Diagnosis of fetal cortical abnormalities by new reference charts for assessment of sylvian fissure biometry.

OBJECTIVE: To develop novel fetal reference ranges for the characterization of the normal appearance of the Sylvian fissures (SF) along gestation and to apply them to fetuses with cortical abnormalities affecting the SF. METHODS: In this cross-sectional study, we used three-dimensional sonographic multiplanar reformatting (3D-MPR) to examine the fetal SF. Normal development was assessed in the second and third trimesters. SF parameters were evaluated in predefined axial and coronal planes: insular height and length, SF depth, and the extent of the coverage of the insula by the frontal and temporal lobes. Intra-observer variability and inter-rater reliability for the studied parameters were evaluated. The new reference charts were applied to 19 fetuses with cortical abnormalities involving the SF who had appropriate sonographic volumes for 3D-MPR analysis. Their diagnoses were confirmed by autopsy, fetal or postnatal MRI, genetic findings related to cortical malformations, or an abnormal cortical imaging pattern with similar MRI findings in an affected sibling. We applied the two previously published references for the evaluation of fetal SF development to these cases and compared the ability of the references to correctly detect SF abnormalities. RESULTS: The study included 189 fetuses of low-risk singleton pregnancies between 24 and 34 gestational weeks. The insular length or height increased with gestational age in the axial and coronal planes with adjusted R2  = 0.621, p < 0.0001 and R2  = 0.384, p < 0.0001, respectively. The SF depth also increased with gestational age in the axial and coronal planes with adjusted R2  = 0.695, p < 0.0001 and R2  = 0.219, p = 0.008, respectively. The extent of the coverage of the insula by the frontal and temporal lobes in the coronal plane increased with gestational age (adjusted R2  = 0.627, p < 0.0001 and R2  = 0.589, p < 0.0001, respectively). The interclass correlation coefficients of the intra- and inter-rater reliability of the studied parameters ranged between 0.71 and 0.97. The cortical anomalies in the 19 fetuses were polymicrogyria (7), simplified gyral pattern (3), dysgyria (3), lissencephaly (2), cortical malformation related to tubulinopathy (1), brain atrophy (1), cortical dysplasia (1), and cobblestone malformation (1). Three of the fetuses had multiple cortical anomalies. In 17 of 19 (89%) cases, at least one of our 6 SF parameters was found to be out of the normal range. In the coronal plane, SF height and depth were measured below 2SD in 9 (47%) and 4 (21%) cases, respectively. In the axial plane, SF length and depth were out of the normal ranges in six (31.5%) and four (21%), correspondingly. In the coronal plane, the opercular coverage by the frontal and temporal lobes was below 2 SD in 10 (52%) and 11 (57%), respectively. The scoring of the SF operculization by Quarello et al. was abnormal in 8 cases (42%). The measurement of the SF angle according to Poon et al. was abnormal in 14 cases (74%). CONCLUSIONS: The fetal SF is a complex developing structure that can be reliably characterized by sonographic parameters. One abnormal parameter is sufficient to raise the suspicion of SF malformation. Our new SF parameters might facilitate the detection of prenatal cortical abnormalities affecting the SF.

Biallelic mutations in EXOC3L2 cause a novel syndrome that affects the brain, kidney and blood.

BACKGROUND: Dandy-Walker malformation features agenesis/hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle and enlargement of posterior fossa. Although Dandy-Walker malformation is relatively common and several genes were linked to the syndrome, the genetic cause in the majority of cases is unknown. OBJECTIVE: To identify the mutated gene responsible for Dandy-Walker malformation, kidney disease and bone marrow failure in four patients from two unrelated families. METHODS: Medical assessment, sonographic, MRI and pathological studies were used to define phenotype. Chromosomal microarray analysis and whole-exome sequence were performed to unravel the genotype. RESULTS: We report four subjects from two unrelated families with homozygous mutations in the Exocyst Complex Component 3-Like-2 gene (EXOC3L2).EXOC3L2 functions in trafficking of post-Golgi vesicles to the plasma membrane. In the first family a missense mutation in a highly conserved amino acid, p.Leu41Gln, was found in three fetuses; all had severe forms of Dandy-Walker malformation that was detectable by prenatal ultrasonography and confirmed by autopsy. In the second family, the affected child carried a nonsense mutation, p.Arg72*, and no detected protein. He had peritrigonal and cerebellar white matter abnormalities with enlargement of the ventricular trigones, developmental delay, pituitary hypoplasia, severe renal dysplasia and bone marrow failure. CONCLUSION: We propose that biallelic EXOC3L2 mutations lead to a novel syndrome that affects hindbrain development, kidney and possibly the bone marrow.

The Expression of Neuropilin-1 in Human Placentas From Normal and Preeclamptic Pregnancies.

Preeclampsia (PET) is a hypertensive disorder that affects 2% to 8% of pregnant women. Recent observations support the hypothesis that upregulation of placental anti-angiogenic factors are responsible for the clinical manifestations of the disease. Neuropilin-1 (NP-1) is a transmembrane protein that acts as a coreceptor for vascular endothelial growth factor and as a regulatory protein in the immune system. The aim of the study was to evaluate the expression of NP-1 in PET and normal placentas. Nineteen placental specimens from severe PET pregnancies were compared with 20 placental specimens of women with low-risk pregnancy. All the specimens underwent immunohistochemical staining with anti-human NP-1 antibody. The degree of NP-1 staining was measured both for intensity and extent. Our study demonstrated NP-1 immunoreactivity mainly in the decidual cells, the intermediate trophoblast, and the syncytiotrophoblast, particularly in the areas in the syncytial knots and shed particles. The particles were strongly NP-1 immunoreactive. The expression of NP-1 in the syncytiotrophoblast was lower in placentas of PET compared with control (P=0.017). Shedding of syncytiotrophoblast particles from placenta to maternal blood occurs in normal pregnancies and is enhanced during PET and contributes to the maternal vascular injury that characterizes PET. Our new observation that shows strong NP-1 immunoreactivity of these particles, and decreased NP1 expression in syncytiotrophoblast of PET placentas in comparison to the control group, may imply a role of NP-1 in PET.

Sonography of the fetal cochlea in the early second trimester of pregnancy.

OBJECTIVES: To examine the feasibility of imaging the fetal cochlea in the early second trimester. METHODS: This study included 42 healthy fetuses of low-risk pregnancies between 14 and 16 weeks. The coronal head sections via sagittal and lateral acoustic windows were used for cochlear visualization. The coronal plane was directed across the thalamus, oriented to the petrous part of the temporal bones. All fetuses were examined by 2-dimensional(2D) transvaginal sonography. Transabdominal scans were added in 11 fetuses at 16 weeks. Three-dimensional (3D) multiplanar reconstruction was used for coronal plane reformatting in cases with inappropriate head positioning for 2D scanning. RESULTS: Because of temporal bone hypomineralization in the early second trimester, sonographic depiction of the cochlear labyrinth was possible. On coronal imaging, the cochleas showed ringlike echogenic borders containing hypoechoic liquid content. The cochlear modiolus appeared as a central echogenic round spot ("cochlear target sign"). The cochleas were observed caudad to the temporal lobes, separated by the clivus. Shifting of the coronal plane showed progressive coiling of the basal cochlear turn toward the second turn ("cochlear whirlpool sign"). Two-dimensional transvaginal scanning showed at least 1 cochlea in 79% (33 of 42) of the cases. Adding 3D multiplanar reconstruction, at least 1 cochlear target sign was observed in 83% (35 of 42). The cochlear whirlpool sign on at least one side was shown in 57% (24 of 42). The maximal cochlear diameter was measured in fetuses with clear cochlear margin visualization. In this subgroup, the mean gestational age ± SD was 15.8 ± 0.5 weeks, and the mean maximal cochlear diameter was 6.4 ± 0.8 mm. CONCLUSIONS: Prenatal sonographic inner ear depiction was previously considered impossible. Using a unique time window in the early second trimester, we achieved feasible fetal cochlear imaging.

Autosomal dominant TUBB3-related syndrome: Fetal, radiologic, clinical and morphological features.

OBJECTIVE: To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome. METHODS: We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses. RESULTS: The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal. CONCLUSIONS: TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 - associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.

Cyclosporin A inhibits Al-induced cytochrome c release from mitochondria in aged rabbits.

Neurodegenerative diseases including Alzheimer's disease are characterized by a progressive and selective neuronal loss via an apoptosis mechanism, and there is a growing body of evidence which supports a central role of mitochondria in this apoptotic cell death. Release of cytochrome c from the mitochondria to the cytosol is considered a critical step in apoptosis. Here we report that aluminum maltolate induces cytochrome c translocation into the cytosol as early as 3 hours in aged but not in young rabbit hippocampus. Pretreatment with cyclosporin A, an inhibitor of the mitochondria permeability transition pore (MTP), blocks cytochrome crelease. Therefore, it appears that aluminum maltolate-induced cytochrome c release results from opening of the MTP. This effect implicates aging as a prerequisite factor, since the MTP does not open in young animals. Mitochondrial injury thus may represent a primary initiator of neurodegeneration.

The pathogenic role of anti-thyroglobulin antibody on pregnancy: evidence from an active immunization model in mice.

BACKGROUND: The presence of antibodies to thyroglobulin (Tg) is associated with fetal loss even in the absence of thyroid dysfunction. The aim of this study was to examine whether active immunization with Tg could elicit anti-Tg autoantibodies and reproductive failure without interfering with thyroid function. METHODS: BALB/c mice that were immunized with human Tg in complete Freund's adjuvant (CFA) or injected with only CFA were studied for the development of antibodies to Tg, T4, dsDNA, ssDNA and cardiolipin. Total T4, free T4 and thyroid-stimulating hormone (TSH) levels were also assessed before and during pregnancy. Percentages of resorbed fetuses (the equivalent to human missed abortion) were compared and autoantibody presence on the placentae and fetuses was examined. RESULTS: Following immunization, high levels of anti-Tg were observed in mice immunized with Tg, compared with mice injected with CFA [0.83 +/- 0.23 versus 0.012 +/- 0.016 respectively; mean +/- SD optical density (OD) at 405 nm; P < 0.001]. The specificity of binding to Tg was confirmed by competition assay. Although total T4 levels were increased in comparison with control mice, this was associated with the presence of antibodies to T4. Indeed, free T4 levels and TSH were similar to control mice. Mice were killed after 14 days of pregnancy. The thyroid function and the histology of the thyroid glands were normal. Increased fetal wastage was found among the Tg-immunized mice compared with the CFA-injected mice (P = 0.04), with lower fetal and placental weights (fetal weights: 194 +/- 4 mg versus 240 +/- 6 mg; placental weights: 105 +/- 2 mg versus 130 +/- 3; P < 0.001 for both). Antibodies to Tg were demonstrated only on the placentae of Tg-immunized mice. CONCLUSION: Immunization with Tg results in the production of Tg antibodies and fetal resorption. These effects occur in the absence of thyroid dysfunction.