H̱olon, Israel
H̱olon, Israel

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Leshinsky-Silver E.,Wolfson Medical Center | Leshinsky-Silver E.,Mitochondrial Disease Center | Leshinsky-Silver E.,Tel Aviv University | Malinger G.,Tel Aviv University | And 18 more authors.
European Journal of Human Genetics | Year: 2011

Aicardi-Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLGα, POLGΒ, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9 kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components. © 2011 Macmillan Publishers Limited All rights reserved.


Robles Fradejas M.,Prenatal Diagnosis Unit | Gonzalo Garcia I.,Prenatal Diagnosis Unit | De las Casas Quispe A.C.,Prenatal Diagnosis Unit | Martin Garcia A.,Prenatal Diagnosis Unit | And 2 more authors.
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2016

Objectives: To describe a case diagnosed with intracranial teratoma in week 32 of gestation, as well as review of the literature in order to discern the appropriate treatment method and general prognosis of this anomaly. Methods: A literature search was performed on the prenatal diagnosis of congenital intracranial teratomas in MEDLINE, EMBASE, Cochrane library data bases. Evaluated in this review are parameters such as time of prenatal diagnosis, associated pathology, size of tumors, method of terminating pregnancy, perinatal outcome and histological study of the tumor. Results: A total of 49 cases were found, of which 12 were finished gestation, 28 cesarean section was performed and only nine had vaginal delivery. All died in the neonatal period except in three cases with intrauterine death after diagnosis. Conclusion: As the incidence of intracranial immature teratomas is very low and the prognosis is poor, their prenatal diagnosis and obstetric management present a great challenge for the planning of a follow-up and treatment of the disease in accordance with the preferences of the parents. © 2016 Informa UK Limited, trading as Taylor & Francis Group.


Leshinsky-Silver E.,Wolfson Medical Center | Leshinsky-Silver E.,Mitochondrial Disease Center | Lev D.,Mitochondrial Disease Center | Lev D.,Institute of Medical Genetics | And 8 more authors.
Molecular Genetics and Metabolism | Year: 2010

Leigh syndrome can be caused by defects in both nuclear and mitochondrial genes involved in energy metabolism. Recently, an increasing number of mutations in mitochondrial DNA encoding regions, especially in NADH dehydrogenase (respiratory chain complex I) subunits, have been reported as causative of early onset Leigh syndrome. We describe a patient whose fetal brain ultrasound demonstrated periventricular pseudocyst suggestive of a possible mitochondrial disorder who presented postnatally with Leigh syndrome. A muscle biopsy demonstrated a partial decrease in complex I and pyruvate dehydrogenase (PDH-E1α) activity. Sequencing of the PDH-E1 alpha gene did not reveal any mutation. Sequencing of the mtDNA revealed a novel heteroplasmic G10254A (D66N) mutation in the ND3 gene. This change results in a substitution of aspartic acid to asparagine in a highly conserved domain of the ND3 subunit. The mutation could not be detected in the mother's blood or urine sediment. Blue native gel electrophoresis of muscle mitochondria revealed a normal size, albeit a decreased level of complex I. The G10254A substitution in the mtDNA-ND3 gene is another cause of maternally inherited Leigh syndrome. This case demonstrates that periventricular pseudocysts may be the initial in utero presentation in patients with mitochondrial disorders. We emphasize the importance of screening the mtDNA in pediatric patients as the first step in molecular diagnosis of Leigh syndrome. © 2010 Elsevier Inc. All rights reserved.


Haratz K.,Fetal Neurology Clinic | Haratz K.,Genetics Institute | Haratz K.,Federal University of São Paulo | Vinkler C.,Fetal Neurology Clinic | And 12 more authors.
Fetal Diagnosis and Therapy | Year: 2011

Hemifacial microsomia (OMIM164210) is a condition featuring unilateral ear anomalies and ocular epibulbar dermoids associated with unilateral underdevelopment of the craniofacial bony structures. Other associated anomalies have also been described, especially spinal malformations, and the term oculoauriculovertebral dysplasia spectrum (OVAS) was suggested to include the three predominant systems involved. Both genetic and environmental causes are implied in the pathogenesis of the syndrome, with a 3% recurrence rate according to reports of both vertical transmission and affected siblings. No specific gene was identified, albeit mutations in chromosome 10 and deficiencies of genes in the endothelin pathway in mice exhibited the same clinical features. We hereby describe the first case of prenatal diagnosis of spinal and rib malformations associated to hemifacial microsomia by means of 2-D and 3-D ultrasound in a 23-week fetus. The sonographic study depicted fetal scoliosis due to the presence of hemivertebrae, Sprengel's deformity of the left shoulder, ribs fusion, asymmetric ears with unilateral microtia, mandible unilateral hypoplasia as well as single umbilical artery and a 'golf ball' sign in the left ventricle of the heart. The diagnosis of OVAS was suggested and the family received proper genetic consultation. After termination of the pregnancy, the syndrome was confirmed by postmortem 3-D computed tomography study. In view of the grim outcome, prenatal death rate and high mortality and morbidity when three or more systems are involved, prenatal diagnosis and appropriate counseling are warranted. Copyright © 2011 S. Karger AG, Basel.


Lenis-Cordoba N.,Prenatal Diagnosis Unit | Sanchez M.A.,Prenatal Diagnosis Unit | Bello-Munoz J.C.,Hospital Universitari Vall d Hebron | Sagala-Martinez J.,Prenatal Diagnosis Unit | And 3 more authors.
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2013

Aim: To compare the rate of pregnancy loss between twin pregnancies undergoing a genetic amniocentesis (AC) and a control group with similar characteristics. Methods: Prospective observational study on a population of twin pregnancies referred to our prenatal diagnosis unit for screening from 1990 to 2010. Those women referred for an AC were compared with those without indication for the procedure. Primary outcomes were pregnancy loss within the 4 weeks after procedure and pregnancy loss before 24 weeks. Secondary outcome included neonatal morbidity, gestational age at delivery and birth weight. Results: Maternal characteristics were similar for both groups, except for maternal age. There was neither difference in the pregnancy loss rate within 4 weeks (2.7 versus 2.6%) nor in the loss rate before 24 weeks of gestation (1.2 versus 1.1%). Gestational age at birth was 36 weeks for both groups. Chorionicity and gestational age at procedure played no role in modifying the risk. Conclusion: Based on our results, there is no difference in the pregnancy loss rate in twin gestations, regardless of chorionicity or gestational age at procedure, either within 4 weeks after the procedure or before 24 weeks, in patients who undergo AC when compared with patients who do not. © 2013 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.


Micale L.,Laboratory of Medical Genetics | Turturo M.G.,Laboratory of Medical Genetics | Fusco C.,Laboratory of Medical Genetics | Fusco C.,University of Foggia | And 9 more authors.
European Journal of Human Genetics | Year: 2010

Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta, which can occur sporadically as an autosomal dominant condition or as one component of the Williams-Beuren syndrome, a complex developmental genomic disorder associated with cardiovascular, neurobehavioral, craniofacial, and metabolic abnormalities, caused by a microdeletion at 7q11.23. We report the identification of seven novel mutations within the elastin gene in 31 familial and sporadic cases of nonsyndromic SVAS. Five are frameshift mutations within the coding region of the ELN gene that result in premature stop codons (PTCs); the other two mutations abolish the donor splice site of introns 3 and 28, respectively, and are predicted to alter splicing efficiency resulting in the generation of a PTC within the same introns of the gene. In vitro analysis using minigenes and cycloheximide showed that some selected frameshift mutant alleles are substrates of nonsense-mediated mRNA decay (NMD), confirming that the functional haploinsufficiency of the ELN gene is the main pathomechanism underlying SVAS. Interestingly, molecular analysis on patient fibroblasts showed that the c.20445GC mutant allele encodes for an aberrant shorter form of the elastin polypeptide that may hamper the normal assembly of elastin fibers in a dominant-negative manner. © 2010 Macmillan Publishers Limited All rights reserved.


Gerundino F.,University of Florence | Giachini C.,University of Florence | Contini E.,University of Florence | Benelli M.,University of Florence | And 22 more authors.
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2016

Objective: The aim of this study was to validate noninvasive prenatal testing (NIPT) for fetal aneuploidies by whole-genome massively parallel sequencing (MPS). Methods: MPS was performed on cell-free DNA (cfDNA) isolated from maternal plasma in two groups: a first set of 186 euploid samples and a second set of 195 samples enriched of aneuploid cases (n = 69); digital PCR for fetal fraction (FF) assessment was performed on 178/381 samples. Cases with <10 × 106 reads (n = 54) were excluded for downstream data analysis. Follow-up data (invasive testing results or neonatal information) were available for all samples. Performances in terms of specificity/sensitivity and Z-score distributions were evaluated. Results: All positive samples for trisomy 21 (T21) (n = 43), trisomy 18 (T18) (n = 6) and trisomy 13 (T13) (n = 7) were correctly identified (sensitivity: 99.9%); 5 false positive results were reported: 3 for T21 (specificity = 98.9%) and 2 for T13 (specificity = 99.4%). Besides FF, total cfDNA concentration seems another important parameter for MPS, since it influences the number of reads. Conclusions: The overall test accuracy allowed us introducing NIPT for T21, T18 and T13 as a clinical service for pregnant women after 10 + 4 weeks of gestation. Sex chromosome aneuploidy assessment needs further validation due to the limited number of aneuploid cases in this study. © 2016 Informa UK Limited, trading as Taylor & Francis Group.


Carmi-Nawi N.,Macabi Health Services | Carmi-Nawi N.,Prenatal Diagnosis Unit | Malinger G.,Tel Aviv University | Mandel H.,Metabolic Disease Unit | And 7 more authors.
Journal of Child Neurology | Year: 2011

Molybdenum cofactor deficiency is a rare autosomal recessive disorder that may present during the neonatal period with intractable seizures and be mistaken for ischemic encephalopathy. We describe a patient whose prenatal sonography at 35 weeks' gestation revealed diffuse brain damage with multiple subcortical cavities, ventriculomegaly, dysgenesis of the corpus callosum, and a hypoplastic cerebellum with an enlarged cisterna magna. Magnetic resonance imaging (MRI) later revealed brain atrophy, and multicystic encephalomalacia with hypoplastic vermis and cerebellum. Neurological examination at 10 months showed microcephaly, profound mental retardation, and spasticity. Uric acid was low, and taurine and xanthine were increased in the urine. A sulfite test was positive. The diagnosis of molybdenum cofactor deficiency was made. Sulfite oxidase activity in fibroblasts was undetectable. The patient was found to be homozygous for the 251-418del in the MOCS1 gene. This is the first description of the prenatal development of severe brain disruption in molybdenum cofactor deficiency. © 2011 The Author(s).

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