (n = 5), and family histories of BPNH (n = 7) and seizures (n = 7). Respiratory problems (n = 3), cerebral white-matter hyperintensities (n = 2), articulation hyperlaxity (n = 3), dysmorphism (n = 2) and family histories of miscarriage (n = 4) were occasionally found, confirming the large phenotypic spectrum of the disease. Mild to moderate mental retardation was mentioned in only two patients, and a thin corpus callosum in one. More interestingly, three of the patients (patients 8, 9, 15) from two families had BPNH-EDS with mutations in FLNA (FLNA-BPNH-EDS). The EDS-associated signs were variable in their distribution and severity. Valvular dystrophy, joint hypermobility and dislocations, skin anomalies and dysmorphic facial features were variably observed (table 1). AA, the most
Box 1. Databases ClustalW software: http://www.ebi.ac.uk/clustalw/ Ensembl: http://www.ensembl.org/index.html Entrez Nucleotide: http://www.ncbi.nlm.nih.gov/sites/entrez Primer3: http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www. cgi Splice Site Prediction by Neural Network: http://www.fruitfly.org/ seq_tools/splice.html GenBank accession numbers for protein alignment. FLNA paralogues: FLNB (NP_001448), FLNC (NP_001449) and FLNA orthologues: Mus musculus (NP_03435), Rattus norvegicus (XP_238167), Bos taurus (XP_614269), Gallus gallus (NP_989905), Canis familiaris (XP_867483) and Xenopus tropicalis (ENSXETP0000031246)
J Neurol Neurosurg Psychiatry 2009;80:1394–1398. doi:10.1136/jnnp.2008.162263
severe cardiovascular complication associated with this condition8 13 was present in all three FLNA-BPNH-EDS patients. One (patient 8) had aortic surgery at age 38; the other two were treated with beta-blockers. Furthermore, the father of patient 15, who also had BPNH (fig 1), died during a second operation for AA. The mother of patient 8 (fig 1) was also operated on for aortic dissection at age 54, but it is not known whether she had BPNH. To date, only eight FLNA-BPNH-EDS patients have been described, and two of them had AA.3 13 14 These observations show that FLNA-BPNH-EDS patients are at risk for AA complicated by aortic dissection and should be screened for cardiovascular complications. The 12 mutations described here are private and distributed throughout the gene, as in previous studies.3 9 Nine of them are expected to produce truncated proteins. We also identified three missense mutations clustered in exon 2 (fig 1), in a region encoding the CH1 domain of the ABD, which is critical for binding to actin filaments and is a known hotspot for both nonsense and missense mutations that cause PNH.3 So far, 10 different missense mutations have been identified, five of which are in the CH1 domain.3 14 16 No significant associations between specific types of mutations or their locations and the severity of the PNH phenotype have been reported.3 Our results confirm the absence of phenotype–genotype correlations in FLNA-BPNH, except for missense germline mutations and distal truncating mutations that are compatible with the survival of affected males.3 One of the most demonstrative examples of the absence of phenotype–genotype correlations concerns the FLNA-BPNH-EDS subgroup of patients. Although four of the eight missense mutations now reported in the CH1 domain (p.Ala39Gly, p.Ala128Val, p.Ile119Asn, p.Val122Gly) were associated with FLNA-BPNH-EDS, three different frameshift mutations (c.2762delG, c.4038delG, c.4147delG) have been identified in other patients, one of whom inherited the mutation c.4038delG from his mother who had classical BPNH.3 The clinical features of EDS may therefore reflect variable expressivity, probably due to genetic modifying factors, or result from somatic mosaicism.3 However, as noted in a previous study, X inactivation was random in half of the patients (table 2), and skewing of X inactivation appears to have no effect on disease severity.8 Acknowledgements: The authors are grateful to the family members who agreed to participate in this study, and to the clinicians who referred their patients: R Barbier, T Billette, A Goldenberg, C Espil-Taris, A Biraben, H Journel, G Viot, A David, M-C Addor. They also thank M Ruberg, G Stevanin and C Depienne for critical reading of the manuscript. Funding: This work was supported by GIS (projects no 04/59 and 05/46) and from the Programme Hospitalier de Recherche Clinique national no 04/07, the Institut des Maladies Rares, INSERM, the Ministe`re de l’Enseignement Supe´rieur et de la Recherche and the Ministe`re de la Sante´. The experimental work was performed on the Plateforme Ge´notypage Se´quenc¸age (PGS) of Bordeaux. The PGS was constituted thanks to grants from the Conseil Re´gional d’Aquitaine (no 20030304002FA and no 20040305003FA) and from the FEDER (no 2003227). Competing interests: None. Patient consent: Obtained. Provenance and peer review: Not commissioned; externally peer reviewed.
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