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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 -
Journal of Neuroimaging : Official... 2023Autosomal recessive cobblestone-like cortical malformation of the brain, with no eye or muscle involvement, has been reported in patients with biallelic mutations in...
BACKGROUND AND PURPOSE
Autosomal recessive cobblestone-like cortical malformation of the brain, with no eye or muscle involvement, has been reported in patients with biallelic mutations in ADGRG1 (formerly GPR56) and in other brain surface defects (eg, variants in COL3A1). We reported the intra-uterine brain MRI (iu-MRI), post-mortem MRI (pm-MRI), and neuropathology findings of a new ADGRG1 mutation in a fetus at early gestation. Imaging findings were compared with those of the sibling harboring the same mutation, to provide insights about the evolving morphology of such malformation.
METHODS
A 21-week fetus underwent iu-MRI for a suspected cortical anomaly on ultrasound. After the MRI results, the termination of the pregnancy was carried out. A pm-MRI scan and autopsy were performed. A neuropathology-imaging correlation was achieved. The 5-year old sibling affected by developmental impairment also underwent a brain MRI. Both subjects underwent a genetic investigation.
RESULTS
Two patterns of abnormality of the cerebral surface were identified on both fetal MRI: one at the vertex resembling a cobblestone-cortex due to neuronal overmigration into the subarchnoid space and the other in the occipital areas resembling polymicrogyria. These details closely matched the neuropathology findings. MRI findings of the sibling consisted of typical ADGRG1/GPR56-related brain findings showing a polymicrogyric-like cortex, also reported as bilateral frontal-parietal polymicrogyria. A flattened pons and small cerebellar vermis were present in both cases. Genetic testing demonstrated a novel homozygous variant c.1484T>C in the c gene in both cases.
CONCLUSION
Our findings provide further evidence of the overlap of ADGRG1/GPR56-related brain dysgenesis with cobblestone-like cortical malformation of the brain.
Topics: Child, Preschool; Female; Humans; Pregnancy; Brain; Magnetic Resonance Imaging; Mutation; Nervous System Malformations; Polymicrogyria; Prenatal Diagnosis
PubMed: 37259271
DOI: 10.1111/jon.13130 -
Fetal Diagnosis and Therapy 2023We aimed to evaluate the neuroimaging findings and long-term neurodevelopmental outcomes of fetuses and children following intrauterine blood transfusion (IUT) for parvo...
INTRODUCTION
We aimed to evaluate the neuroimaging findings and long-term neurodevelopmental outcomes of fetuses and children following intrauterine blood transfusion (IUT) for parvo B19 infection-induced anemia compared to those with RBC alloimmunization.
METHODS
We conducted a retrospective cohort study including women who underwent an IUT due to fetal anemia between 2006 and 2019 in a tertiary, university-affiliated medical center. The cohort was divided into two groups: a study group - fetuses affected by congenital parvo B19 infection; and a control group - fetuses affected by RBC alloimmunization. Retrospective data such as antenatal sonographic evaluations, fetal brain MRI results, and short-term fetal and neonatal outcomes were collected. All children underwent a neurodevelopmental evaluation after birth using a Vineland questionnaire. Primary outcome was defined as the presence or absence of neurodevelopmental delay. Secondary outcome was defined as the presence of abnormal fetal neuroimaging findings such as cerebellar hypoplasia, polymicrogyria, intracranial hemorrhage, or severe ventriculomegaly.
RESULTS
Overall, 71 fetuses requiring at least one IUT were included in the study. Of these, 18 were affected by parvo B19 infection and 53 by RBC alloimmunization with various associated antibodies. Fetuses in the parvo B19 group presented at an earlier gestational age (22.91 ± 3.36 weeks vs. 27.37 ± 4.67 weeks, p = 0.002) and were more affected by hydrops (93.33% vs. 16.98%, p < 0.001). Three fetuses out of the 18 (16.67%) fetuses in the parvo B19 group died in utero following the IUT. Abnormal neuroimaging findings were detected in 4/15 (26.7%) of the parvo B19 survivors versus 2/53 (3.8%) of fetuses affected by RBC alloimmunization (p = 0.005). There was no difference in long-term neurodevelopmental delay rates between the children in the study and control groups, as assessed at the average age of 3.65 and 6.53 years, accordingly.
CONCLUSION
Fetal anemia due to parvo B19, treated with IUT, might be associated with increased rates of abnormal neurosonographic findings. The correlation between those findings and long-term adverse neurodevelopmental outcomes requires further investigation.
Topics: Child; Infant, Newborn; Pregnancy; Female; Humans; Child, Preschool; Infant; Retrospective Studies; Blood Transfusion, Intrauterine; Parvovirus B19, Human; Parvoviridae Infections; Fetal Diseases; Anemia; Neuroimaging
PubMed: 37231949
DOI: 10.1159/000530993 -
Journal of Neurosurgery. Case Lessons May 2023Schizencephaly is an uncommon central nervous system malformation. Intracranial lipomas are also rare, accounting for approximately 0.1% of brain "tumors." They are...
BACKGROUND
Schizencephaly is an uncommon central nervous system malformation. Intracranial lipomas are also rare, accounting for approximately 0.1% of brain "tumors." They are believed to be derived from a persistent meninx primitiva, a neural crest-derived mesenchyme that develops into the dura and leptomeninges.
OBSERVATIONS
The authors present a case of heterotopic adipose tissue and a nonshunting arterial vascular malformation arising within a schizencephalic cleft in a 22-year-old male. Imaging showed right frontal gray matter abnormality and an associated suspected arteriovenous malformation with evidence of hemorrhage. Brain magnetic resonance imaging revealed right frontal polymicrogyria lining an open-lip schizencephaly, periventricular heterotopic gray matter, fat within the schizencephalic cleft, and gradient echo hypointensity concerning for prior hemorrhage. Histological assessment demonstrated mature adipose tissue with large-bore, thick-walled, irregular arteries. Mural calcifications and subendothelial cushions suggesting nonlaminar blood flow were observed. There were no arterialized veins or direct transitions from the arteries to veins. Hemosiderin deposition was scant, and hemorrhage was not present. The final diagnosis was consistent with ectopic mature adipose tissue and arteries with meningocerebral cicatrix.
LESSONS
This example of a complex maldevelopment of derivatives of the meninx primitiva in association with cortical maldevelopment highlights the unique challenges from both a radiological and histological perspective during diagnostic workup.
PubMed: 37218736
DOI: 10.3171/CASE2388 -
International Journal of Developmental... Jun 2023Warburg Micro (WARBM) syndrome is a rare heterogeneous recessive genetic disorder characterized by ocular, neurological, and endocrine problems. To date, disease-causing...
BACKGROUND
Warburg Micro (WARBM) syndrome is a rare heterogeneous recessive genetic disorder characterized by ocular, neurological, and endocrine problems. To date, disease-causing variants in four genes have been identified to cause this syndrome; of these, RAB3GAP1 variants are the most frequent. Very little is known about WARBM syndrome in rural populations.
OBJECTIVES
This study aims to investigate the genetics underpinnings of WARBM syndrome in a Pashtun family with two patients from Pakistan. The patients presented with spastic diplegia, severe intellectual disability, microphthalmia, microcornea, congenital cataracts, optic atrophy, and hypogonadism.
METHODS
Magnetic resonance imaging (MRI) analysis revealed pronounced cerebral atrophy including corpus callosum hypoplasia and polymicrogyria. Exome sequencing and subsequent filtering identified a novel homozygous missense variant NM_001172435: c.2891A>G, p.Gln964Arg in the RAB3GAP1 gene. The variant was validated, and its segregation confirmed, by Sanger sequencing.
RESULTS
Multiple prediction tools assess this variant to be damaging, and structural analysis of the protein shows that the mutant amino acid residue affects polar contact with the neighboring atoms. It is extremely rare and is absent in all the public databases. Taken together, these observations suggest that this variant underlies Micro syndrome in our family and is extremely important for management and family planning.
CONCLUSIONS
Identification of this extremely rare variant extends the mutations spectrum of Micro syndrome. Screening more families, especially in underrepresented populations, will help unveil the mutation spectrum underlying this syndrome.
Topics: Humans; Intellectual Disability; Pakistan; Exome Sequencing; rab3 GTP-Binding Proteins; Optic Atrophy; Hypogonadism; Cataract; Mutation
PubMed: 37186309
DOI: 10.1002/jdn.10264