Publications by authors named "Catherine Fallet-Bianco"

52 Publications

Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations.

J Clin Immunol 2021 Feb 3. Epub 2021 Feb 3.

INSERM UMR1163, Imagine Institute, Université de Paris, Paris, France.

Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein-Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.
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http://dx.doi.org/10.1007/s10875-021-00985-wDOI Listing
February 2021

De novo mutations of are responsible for arthrogryposis broadening the -related phenotypes.

J Med Genet 2020 Sep 14. Epub 2020 Sep 14.

Institut National de la Santé et de la Recherche Médicale (Inserm), UMR-1195, Université Paris Saclay, Le Kremlin Bicêtre, 94276, France

Background: Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in in three unrelated individuals with AMC.

Methods: Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo.

Results: AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement.

Conclusion: We show for the first time that variants are responsible for early-onset motor defect leading to AMC indicating a critical role of in prenatal motor development and broadening the phenotypic spectrum of variants in .
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http://dx.doi.org/10.1136/jmedgenet-2020-107166DOI Listing
September 2020

A case report of severe tuberous sclerosis complex detected in utero and linked to a novel duplication in the TSC2 gene.

BMC Neurol 2020 Sep 1;20(1):324. Epub 2020 Sep 1.

Department of Neuroscience, Université de Montréal, Montreal, QC, Canada.

Background: Disease severity is tremendously variable in tuberous sclerosis complex (TSC). In contrast with the detailed guidelines available for TSC diagnosis and management, clinical practice lacks adequate tools to evaluate the prognosis, especially in the case of in utero diagnosis. In addition, the correlation between genotypes and phenotypes remains a challenge, in part due to the large number of mutations linked to TSC. In this report, we describe a case of severe TSC diagnosed in utero and associated with a specific mutation in the gene tuberous sclerosis complex 2 (TSC2).

Case Presentation: A mother was referred for a thorough investigation following the observation by ultrasound of cardiac abnormalities in her fetus. The mother was healthy and reported frequent, intense and long-lasting hiccups/spasms in the fetus. The fetus of gestational age 33 weeks and 4 days was found to have multiple cardiac tumors with cardiac ultrasound. Brain magnetic resonance imaging (MRI) performed in utero revealed the presence of sub-ependymal nodules and of abnormal signals disseminated in the white matter, in the cerebral cortex and in the cerebellum. Following diagnosis of definite TSC, pregnancy interruption was chosen by the parents. Genetic testing of the fetus exposed a duplication in exon 41 of TSC2 (c.5169dupA), which was absent in the parents. The autopsy ascertained the high severity of brain damage characterized by an extensive disorganisation of white and grey matter in most cerebral lobes.

Conclusions: This case presentation is the first to depict the association between a de novo TSC2 c.5169dupA and multi-organ manifestation together with indications of a particularly high disease severity. This report can help physicians to perform early clinical diagnosis of TSC and to evaluate the prognosis.
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http://dx.doi.org/10.1186/s12883-020-01905-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460776PMC
September 2020

Expanding the phenotypic and molecular spectrum of RNA polymerase III-related leukodystrophy.

Neurol Genet 2020 Jun 11;6(3):e425. Epub 2020 May 11.

Department of Neurology and Neurosurgery (S.P., L.G., M.A.M.-R., L.T.T., K.G., L.D., M. Srour, K.P., G.B.), McGill University; Child Health and Human Development Program (S.P., M.A.M.-R., L.T.T., K.G., L.D., M. Srour, G.B.), Research Institute of the McGill University Health Centre; Department of Pediatrics (L.G., L.T.T., K.G., L.D., M. Srour, G.B.), McGill University, Montreal, Quebec, Canada; Division of Clinical and Metabolic Genetics (L.G.), Division of Neurology, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Pathology (C.F.-B.), CHU Sainte-Justine, Université de Montreal, Quebec, Canada; Division of Pathology and Laboratory Medicine (M.K.D.), Phoenix Children's Hospital, AZ; Department of Human Genetics (L.T.T., K.G., L.D., G.B.), McGill University, Montreal, Quebec, Canada; McGill University (K.P.), Brain Tumour Research Center Montreal Neurological Institute and Hospital, Quebec, Canada; Department of Neurology (D.L.R.), Department of Clinical Genomics, Department of Pediatrics, Mayo Clinic, Rochester, MN; Department of Pediatrics (M. Saito), University of California Riverside School of Medicine, Riverside Medical Clinic, CA; Department of Pediatrics (S.C.), Beaver Medical Group, Redlands, CA; Division of Pediatric Neurology (S.L.), Department of Pediatrics, Klinikum Dritter Orden, Munich, Germany; Institute of Human Genetics (B.A., T.B.H.), Technische Universität München, Munich, Germany; Institute of Medical Genetics and Applied Genomics (T.B.H.), University of Tübingen, Germany; Department of Neurology (I.T.-M., F.I.M., N.R.-E.), Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Canary Islands, Spain; Department of Neurology (D.P.), Children's Hospital of Eastern Ontario, University of Ottawa, Ontario, Canada; Department of Pediatrics (S.N.) and Department of Neurology (A.G.), Wake Forest School of Medicine, Winston-Salem, NC; Adult and Paediatric National Metabolic Service (E.G.), Starship Children's Hospital, Auckland, New Zealand; and Division of Medical Genetics (G.B.), Department of Specialized Medicine, Montreal Children's Hospital and McGill University Health Centre, Quebec, Canada.

Objective: To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.

Methods: We performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.

Results: Each patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript.

Conclusions: We describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology.
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http://dx.doi.org/10.1212/NXG.0000000000000425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238899PMC
June 2020

Second report of RING finger protein 113A (RNF113A) involvement in a Mendelian disorder.

Am J Med Genet A 2020 03 3;182(3):565-569. Epub 2019 Dec 3.

Department of Biochemistry and Genetics, Angers University Hospital, Angers, France.

RING Finger Protein 113 A (RNF113A, MIM 300951) is a highly conserved gene located on chromosome Xq24-q25, encoding a protein containing two conserved zinc finger domains involved in DNA alkylation repair and premessenger RNA splicing. To date, only one pathogenic variant of RNF113A, namely c.901C>T; p.Gln301Ter, has been reported in humans by Tarpey et al. in 2009. Thereafter, Corbett et al. stated that this variant was responsible for an X-linked form of nonphotosensitive trichothiodystrophy associated with profound intellectual disability, microcephaly, partial corpus callosum agenesis, microphallus, and absent or rudimentary testes. This variant was then shown to alter DNA alkylation repair, providing an additional argument supporting its pathogenicity and important clues about the underlying pathophysiology of nonphotosensitive trichothiodystrophy. Using exome sequencing, we identified exactly the same RNF113A variant in two fetuses affected with abnormalities similar to those previously reported by Corbett et al. To our knowledge, this is the second report of a RNF113A pathogenic variant in humans.
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http://dx.doi.org/10.1002/ajmg.a.61384DOI Listing
March 2020

Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum.

Am J Med Genet A 2019 03 16;179(3):386-396. Epub 2019 Jan 16.

The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia.
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http://dx.doi.org/10.1002/ajmg.a.61025DOI Listing
March 2019

N° 365 -Autopsies fœtales et périnatales en cas d'anomalies fœtales diagnostiquées avant la naissance avec une analyse chromosomique normale.

J Obstet Gynaecol Can 2018 10;40(10):1367-1377.e6

Montréeal (Qc).

Objectif: Examiner les données sur les autopsies fœtales et périnatales, le processus de consentement et les options de collecte de renseignements à la suite d'un diagnostic prénatal d'anomalies non chromosomiques afin d'aider les fournisseurs de soins à offrir du conseil postnatal au sujet du diagnostic et des éventuels risques de récurrence. RéSULTATS: Offrir de meilleurs conseils sur les autopsies fœtales et périnatales aux femmes et aux familles qui ont reçu un diagnostic prénatal d'anomalie fœtale non chromosomique. ÉVIDENCE: Nous avons examiné des études publiées récupérées au moyen de recherches dans PubMed, Medline, CINAHL et la Bibliothèque Cochrane en 2010, en 2011 et en 2017 à l'aide de mots-clés appropriés (« fetal autopsy postmortem », « autopsy », « perinatal postmortem examination », « autopsy protocol », « postmortem magnetic resonance imaging », « autopsy consent », « tissue retention » et « autopsy evaluation »). Nous n'avons tenu compte que des résultats provenant de revues systématiques, d'essais cliniques, randomisés ou non, et d'études observationnelles. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et dans des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. AVANTAGES, DéSAVANTAGES ET COUTS: La présente mise à jour renseigne les lecteurs sur : 1) les avantages de l'autopsie fœtale ou périnatale; 2) le processus de consentement; et 3) les autres options offertes aux familles qui refusent l'autopsie. Elle met également en évidence la nécessité d'adopter une démarche normalisée pour la réalisation des autopsies fœtales et périnatales, et met l'accent sur les prélèvements additionnels qui peuvent être pertinents. Les auteurs sont conscients que l'accès aux ressources et aux services mentionnés varie d'un endroit l'autre au Canada; les recommandations formulées ont donc pour but de promouvoir l'accès et de fournir une norme minimale aux provinces et aux territoires du pays.

Valeurs: La qualité des données a été évaluée au moyen des critères énoncés dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs (tableau). RECOMMANDATIONS.
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http://dx.doi.org/10.1016/j.jogc.2018.08.006DOI Listing
October 2018

No. 365-Fetal and Perinatal Autopsy in Prenatally Diagnosed Fetal Abnormalities with Normal Chromosome Analysis.

J Obstet Gynaecol Can 2018 10;40(10):1358-1366.e5

Montréal, QC.

Objective: To review the information on fetal and perinatal autopsies, the process of obtaining consent, and the alternative information-gathering options following a prenatal diagnosis of non-chromosomal anomalies in order to assist health care providers in providing postnatal counselling regarding diagnosis and potential recurrence risks.

Outcomes: To provide better counselling about fetal and perinatal autopsies for women and families who are dealing with a prenatally diagnosed non-chromosomal fetal anomaly.

Evidence: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2010, 2011, and 2017, using appropriate key words (fetal autopsy postmortem, autopsy, perinatal postmortem examination, autopsy protocol, postmortem magnetic resonance imaging, autopsy consent, tissue retention, autopsy evaluation). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

Benefits, Harms, And Costs: This update educates readers about (1) the benefits of a fetal perinatal autopsy, (2) the consent process, and (3) the alternatives when the family declines autopsy. It also highlights the need for a standardized approach to fetal and perinatal autopsies, emphasizing pertinent additional sampling when indicated. The authors recognize that there is variability across Canada in access to the cited services and resources. As such, these recommendations were developed in an attempt to promote access and to provide a minimum standard for all provinces and territories across the country.

Values: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table).

Recommendations:
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http://dx.doi.org/10.1016/j.jogc.2018.05.017DOI Listing
October 2018

Neuropathology of holoprosencephaly.

Am J Med Genet C Semin Med Genet 2018 06;178(2):214-228

Department of Pathology, CHU Sainte-Justine-Chemin de la Côte Sainte-Catherine, Université de Montreal, Montreal, Québec, Canada.

Holoprosencephaly (HPE) is a primary disorder of neural induction and patterning of the rostral neural tube resulting in noncleavage of the forebrain with failure to form two separate distinct hemispheres. The spectrum of HPE is very broad and encompasses various neuropathological phenotypes of different severity. The recent literature has demonstrated that the phenotypic variability of HPE ranges from aprosencephaly-atelencephaly, at the most severe end, to milder forms such as the "middle interhemispheric variant" of HPE at the less severe end of the spectrum. Between them, different intermediate forms demonstrate a continuum in a wide phenotypic spectrum rather than well-defined categories. Although the term "HPE" suggests a disorder affecting only the prosencephalon, other brain structures are involved, underlining the complexity of the malformation. Because of close spatiotemporal interactions and common signaling pathways contributing to the development of both brain and face, concomitant facial and ocular anomalies are associated with brain malformation. In this review, the characteristic neuropathological features of the various forms of HPE are described as well as their associated brain, face, and ocular malformations, to delineate the different phenotypes.
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http://dx.doi.org/10.1002/ajmg.c.31623DOI Listing
June 2018

Genomic study of severe fetal anomalies and discovery of GREB1L mutations in renal agenesis.

Genet Med 2018 07 26;20(7):745-753. Epub 2017 Oct 26.

CHU Sainte-Justine, Montreal, Quebec, Canada.

Purpose: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies.

Methods: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia.

Results: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort.

Conclusion: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.
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http://dx.doi.org/10.1038/gim.2017.173DOI Listing
July 2018

Fetoscopic patch coverage of experimental myelomenigocele using a two-port access in fetal sheep.

Childs Nerv Syst 2017 Jul 26;33(7):1177-1184. Epub 2017 May 26.

Service de Médecine Foetale, Hôpital Armand Trousseau, APHP, 26 avenue du Docteur Arnold Netter, 75012, Paris, France.

Purpose: This study aims to assess the feasibility and the effectiveness of a fetoscopic myelomeningocele (MMC) coverage using a sealed inert patch through a two-port access, in the sheep model.

Methods: Forty-four fetuses underwent surgical creation of a MMC defect at day 75 and were divided into four groups according to the MMC repair technique, performed at day 90. Group 1 remained untreated. Group 2 had an open surgery using suture of the defect. Groups 3 and 4 underwent defect coverage using a Gore®-polytetrafluoroethylene patch secured with surgical adhesive (Bioglue®), with an open approach (group 3) and a fetoscopic one (group 4). Lambs were killed at term, and histological examinations were performed.

Results: Fetoscopic patch coverage was achieved in all the lambs of group 4. All the fetuses of group 2 had a complete closure of the defect whereas only 38% in group 3 and 14% in group 4. Fetal loss rate seems to be lower in group 4 than in groups 2 and 3.

Conclusion: Fetoscopic coverage of MMC defect can be performed using a sealed patch through a two-port access, but the patch and glue correction may not be the ideal technique to repair fetal MMC.
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http://dx.doi.org/10.1007/s00381-017-3461-7DOI Listing
July 2017

Epileptic Phenotype of Two Siblings with Asparagine Synthesis Deficiency Mimics Neonatal Pyridoxine-Dependent Epilepsy.

Neuropediatrics 2016 Dec 14;47(6):399-403. Epub 2016 Aug 14.

Département de Pathologie, CHU Sainte-Justine-Université de Montréal, Quebec, Canada.

We report the cases of a brother and a sister of nonconsanguineous parents who developed progressive microcephaly and had tremor, irritability, spasticity, startle reflexes, and permanent erratic myoclonus since birth. Focal clonic seizures, status epilepticus, and infantile spasms appeared later, during the first months of life, while erratic myoclonic jerks persisted. Electroencephalogram initially showed multifocal spikes that evolved into modified hypsarrhythmia and then discontinuous activity, evoking the progressive nature of the condition. Magnetic resonance imaging showed brain atrophy and poor myelination. Plasma and cerebrospinal fluid asparagine levels were normal or moderately reduced on repeat testing. Both infants died at the age of 8 months in status epilepticus. Neuropathology of the brother revealed diffuse neuronal loss and astrocytic gliosis predominating in superficial layers of temporal and frontal lobes and in thalamus with almost absent myelin, as a consequence of the neuronal death. Whole exome sequencing of the siblings and parents revealed compound heterozygous c.1439C > T (p.Ser480Phe) and c.1648C > T (p.Arg550Cys) mutations in the gene, indicating asparagine synthetase (ASNS) deficiency. Electroclinical epileptic phenotype and neuropathological findings of ASNS deficiency are reminiscent of neonatal pyridoxine-dependent epilepsy, thus suggesting common pathophysiological mechanism possibly related to cytotoxic glutamate accumulation.
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http://dx.doi.org/10.1055/s-0036-1586222DOI Listing
December 2016

Joubert Syndrome in French Canadians and Identification of Mutations in CEP104.

Am J Hum Genet 2015 Nov 17;97(5):744-53. Epub 2015 Oct 17.

Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Université de Montréal, Montreal, QC H3T 1J4, Canada; Department of Neurosciences, Université de Montréal, Montreal, QC H3T 1J4, Canada. Electronic address:

Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.
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http://dx.doi.org/10.1016/j.ajhg.2015.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667103PMC
November 2015

Mosaic parental germline mutations causing recurrent forms of malformations of cortical development.

Eur J Hum Genet 2016 Apr 23;24(4):611-4. Epub 2015 Sep 23.

Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France.

To unravel missing genetic causes underlying monogenic disorders with recurrence in sibling, we explored the hypothesis of parental germline mosaic mutations in familial forms of malformation of cortical development (MCD). Interestingly, four families with parental germline variants, out of 18, were identified by whole-exome sequencing (WES), including a variant in a new candidate gene, syntaxin 7. In view of this high frequency, revision of diagnostic strategies and reoccurrence risk should be considered not only for the recurrent forms, but also for the sporadic cases of MCD.
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http://dx.doi.org/10.1038/ejhg.2015.192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929884PMC
April 2016

Rare ACTG1 variants in fetal microlissencephaly.

Eur J Med Genet 2015 Aug 16;58(8):416-8. Epub 2015 Jul 16.

Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Institut Imagine-INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Paris, France. Electronic address:

Heterozygous ACTG1 mutations are responsible for Baraitser-Winter cerebrofrontofacial syndrome which cortical malformation is characterized by pachygyria with frontal to occipital gradient of severity. We identified by whole exome sequencing in a cohort of 12 patients with prenatally diagnosed microlissencephaly, 2 foetal cases with missense mutations in the ACTG1 gene and in one case of living patient with typical Baraitser-Winter syndrome. Both foetuses and child exhibited microcephaly and facial dysmorphism consisting of microretrognatism, hypertelorism and low-set ears. Brain malformations included lissencephaly with an immature cortical plate, dysmorphic (2/3) or absent corpus callosum and vermian hypoplasia (2/3). Our results highlight the powerful diagnostic value of exome sequencing for patients with microlissencephaly, that may expand the malformation spectrum of ACTG1-related Baraitser-Winter cerebrofrontofacial syndrome and may suggest that ACTG1 could be added to the list of genes for assessing microlissencephaly.
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http://dx.doi.org/10.1016/j.ejmg.2015.06.006DOI Listing
August 2015

Disruption of CLPB is associated with congenital microcephaly, severe encephalopathy and 3-methylglutaconic aciduria.

J Med Genet 2015 May 3;52(5):303-11. Epub 2015 Feb 3.

CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Canada Department of Neurosciences, Université de Montréal, Montreal, Canada Department of Pediatrics, Université de Montréal, Montreal, Canada.

Background: The heterogeneous group of 3-methylglutaconic aciduria disorders includes several inborn errors of metabolism that affect mitochondrial function through poorly understood mechanisms. We describe four newborn siblings, from a consanguineous family, who showed microcephaly, small birth weight, severe encephalopathy and 3-methylglutaconic aciduria. Their neurological examination was characterised by severe hypertonia and the induction of prolonged clonic movements of the four limbs upon minimal tactile stimulation.

Methods And Results: Using homozygosity mapping and exome sequencing, we identified a homozygous truncating mutation (p.I562Tfs*23) in CLPB segregating with the disease in this family. CLPB codes for a member of the family of ATPases associated with various cellular activities (AAA(+) proteins) whose function remains unknown. We found that CLPB expression is abolished in fibroblasts from the patients. To investigate the function of this gene, we interfered with the translation of the zebrafish clpb orthologue using an antisense morpholino. The clpb morphants showed an abnormal touch-evoked response with increased swim velocity and tail beat frequency. This motor phenotype is reminiscent of that observed in the patients and is suggestive of increased excitability in neuronal circuits. Interestingly, knocking down clpb reduced the number of inhibitory glycinergic interneurons and increased a population of excitatory glutamatergic neurons in the spinal cord.

Conclusions: Altogether, our study suggests that disruption of CLPB causes a novel form of neonatal encephalopathy associated with 3-methylglutaconic aciduria.
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http://dx.doi.org/10.1136/jmedgenet-2014-102952DOI Listing
May 2015

Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly.

Acta Neuropathol Commun 2014 Jul 25;2:69. Epub 2014 Jul 25.

Institut Imagine, Université Paris Descartes - Sorbonne Paris Cités, Paris, France.

Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as "Tubulinopathies". To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2-3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).
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http://dx.doi.org/10.1186/2051-5960-2-69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222268PMC
July 2014

Involvement of the subplate zone in preterm infants with periventricular white matter injury.

Brain Pathol 2014 03 18;24(2):128-41. Epub 2014 Feb 18.

Inserm U676, Paris; Croatian Institute for Brain Research, Medical School, University of Zagreb, Zagreb.

Studies of periventricular white matter injury (PWMI) in preterm infants suggest the involvement of the transient cortical subplate zone. We studied the cortical wall of noncystic and cystic PWMI cases and controls. Non-cystic PWMI corresponded to diffuse white matter lesions, the predominant injury currently detected by imaging. Glial cell populations were analyzed in post-mortem human frontal lobes from very preterm [24–29 postconceptional weeks (pcw)] and preterm infants (30–34 pcw) using immunohistochemistry for glial fibrillary acidic protein (GFAP), monocarboxylate transporter 1(MCT1), ionized calcium-binding adapter molecule 1 (Iba1), CD68 and oligodendrocyte lineage (Olig2). Glial activation extended into the subplate in non-cystic PWMI but was restricted to the white matter in cystic PWMI. Two major age-related and laminar differences were observed in non-cystic PWMI: in very preterm cases, activated microglial cells were increased and extended into the subplate adjacent to the lesion, whereas in preterm cases, an astroglial reaction was seen not only in the subplate but throughout the cortical plate. There were no differences in Olig2-positive pre-oligodendrocytes in the subplate inPWMI cases compared with controls. The involvement of gliosis in the deep subplate supports the concept of the complex cellular vulnerability of the subplate zone during the preterm period and may explain widespread changes in magnetic resonance signal intensity in early PWMI.
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http://dx.doi.org/10.1111/bpa.12096DOI Listing
March 2014

The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

Brain 2014 Jun;137(Pt 6):1676-700

1 Institut Cochin, Université Paris-Descartes, CNRS (UMR 8104), Paris, France2 Inserm, U1016, Paris, France.

Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.
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http://dx.doi.org/10.1093/brain/awu082DOI Listing
June 2014

Cytomegalovirus-induced brain malformations in fetuses.

J Neuropathol Exp Neurol 2014 Feb;73(2):143-58

From the Inserm (NT, A-LD, SK-S, JN, SC, ZC, TVDA, PG, HA-B); Univ Paris Diderot, Sorbonne Paris Cité (NT, A-LD, S-KS, JN, SC, TVDA, PG, HAB); Paediatric Otorhinolaryngology Department, Robert Debré Hospital (NT, TVDA); Department of Pathology, Sainte-Anne/Cochin Hospital (CF-B, A-LD); and Biology of Development Department, Robert Debré Hospital (A-LD, SK-S), Paris; Department of Pathology, Charles Nicolle Hospital, Rouen (AL); Department of Pathology, Morvan Hospital, Brest (PM); Obstetrics Department, Béclère Hospital, Clamart (OP); and Obstetrics Department, Foch Hospital, Suresnes (OP), France; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (JAG); Centre for the Developing Brain, King's College, St. Thomas' Campus, London, United Kingdom (PG); and Department of Pathology, Lariboisière Hospital, Paris, France (HA-B).

Neurologic morbidity associated with congenital cytomegalovirus (CMV) infection is a major public health concern. The pathogenesis of cerebral lesions remains unclear. We report the neuropathologic substrates, the immune response, and the cellular targets of CMV in 16 infected human fetal brains aged 23 to 28.5 gestational weeks. Nine cases were microcephalic, 10 had extensive cortical lesions, 8 had hippocampal abnormalities, and 5 cases showed infection of the olfactory bulb. The density of CMV-immunolabeled cells correlated with the presence of microcephaly and the extent of brain abnormalities. Innate and adaptive immune responses were present but did not react against all CMV-infected cells. Cytomegalovirus infected all cell types but showed higher tropism for stem cells/radial glial cells. The results indicate that 2 main factors influence the neuropathologic outcome at this stage: the density of CMV-positive cells and the tropism of CMV for stem/progenitor cells. This suggests that the large spectrum of CMV-induced brain abnormalities is caused not only by tissue destruction but also by the particular vulnerability of stem cells during early brain development. Florid infection of the hippocampus and the olfactory bulb may expose these patients to the risk of neurocognitive and sensorineural handicap even in cases of infection at late stages of gestation.
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http://dx.doi.org/10.1097/NEN.0000000000000038DOI Listing
February 2014

Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases.

Acta Neuropathol 2013 Sep 3;126(3):427-42. Epub 2013 Jul 3.

Department of Pathology, Lariboisière Hospital, APHP, 2 Rue Ambroise Paré, 75010, Paris, France.

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.
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http://dx.doi.org/10.1007/s00401-013-1146-1DOI Listing
September 2013

Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly.

Am J Hum Genet 2012 Dec;91(6):1135-43

Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Biochimie, Paris 75877, France.

Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.
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http://dx.doi.org/10.1016/j.ajhg.2012.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516603PMC
December 2012

Antenatal spectrum of CHARGE syndrome in 40 fetuses with CHD7 mutations.

J Med Genet 2012 Nov 28;49(11):698-707. Epub 2012 Sep 28.

INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.

Background: CHARGE syndrome is a rare, usually sporadic disorder of multiple congenital anomalies ascribed to a CHD7 gene mutation in 60% of cases. Although the syndrome is well characterised in children, only one series of 10 fetuses with CHARGE syndrome has been reported to date. Therefore, we performed a detailed clinicopathological survey in our series of fetuses with CHD7 mutations, now extended to 40 cases. CHARGE syndrome is increasingly diagnosed antenatally, but remains challenging in many instances.

Method: Here we report a retrospective study of 40 cases of CHARGE syndrome with a CHD7 mutation, including 10 previously reported fetuses, in which fetal or neonatal clinical, radiological and histopathological examinations were performed.

Results: Conversely to postnatal studies, the proportion of males is high in our series (male to female ratio 2.6:1) suggesting a greater severity in males. Features almost constant in fetuses were external ear anomalies, arhinencephaly and semicircular canal agenesis, while intrauterine growth retardation was never observed. Finally, except for one, all other mutations identified in our antenatal series were truncating, suggesting a possible phenotype-genotype correlation.

Conclusions: Clinical analysis allowed us to refine the clinical description of CHARGE syndrome in fetuses, describe some novel features and set up diagnostic criteria in order to help the diagnosis of CHARGE syndrome after termination of pregnancies following the detection of severe malformations.
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http://dx.doi.org/10.1136/jmedgenet-2012-100926DOI Listing
November 2012

Central nervous system malformations and deformations in FGFR2-related craniosynostosis.

Am J Med Genet A 2012 Nov 17;158A(11):2797-806. Epub 2012 Sep 17.

Craniofacial Development and Stem Cell Biology, Comprehensive Biomedical Research Centre, Dental Institute, King's College London, Guy's Hospital, London, United Kingdom.

Central nervous system anomalies in Pfeiffer syndrome (PS) due to mutations in the FGFR2 gene are poorly understood, even though PS is often associated with serious cognitive impairment. The aim of this study is to describe the neuropathological phenotype in PS. We present four severe fetal cases of sporadic PS with FGFR2 mutations who underwent termination followed by fetopathological and neuropathological examination. We studied the expression pattern of Fgfr2 in the mouse brain using radioactive fluorescence in situ hybridization. PS is associated with brain deformations due to the abnormal skull shape, but FGFR2 mutations also induce specific brain developmental anomalies: megalencephaly, midline disorders, amygdala, and hippocampus malformations, and ventricular wall alterations. The expression pattern of Fgfr2 in mice matches the distribution of malformations in humans. The brain anomalies in PS result from the combination of mechanical deformations and intrinsic developmental disorders due to FGFR2 hyperactivity. Several similarities are noted between these anomalies and the brain lesions observed in other syndromes due to mutations in FGF-receptor genes. The specific involvement of the hippocampus and the amygdala should encourage the precise cognitive screening of patients with mild forms of PS.
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http://dx.doi.org/10.1002/ajmg.a.35598DOI Listing
November 2012

Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies.

Brain 2012 Feb 9;135(Pt 2):469-82. Epub 2012 Feb 9.

Institut de Pathologie, Centre de Biologie-Pathologie, CHU Lille, 33.3.20446983, France.

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).
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http://dx.doi.org/10.1093/brain/awr357DOI Listing
February 2012

Microglial reaction in axonal crossroads is a hallmark of noncystic periventricular white matter injury in very preterm infants.

J Neuropathol Exp Neurol 2012 Mar;71(3):251-64

INSERM U676, Hôpital Robert Debré, 48 Blvd Sérurier, 75019 Paris, France.

Disabilities after brain injury in very preterm infants have mainly been attributed to noncystic periventricular white matter injury (PWMI). We analyzed spatiotemporal patterns of PWMI in the brains of 18 very preterm infants (25-29 postconceptional weeks [pcw]), 7 preterm infants (30-34 pcw), and 10 preterm controls without PWMI. In very preterm infants, we examined PWMI in detail in 2 axonal crossroad areas in the frontal lobe: C1 (lateral to the lateral angle of the anterior horn of the lateral ventricle, at the exit of the internal capsule radiations) and C2 (above the corpus callosum and dorsal angle of the anterior horn). These brains had greater microglia-macrophage densities and activation but lesser astroglial reaction (glial fibrillary acidic protein and monocarboxylate transporter 1 expression) than in preterm cases with PWMI. In preterm infants, scattered necrotic foci were rimmed by axonal spheroids and ionized calcium binding adaptor molecule 1-positive macrophages. Diffuse lesions near these foci consisted primarily of hypertrophic and reactive astrocytes associated with fewer microglia. No differences in Olig2-positive preoligodendrocytes between noncystic PWMI and control cases were found. These data show that the growing axonal crossroad areas are highly vulnerable to PWMI in very preterm infants and highlight differences in glial activation patterns between very preterm and preterm infants.
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http://dx.doi.org/10.1097/NEN.0b013e3182496429DOI Listing
March 2012

The histopathological spectrum of cutaneous meningeal heterotopias: clues and pitfalls.

Histopathology 2011 Sep;59(3):407-20

Pathology Department, Hôpital Saint Louis, Paris 7 University, Assistance Publique Hopitaux de Paris, Paris, France.

Aims: To describe the histopathological features of heterotopic cutaneous meningeal tissue.

Methods And Results: Nineteen cases were collected between 1993 and 2010. Immunohistochemistry for epithelial membrane antigen (EMA), neuron specific enolase (NSE), S100, glial fibrillary acid protein (GFAP), progesterone receptor (PR), CD31, glucose transporter-1 (Glut-1), podoplanin and NKI-C3 was performed. Lesions were congenital (100%) and presented as aplasia cutis with alopecia (63%) or lumps (37%), on the scalp (18 of 19) and sacral region. Resonance magnetic imaging revealed four underlying anomalies of the neuraxis. Histopathological analysis showed meningeal tissue arranged in four variably associated architectural patterns: fibrous (100%), pseudovascular (100%), cellular (68%) and pseudomyxoid (32%). Other features included collagen bodies (58%), calcifications (26%) and dermal melanocytes (32%). Heterotopic brain tissue or heterotopic ependymal cyst was associated in two cases. Arachnoidal cells expressed EMA and NSE, but not S100 protein, CD31 or GFAP. They expressed podoplanin (93%), especially in pseudovascular areas, NKI-C3 (79%), and less frequently Glut-1 (46%) and PR (30%).

Conclusions: Histopathological features of cutaneous meningeal heterotopias are various and sometimes misleading. Fibrous lesions should not be misdiagnosed as aplasia cutis. Podoplanin-positive pseudovascular spaces represent the main pitfall and should not be diagnosed as lymphangioma. Correct diagnosis is confirmed by EMA and NSE coexpression within the lesion.
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http://dx.doi.org/10.1111/j.1365-2559.2011.03968.xDOI Listing
September 2011

Long-standing prion dementia manifesting as posterior cortical atrophy.

Alzheimer Dis Assoc Disord 2012 Jul-Sep;26(3):289-92

Assistance Publique-Hôpitaux de Paris, Département de Neurologie, Paris, France.

Prion diseases commonly manifest with the phenotype of subacute myoclonic encephalopathy. However, genetic forms of prion disease may have prolonged evolution mimicking neurodegenerative disease. We present the clinical and neuropathological features of a family with an early and long-standing dementia manifesting with posterior cortical atrophy and related to a 120 bp insertional mutation of the prion protein gene. Two cases exhibited mixed prion and Aβ pathology. The differential diagnosis with Alzheimer disease is discussed.
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http://dx.doi.org/10.1097/WAD.0b013e318231e449DOI Listing
January 2013

The fetal cerebellum: development and common malformations.

J Child Neurol 2011 Dec 27;26(12):1483-92. Epub 2011 Sep 27.

Service de Radiologie, Hôpital d'Enfants Armand-Trousseau, Paris, France.

The cerebellum undergoes a protracted development, making it particularly vulnerable to a broad spectrum of developmental events. Acquired destructive and hemorrhagic insults may also occur. The main steps of cerebellar development are reviewed. The normal imaging patterns of the cerebellum in prenatal ultrasound and magnetic resonance imaging (MRI) are described with emphasis on the limitations of these modalities. Because of confusion in the literature regarding the terminology used for cerebellar malformations, some terms (agenesis, hypoplasia, dysplasia, and atrophy) are clarified. Three main pathologic settings are considered and the main diagnoses that can be suggested are described: retrocerebellar fluid enlargement with normal or abnormal biometry (Dandy-Walker malformation, Blake pouch cyst, vermian agenesis), partially or globally decreased cerebellar biometry (cerebellar hypoplasia, agenesis, rhombencephalosynapsis, ischemic and/or hemorrhagic damage), partially or globally abnormal cerebellar echogenicity (ischemic and/or hemorrhagic damage, cerebellar dysplasia, capillary telangiectasia). The appropriate timing for performing MRI is also discussed.
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http://dx.doi.org/10.1177/0883073811420148DOI Listing
December 2011

Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions.

J Clin Invest 2010 Oct;120(10):3668-72

INSERM U1016, Département de Génétique et Développement, Institut Cochin, Université Paris-Descartes, Paris, France.

Patients with Kallmann syndrome (KS) have hypogonadotropic hypogonadism caused by a deficiency of gonadotropin-releasing hormone (GnRH) and a defective sense of smell related to olfactory bulb aplasia. Based on the findings in a fetus affected by the X chromosome–linked form of the disease, it has been suggested that hypogonadism in KS results from the failed embryonic migration of neuroendocrine GnRH1 cells from the nasal epithelium to the forebrain. We asked whether this singular observation might extend to other developmental disorders that also include arrhinencephaly. We therefore studied the location of GnRH1 cells in fetuses affected by different arrhinencephalic disorders, specifically X-linked KS, CHARGE syndrome, trisomy 13, and trisomy 18, using immunohistochemistry. Few or no neuroendocrine GnRH1 cells were detected in the preoptic and hypothalamic regions of all arrhinencephalic fetuses, whereas large numbers of these cells were present in control fetuses. In all arrhinencephalic fetuses, many GnRH1 cells were present in the frontonasal region, the first part of their migratory path, as were interrupted olfactory nerve fibers that formed bilateral neuromas. Our findings define a pathological sequence whereby a lack of migration of neuroendocrine GnRH cells stems from the primary embryonic failure of peripheral olfactory structures. This can occur either alone, as in isolated KS, or as part of a pleiotropic disease, such as CHARGE syndrome, trisomy 13, and trisomy 18.
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http://dx.doi.org/10.1172/JCI43699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947242PMC
October 2010