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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 -
Neuropathology : Official Journal of... Feb 2020Stroke is a major cause of mortality and morbidity with a wide variety of etiological risk factors. Cerebral small vessel disease (SVD) is an important cause of stroke...
Stroke is a major cause of mortality and morbidity with a wide variety of etiological risk factors. Cerebral small vessel disease (SVD) is an important cause of stroke in the young with several hereditary disorders affecting these small blood vessels. Mutations in the COL4A1 gene (COL4A1) have been shown to be associated with a broad range of disorders including hemorrhagic stroke, myopathy, glaucoma and others. We report a rare case of stroke in an intellectually disabled 18-year-old girl with radiological evidence of basal ganglia microbleeds, periventricular white matter signal changes and porencephalic cyst. Ophthalmic examination revealed bilateral microcornea and Axenfeld-Rieger anomaly. At autopsy there were hemorrhagic lesions at multiple sites within the brain. Histology revealed thickened small-caliber vessels which demonstrated disruption and fragmentation of the basement membrane by collagen type IV alpha 1 immunohistochemistry and by electron microscopy. A missense COL4A1 mutation involving glycine residue was detected in the patient. The present case illustrates the clinicopathological spectrum of COL4A1-related cerebral SVD presenting as hemorrhagic stroke in the young with porencephaly, intellectual disability, and Axenfield-Rieger anomaly and thus adds to the clinical heterogeneity of this genetic disorder.
Topics: Adolescent; Cerebral Small Vessel Diseases; Collagen Type IV; Female; Humans; Intracranial Hemorrhages; Mutation; Stroke
PubMed: 31808207
DOI: 10.1111/neup.12607 -
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 -
Journal of AAPOS : the Official... Dec 2019
Topics: Cataract; Collagen Type IV; Humans; Infant; Mutation; Ophthalmology; Porencephaly
PubMed: 31580895
DOI: 10.1016/j.jaapos.2019.09.004 -
Canadian Journal of Ophthalmology.... Oct 2019
Topics: Abnormalities, Multiple; Female; Hemianopsia; Humans; Magnetic Resonance Imaging; Middle Aged; Occipital Lobe; Porencephaly; Tomography, Optical Coherence; Visual Acuity; Visual Fields
PubMed: 31564367
DOI: 10.1016/j.jcjo.2019.01.012 -
Brain & Development Jan 2020COL4A1-related disorder is recognized as a systemic disease because the alpha 1 chain of type IV collagen, encoded by COL4A1, is essential for basement membrane...
COL4A1-related disorder is recognized as a systemic disease because the alpha 1 chain of type IV collagen, encoded by COL4A1, is essential for basement membrane stability. However, muscular manifestations related to this disorder are rarely reported. We report the case of a 2-year-old boy with porencephaly, who harbored a de novo COL4A1 mutation of c.1853G > A, p. (Gly618Glu) and exhibited recurrent rhabdomyolysis with viral or bacterial infections. Moreover, he developed obstructive hypertrophic cardiomyopathy which required surgical intervention. Skeletal muscle biopsy revealed findings compatible with fiber-type disproportion. Ultrastructural study demonstrated the similar findings previously reported in mice with Col4a1 mutation including collagen disarray and reduction of electron density in the basement membrane of capillary endothelial cells and muscle fibers. Dilated endoplasmic reticulum in the capillary endothelial cells is also noted. This report adds another disease spectrum of COL4A1 mutation which include porencephaly, hypertrophic cardiomyopathy, rhabdomyolysis and fiber-type disproportion.
Topics: Cardiomyopathy, Hypertrophic; Child, Preschool; Collagen Type IV; Humans; Male; Muscle, Skeletal; Mutation; Porencephaly; Rhabdomyolysis
PubMed: 31540749
DOI: 10.1016/j.braindev.2019.09.001 -
Journal of AAPOS : the Official... Dec 2019
Topics: Brain Diseases; Cataract; Collagen Type IV; Humans; Infant; Mutation; Porencephaly
PubMed: 31525464
DOI: 10.1016/j.jaapos.2019.07.002 -
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 AAPOS : the Official... Aug 2019COL4A1 mutations present with a spectrum of clinical phenotypes often involving the cerebrovascular and ophthalmic systems. We report 2 cases of COL4A1 mutations that...
COL4A1 mutations present with a spectrum of clinical phenotypes often involving the cerebrovascular and ophthalmic systems. We report 2 cases of COL4A1 mutations that presented with congenital cataracts and porencephaly. Both patients had posterior cortical cataracts and radiographically defined bilateral posterior lenticonus. Considering the long-term clinical implications of these mutations, posterior cortical cataracts, bilateral posterior lenticonus, and porencephaly should raise clinical suspicion for COL4A1 mutations.
Topics: Abnormalities, Multiple; Brain; Cataract; Collagen Type IV; DNA; DNA Mutational Analysis; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Mutation; Pedigree; Phenotype; Porencephaly
PubMed: 31128271
DOI: 10.1016/j.jaapos.2019.04.003