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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 -
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 -
Cureus Nov 2019Phentermine is a sympathomimetic amine used for the short-term weight loss that has been associated with ischemic and hemorrhagic strokes in adults. The effects of this...
Phentermine is a sympathomimetic amine used for the short-term weight loss that has been associated with ischemic and hemorrhagic strokes in adults. The effects of this medication on a developing fetus are not well studied. We present the case of a woman who was taking phentermine during the first two trimesters of pregnancy and subsequently delivered a child with bilateral porencephalic cysts likely due to a prenatal stroke.
PubMed: 31890378
DOI: 10.7759/cureus.6170 -
Radiology Case Reports Jan 2020Prothrombotic conditions are known risk factors for porencephalic cyst formation and cerebral vein thrombosis. Intracerebral hemorrhage is a potential complication of a...
Prothrombotic conditions are known risk factors for porencephalic cyst formation and cerebral vein thrombosis. Intracerebral hemorrhage is a potential complication of a cerebral vein thrombosis. Porencephaly is a risk factor for intracerebral hemorrhage and cerebral vein thrombosis formation. We present the case of an adult patient with a past medical history of epilepsy and congenital porencephalic cyst with de novo mutation of the COL4A1 gene who presented for episodes of generalized tonic-clonic seizure after a substantial symptom-free period. A brain CT scan showed an intracerebral hemorrhage with porencephalic cyst and superior sagittal sinus thrombosis despite negative thrombophilia work-up. A CT perfusion study, CT angiography, and brain MRI confirmed the diagnosis. The cause-and-effect relationship between porencephalic cysts, cerebral venous thrombosis, and intracerebral hemorrhage is still not clear in the literature.
PubMed: 31762865
DOI: 10.1016/j.radcr.2019.10.028 -
Biology Open Aug 2019The Deciphering the Mechanisms of Developmental Disorders (DMDD) program uses a systematic and standardised approach to characterise the phenotype of embryos stemming...
The Deciphering the Mechanisms of Developmental Disorders (DMDD) program uses a systematic and standardised approach to characterise the phenotype of embryos stemming from mouse lines, which produce embryonically lethal offspring. Our study aims to provide detailed phenotype descriptions of homozygous mutants produced in DMDD and harvested at embryonic day 14.5. This shall provide new information on the role plays in organogenesis and demonstrate the capacity of the DMDD database for identifying models for researching inherited disorders. The DMDD mutants survived organogenesis and thus revealed the full spectrum of organs and tissues, the development of which depends on encoded proteins. They showed defects in the brain, cranial nerves, visual system, lungs, endocrine glands, skeleton, subepithelial tissues and mild to severe cardiovascular malformations. Together, this makes the DMDD line a useful model for identifying the spectrum of defects and for researching the mechanisms underlying autosomal dominant porencephaly 2 (OMIM # 614483), a rare human disease. Thus we demonstrate the general capacity of the DMDD approach and webpage as a valuable source for identifying mouse models for rare diseases.
PubMed: 31331924
DOI: 10.1242/bio.042895 -
Human Genetics Oct 2019Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The...
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.
Topics: Alleles; Amino Acid Substitution; Collagen Type IV; Computational Biology; Congenital Abnormalities; DNA Mutational Analysis; Databases, Genetic; Evolution, Molecular; Female; Genetic Association Studies; Genetic Loci; Genomics; Heterozygote; Humans; Kidney; Kidney Diseases, Cystic; Male; Mutation; Nephrotic Syndrome; Phenotype; Urinary Tract; Web Browser; Exome Sequencing
PubMed: 31230195
DOI: 10.1007/s00439-019-02042-4 -
Journal of Critical Care Medicine... Apr 2019Patient-controlled analgesia with morphine is routinely used for postoperative pain management. Due to the safety profiles of the technique, which are patient/disease...
INTRODUCTION
Patient-controlled analgesia with morphine is routinely used for postoperative pain management. Due to the safety profiles of the technique, which are patient/disease related or technique/equipment related, severe respiratory depression requiring opioid antagonists or airway management are uncommon.
CASE PRESENTATION
The case of a patient with right colon carcinoma who was operated on for hemicolectomy under general anaesthesia and who presented with apnoea, after postoperatively receiving an initial bolus of 1mg of morphine. A large post-traumatic porencephalic cyst of the left brain hemisphere, previously undiagnosed, was found on the computed tomography scan. We excluded human errors, technique and equipment factors, and the patient did not have any other predisposing conditions like sleep apnoea, obesity, recent head injury or concurrent use of other sedatives. Previously the patient had been entirely asymptomatic, and her increased susceptibility to respiratory depression was the only clinical manifestation of porencephaly.
CONCLUSION
Adult acquired porencephaly is seldom reported in the literature, clinical manifestations depending on the location and size of the cyst. In the present reported case, increased susceptibility to low-dose opioids might be associated with the structural and functional reorganisation of the brain after head trauma with the occurrence of the porencephalic cyst of the brain.
PubMed: 31161144
DOI: 10.2478/jccm-2019-0011 -
Human Genome Variation 2018Porencephaly and schizencephaly are congenital brain disorders that can be caused by mutations, though the underlying mechanism and developmental processes are poorly...
Porencephaly and schizencephaly are congenital brain disorders that can be caused by mutations, though the underlying mechanism and developmental processes are poorly understood. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in (c.2645_2646delinsAA, p.Gly882Glu). Our results suggest that the onset of damage that potentially results in schizencephaly occurs mid-pregnancy.
PubMed: 29760938
DOI: 10.1038/s41439-018-0005-y -
Journal of Community Hospital Internal... 2018We present a case of a 56-year-old male with a history of perinatal intracerebral hemorrhage who presented to the emergency department after a witnessed new-onset...
We present a case of a 56-year-old male with a history of perinatal intracerebral hemorrhage who presented to the emergency department after a witnessed new-onset generalized tonic-clonic seizure. Computerized tomography and magnetic resonance imaging of the head revealed a large frontal lobe porencephalic cyst, with encephalomalacia in the right parietal lobe and temporal lobe (the patient did not have any prior cranial imaging). The patient has subsequently remained seizure-free on levetiracetam. Porencephalic cyst is a rare condition of cerebrospinal fluid accumulation in the brain parenchyma that is usually related to perinatal vascular events. These cysts can have a wide array of clinical presentations. This can include partial or generalized seizures, which are usually managed by antiepileptics.
PubMed: 29686797
DOI: 10.1080/20009666.2018.1454788