[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Early onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found mutated in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients. METHODS: We have screened KCNQ2 in a cohort of 71 patients with an EOEE, without any brain structural abnormality. To be included in the cohort, patient's epilepsy should begin before three months of age and be associated with abnormal interictal EEG and neurological impairment. Brain MRI should not show any structural abnormality that could account for the epilepsy. RESULTS: Out of those 71 patients, 16 had a de novo mutation in KCNQ2 (23%). Interestingly, in the majority of the cases, the initial epileptic features of these patients were comparable to those previously described in the case of benign familial neonatal epilepsy (BFNE) also caused by KCNQ2 mutations. However, in contrast to BFNE, the interictal background EEG was altered and displayed multifocal spikes or a suppression-burst pattern. The ongoing epilepsy and development were highly variable but overall severe: 15/16 had obvious cognitive impairment, half of the patients became seizure-free, 5/16 could walk before the age of 3 and only 2/16 patient acquired the ability to speak. CONCLUSION: This study confirms that KCNQ2 is frequently mutated in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the evolution is highly variable in terms of epilepsy and of cognitive evolution.
[Show abstract][Hide abstract] ABSTRACT: Rett syndrome (RTT) is a neurodevelopmental disorder with one principal phenotype and several distinct, atypical variants (Zappella, early seizure onset and congenital variants). Mutations in MECP2 are found in most cases of classic RTT but at least two additional genes, CDKL5 and FOXG1, can underlie some (usually variant) cases. There is only limited correlation between genotype and phenotype. The Rett Networked Database (http://www.rettdatabasenetwork.org/) has been established to share clinical and genetic information. Through an "adaptor" process of data harmonization, a set of 293 clinical items and 16 genetic items was generated; 62 clinical and 7 genetic items constitute the core dataset; 23 clinical items contain longitudinal information. The database contains information on 1838 patients from 11 countries (December 2011), with or without mutations in known genes. These numbers can expand indefinitely. Data are entered by a clinician in each center who supervises accuracy. This network was constructed to make available pooled international data for the study of RTT natural history and genotype-phenotype correlation and to indicate the proportion of patients with specific clinical features and mutations. We expect that the network will serve for the recruitment of patients into clinical trials and for developing quality measures to drive up standards of medical management.
Human Mutation 03/2012; 33(7):1031-6. · 5.21 Impact Factor
[Show abstract][Hide abstract] 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.
Journal of neurology, neurosurgery, and psychiatry 12/2009; 80(12):1394-8. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rett syndrome is a severe neurodevelopmental disorder representing one of the most common genetic causes of mental retardation in girls. The classic form is caused by MECP2 mutations. In two patients affected by the congenital variant of Rett we have recently identified mutations in the FOXG1 gene encoding a brain specific transcriptional repressor, essential for early development of the telencephalon.
60 MECP2/CDKL5 mutation negative European Rett patients (classic and variants), 43 patients with encephalopathy with early onset seizures, and four atypical Rett patients were analysed for mutations in FOXG1.
Mutations have been identified in four patients, independently classified as congenital Rett variants from France, Spain and Latvia. Clinical data have been compared with the two previously reported patients with mutations in FOXG1. In all cases hypotonia, irresponsiveness and irritability were present in the neonatal period. At birth, head circumference was normal while a deceleration of growth was recognised soon afterwards, leading to severe microcephaly. Motor development was severely impaired and voluntary hand use was absent. In contrast with classic Rett, patients showed poor eye contact. Typical stereotypic hand movements with hand washing and hand mouthing activities were present continuously. Some patients showed abnormal movements of the tongue and jerky movements of the limbs. Brain magnetic resonance imaging showed corpus callosum hypoplasia in most cases, while epilepsy was a variable sign. Scoliosis was present and severe in the older patients. Neurovegetative symptoms typical of Rett were frequently present.
Journal of Medical Genetics 08/2009; 47(1):49-53. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA (Xq28) and ARFGEF2 (20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned.
We report the clinical and imaging features of three unrelated patients with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles, associated with a de novo deletion of the 5q14.3-15 region. We used microarray-based comparative genomic hybridization to define the boundaries of the deletions.
The three patients shared a common deleted region spanning 5.8 Mb and containing 14 candidate genes.
We identified a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. This observation reinforces the extreme clinical and genetic heterogeneity of PH. Array comparative genomic hybridization is a powerful diagnostic tool for characterizing causative chromosomal rearrangements of limited size, identifying potential candidate genes for, and improving genetic counseling in, malformations of cortical development.
[Show abstract][Hide abstract] ABSTRACT: Mutations in the MECP2 (Methyl-CpG-binding protein) gene have been reported to cause Rett syndrome (RTT), an X-linked progressive encephalopathy. Recent studies have identified large gene rearrangements that escape the common PCR-based mutation screening strategy and mutations in a novel MeCP2 isoform (named MECP2B). We have collected the results of MECP2 mutational analysis concerning 424 RTT patients conducted in eight laboratories in France. In total, 121 different MECP2 mutations were identified. R168X (11.5%) is the most common of MECP2 mutations, followed by R270X (9%), R255X (8.7%), T158 M (8.3%) and R306C (6.8%). Only eight mutations had relative frequency>3%. Large and complex rearrangements not previously detected using only a PCR-based strategy represent 5.8% of MECP2 mutations. On the contrary, mutation in exon 1 appears to be rare (less than 0.5%). These data demonstrate the high allelic heterogeneity of RTT in France and suggest that routine mutation screening in MECP2 should include quantitative analysis of the MECP2 gene. This study represents an important instrument for molecular diagnosis strategy and genetic counseling in RTT families.
European Journal of Medical Genetics 01/2006; 49(1):9-18. · 1.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent reports have demonstrated that mutations in the OPHN1 gene were responsible for a syndromic rather than non-specific mental retardation. Abnormalities of the posterior fossa with cerebellar hypoplasia have been demonstrated in all male patients reported to date. We report here a new family with X-linked mental retardation due to mutation in OPHN1 and present unpublished data about two families previously reported, concerning the facial and psychological phenotype of affected males and carrier females. Our study confirms that cerebellar hypoplasia is a hallmark of this syndrome. In addition, affected males display facial similarities that can help the diagnosis. Most carrier females have mild mental retardation and subtle facial changes.
American Journal of Medical Genetics Part A 12/2005; 138(4):314-7. · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mental retardation (MR) affects 2-3% of the human population and some of these cases are genetically determined. Although several genes responsible for MR have been identified, many cases have still not been explained.
We have identified a pericentric inversion of the X chromosome inv(X)(p22.3;q13.2) segregating in a family where two male carriers have severe MR while female carriers are not affected.
The molecular characterisation of this inversion led us to identify two new genes which are disrupted by the breakpoints: KIAA2022 in Xq13.2 and P2RY8 in Xp22.3. These genes were not previously fully characterised in humans. KIAA2022 encodes a protein which lacks significant homology to any other known protein and is highly expressed in the brain. P2RY8 is a member of the purine nucleotide G-protein coupled receptor gene family. It is located in the pseudo-autosomal region of the X chromosome and is not expressed in brain.
Because the haploinsufficiency of P2RY8 in carrier mothers does not have a phenotypic consequence, we propose that the severe MR of the affected males in this family is due to the absence of the KIAA2022 gene product. However, screening 20 probands from X linked MR families did not reveal mutations in KIAA2022. Nonetheless, the high expression of this gene in fetal brain and in the adult cerebral cortex could be consistent with a role in brain development and/or cognitive function.
Journal of Medical Genetics 11/2004; 41(10):736-42. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two half-brothers with similar malformed genitals, who both inherited a maternally derived t(X;5)(q13;p15) translocation, have a phenotype consistent with partial androgen sensitivity syndrome. The aim was to identify the gene disrupted by the X chromosome breakpoint.
The breakpoint was localized using fluorescence in situ hybridization to metaphase spreads of the translocation.
The breakpoint on the X chromosome of the X;5 translocation was localized to a 30-kb region. This region does not contain any identified genes or transcripts. However, the breakpoint is approximately 134 kb from the 5' end of the androgen receptor (AR) gene.
Genetic defects of the AR gene are collectively called androgen insensitivity syndrome and include a range of phenotypes from normal males, often with associated sterility, to XY females. The phenotype seen in the males with the t(X;5) is consistent with this syndrome. The analysis of the chromosomal abnormality suggests that this translocation may remove one or more upstream regulatory elements of the AR gene that are essential for its normal expression and its role in typical external masculinization.
Hormone Research 02/2004; 62(4):208-14. · 2.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-syndromic X linked mental retardation (MRX) is a heterogeneous group of conditions in which all patients have mental retardation as the only constant phenotypic feature. We have identified a female patient with mental retardation and a balanced translocation involving chromosomes X and 21, t(X;21)(p11.2;q22.3). Physical mapping of the translocation breakpoint on the human X chromosome was performed using fluorescence in situ hybridisation. We have mapped the X chromosome breakpoint to a 21 kb DNA fragment upstream of the first exon of the KLF8 (ZNF741) gene in Xp11.21. We have subsequently shown that the KLF8 transcript is no longer detected in cells from the patient, although KLF8 expression is otherwise normally present in control lymphoblasts. Mutation screening of probands from 20 unrelated XLMR families linked to the proximal short arm of the human X chromosome failed to show any mutation in the coding region of the KLF8 gene.
Journal of Medical Genetics 03/2002; 39(2):113-7. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rett syndrome is a neurodevelopmental disorder affecting only girls; 99.5% of Rett syndrome cases are sporadic, although several familial cases have been reported. Mutations in the MECP2 gene were identified in approximately 70-80% of sporadic Rett syndrome cases.
We have screened the MECP2 gene coding region for mutations in five familial cases of Rett syndrome and studied the patterns of X chromosome inactivation (XCI) in each girl.
We found a mutation in MECP2 in only one family. In the four families without mutation in MECP2, we found that (1) all mothers exhibit a totally skewed pattern of XCI; (2) six out of eight affected girls also have a totally skewed pattern of XCI; and (3) it is the paternally inherited X chromosome which is active in the patients with a skewed pattern of XCI. Given that the skewing of XCI is inherited in our families, we genotyped the whole X chromosome using 32 polymorphic markers and we show that a locus potentially responsible for the skewed XCI in these families could be located on the short arm of the X chromosome.
These data led us to propose a model for familial Rett syndrome transmission in which two traits are inherited, an X linked locus abnormally escaping X chromosome inactivation and the presence of a skewed XCI in carrier women.
Journal of Medical Genetics 08/2001; 38(7):435-42. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: FG syndrome is an X-linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints.
American Journal of Medical Genetics 12/2000; 95(2):178-81.
[Show abstract][Hide abstract] ABSTRACT: The authors report a family in which two boys had severe neonatal encephalopathy of unknown origin. They both presented with the same condition and died of severe apnea before they were 1 year old. Their sister has a classic form of Rett syndrome.
Because mutations in the methyl-CpG-binding protein 2 (MECP2) gene have been identified in 70 to 80% of the sporadic cases of Rett syndrome, the authors looked for a mutation in the MECP2 gene in this family.
The authors identified a missense mutation (T158M) in the affected girl and subsequently showed that one of her affected brothers, for whom DNA was available, carried the same mutation. The mother of the patients is a carrier of the T158M mutation. X-chromosome inactivation studies showed that the mother has a completely skewed X-chromosome inactivation pattern that favors the expression of the normal allele; this explains why she does not exhibit any phenotypic manifestation. In addition, the MECP2 mutation appeared on the grandpaternal X chromosome in this family.
An MECP2 mutation can be identified in boys, even though they do not present a Rett syndrome phenotype.
[Show abstract][Hide abstract] ABSTRACT: We are conducting a systematic transcriptional mapping of the Xq12-q21 region of the human X chromosome in order to identify new genes potentially involved in X-linked mental retardation phenotypes. In silico analysis using the sequence of the genomic clones originating from this region of the human X chromosome allowed us to characterize a new gene belonging to the T-box family of transcriptional regulators. These genes were shown to be critical for proper development of both vertebrates and invertebrates. We show here that this new gene, called TBX22, is composed of seven exons spanning 8.7 kilobases of genomic DNA in Xq21.1. The TBX22 mRNA is 2099 base pairs long and encodes a 400-amino-acids protein containing a T-domain in its NH(2)-terminal region which has the unique feature of missing 20 amino-acids relative to the other known T-domains. TBX22 transcripts were exclusively found in a human fetal cDNA library and no homologous gene could be detected in the mouse genome. In addition, phylogenetic studies performed using all the known T-domain-containing proteins show that TBX22 is not directly related to any of them. These data indicate that TBX22 may be the first identified member of a new family of T-domain-containing proteins.