Publications by authors named "Caroline Lacoste"

29 Publications

  • Page 1 of 1

Clinical study of 19 patients with SCN8A-related epilepsy: Two modes of onset regarding EEG and seizures.

Epilepsia 2019 05 26;60(5):845-856. Epub 2019 Apr 26.

Pediatric Neurology Department, Timone Children Hospital, Reference Center for Rare Epilepsies, APHM, Marseille, France.

Objective: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers.

Methods: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein.

Results: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases.

Significance: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.
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http://dx.doi.org/10.1111/epi.14727DOI Listing
May 2019

Correction: IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

Genet Med 2019 Aug;21(8):1897-1898

INSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
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http://dx.doi.org/10.1038/s41436-018-0327-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608434PMC
August 2019

Nivolumab-induced alopecia areata: A reversible factor of good prognosis?

JAAD Case Rep 2018 Sep 14;4(8):761-765. Epub 2018 Sep 14.

Centre Sabouraud, Hôpital Saint Louis, Paris, France.

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http://dx.doi.org/10.1016/j.jdcr.2018.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141643PMC
September 2018

IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

Genet Med 2019 04 12;21(4):837-849. Epub 2018 Sep 12.

INSERM, U 1127, CNRS UMR 7225, Sorbonne Universites, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle epiniere, ICM, Paris, France.

Purpose: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences.

Methods: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms.

Results: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments.

Conclusion: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.
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http://dx.doi.org/10.1038/s41436-018-0268-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752297PMC
April 2019

Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility.

Am J Hum Genet 2018 03 8;102(3):364-374. Epub 2018 Feb 8.

Aix Marseille Univ, INSERM, MMG, 13385 Marseille, France; Service de pédiatrie multidisciplinaire, Hôpital de la Timone Enfants, APHM, 13385 Marseille, France. Electronic address:

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
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http://dx.doi.org/10.1016/j.ajhg.2018.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985364PMC
March 2018

Missense mutation of TTC7A mimicking tricho-hepato-enteric (SD/THE) syndrome in a patient with very-early onset inflammatory bowel disease.

Eur J Med Genet 2018 Apr 23;61(4):185-188. Epub 2017 Nov 23.

Faculté de Médecine, Inserm UMRS 910, Aix-Marseille Université, Marseille, France; Service de Pédiatrie Multidisciplinaire, Hôpital d'enfants de la Timone, 264 rue Saint Pierre, APHM, 13005 Marseille, France.

Tricho-hepato-enteric syndrome (SD/THE) and Multiple intestinal atresia with combined immune deficiency (MIA-CID) are autosomal recessive disorders that present immunological and gastrointestinal features. There are two different phenotypes of patients with TTC7A mutations: the severe form, caused by null mutations and leading to the classical MIA-CID; and the mild form, caused by missense mutations and leading to predominant features of VEO-IBD, less severe immunological involvement and hair abnormalities. We expand the knowledge about TTC7A deficiency, describing a patient with the mild phenotype of TTC7A deficiency but presenting overlapping features of SD/THE and MIA-CID: intestinal atresia and inflammatory bowel disease evocative of MIA-CID, but also dental abnormalities, huge forehead, liver abnormalities, autoimmune thyroiditis and hypogammaglobulinemia, evocative of SD/THE.
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http://dx.doi.org/10.1016/j.ejmg.2017.11.014DOI Listing
April 2018

Proliferative Nodules vs Melanoma Arising in Giant Congenital Melanocytic Nevi During Childhood.

JAMA Dermatol 2016 10;152(10):1147-1151

Department of Dermatology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Descartes-Sorbonne University, Paris, France7Department of Pathology, Necker-Enfants Malades Hospital, Paris, France.

Importance: The differential diagnosis between proliferative nodules (PNs) and melanoma arising in congenital melanocytic nevi (CMN) is crucial, as patients with PNs most often experience no increased risk of melanoma with metastases and death.

Objective: To analyze the utility of immunohistochemistry and fluorescence in situ hybridization (FISH) in distinguishing PNs from childhood and adult-onset melanoma arising in CMN.

Design, Setting, And Participants: A case series was conducted from June 29, 1989, to November 12, 2009, of 13 children with PNs arising in CMN in childhood and 5 children with melanomas arising in CMN in childhood. Five patients with giant CMN with no nodules were included as negative controls, and 6 patients with melanomas arising in CMN in adulthood were included as positive controls. Follow-up ranged from 3 to 21 years in all children (mean, 9.9 years) and from 3 months to 7 years in adults. Specimens were selected for immunohistochemistry and FISH. All histopathologic sections were reviewed by 2 dermatopathologists who examined all nodules arising at different ages in the same patient and, in the case of melanoma, all locations. Data analysis was performed from January 1, 2013, to January 31, 2015.

Main Outcomes And Measures: The ability to distinguish melanoma from PN using immunohistochemistry and/or FISH.

Results: Of the 13 patients (5 boys and 8 girls) with PNs present at birth, all PNs were stable (mean follow-up, 9 years). Eight patients with PNs and 4 of 5 patients with childhood-onset melanoma showed homogeneous staining for HMB45, while heterogeneous staining for HMB45 was seen in 3 of 6 patients with adult-onset melanoma. Expression of p16 was strongly positive in most patients with childhood-onset PNs (10 of 11 patients) and melanoma (all patients) but negative in 4 patients with adult-onset melanoma. Patients with PNs and the 5 patients with childhood-onset melanoma had numerical chromosomal aberrations never observed in the adjacent CMN. The 2 children with FISH-positive PNs are melanoma free after 7 and 4 years. Only 1 patient with childhood-onset melanoma had a FISH aberration compared with 4 patients with adult-onset melanoma.

Conclusions And Relevance: Immunohistochemistry and the 4-probe FISH melanoma analysis are not useful for distinguishing PN from childhood-onset melanoma as opposed to adult-onset melanoma. Numerical anomalies seen in PNs but not in the adjacent CMN could be the result of a chromosomal segregation malfunction resulting in the development of nodules.
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http://dx.doi.org/10.1001/jamadermatol.2016.2667DOI Listing
October 2016

A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity.

Epilepsia 2016 05 31;57(5):e87-93. Epub 2016 Mar 31.

Mediterranean Neurobiology Institute INMED, Aix-Marseille University, Marseille, France.

Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2(V175L) ) found in a patient presenting EOEE. We observed that the mutation produced a 25-40 mV hyperpolarizing shift of the conductance-voltage relationship of both the homomeric Kv7.2(V175L) and heteromeric Kv7.2(V175L) /Kv7.3 channels compared to wild-type channels and a 10 mV hyperpolarizing shift of Kv7.2(V175L) /Kv7.2/Kv7.3 channels in a 1:1:2 ratio mimicking the patient situation. Mutant channels also displayed faster activation kinetics and an increased current density that was prevented by 1 μm linopirdine. The p.V175L mutation did not affect the protein expression of Kv7 channels and its localization at the axon initial segment. We conclude that p.V175L is a gain of function mutation. This confirms previous observations showing that mutations having opposite consequences on M channels can produce EOEE. These findings alert us that drugs aiming to increase Kv7 channel activity might have adverse effects in EOEE in the case of gain-of-function variants.
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http://dx.doi.org/10.1111/epi.13366DOI Listing
May 2016

Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases.

Epilepsia 2015 Dec 29;56(12):1931-40. Epub 2015 Oct 29.

Pediatric Neurology Department, Timone Children Hospital, Marseille, France.

Objective: Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening.

Methods: We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH).

Results: We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%.

Significance: Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.
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http://dx.doi.org/10.1111/epi.13214DOI Listing
December 2015

[Dermatological manifestations of monoclonal gammopathies: contribution of cutaneous histopathology].

Ann Pathol 2015 Aug 15;35(4):281-93. Epub 2015 Jul 15.

Département de pathologie, hôpital Henri-Mondor, Assistance publique-Hôpitaux de Paris (AP-HP), faculté de médecine, université Paris-Est-Créteil, 94010 Créteil cedex, France.

Skin manifestations associated with monoclonal gammapathy are common and can present with various clinical and pathological aspects. They can be the first events leading to the diagnosis of monoclonal gammapathy. They may be present either as specific lesions, including lymphoplasmacytic or pure plasma cell neoplastic infiltrates and monoclonal immunoglobulin deposits, or as non-specific dermatitis, such as leukocytoclastic vasculitis, neutrophilic dermatoses, mucinoses or xanthomatosis, giving little clues for the diagnosis of the underlying disease.
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http://dx.doi.org/10.1016/j.annpat.2015.05.001DOI Listing
August 2015

A mutation in the Gardos channel is associated with hereditary xerocytosis.

Blood 2015 Sep 6;126(11):1273-80. Epub 2015 Jul 6.

Aix-Marseille Université, INSERM, Unité Mixte de Recherche S910, Marseille, France; Assistance Publique-Hopitaux de Marseille, Département de Génétique Médicale, Hôpital d'Enfants de la Timone, Marseille, France; Assistance Publique-Hopitaux de Marseille, Laboratoire de Biochimie, Hôpital Conception, Marseille, France;

The Gardos channel is a Ca(2+)-sensitive, intermediate conductance, potassium selective channel expressed in several tissues including erythrocytes and pancreas. In normal erythrocytes, it is involved in cell volume modification. Here, we report the identification of a dominantly inherited mutation in the Gardos channel in 2 unrelated families and its association with chronic hemolysis and dehydrated cells, also referred to as hereditary xerocytosis (HX). The affected individuals present chronic anemia that varies in severity. Their red cells exhibit a panel of various shape abnormalities such as elliptocytes, hemighosts, schizocytes, and very rare stomatocytic cells. The missense mutation concerns a highly conserved residue among species, located in the region interacting with Calmodulin and responsible for the channel opening and the K(+) efflux. Using 2-microelectrode experiments on Xenopus oocytes and patch-clamp electrophysiology on HEK293 cells, we demonstrated that the mutated channel exhibits a higher activity and a higher Ca(2+) sensitivity compared with the wild-type (WT) channel. The mutated channel remains sensitive to inhibition suggesting that treatment of this type of HX by a specific inhibitor of the Gardos channel could be considered. The identification of a KCNN4 mutation associated with chronic hemolysis constitutes the first report of a human disease caused by a defect of the Gardos channel.
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http://dx.doi.org/10.1182/blood-2015-04-642496DOI Listing
September 2015

Incidence of ATRX mutations in myelodysplastic syndromes, the value of microcytosis.

Am J Hematol 2015 Aug;90(8):737-8

Service D'hématologie, Groupe Hospitalier De L'institut Catholique De Lille, Lille, France.

Acquired α-thalassemia myelodysplastic syndrome (MDS) (ATMDS) is an acquired syndrome characterized by a somatic point mutation or splicing defect in the ATRX gene in patients with myeloid disorders, primarily MDS. In a large MDS patient series, the incidence of ATMDS was below 0.5%. But no large series has yet assessed the incidence of ATMDS in microcytic MDS. In this study, we focused on patients with MDS and unexplained microcytosis, which was defined as absence of iron deficiency, inflammatory disease, or history of inherited hemoglobinopathy. Our data confirm the low frequency of ATRX mutations in MDS: 0% in an unselected clinical trial cohort of 80 low risk MDS, 0.2-0.8% in a multicenter registry of 2,980 MDS and 43% of MDS with unexplained microcytosis in this same registry. In addition, we reported four novel mutations of the ATRX gene in ATMDS. This study further determines the frequency of ATRX mutations and highlights the importance of microcytosis to detect ATRX mutations within MDS patients.
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http://dx.doi.org/10.1002/ajh.24073DOI Listing
August 2015

A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels.

Neurobiol Dis 2015 Aug 22;80:80-92. Epub 2015 May 22.

Aix-Marseille Université, Institut de Neurobiologie de la Méditerranée (INMED), Marseille, France; INSERM, UMR_S 901, Marseille, France. Electronic address:

Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit cause either benign epilepsy or early onset epileptic encephalopathy (EOEE). It has been proposed that the disease severity rests on the inhibitory impact of mutations on M current density. Here, we have analyzed the phenotype of 7 patients carrying the p.A294V mutation located on the S6 segment of the Kv7.2 pore domain (Kv7.2(A294V)). We investigated the functional and subcellular consequences of this mutation and compared it to another mutation (Kv7.2(A294G)) associated with a benign epilepsy and affecting the same residue. We report that all the patients carrying the p.A294V mutation presented the clinical and EEG characteristics of EOEE. In CHO cells, the total expression of Kv7.2(A294V) alone, assessed by western blotting, was only 20% compared to wild-type. No measurable current was recorded in CHO cells expressing Kv7.2(A294V) channel alone. Although the total Kv7.2(A294V) expression was rescued to wild-type levels in cells co-expressing the Kv7.3 subunit, the global current density was still reduced by 83% compared to wild-type heteromeric channel. In a configuration mimicking the patients' heterozygous genotype i.e., Kv7.2(A294V)/Kv7.2/Kv7.3, the global current density was reduced by 30%. In contrast to Kv7.2(A294V), the current density of homomeric Kv7.2(A294G) was not significantly changed compared to wild-type Kv7.2. However, the current density of Kv7.2(A294G)/Kv7.2/Kv7.3 and Kv7.2(A294G)/Kv7.3 channels were reduced by 30% and 50% respectively, compared to wild-type Kv7.2/Kv7.3. In neurons, the p.A294V mutation induced a mislocalization of heteromeric mutant channels to the somato-dendritic compartment, while the p.A294G mutation did not affect the localization of the heteromeric channels to the axon initial segment. We conclude that this position is a hotspot of mutation that can give rise to a severe or a benign epilepsy. The p.A294V mutation does not exert a dominant-negative effect on wild-type subunits but alters the preferential axonal targeting of heteromeric Kv7 channels. Our data suggest that the disease severity is not necessarily a consequence of a strong inhibition of M current and that additional mechanisms such as abnormal subcellular distribution of Kv7 channels could be determinant.
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http://dx.doi.org/10.1016/j.nbd.2015.04.017DOI Listing
August 2015

Variable clinical expression in patients with mosaicism for KCNQ2 mutations.

Am J Med Genet A 2015 Oct 10;167A(10):2314-8. Epub 2015 May 10.

Inserm, UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Marseille, France.

Mutations in the KCNQ2 gene, encoding a potassium channel subunit, were reported in patients presenting epileptic phenotypes of varying severity. Patients affected by benign familial neonatal epilepsy (BFNE) are at the milder end of the spectrum, they are affected by early onset epilepsy but their subsequent neurological development is usually normal. Mutations causing BFNE are often inherited from affected parents. Early infantile epileptic encephalopathy type 7 (EIEE7) is at the other end of the severity spectrum and, although EIEE7 patients have early onset epilepsy too, their neurological development is impaired and they will present motor and intellectual deficiency. EIEE7 mutations occur de novo. Electrophysiological experiments suggested a correlation between the type of mutation and the severity of the disease but intra and interfamilial heterogeneity exist. Here, we describe the identification of KCNQ2 mutation carriers who had children affected with a severe epileptic phenotype, and found that these individuals were mosaic for the KCNQ2 mutation. These findings have important consequences for genetic counseling and indicate that neurological development can be normal in the presence of somatic mosaicism for a KCNQ2 mutation.
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http://dx.doi.org/10.1002/ajmg.a.37152DOI Listing
October 2015

Malignant Melanoma Arising in Patients with a Large Congenital Melanocytic Naevus: Retrospective Study of 10 Cases with Cytogenetic Analysis.

Acta Derm Venereol 2015 Jul;95(6):686-90

Department of Pathology, Necker-Enfants Malades Hospital, APHP, Paris Descartes - Sorbonne Paris Cité university, Institut Imagine, 75015 Paris, France.

Large congenital melanocytic naevi (LCMN) represent the main risk factor for development of melanoma in childhood. This retrospective study of 10 cases of melanoma in patients with LCMN used fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) (6 cases) to elucidate the clinical, histological, and cytogenetic characteristics of this rare disorder. Six melanomas were found within the LCMN, the others in lymph nodes, subcutis and brain. The LCMN was located on the trunk in 8 cases, with satellite naevi in 6 cases. Two distinct groups emerged: 5 melanomas that developed before the age of 10 years and the other after 20 years. The mortality rate was 60% and clearly correlated with clinical stage at diagnosis. Histological diagnosis was difficult in only 2 patients in whom neither immunohistochemistry nor FISH were helpful. Otherwise, CGH showed a high number of chromosomal aberrations leading to a formal diagnosis.
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http://dx.doi.org/10.2340/00015555-2049DOI Listing
July 2015

Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.

Orphanet J Rare Dis 2013 May 22;8:80. Epub 2013 May 22.

INSERM, UMR_S 910 Faculté de médecine, Marseille, France.

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 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 de novo in neonatal onset epileptic encephalopathy. We show here that despite a relatively stereotyped beginning of the condition, the neurological and epileptic evolution is variable.
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http://dx.doi.org/10.1186/1750-1172-8-80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670812PMC
May 2013

[Case for diagnosis: An unusual lymph node fine needle aspiration].

Ann Pathol 2013 Feb 4;33(1):62-5. Epub 2013 Feb 4.

Service d'anatomie et de cytologie pathologique, hôpital Lariboisière, 2, rue A.-Paré, 75010 Paris, France.

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http://dx.doi.org/10.1016/j.annpat.2012.09.006DOI Listing
February 2013

A new ATRX mutation in a patient with acquired α-thalassemia myelodysplastic syndrome.

Hemoglobin 2012 24;36(6):581-5. Epub 2012 Oct 24.

Service d'Onco-Hématologie, Hôpital Saint Vincent de Paul, Université Catholique de Lille, Université Nord de France, Lille, France.

Acquired α-thalassemia (α-thal) myelodysplastic syndrome (ATMDS) is a rare acquired syndrome characterized by a somatic point mutation in the ATRX gene in patients with chronic myeloid disorders. We describe the case of a 78-year-old man with myelodysplastic syndrome (MDS) and striking microcytic, hypochromic anemia. Brilliant cresyl blue supravital stain of the peripheral blood and hemoglobin (Hb) electrophoresis showed the presence of Hb H. Sequence analysis of unfractionated peripheral blood DNA identified a G>T transition at codon 524 in exon 7 of the ATRX gene. To the best of our knowledge, it is the first description of this point mutation of the ATRX gene in an ATMDS.
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http://dx.doi.org/10.3109/03630269.2012.724040DOI Listing
April 2013

SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.

Am J Hum Genet 2012 Apr 22;90(4):689-92. Epub 2012 Mar 22.

UMR_S 910, Inserm-Faculté de Médecine, Aix-Marseille Université, Marseille, France.

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.
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http://dx.doi.org/10.1016/j.ajhg.2012.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322239PMC
April 2012

A novel mutation in the PORCN gene underlying a case of almost unilateral focal dermal hypoplasia.

Arch Dermatol 2012 Jan;148(1):85-8

Laboratoire Associé Institut National de la Santé et de la Récherche Médicale Unité Mixte de Récherche en Santé 910, Université Saint Joseph, Beirut, Lebanon.

Background: Focal dermal hypoplasia (also known as Goltz syndrome) is an X-linked dominant syndrome characterized by patchy hypoplastic skin with soft-tissue, skeletal, dental, and ocular defects that are secondary to mutations in the PORCN gene. To our knowledge, only 5 cases of focal dermal hypoplasia with unilateral presentation have been reported, and molecular studies were not performed in any of the cases.

Observations: A 17-year-old girl was seen with features of almost unilateral focal dermal hypoplasia. These included left cleft hand, dental dysplasia, left mammary hypoplasia, deviation of the sacral line, raspberrylike papillomas in the perianal region, syndactyly of the second and third digits of the left foot, and linear streaks of dermal hypoplasia and pigmented lesions on her left hemibody.

Conclusions: Mutation analysis of PORCN revealed a novel heterozygous mutation in exon 10, c.854-855insACCTGAC; [p.T285fsX316], resulting in a premature stop signal. Analysis of the X-chromosome inactivation status was performed on blood and skin DNA samples, showing random inactivation in blood and unaffected skin and skewed inactivation in affected skin, highlighting the role of X-chromosome inactivation in X-linked disease expression.
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http://dx.doi.org/10.1001/archdermatol.2011.343DOI Listing
January 2012

[A rare testicular tumor].

Ann Pathol 2011 Apr 30;31(2):119-23. Epub 2011 Mar 30.

Service d'anatomie pathologique, hôpital Saint-Louis, AP-HP, 1, avenue Claude-Vellefaux, 75010 Paris, France.

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http://dx.doi.org/10.1016/j.annpat.2011.02.004DOI Listing
April 2011

Exclusion of EGFR, HRAS, DSP, JUP, CTNNB1, PLEC1, and EPPK1 as functional candidate genes in 7 families with syndromic diarrhoea.

J Pediatr Gastroenterol Nutr 2009 Apr;48(4):501-3

Service de Pédiatrie Multidisciplinaire, Hôpital d'enfants de la Timone, Marseille, France.

Syndromic diarrhoea (SD) is a rare disease associating intractable diarrhoea and hair abnormalities. In an attempt to identify the gene causative for SD, we studied several functional candidate genes, based on their implication in overlapping phenotypes in mice (EGFR) or in humans (HRAS, JUP, DSP EPPK1, PLEC1, and CTNNB1) in 8 patients affected by SD. Except for EGFR and HRAS, all selected genes encode for cell adhesion proteins. Using direct sequencing or linkage analysis, we excluded all of the candidate genes as the disease-causing gene in our group of patients; however, the hypothesis of intercellular junctions defect in SD remains seductive.
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http://dx.doi.org/10.1097/MPG.0b013e3181846aabDOI Listing
April 2009

Partial duplications of the ATRX gene cause the ATR-X syndrome.

Eur J Hum Genet 2007 Oct 20;15(10):1094-7. Epub 2007 Jun 20.

Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium.

ATR-X syndrome is a rare syndromic X-linked mental retardation disorder. We report that some of the patients suspected of ATR-X carry large intragenic duplications in the ATRX gene, leading to an absence of ATRX mRNA and of the protein. These findings underscore the need for including quantitative analyses to mutation analysis of the ATRX gene.
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http://dx.doi.org/10.1038/sj.ejhg.5201878DOI Listing
October 2007

MAU-8 is a Phosducin-like Protein required for G protein signaling in C. elegans.

Dev Biol 2006 Jun 3;294(1):181-91. Epub 2006 Apr 3.

INSERM UMR 641, Université de la Méditerranée, Faculté de Médecine Secteur Nord, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France.

The mau-8(qm57) mutation inhibits the function of GPB-2, a heterotrimeric G protein beta subunit, and profoundly affects behavior through the Galphaq/Galphao signaling network in C. elegans. mau-8 encodes a nematode Phosducin-like Protein (PhLP), and the qm57 mutation leads to the loss of a predicted phosphorylation site in the C-terminal domain of PhLP that binds the Gbetagamma surface implicated in membrane interactions. In developing embryos, MAU-8/PhLP localizes to the cortical region, concentrates at the centrosomes of mitotic cells and remains associated with the germline blastomere. In adult animals, MAU-8/PhLP is ubiquitously expressed in somatic tissues and germline cells. MAU-8/PhLP interacts with the PAR-5/14.3.3 protein and with the Gbeta subunit GPB-1. In mau-8 mutants, the disruption of MAU-8/PhLP stabilizes the association of GPB-1 with the microtubules of centrosomes. Our results indicate that MAU-8/PhLP modulates G protein signaling, stability and subcellular location to regulate various physiological functions, and they suggest that MAU-8 might not be limited to the Galphaq/Galphao network.
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http://dx.doi.org/10.1016/j.ydbio.2006.02.039DOI Listing
June 2006

Point processes for unsupervised line network extraction in remote sensing.

IEEE Trans Pattern Anal Mach Intell 2005 Oct;27(10):1568-79

CREATIS, INSA, 7 rue Jean Capelle, bat. Blaise Pascal, F-69621 Villeurbanne Cedex, France.

This paper addresses the problem of unsupervised extraction of line networks (for example, road or hydrographic networks) from remotely sensed images. We model the target line network by an object process, where the objects correspond to interacting line segments. The prior model, called "Quality Candy," is designed to exploit as fully as possible the topological properties of the network under consideration, while the radiometric properties of the network are modeled using a data term based on statistical tests. Two techniques are used to compute this term: one is more accurate, the other more efficient. A calibration technique is used to choose the model parameters. Optimization is done via simulated annealing using a Reversible Jump Markov Chain Monte Carlo (RJMCMC) algorithm. We accelerate convergence of the algorithm by using appropriate proposal kernels. The results obtained on satellite and aerial images are quantitatively evaluated with respect to manual extractions. A comparison with the results obtained using a previous model, called the "Candy" model, shows the interest of adding quality coefficients with respect to interactions in the prior density. The relevance of using an offline computation of the data potential is shown, in particular, when a proposal kernel based on this computation is added in the RJMCMC algorithm.
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http://dx.doi.org/10.1109/TPAMI.2005.206DOI Listing
October 2005

Phenylphenols, biphenols, bisphenol-A and 4-tert-octylphenol exhibit alpha and beta estrogen activities and antiandrogen activity in reporter cell lines.

Mol Cell Endocrinol 2002 Jul;193(1-2):43-9

INSERM Unité 439, Pathologie Moléculaire des Récepteurs Nucléaires, 70 rue de Navacelles, 34090 Montpellier, France.

We previously demonstrated the interactions of different chemical compounds with estrogen receptors ERalpha and ERbeta and the androgen receptor (AR) using different reporter cell lines. In this study, we characterize the ERalpha, ERbeta and AR activity of different biphenyls using the same tools. We provide evidence that several phenyl derivatives present both estrogenic and antiandrogenic activity. The extent of hydroxylation and the position of the hydroxyl function were important in determining their estrogenicity and antiandrogenicity. Of the tested compounds, bisphenol-A and 4,4' biphenol had very high estrogenic activity, although it was lower than that of the strong estrogenic alkylphenol, 4-tert-octylphenol. Bisphenol-A and 4,4' biphenol were able to activate ERs at concentrations lower than 1 microM, whereas the other compounds only activated at concentrations above 1 microM. Interestingly, 4,4' biphenol was a better agonist for ERbeta than for ERalpha. No androgenic activity was detected for any of these compounds. Bisphenol-A, 3-OH phenylphenol, 4-OH phenylphenol and 4,4' biphenol exhibited antiandrogenic activity close to that of 4-tert-octylphenol (IC(50) approximately 5 microM). In whole cell binding assays, these compounds displaced [3H] R1881 with Ki = 10 microM. Although these Ki values seem high in comparison with that of hydroxyflutamide (0.4 microM), one must keep in mind that environmental chemicals can accumulate in adipose tissues for several years. In conclusion, these environmental chemicals may have a negative impact on androgen action during fetal and post-natal life.
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http://dx.doi.org/10.1016/s0303-7207(02)00094-1DOI Listing
July 2002