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Ultrasound in Obstetrics & Gynecology :... Feb 2024Microcephaly with simplified gyral pattern (MSG) is an intrinsic genetic central nervous system disorder, characterized by microcephaly (a reduction of brain volume) and...
Microcephaly with simplified gyral pattern (MSG) is an intrinsic genetic central nervous system disorder, characterized by microcephaly (a reduction of brain volume) and a simplified gyral pattern (a reduced number of gyri and shallow sulci associated with normal cortical thickness and neuroanatomical architecture), related to a reduced number of neuronal progenitors in the germinal matrix. We report the first prenatal series of MSG and define the prenatal imaging pattern, which should inform diagnosis and guide prenatal counseling in cases of fetal microcephaly. In this single-center retrospective study of fetuses with MSG, we assessed features on ultrasound and magnetic resonance imaging (MRI), as well as genetic and neuropathological/postnatal data. We included eight patients who had been referred following observation of microcephaly. Ultrasound examination confirmed microcephaly, with a mean growth delay in head circumference of 3.4 weeks, associated with both a lack of gyration and a lack of opercularization of the Sylvian fissure and without any extracephalic anomaly. Fetal brain MRI confirmed lack of gyration with normal cortical thickness and normal intensity of the white matter in all cases. These MRI features led to exclusion of migration/corticogenesis disorders (lissencephaly/polymicrogyria), instead suggesting MSG. The posterior fossa was normal in seven of the eight cases. The corpus callosum was thin in four cases, hypoplastic in two and dysgenetic in two. In four cases, the pregnancy was terminated. The diagnosis of MSG was confirmed from neuropathological and postnatal MRI data. MSG was associated with a genetic diagnosis of RTTN (n = 1) and ASPM (n = 2) biallelic variants in three of the six cases in which genetic work-up was performed. Mild or moderate intellectual deficit with speech delay was present in the three surviving children who were at least 5 years of age at their last examination, without seizures. In conclusion, in the presence of isolated fetal microcephaly with lack of gyration on ultrasound, fetal cerebral MRI is key to diagnosing MSG, which, in the majority of cases, affects the supratentorial space exclusively, and to ruling out other cortical malformations that show a similar sonographic pattern. In addition to imaging, genetic assessment may guide prenatal counseling, since the prenatal prognosis of MSG is different from that of both diffuse polymicrogyria and lissencephaly. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Child; Female; Pregnancy; Humans; Microcephaly; Retrospective Studies; Polymicrogyria; Prenatal Diagnosis; Nervous System Malformations; Magnetic Resonance Imaging; Lissencephaly; Ultrasonography, Prenatal
PubMed: 37551048
DOI: 10.1002/uog.27450 -
Seizure Oct 2023To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting.
PURPOSE
To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting.
METHODS
In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety.
RESULTS
Forty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were "responders" and 12 (29%) were "super-responders". Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively.
CONCLUSIONS
In this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.
PubMed: 37506564
DOI: 10.1016/j.seizure.2023.07.009 -
JAMA Neurology Sep 2023Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and...
IMPORTANCE
Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.
OBJECTIVE
To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations.
DESIGN, SETTING, AND PARTICIPANTS
This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control.
MAIN OUTCOMES AND MEASURES
The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed.
RESULTS
In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families.
CONCLUSIONS AND RELEVANCE
This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.
Topics: Humans; Polymicrogyria; Exome Sequencing; Retrospective Studies; Mutation, Missense; Siblings; Nerve Tissue Proteins; Connexins
PubMed: 37486637
DOI: 10.1001/jamaneurol.2023.2363 -
Journal of Infection and Chemotherapy :... Nov 2023Human cytomegalovirus (HCMV) is the major cause of neurological sequelae in infants. Immune control of primary HCMV infection appears to depend on the interaction...
Human cytomegalovirus (HCMV) is the major cause of neurological sequelae in infants. Immune control of primary HCMV infection appears to depend on the interaction between humoral and cell-mediated immune responses. We report the case of an HCMV-transmitter mother observed with dissociation between humoral and cell-mediated immune responses. The patient had immunoglobulin (Ig) G and M positivity at 11 weeks of gestation and showed fetal hyperechoic bowel and minimal ascites at 21 weeks of gestation. At 25 weeks of gestation, the polymerase chain reaction result for HCMV using amniotic fluid was positive. The numbers of spots in the enzyme-linked immunosorbent spot (ELISPOT) assay at 25, 36, and 39 weeks of gestation were three, five, and six spots/2 × 10 peripheral blood mononuclear cells, respectively. Furthermore, IgG avidity indexes (AIs) at 21, 25, 36, and 39 weeks of gestation were 37.6, 49.7, 72.5, and 74.3, respectively. At 40 weeks of gestation, the patient delivered a symptomatic infected newborn with a weight of 2,384 g (-2.6 SD) and a head circumference of 30 cm (-2.6 SD). The neonate had a petechial rash and bilateral hearing loss although did not show liver dysfunction or thrombocytopenia. Cranial magnetic resonance imaging revealed mild ventriculomegaly, left lateral/parietal polymicrogyria, and a punctate white matter lesion. This case showed that IgG AI increased with increasing gestational age, whereas the numbers of spots in the ELISPOT assay had no change. The dissociation between humoral and cell-mediated immune responses may be characteristic of the immune response of a transmitter mother.
Topics: Infant, Newborn; Infant; Humans; Pregnancy; Female; Cytomegalovirus; Cytomegalovirus Infections; Pregnant Women; Pregnancy Complications, Infectious; Immunity, Humoral; Leukocytes, Mononuclear; Antibodies, Viral; Immunoglobulin G
PubMed: 37451620
DOI: 10.1016/j.jiac.2023.07.004 -
The Journal of Maternal-fetal &... Dec 2023The septum pellucidum is a virtual cavity located at the anterior part of the brain midline, which only in fetal life has a certain amount of fluid inside. The presence... (Review)
Review
OBJECTIVE
The septum pellucidum is a virtual cavity located at the anterior part of the brain midline, which only in fetal life has a certain amount of fluid inside. The presence of an obliterated cavum septi pellucidi (oCSP) in the prenatal period is poorly described in the literature but, nevertheless, it constitutes an important clinical dilemma for the fetal medicine specialist in terms of significance and prognosis. Moreover, its occurrence is increasing maybe because of the widespread of high-resolution ultrasound machine. The aim of this work is to review the available literature regarding the oCSP along with the description of a case-report of oCSP with an unexpected outcome.
METHODS
A search of the literature through Pubmed was performed up to December 2022 with the aim to identify all cases of oCSP previously described, using as keywords "cavum septi pellucidi," "abnormal cavum septi pellucidi," "fetus," and "septum pellucidum." Along with the narrative review, we describe a case-report of oCSP.
RESULTS
A 39 years old woman was diagnosed with a nuchal translucency between the 95° and 99° centile in the first trimester and an oCSP and "hookshaped" gallbladder at 20 weeks. Left polymicrogyria was found at fetal magnetic resonance imaging (MRI). Standard karyotype and chromosomal microarray analysis (CMA) were normal. After birth, the newborn presented signs of severe acidosis, untreatable seizures and multiorgan failure leading to death. A targeted gene analysis of the epilepsy panel revealed the presence of a pathogenic variant involving the gene. The literature review identified four articles reporting on the oCSP of which three were case report and one was a case-series. The reported rate of associated cerebral findings is around 20% and the rate of adverse neurological outcome is around 6%, which is higher than the background risk of the general population.
CONCLUSIONS
This case-report and review of the literature shows that oCSP is a clinical entity poorly described so far and that, despite the generally good prognosis, it requires caution in counseling. The diagnostic work-up should include neurosonography while fetal MRI may be always indicated for non-isolated cases only, depending on local facilities. Targeted gene analysis or whole exome sequencing may be indicated for non-isolated cases.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Adult; Septum Pellucidum; Brain; Epilepsy; Fetus; Prenatal Care; Magnetic Resonance Imaging
PubMed: 37414745
DOI: 10.1080/14767058.2023.2232075 -
Genes, Chromosomes & Cancer Dec 2023Heterozygous germline or somatic variants in AKT3 gene can cause isolated malformations of cortical development (MCDs) such as focal cortical dysplasia, megalencephaly...
Heterozygous germline or somatic variants in AKT3 gene can cause isolated malformations of cortical development (MCDs) such as focal cortical dysplasia, megalencephaly (MEG), Hemimegalencephaly (HME), dysplastic megalencephaly, and syndromic forms like megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, and megalencephaly-capillary malformation syndrome. This report describes a new case of HME and capillary malformation caused by a somatic AKT3 variant that differs from the common p.E17K variant described in literature. The patient's skin biopsy from the angiomatous region revealed an heterozygous likely pathogenic variant AKT3:c.241_243dup, p.(T81dup) that may affect the binding domain and downstream pathways. Compared to previously reported cases with a common E17K mosaic variant, the phenotype is milder and patients showed segmental overgrowth, an uncommon characteristic in AKT3 variant cases. These findings suggest that the severity of the disease may be influenced not only by the level of mosaicism but also by the type of variant. This report expands the phenotypic spectrum associated with AKT3 variants and highlights the importance of genomic analysis in patients with capillary malformation and MCDs.
Topics: Humans; Mutation; Megalencephaly; Vascular Malformations; Phenotype; Proto-Oncogene Proteins c-akt
PubMed: 37395289
DOI: 10.1002/gcc.23188 -
The Journal of Gene Medicine Oct 2023Population diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity,...
BACKGROUND
Population diversity is important and rare disease isolates can frequently reveal novel homozygous or biallelic mutations that lead to expanded clinical heterogeneity, with diverse clinical presentations.
METHODS
The present study describes two consanguineous families with a total of seven affected individuals suffering from a clinically similar severe syndromic neurological disorder, with abnormal development and central nervous system (CNS) and peripheral nervous system (PNS) abnormalities. Whole exome sequencing (WES) and Sanger sequencing followed by 3D protein modeling was performed to identify the disease-causing gene. RNA was extracted from the fresh blood of both families affected and healthy individuals.
RESULTS
The families were clinically assessed in the field in different regions of Khyber Pakhtunkhwa. Magnetic resonance imagining was obtained in the probands and blood was collected for DNA extraction and WES was performed. Sanger sequencing confirmed a homozygous, likely pathogenic mutation (GRCh38: chr17:42684199G>C; (NM_003632.3): c.333G>C);(NP_003623.1): p.(Trp111Cys) in the CNTNAP1 gene in family A, previously associated with Congenital Hypo myelinating Neuropathy 3 (CHN3; OMIM # 618186) and a novel nonsense variant in family B, (GRCh38: chr16: 57654086C>T; NC_000016.10 (NM_001370440.1): c.721C>T); (NP_001357369.1): p.(Gln241Ter) in the ADGRG1 gene previously associated with bilateral frontoparietal polymicrogyria (OMIM # 606854); both families have extended CNS and PNS clinical manifestations. In addition, 3D protein modeling was performed for the missense variant, p.(Trp111Cys), identified in the CNTNAP1, suggesting extensive secondary structure changes that might lead to improper function or downstream signaling. No RNA expression was observed in both families affected and healthy individuals hence showing that these genes are not expressed in blood.
CONCLUSIONS
In the present study, two novel biallelic variants in the CNTNAP1 and ADGRG1 genes in two different consanguineous families with a clinical overlap in the phenotype were identified. Thus, the clinical and mutation spectrum is expanded to provide further evidence that CNTNAP1 and ADGRG1 are very important for widespread neurological development.
Topics: Humans; Consanguinity; Mutation; Mutation, Missense; Genes, Recessive; Phenotype; Cell Adhesion Molecules, Neuronal
PubMed: 37178061
DOI: 10.1002/jgm.3513 -
Basic & Clinical Pharmacology &... Oct 2023GPR56/ADGRG1 is an adhesion G protein-coupled receptor (GPCR) and mutations on this receptor cause cortical malformation due to the over-migration of neural progenitor...
GPR56/ADGRG1 is an adhesion G protein-coupled receptor (GPCR) and mutations on this receptor cause cortical malformation due to the over-migration of neural progenitor cells on brain surface. At pial surface, GPR56 interacts with collagen III, induces Rho-dependent activation through Gα and inhibits the neuronal migration. In human glioma cells, GPR56 inhibits cell migration through Gα -dependent Rho pathway. GPR56-tetraspanin complex is known to couple Gα . GPR56 is an aGPCR that couples with various G proteins and signals through different downstream pathways. In this study, bilateral frontoparietal polymicrogyria (BFPP) mutants disrupting GPR56 function but remaining to be expressed on plasma membrane were used to study receptor signalling through Gα , Gα and Gα with BRET biosensors. GPR56 showed coupling with all three G proteins and activated heterotrimeric G protein signalling upon stimulation with Stachel peptide. However, BFPP mutants showed different signalling defects for each G protein indicative of distinct activation and signalling properties of GPR56 for Gα , Gα or Gα . β-arrestin recruitment was also investigated following the activation of GPR56 with Stachel peptide using BRET biosensors. N-terminally truncated GPR56 showed enhanced β-arrestin recruitment; however, neither wild-type receptor nor BFPP mutants gave any measurable recruitment upon Stachel stimulation, pointing different activation mechanisms for β-arrestin involvement.
Topics: Humans; Receptors, G-Protein-Coupled; Mutation; GTP-Binding Proteins; Peptides; beta-Arrestins
PubMed: 37056198
DOI: 10.1111/bcpt.13873 -
Journal of Neuropathology and... Sep 2023
PubMed: 36864686
DOI: 10.1093/jnen/nlad017