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1.
Ultrasound Obstet Gynecol ; 62(6): 867-874, 2023 12.
Article in English | MEDLINE | ID: mdl-37519281

ABSTRACT

OBJECTIVE: Placental infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to placental insufficiency and in-utero fetal death (IUFD). The objective of this study was to confirm and quantify the extent to which fetoplacental infection with SARS-CoV-2 is a cause of fetal death. METHODS: This was a multicenter retrospective cohort study of fetal deaths that underwent postmortem examination between January 2020 and January 2022 in three fetal pathology units in Paris, France. All cases of IUFD and termination of pregnancy (TOP) occurring in 31 maternity hospitals in the Paris region undergo detailed placental pathological examination in these units. Databases were searched for cases of IUFD and TOP. Cases with fetal malformation or cytogenetic abnormality were excluded to avoid bias. We included cases of IUFD with a placental or undetermined cause and cases of TOP in the context of severe intrauterine growth restriction (IUGR). Placentas were sent to a single virology unit for reverse-transcription polymerase chain reaction (RT-PCR) testing by a single laboratory technician blinded to the initial postmortem examination report. Our primary endpoint was the proportion of positive placental SARS-CoV-2 RT-PCR tests in the cohort. RESULTS: Among 147 722 deliveries occurring over 2 years, 788 postmortem examinations for IUFD and TOP for severe IUGR were recorded, of which 462 (58.6%) were included. A total of 13/462 (2.8%) placentas tested positive for SARS-CoV-2 by RT-PCR. Wild-type virus and alpha and delta variants were identified. All positive cases had histological lesions consistent with placental dysfunction. There was a strong correlation between SARS-CoV-2 placentitis and the presence of chronic intervillositis and/or massive fibrin deposits in the placenta. When both lesion types were present, the specificity and negative predictive value for the diagnosis of placental SARS-CoV-2 infection were 0.99 (95% CI, 0.98-1.00) and 0.96 (95% CI, 0.94-0.98), respectively. CONCLUSIONS: At the height of the SARS-CoV-2 pandemic, the cause of more than half of fetal deaths in the Paris area was determined by postmortem analysis to be of placental or undetermined origin. Of these cases, 2.8% were due to placental SARS-CoV-2 infection with a specific pattern of histological involvement. This study highlights the need for SARS-CoV-2 screening in stillbirth assessment. The impact of vaccination coverage remains to be established. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Female , Pregnancy , Humans , COVID-19/diagnosis , SARS-CoV-2 , Placenta/pathology , Retrospective Studies , Fetal Death/etiology
2.
Clin Genet ; 93(6): 1141-1147, 2018 06.
Article in English | MEDLINE | ID: mdl-29508392

ABSTRACT

Ephrin B2, one of the ligand of the EphB receptors, is involved in a complex signaling pathway regulating the development of the nervous system, neuronal migration, erythropoiesis and vasculogenesis. We report a patient with a de novo variant in EFNB2 and a family in which segregates a 610-kb deletion at chromosome 13q33 encompassing only ARGLU1 and EFNB2 genes. The de novo variant was observed in a patient with anal stenosis, hypoplastic left ventricle and mild developmental delay. The deletion was identified in 2 sibs with congenital heart defect and mild developmental delay. One of the affected sibs further had myoclonic epilepsy and bilateral sensorineural hearing loss. The carrier mother was apparently asymptomatic. Because EFNB2 is located in the subtelomeric region of 13q chromosome, we reviewed the previous reports of terminal 13q deletion. We suggest that haploinsufficiency of the EFNB2 could be at the origin of several clinical features reported in 13qter deletions, including intellectual disability, seizures, congenital heart defects, anorectal malformation and hearing loss.


Subject(s)
Chromosome Disorders/genetics , Ephrin-B2/genetics , Haploinsufficiency/genetics , Neurodevelopmental Disorders/genetics , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 13/genetics , Female , Genetic Association Studies , Humans , Infant , Infant, Newborn , Male , Pedigree
3.
Ultrasound Obstet Gynecol ; 50(1): 79-87, 2017 Jul.
Article in English | MEDLINE | ID: mdl-27706859

ABSTRACT

OBJECTIVE: Diffusion-weighted magnetic resonance imaging (DWI) is a sensitive method for assessing brain maturation and detecting brain lesions, providing apparent diffusion coefficient (ADC) values as a measure of water diffusion. Abnormal ADC values are seen in ischemic brain lesions, such as those associated with acute or chronic hypoxia. The aim of this study was to assess whether ADC values in the fetal brain were different in fetuses with severe intrauterine growth restriction (IUGR) compared with normal controls. METHODS: Brain magnetic resonance imaging (MRI) with single-shot axial DWI (b = 0 and b = 700 s/mm2 ) was performed in 30 fetuses with severe IUGR (estimated fetal weight < 3rd centile with absent or reversed umbilical artery Doppler flow) and in 24 normal controls of similar gestational age. Brain morphology and biometry were analyzed. ADC values were measured in frontal and occipital white matter, centrum semiovale, thalami, cerebellar hemisphere and pons. Frontal-occipital and frontal-cerebellar ADC ratios were calculated, and values were compared between IUGR fetuses and controls. RESULTS: There was no difference in gestational age at MRI between IUGR and control fetuses (IUGR, 30.2 ± 1.6 weeks vs controls, 30.7 ± 1.4 weeks). Fetal brain morphology and signals were normal in all fetuses. Brain dimensions (supratentorial ± infratentorial) were decreased (Z-score, < -2) in 20 (66.7%) IUGR fetuses. Compared with controls, IUGR fetuses had significantly lower ADC values in frontal white matter (1.97 ± 0.23 vs 2.17 ± 0.22 × 10-3 mm2 /s; P < 0.0001), thalami (1.04 ± 0.15 vs 1.13 ± 0.10 ×10-3 mm2 /s; P = 0.0002), centrum semiovale (1.86 ± 0.22 vs 1.97 ± 0.23 ×10-3 mm2 /s; P = 0.01) and pons (0.85 ± 0.19 vs 0.94 ± 0.12 ×10-3 mm2 /s; P = 0.043). IUGR fetuses had a lower frontal-occipital ADC ratio than did normal fetuses (1.00 ± 0.11 vs 1.08 ± 0.05; P = 0.003). CONCLUSIONS: ADC values in IUGR fetuses were significantly lower than in normal controls in the frontal white matter, thalami, centrum semiovale and pons, suggesting abnormal maturation in these regions. However, the prognostic value of these ADC changes is still unknown. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Subject(s)
Fetal Growth Retardation/diagnostic imaging , Prenatal Diagnosis , Adult , Case-Control Studies , Diffusion Magnetic Resonance Imaging , Female , Gestational Age , Humans , Pregnancy , Pregnancy Outcome , Retrospective Studies
4.
Ultrasound Obstet Gynecol ; 49(5): 617-622, 2017 May.
Article in English | MEDLINE | ID: mdl-27197901

ABSTRACT

OBJECTIVE: Fetal serum ß2-microglobulin has been shown to predict postnatal renal outcome in cases of fetal obstructive uropathy. We assessed the value of serial measurements of fetal serum ß2-microglobulin in the prediction of postnatal renal outcome. METHODS: We retrospectively studied renal outcome in 42 fetuses with bilateral or low urinary tract obstruction that had fetal blood sampling on at least two occasions to assay serum levels of ß2-microglobulin. Amniotic fluid volume at the time of each sampling was recorded. We classified renal outcome as either favorable (when postnatal renal function was normal) or adverse (when postnatal chronic renal failure occurred or when renal dysplasia at autopsy was noted). A ß2-microglobulin cut-off of 5 mg/L and amniotic fluid index of 5 cm were used to predict postnatal renal outcome. RESULTS: Renal outcome was adverse in 28 cases and favorable in 14. In 12 (28.6%) cases, fetal serum ß2-microglobulin concentration differed between the first and last measurement. Prediction of postnatal renal outcome was correct in 11 of these cases based on the last ß2-microglobulin measurement. The sensitivity of ß2-microglobulin in predicting renal outcome was significantly higher (P = 0.005) when using the last rather than the first measurement (96.4% vs 64.3%), with similar specificity for both measurements (85.7% vs 78.6%, non-significant). The sensitivity of amniotic fluid volume was also significantly higher (P = 0.005) when using the last rather than the first measurement (75.0% vs 35.7%), with similar specificity for both measurements (64.3% vs 71.4%, non-significant). CONCLUSION: Sequential measurement of serum ß2-microglobulin, performed for adverse ultrasound findings, such as renal parenchymal abnormality or decreasing amniotic fluid volume, predicts postnatal renal outcome more accurately than does a single assay. This may be due to possible worsening of renal injury with increasing duration of urinary tract obstruction. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Subject(s)
Biomarkers/blood , Kidney/physiology , Prenatal Diagnosis , Ureteral Obstruction/diagnosis , Urethral Obstruction/diagnosis , beta 2-Microglobulin/blood , Child , Child, Preschool , Female , Fetal Diseases/blood , Fetal Diseases/diagnosis , France , Gestational Age , Glomerular Filtration Rate , Humans , Infant , Infant, Newborn , Kidney/abnormalities , Predictive Value of Tests , Pregnancy , Pregnancy Outcome , Retrospective Studies , Ureteral Obstruction/blood , Urethral Obstruction/blood
5.
Ultrasound Obstet Gynecol ; 46(3): 306-11, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25412852

ABSTRACT

OBJECTIVES: To assess the value of fetal urine biochemistry before 23 weeks of gestation in cases of lower urinary tract obstruction (LUTO) to refine prognosis and to select potential candidates for in-utero intervention. METHODS: This was a retrospective study including 72 cases of LUTO with fetal urine sampled before 23 weeks and assayed for total protein, ß-2-microglobulin, sodium, chloride, calcium, phosphorus, glucose and gamma-glutamyl transpeptidase (GGTP). Two groups were defined according to renal outcome: 1) bilateral renal dysplasia on histological examination or renal failure at birth; 2) normal postnatal renal function or histologically normal appearance of the kidneys. Correlations between fetal urinary biochemical markers and postnatal renal function were studied. RESULTS: LUTO was isolated in 56/72 (77.8%) cases and was associated with other malformations in 16/72 (22.2%) cases. High GGTP levels (236 IU/L vs 5 IU/L; P < 0.0001) were observed in fetal urine in the five cases of urodigestive fistula. A significant difference between outcome groups was observed for ß-2-microglobulin (P = 0.0017), sodium (P = 0.0008), chloride (P = 0.0028) and calcium (P = 0.0092) but not for protein, glucose or phosphorus. Sensitivity and specificity in defining a poor renal prognosis were 80.6% and 89% for ß-2-microglobulin, 61.3% and 100% for sodium and 64.5% and 100% for calcium, respectively. CONCLUSIONS: Fetal urinalysis before 23 weeks of gestation allowed distinction between three groups: 1) fetuses with normal urine biochemistry for which fetal therapy should be discussed; 2) fetuses with abnormal urine biochemistry for which prognosis for renal outcome is poor and for which the benefit of fetal therapy is likely to be compromised; 3) fetuses with urodigestive fistula.


Subject(s)
Duodenum/abnormalities , Fetal Diseases/diagnosis , Fetal Therapies , Prenatal Diagnosis/methods , Urethral Obstruction/diagnosis , Urinary Bladder/abnormalities , Adolescent , Adult , Biomarkers/urine , Female , Fetal Diseases/therapy , Fetal Diseases/urine , Gestational Age , Humans , Linear Models , Pregnancy , Pregnancy Trimester, First , Pregnancy Trimester, Second , Prognosis , Renal Insufficiency/diagnosis , Renal Insufficiency/etiology , Renal Insufficiency/prevention & control , Retrospective Studies , Sensitivity and Specificity , Urethral Obstruction/etiology , Urethral Obstruction/therapy , Urethral Obstruction/urine , Young Adult
7.
Ultrasound Obstet Gynecol ; 41(2): 185-9, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23090907

ABSTRACT

OBJECTIVES: To determine whether the prognostic value of fetal serum ß-2-microglobulin is altered and whether the occurrence of fetal urinary ascites prevents kidney damage in cases of fetal obstructive uropathy with urinary ascites. METHODS: This was a retrospective study of cases of fetal bilateral obstructive uropathy that occurred between 2006 and 2010, for which both fetal serum and ascites samples were sent to our laboratory for analysis. ß-2-microglobulin was assayed in both fetal serum and the corresponding ascites. Renal outcome was analyzed. Histological features of the kidney in cases of termination of pregnancy and renal function of liveborn infants were recorded. RESULTS: Fourteen cases with analysis of fetal serum and fetal ascites in a context of urinary obstruction were included. Renal outcome was unfavorable in eight cases (57%) and favorable in six (43%). When fetal serum ß-2-microglobulin was < 5 mg/L, renal outcome was favorable in all cases (4/4). When fetal serum ß-2-microglobulin was ≥ 5 mg/L, 8/10 cases (80%) had an unfavorable renal outcome (sensitivity, 100%; specificity, 66%). CONCLUSION: Fetal serum ß-2-microglobulin reliably predicts postnatal renal outcome in obstructive uropathy complicated by urinary ascites. Moreover, urine extravasation does not seem to protect fetal renal function.


Subject(s)
Ascites/embryology , Fetal Diseases , Urethral Obstruction/embryology , beta 2-Microglobulin/blood , Ascites/complications , Ascites/metabolism , Biomarkers/blood , Female , Gestational Age , Glomerular Filtration Rate/physiology , Humans , Kidney Diseases/embryology , Kidney Diseases/physiopathology , Pregnancy , Pregnancy Outcome , Prenatal Diagnosis/methods , Prognosis , Retrospective Studies , Urethral Obstruction/complications
8.
Am J Med Genet A ; 161A(1): 208-13, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23239632

ABSTRACT

We report on the first prenatally diagnosed interstitial 8p23.1 maternally inherited deletion. At 20 weeks of gestation (WG) the fetus was diagnosed with a complete atrioventricular canal. In infancy, the mother underwent a two-step cardiac surgery for an interrupted aortic arch type A associated to an inlet ventricular septal defect (VSD). A straddling of the tricuspid valve type B was confirmed during surgery. The outcome showed no cardiac failure or conduction anomalies. However, she presented with moderate intellectual disability. Classical and molecular cytogenetic studies on amniotic and maternal lymphocytes cells showed a nearly identical interstitial deletion of the 8p23.1 region encompassing the GATA4 gene locus (Mother: nt 6,913,337-12,580,828, fetus: nt 7,074,449-12,580,828) with no modification of the telomeric region. The relevance of our report is not only the maternal syndromic interstitial 8p23.1 deletion, but also maternal transmission which has never been reported before. The maternal and fetal phenotypes were not identical, however, even though they had the same cellular and molecular background: an alteration of the epithelial mesenchymal transition of the atrioventricular valvulo-septal complex where GATA4 plays a positive role in the regulation. We reviewed all cases of interstitial 8p23.1 deletions diagnosed either prenatally or postnatally.


Subject(s)
Heart Septal Defects, Ventricular/genetics , Prenatal Diagnosis , Cardiac Surgical Procedures , Chromosome Deletion , Chromosomes, Human, Pair 8/genetics , Female , Follow-Up Studies , GATA4 Transcription Factor/genetics , Gene Deletion , Genome-Wide Association Study , Heart Septal Defects, Ventricular/diagnosis , Heart Septal Defects, Ventricular/surgery , Humans , In Situ Hybridization, Fluorescence , Karyotype , Microarray Analysis , Phenotype , Polymorphism, Single Nucleotide , Pregnancy , Tricuspid Valve/abnormalities , Tricuspid Valve/surgery , Young Adult
9.
Clin Genet ; 82(2): 187-92, 2012 Aug.
Article in English | MEDLINE | ID: mdl-21554265

ABSTRACT

ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome is a rare autosomal recessive disorder characterised by severe immunodeficiency, craniofacial anomalies and chromosome instability. Chromosome analyses from blood samples show a high frequency of decondensation of pericentromeric heterochromatin (PH) and rearrangements involving chromosomes 1 and 16. It is the first and, as far as we know, the only disease associated with a mutation in a DNA methyltransferase gene, DNMT3B, with significant hypomethylation of the classical satellite DNA, the major component of the juxtacentromeric heterochromatin. To better understand the complex links between the hypomethylation of the satellite DNA, the cytogenetic anomalies and the clinical features of ICF syndrome, we performed three-dimensional (3D) FISH on preserved cells from a patient with a suspected ICF phenotype. Analysis of DNMT3B did not reveal any mutation in our patient, making this case an ICF type 2. The results of 3D-FISH showed a statistically significant change in the intranuclear position of PH of chromosome 1 in cells of the patient as compared to normal cells. It is difficult to understand how a defect in the methylation pathway can be responsible for the various symptoms of this condition. From our observations we suggest a mechanistic link between the reorganisation of the nuclear architecture and the altered gene expression.


Subject(s)
Cell Nucleus/genetics , Centromere , Heterochromatin/chemistry , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Adolescent , Chromosome Aberrations , Chromosomes, Human, Pair 1 , Chromosomes, Human, Pair 9 , DNA Methylation , DNA, Satellite , Face/abnormalities , Female , Humans , In Situ Hybridization, Fluorescence , Primary Immunodeficiency Diseases
11.
Mol Cell Endocrinol ; 346(1-2): 21-8, 2011 Oct 22.
Article in English | MEDLINE | ID: mdl-21645587

ABSTRACT

GnRH and its receptor GnRHR are key regulators of the hypothalamo-pituitary axis. They modulate the secretion of LH and FSH gonadotropins and therefore, the development and maturation of gonads in fetal life as well as after birth. Congenital functional defect of this axis results in isolated hypogonadotropic hypogonadism (IHH). Several natural mutations causing IHH without anosmia have now been identified in GnRHR or GnRH genes. These mutations inactivate GnRHR or its ligand function and cause highly variable phenotypes, ranging from partial to complete gonadotropic deficiencies. The present review describes the published natural GnRHR mutations and tries to correlate them with the corresponding phenotypes according to the different steps of the GnRH system development.


Subject(s)
Gonadotropin-Releasing Hormone/deficiency , Gonadotropin-Releasing Hormone/genetics , Mutation , Receptors, LHRH/genetics , Animals , Developmental Biology , Humans , Hypogonadism/genetics , Phenotype
12.
Neurology ; 73(12): 962-9, 2009 Sep 22.
Article in English | MEDLINE | ID: mdl-19770472

ABSTRACT

OBJECTIVE: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations. METHODS: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family. RESULTS: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1). CONCLUSIONS: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.


Subject(s)
Genetic Predisposition to Disease/genetics , Head/abnormalities , Microcephaly/genetics , Mutation/genetics , Nerve Tissue Proteins/genetics , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Female , Genetic Testing , Genotype , Head/diagnostic imaging , Head/pathology , Humans , Infant , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Magnetic Resonance Imaging , Male , Microcephaly/diagnostic imaging , Microcephaly/pathology , Phenotype , Pyramidal Tracts/physiopathology , Radiography , Seizures/genetics , Seizures/physiopathology , Skull/abnormalities , Skull/diagnostic imaging , Skull/pathology , Young Adult
13.
Placenta ; 30(8): 731-4, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19577294

ABSTRACT

We present evidence of a first-trimester discordant renin-angiotensin system (RAS) response and structural abnormalities of the kidneys in twins with twin-to-twin transfusion syndrome (TTTS). A dark red fetus and a pale fetus were spontaneously delivered at 13.5 weeks of gestation following a double intra-uterine death. Pathological examination confirmed the placentation as monochorionic, with arteriovenous anastomoses on the chorionic plate. The donor twin had a normal heart and mildly hypoplastic kidneys, and the recipient twin had cardiomegaly and hypertrophic kidneys. Immunohistochemical analysis of the kidneys showed secretion of renin occurring in the donor but not in the recipient twin, more intense expression of angiotensin II receptor type 1 in the donor, and modifications of renal architectures in both twins. Renin protein appeared qualitatively higher in the placental territory of the recipient compared to that of donor. These findings indicate that hemodynamic discordance caused by vascular anastomoses may lead to serious physiologic and organic consequences as early as the first trimester. To our knowledge, this case presents the earliest first-trimester TTTS confirmed by a complete anatomopathological examination and is the first TTTS case to show a first-trimester discordant RAS response confirmed by immunohistochemistry.


Subject(s)
Fetofetal Transfusion/physiopathology , Renin-Angiotensin System/physiology , Actins/metabolism , Adult , Female , Fetal Death/pathology , Fetal Death/physiopathology , Fetofetal Transfusion/pathology , Gestational Age , Humans , Immunohistochemistry , Kidney/abnormalities , Kidney/metabolism , Male , Pregnancy , Receptor, Angiotensin, Type 1/metabolism , Renin/metabolism
14.
AJNR Am J Neuroradiol ; 29(1): 110-5, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17947368

ABSTRACT

BACKGROUND AND PURPOSE: The sensitivity of fetal MR imaging is poor with regard to the evaluation of diffuse ischemic white matter (WM) abnormalities. Our purpose was to evaluate the contribution of diffusion-weighted imaging (DWI) in the analysis of microstructural changes in WM and to correlate neuroimaging with neurofetopathologic findings. MATERIALS AND METHODS: We included fetuses with MR imaging, DWI, and a fetopathologic examination. In a region of interest defined by MR imaging, where T1 and T2 intensities were abnormal, the apparent diffusion coefficient (ADC) was measured and immunohistochemical analysis was performed. In fetuses with no WM abnormality in signal intensity, region of interest was defined at random. Histologic reading was performed with a complete blinding of the MR imaging results and ADC values. Three degrees of histologic appearance were defined with regard to vasogenic edema, astrogliosis, microgliosis, neuronal and oligodendrocytic abnormalities, and proliferation or congestion of vessels and were compared with a chi(2) test in groups A (normal ADC) and B (increased ADC) fetuses. RESULTS: We included 12 fetuses in group A and 9 in group B, ranging from 29 to 38 weeks of gestation. All group B fetuses and 1 group A fetus demonstrated WM abnormalities in signal intensity. WM edema and astrogliosis were more common in group B than in group A (7/9 vs 2/12 and 8/9 vs 4/12, respectively). No significant difference was observed between both groups with regard to the other parameters. CONCLUSION: This study showed a strong correlation between increased ADCs and 1) WM abnormalities in signal intensity on MR imaging, and 2) vasogenic edema with astrogliosis of the cerebral parenchyma.


Subject(s)
Brain Ischemia/embryology , Brain Ischemia/pathology , Diffusion Magnetic Resonance Imaging/methods , Nerve Fibers, Myelinated/pathology , Humans , Reproducibility of Results , Sensitivity and Specificity , Statistics as Topic
15.
Hum Mutat ; 28(10): 1020-7, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17559086

ABSTRACT

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.


Subject(s)
Gene Expression Regulation , Muscular Dystrophies/embryology , Muscular Dystrophies/genetics , Alleles , Dystroglycans/metabolism , Female , Genotype , Gestational Age , Humans , Male , Mannosyltransferases/genetics , Microsatellite Repeats , Models, Genetic , Mutation , Phenotype , Polymorphism, Single Nucleotide
16.
Ultrasound Obstet Gynecol ; 29(6): 651-9, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17476704

ABSTRACT

OBJECTIVES: To compare magnetic resonance imaging (MRI) and fetopathological findings in the evaluation of non-cystic fetal posterior fossa anomalies and to describe associated abnormalities. METHODS: This was a prospective study from 2000 to 2005 of fetuses identified on ultrasound as having sonographic suspicion of posterior fossa malformation. All underwent a thorough MRI examination of the fetal brain, after which we classified each fetus as presenting one of the following pathologies: vermian hypoplasia or agenesis, cerebellar and/or brain stem hypoplasia, destructive or dysplastic lesions. All of the pregnancies were then terminated, after which the whole fetus underwent fetopathological examination. We compared the findings from MRI and fetopathological examinations and recorded the associated cerebral and extracerebral abnormalities. RESULTS: Twenty-five fetuses were included. MRI was performed at a mean gestational age of 31 weeks, and fetopathological examination at 33 weeks. In 12 cases we observed vermian hypoplasia, six had partial vermian agenesis, 11 had cerebellar hemisphere hypoplasia, seven had brain stem hypoplasia, four had destructive lesions and six had dysplastic lesions. The two techniques were similar in their performance with respect to the detection of vermian agenesis, brain stem hypoplasia and destructive lesions. There were four false-positive results of MRI for vermian hypoplasia and a poor agreement regarding cerebellar hemisphere hypoplasia. No dysplastic lesions were diagnosed by MRI. None of the posterior fossa malformations was isolated and many cerebral and extracerebral abnormalities were found. CONCLUSION: A systematic analysis of the posterior fossa in fetal MRI makes it possible to diagnose accurately most posterior fossa malformations. These malformations never occurred in isolation in our study.


Subject(s)
Brain Diseases/diagnosis , Cranial Fossa, Posterior/abnormalities , Fetal Diseases/diagnosis , Magnetic Resonance Imaging/standards , Ultrasonography, Prenatal/standards , Cranial Fossa, Posterior/embryology , Cranial Fossa, Posterior/pathology , Female , Humans , Pregnancy , Prospective Studies
17.
Cytogenet Cell Genet ; 92(3-4): 304-9, 2001.
Article in English | MEDLINE | ID: mdl-11435704

ABSTRACT

We identified new transcribed sequences, using a differential display paradigm to select genes expressed in proliferating neuroblasts from mouse telencephalon at 10 days of embryonic development. In this systematic search, we isolated a 361-bp partial 3' untranslated region (3' UTR) homologous to the 3' UTR of the human gene encoding a putative intracellular kinase regulator, glia maturation factor beta (GMFB). We cloned a full-length, 4,311-bp mouse cDNA containing a 270-bp 5' UTR, a 3,615-bp 3' UTR, and an open reading frame of 426 nucleotides encoding a putative 142 amino-acid protein, identical to human GMFB, with the exception of two amino acids. This 4.3-kb transcript is present in a variety of adult tissues and is developmentally regulated as shown by Northern blot analysis. Differential expression in telencephalon was demonstrated by quantification of radioactive relative RT-PCR and confirmed by in situ hybridization. The isolation of this full-length clone of mouse Gmfb should facilitate investigation of the intracellular mechanisms involved in the development of telencephalon.


Subject(s)
Glia Maturation Factor/genetics , Protein Kinases/metabolism , Telencephalon/metabolism , 3' Untranslated Regions/analysis , 3' Untranslated Regions/genetics , Amino Acid Sequence , Animals , Cloning, Molecular , DNA, Complementary/genetics , Expressed Sequence Tags , Gene Expression Regulation, Developmental , Glia Maturation Factor/chemistry , Glia Maturation Factor/pharmacology , Humans , In Situ Hybridization , Mice , Molecular Sequence Data , RNA, Messenger/analysis , RNA, Messenger/genetics , Sequence Alignment , Sequence Homology , Telencephalon/cytology , Telencephalon/embryology , Telencephalon/enzymology
18.
Physiol Genomics ; 7(2): 149-57, 2001 Dec 21.
Article in English | MEDLINE | ID: mdl-11773601

ABSTRACT

Respiratory abnormalities have been described in MASH-1 (mammalian achaete-scute homologous gene) and c-RET ("rearranged during transfection") mutant newborn mice. However, the neural mechanisms underlying these abnormalities have not been studied. We tested the hypothesis that the MASH-1 mutation may impair c-RET expression in brain stem neurons involved in the control of breathing. To do this, we analyzed brain stem c-RET expression and respiratory phenotype in MASH-1 +/+ wild-type, MASH-1 +/- heterozygous, and MASH-1 -/- knock-out newborn mice during the first 2 h of life. In MASH-1 -/- newborns, c-RET gene expression was absent in the noradrenergic nuclei (A2, A5, A6, A7) that contribute to modulate respiratory frequency and in scattered cells of the rostral ventrolateral medulla. The c-RET transcript levels measured by quantitative RT-PCR were lower in MASH-1 -/- and MASH-1 +/- than in MASH-1 +/+ brain stems (P = 0.001 and P = 0.003, respectively). Breath durations were shorter in MASH-1 -/- and MASH-1 +/- than in MASH-1 +/+ mice (P = 0.022) and were weakly correlated with c-RET transcript levels (P = 0.032). Taken together, these results provide evidence that MASH-1 is upstream of c-RET in noradrenergic brain stem neurons important for respiratory rhythm modulation.


Subject(s)
Brain Stem/metabolism , DNA-Binding Proteins/metabolism , Drosophila Proteins , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Respiration , Signal Transduction/physiology , Transcription Factors/metabolism , Adaptation, Physiological , Animals , Animals, Newborn , Basic Helix-Loop-Helix Transcription Factors , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Heterozygote , Homozygote , In Situ Hybridization , Mice , Mice, Knockout , Nerve Net/physiology , Periodicity , Phenotype , Plethysmography , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-ret , RNA, Messenger/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transcription Factors/deficiency , Transcription Factors/genetics
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