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Journal of Medical Genetics Aug 2021Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals...
BACKGROUND
Variants in the type IV collagen gene () cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with variants remain unclear.
METHODS
We examined in 218 individuals with suspected /2-related brain defects. Among those arising from variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.
RESULTS
Pathogenic variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.
CONCLUSIONS
Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and gene testing should be considered when pathogenic variants are strongly suspected.
Topics: Collagen Type IV; Dandy-Walker Syndrome; Female; Humans; Male; Mutation; Pregnancy; Ultrasonography, Prenatal
PubMed: 32732225
DOI: 10.1136/jmedgenet-2020-106896 -
Abnormalities of the Fetal Central Nervous System: Prenatal US Diagnosis with Postnatal Correlation.Radiographics : a Review Publication of... 2020Fetal central nervous system (CNS) abnormalities are second only to cardiac malformations in their frequency of occurrence. Early and accurate diagnosis at prenatal US... (Review)
Review
Fetal central nervous system (CNS) abnormalities are second only to cardiac malformations in their frequency of occurrence. Early and accurate diagnosis at prenatal US is therefore essential, allowing improved prenatal counseling and facilitating appropriate referral. Thorough knowledge of normal intracranial anatomy and adoption of a logical sonographic approach can improve depiction of abnormal findings, leading to a more accurate differential diagnosis earlier in pregnancy. Four standard recommended views-transventricular, falx, cavum, and posterior fossa or transcerebellar views-provide an overview of fetal intracranial anatomy during the second trimester anatomy scan. Essential elements surveyed in the head and neck include the lateral cerebral ventricles, choroid plexus, midline falx, cavum septi pellucidi, cerebellum, cisterna magna, upper lip, and nuchal fold. CNS abnormalities can be organized into six main categories at prenatal US. Developmental anomalies include neural tube defects and neuronal migration disorders. Posterior fossa disorders include Dandy-Walker malformation variants and Chiari II malformation. Ventricular anomalies include aqueductal stenosis. Midline disorders include those on the spectrum of holoprosencephaly, agenesis of the corpus callosum, and septo-optic dysplasia. Vascular anomalies include vein of Galen malformations. Miscellaneous disorders include hydranencephaly, porencephaly, tumors, and intracranial hemorrhage. Correlation with postnatal MRI is helpful for confirmation and clarification of suspected diagnoses after birth. The authors discuss a standard US imaging approach to the fetal CNS and review cases in all categories of CNS malformations, providing postnatal MRI correlation when available.RSNA, 2020.
Topics: Female; Humans; Infant, Newborn; Magnetic Resonance Imaging; Nervous System Malformations; Pregnancy; Ultrasonography, Prenatal
PubMed: 32706613
DOI: 10.1148/rg.2020200034 -
Asian Journal of Psychiatry Dec 2020
Topics: Brain; Capgras Syndrome; Delusions; Humans; Porencephaly
PubMed: 32653846
DOI: 10.1016/j.ajp.2020.102289 -
Ultrasound in Obstetrics & Gynecology :... May 2021To establish the prevalence of COL4A1 and COL4A2 gene mutations in fetuses presenting with a phenotype suggestive of cerebral injury.
OBJECTIVE
To establish the prevalence of COL4A1 and COL4A2 gene mutations in fetuses presenting with a phenotype suggestive of cerebral injury.
METHODS
This was a single-center retrospective analysis of all cases of fetal cerebral anomalies suggestive of COL4A1 or COL4A2 gene mutation over the period 2009-2018. Inclusion criteria were: (1) severe and/or multifocal hemorrhagic cerebral lesions; (2) multifocal ischemic-hemorrhagic cerebral lesions. These anomalies could be of different ages and associated with schizencephaly or porencephaly. Between fetuses with and those without a mutation, we compared gestational age at the time of diagnosis, parity and fetal gender.
RESULTS
Among the 956 cases of cerebral anomaly diagnosed in our center during the 10-year study period, 18 fetuses were identified for inclusion. A pathogenic COL4A1 gene mutation was found in five of these cases, among which four were de-novo mutations. A variant of unknown significance was found in four fetuses: in the COL4A1 gene in one case and in the COL4A2 gene in three cases. No COL4A1 or COL4A2 mutation was found in the remaining nine fetuses. The median (interquartile range) gestational age at diagnosis was significantly lower in cases with a mutation (24 (22-26) weeks) than in cases without a mutation (32 (29.5-34.5) weeks) (P = 0.03).
CONCLUSIONS
A phenotype suggestive of cerebral injury was found in 18 of the 956 (1.9%) cases in our population, in 28% of which there was an associated COL4A1 or COL4A2 mutation. COL4A1 and COL4A2 gene mutations should be sought systematically in cases of severe and/or multifocal hemorrhagic or ischemic-hemorrhagic cerebral lesions, with or without schizencephaly or porencephaly. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Adult; Cerebral Hemorrhage; Collagen Type IV; Female; Gestational Age; Humans; Malformations of Cortical Development; Mutation; Phenotype; Porencephaly; Pregnancy; Pregnancy Outcome; Prenatal Diagnosis; Prevalence; Retrospective Studies; Schizencephaly
PubMed: 32515830
DOI: 10.1002/uog.22106 -
Epilepsy Research Aug 2020Collagen type IV, alpha-1 (COL4A1) variants can cause cerebrovascular diseases, such as porencephaly and cerebral hemorrhage, in addition to other autosomal dominant...
Collagen type IV, alpha-1 (COL4A1) variants can cause cerebrovascular diseases, such as porencephaly and cerebral hemorrhage, in addition to other autosomal dominant hereditary diseases. Patients with COL4A1 variants can present with epilepsy, most commonly focal epilepsy. In this paper, we present five patients, three of whom were examined by the authors, and two who were previously reported. Clinically, these five patients were characterized by the presence of West syndrome (WS), periventricular leukomalacia (PVL), and microcephaly, but none had a history of premature birth or hypoxic ischemic encephalopathy (HIE). Genetic testing results indicated that all patients had heterozygous variants of COL4A1. Genetic testing for the COL4A1 variants should be considered when a patient without a history of prematurity or HIE develops WS with PVL and microcephaly.
Topics: Cerebral Hemorrhage; Child; Child, Preschool; Collagen Type IV; Female; Heterozygote; Humans; Infant; Male; Mutation; Spasms, Infantile
PubMed: 32446163
DOI: 10.1016/j.eplepsyres.2020.106349 -
Neurosurgical Focus Apr 2020The goal of this study was to perform an analysis of a single-center experience with hemispherotomy reoperations for refractory hemispheric pediatric epilepsy due to...
OBJECTIVE
The goal of this study was to perform an analysis of a single-center experience with hemispherotomy reoperations for refractory hemispheric pediatric epilepsy due to persistence of seizures after initial surgery. The authors also identify possible anatomical and neurophysiological reasons for hemispherotomy failure, as well as risk factors and surgical options for this subgroup of patients.
METHODS
A review was performed of the medical records in 18 consecutive cases in which candidates for redo hemispherotomy were treated between 2003 and 2018 at the authors' epilepsy surgery center. Fourteen patients underwent reoperation due to seizure recurrence and were studied herein, whereas in 3 the initial surgical procedure was stopped because of uncontrollable bleeding, and the remaining patient refused to undergo a reoperation in spite of seizure recurrence and went on to have a vagus nerve stimulation device placed.
RESULTS
Among the 14 patients whose seizures recurred and in whom reoperations were done, the etiology of epilepsy consisted of 7 cases with malformations of cortical development (50%), 5 cases of Rasmussen encephalitis (35.8%), 1 case of porencephaly (7.1%), and 1 case of Sturge-Weber syndrome (7.1%). Eleven patients had radiological evidence of incomplete disconnection. After reoperation, 6 patients were Engel class IA, 1 was Engel II, 5 were Engel III, and 2 were Engel IV, within a mean follow-up of 48.4 months.
CONCLUSIONS
Patients with malformations of cortical development have a higher risk of seizure recurrence, and these malformations comprised the main etiology in the reoperation series. Failure of an initial hemispherotomy usually occurs due to incomplete disconnection and needs to be extensively assessed. Outcomes of reoperation are most often favorable, with acceptable complication rates.
Topics: Child; Child, Preschool; Drug Resistant Epilepsy; Encephalitis; Epilepsy; Female; Follow-Up Studies; Hemispherectomy; Humans; Infant; Magnetic Resonance Imaging; Male; Reoperation; Risk Factors; Seizures
PubMed: 32234979
DOI: 10.3171/2020.1.FOCUS19944 -
World Neurosurgery May 2020Hemispherectomy has been shown to be successful in treating medically intractable epilepsy, with favorable seizure-free outcomes. However, the procedure is technically...
BACKGROUND
Hemispherectomy has been shown to be successful in treating medically intractable epilepsy, with favorable seizure-free outcomes. However, the procedure is technically challenging with high rates of in-hospital complications. We present a unique case of functional hemispherectomy complicated by diffuse cerebral vasospasm and subsequent death in a patient with COL4A1 gene mutation.
CASE DESCRIPTION
A 17-year-old boy presented with right hemispheric epilepsy and a previously diagnosed autosomal dominant heterozygous COL4A1 gene mutation (c.4380T>G;p.Cys1460Trp). Functional hemispherectomy was performed without complications. On postoperative day 8, he developed an acute decline in neurologic status requiring urgent intubation for airway protection. Magnetic resonance imaging revealed areas of restricted diffusion throughout bilateral hemispheres that was explained by severe vasospasm and minimal cerebral blood flow seen on cerebral angiography. Intra-arterial calcium channel blocker infusion and balloon angioplasty were attempted without improvement in perfusion. With a worsening clinical picture, he was transitioned to comfort care and died.
CONCLUSIONS
This is the first report in the literature describing global vasospasm and delayed cerebral ischemia following hemispherectomy in a patient carrying COL4A1 gene mutation. We postulate that his COL4A1 gene mutation might have resulted in this exaggerated vasospasm despite minimal residual postoperative subarachnoid hemorrhage burden. This hypothesis needs to be studied in animal models of this genetic disorder.
Topics: Adolescent; Angiography, Digital Subtraction; Brain Ischemia; Cerebral Angiography; Collagen Type IV; Developmental Disabilities; Drug Resistant Epilepsy; Epilepsies, Partial; Fatal Outcome; Hemianopsia; Hemiplegia; Hemispherectomy; Humans; Male; Porencephaly; Postoperative Complications; Vasospasm, Intracranial
PubMed: 32059966
DOI: 10.1016/j.wneu.2020.02.020 -
Epileptic Disorders : International... Feb 2020ESES is a developmental epileptic disorder directly responsible for progressive encephalopathy and neurocognitive regression. The natural history, indications for...
ESES is a developmental epileptic disorder directly responsible for progressive encephalopathy and neurocognitive regression. The natural history, indications for surgical intervention, and predictors for favorable seizure and neuropsychological outcome remain unclear. We performed a retrospective review of children who underwent resective or disconnective surgery for ESES between January 2009 and July 2016 at a large tertiary pediatric center. Information on the patients' demographics, seizure semiology, radiographic and electrographic findings, and surgical management was collected. The primary outcome was seizure freedom at last follow-up visit, and secondary outcomes were neuropsychological improvement and electrographic ESES resolution. We identified 11 children who underwent surgery for ESES. The mean ages were 3.2 years for seizure onset, 7.1 years for formal ESES diagnosis, and 9.4 years for surgery. Seizure etiologies included cortical malformations (four patients), encephalomalacia and gliosis from prior hemorrhage or tumor resections (three patients), developmental porencephaly (one patient), and Rasmussen's encephalitis (one patient); the etiology was unknown in two children. Preoperatively, nine children had motor deficits, seven had speech and language delay, and three had visual field defects. All children had seizures and neuropsychological regression prior to surgical consideration. Focal cortical resections were performed in seven children, and hemispherectomies in four. Post-operatively, nine children experienced decreased seizure frequency, eight had neuropsychological improvement, and nine had resolution of electrographic ESES. Patients with poor surgical outcomes had more significant pre-operative comorbidities, in addition to bilateral ESES activity. In this case series, surgery for a carefully selected group of children with ESES is safe and feasible, yielding rates of seizure freedom and neuropsychological improvement that compare favorably with previous reports for antiepileptic drugs, benzodiazepines, and steroids. As we gain greater understanding into the management of ESES, surgery is an increasingly useful tool for patients with mild or moderate neurodevelopmental delay, focal epileptogenic foci, and hemi-ESES electrographic findings.
Topics: Adolescent; Brain Diseases; Child; Child, Preschool; Cognitive Dysfunction; Epilepsy; Feasibility Studies; Female; Follow-Up Studies; Humans; Male; Neurosurgical Procedures; Outcome and Process Assessment, Health Care; Retrospective Studies; Sleep Wake Disorders; Status Epilepticus
PubMed: 32043470
DOI: 10.1684/epd.2020.1129 -
PloS One 2020Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual...
Optic nerve hypoplasia (ONH) is a congenital malformation with a reduced number of retinal ganglion cell axons in a thin optic nerve. It is a common cause of visual impairment in children and ONH is associated with neurodevelopmental disorders, pituitary hormone deficiencies, and brain malformations. In most cases, the aetiology is unknown, but both environmental factors and genetic causes have been described. This study aimed to identify genetic variants underlying ONH in a well-characterised cohort of individuals with ONH. We performed array comparative genomic hybridization and whole genome sequencing in 29 individuals with ONH. Rare variants were verified by Sanger sequencing and inheritance was assessed in parental samples. We identified 11 rare single nucleotide variants (SNVs) in ten individuals, including a homozygous variant in KIF7 (previously associated with Joubert syndrome), a heterozygous de novo variant in COL4A1 (previously described in an individual with porencephaly), and a homozygous variant in COL4A2. In addition, one individual harboured a heterozygous variant in OPA1 and a heterozygous variant in COL4A1, both were inherited and assessed as variants of unknown clinical significance. Finally, a heterozygous deletion of 341 kb involving exons 7-18 of SOX5 (associated with Lamb-Schaffer syndrome) was identified in one individual. The overall diagnostic yield of pathogenic or likely pathogenic variants in individuals with ONH using whole genome sequencing was 4/29 (14%). Our results show that there is a genetic heterogeneity in ONH and indicate that genetic causes of ONH are not rare. We conclude that genetic testing is valuable in a substantial proportion of the individuals with ONH, especially in cases with non-isolated ONH.
Topics: Adolescent; Adult; Child; Comparative Genomic Hybridization; Cross-Sectional Studies; Exons; Female; Genetic Heterogeneity; Genetic Testing; Genome, Human; Heterozygote; Humans; Male; Optic Nerve; Optic Nerve Hypoplasia; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Retinal Ganglion Cells; SOXD Transcription Factors; Sweden; Whole Genome Sequencing; Young Adult
PubMed: 32040484
DOI: 10.1371/journal.pone.0228622 -
Case Reports in Ophthalmology 2019We report the case of a girl with a novel mutation of the gene (c.2716+2T>C) presenting microcephaly, parenchymal hemorrhages, lissencephaly, and bilateral cataracts,...
We report the case of a girl with a novel mutation of the gene (c.2716+2T>C) presenting microcephaly, parenchymal hemorrhages, lissencephaly, and bilateral cataracts, associated with agenesis of the corpus callosum and hypoplasia of the optic nerve. , located on chromosome 13, encodes the α1 chain of type IV collagen, a key component of the basement membrane in various organs, such as eye, brain, kidneys, and muscles. Different mutations have been described and may remain asymptomatic or determine porencephaly, cerebral hemorrhages, renal cysts, hematuria, and dysgenesis of the anterior segment of the eye.
PubMed: 31966034
DOI: 10.1159/000505017