-
BMJ Case Reports Feb 2024Gould syndrome is an autosomal dominant syndrome due to a COL4A1 or COL4A2 mutation that is commonly characterised by familial porencephaly, seizures, intracranial...
Gould syndrome is an autosomal dominant syndrome due to a COL4A1 or COL4A2 mutation that is commonly characterised by familial porencephaly, seizures, intracranial haemorrhages, cataracts, nephropathies and more. There have been up to 137 identified patients based on a review of the literature. In this case, we describe a male infant that presents with hemiparesis, developmental delay and gait abnormalities at his well-child check. Referral to neurology and a subsequent MRI demonstrated porencephaly and ocular lens abnormalities. Genetic sequencing uncovered a mutation to the COL4A1 gene, suggesting Gould syndrome. There are no family members with similar phenotypes. Mutations to the COL4A1 and COL4A2 genes result in disruption of collagen found in most basement membranes, resulting in a variety of phenotypes that can make diagnosis difficult. Genetic identification of these patients is critical as these patients require a multidisciplinary approach to care and specific counselling on risk reduction techniques.
Topics: Infant; Humans; Male; Porencephaly; Collagen Type IV; Mutation; Basement Membrane; Phenotype; Family
PubMed: 38355202
DOI: 10.1136/bcr-2023-259103 -
Neurology. Genetics Apr 2021We describe a third patient with brain small vessel disease 3 (BSVD3), being the first with a homozygous essential splice site variant in the gene, with a more severe...
OBJECTIVE
We describe a third patient with brain small vessel disease 3 (BSVD3), being the first with a homozygous essential splice site variant in the gene, with a more severe phenotype than the 2 children reported earlier.
METHODS
Analysis of whole exome sequencing (WES) data of the child and parents was performed. We validated the missplicing of the homozygous variant using reverse transcription PCR and Sanger sequencing of the mRNA in a lymphocyte culture.
RESULTS
The patient presented antenatally with porencephaly on ultrasound and MRI. Postnatally, he showed a severe developmental delay, refractory epilepsy, spastic quadriplegia, and a progressive hydrocephalus. WES revealed a homozygous canonical splice site variant NM_024656.3:c.625-2A>C. PCR and Sanger sequencing of the mRNA demonstrated that 2 cryptic splice sites are activated, causing a frameshift in the major transcript and in-frame deletion in a minor transcript.
CONCLUSIONS
We report a third patient with biallelic pathogenic variants in , confirming the role of this gene in autosomal recessive BSVD3.
PubMed: 33709034
DOI: 10.1212/NXG.0000000000000564 -
Matrix Biology : Journal of the... Jan 2016The basal lamina (BM) contains numerous components with a predominance of type IV collagens. Clinical manifestations associated with mutations of the human COL4A1 gene...
The basal lamina (BM) contains numerous components with a predominance of type IV collagens. Clinical manifestations associated with mutations of the human COL4A1 gene include perinatal cerebral hemorrhage and porencephaly, hereditary angiopathy, nephropathy, aneurysms and muscle cramps (HANAC), ocular dysgenesis, myopathy, Walker–Warburg syndrome and systemic tissue degeneration. In Drosophila, the phenotype associated with dominant temperature sensitive mutations of col4a1 include severe myopathy resulting from massive degradation of striated muscle fibers, and in the gut, degeneration of circular visceral muscle cells and epithelial cells following detachment from the BM. In order to determine the consequences of altered BMfunctions due to aberrant COL4A1 protein, we have carried out a series of tests using Drosophila DTS-L3 mutants from our allelic series of col4a1 mutations with confirmed degeneration of various cell types and lowest survival rate among the col4a1 mutant lines at restrictive temperature. Results demonstrated epithelial cell degeneration in the gut, shortened gut, enlarged midgut with multiple diverticulae, intestinal dysfunction and shortened life span. Midgut immunohistochemistry analyses confirmed altered expression and distribution of BM components integrin PSI and PSII alpha subunits, laminin gamma 1, and COL4A1 both in larvae and adults. Global gene expression analysis revealed activation of the effector AMP genes of the primary innate immune system including Metchnikowin, Diptericin, Diptericin B, and edin that preceded morphological changes. Attacin::GFP midgut expression pattern further supported these changes. An increase in ROS production and changes in gut bacterial flora were also noted and may have further enhanced an immune response. The phenotypic features of Drosophila col4a1 mutants confirmed an essential role for type IV collagen in maintaining epithelial integrity, gut morphology and intestinal function and suggest that aberrant structure and function of the COL4A1 protein may also be a significant factor in modulating immunity.
Topics: Animals; Basement Membrane; Collagen Type IV; Disease Models, Animal; Drosophila; Drosophila Proteins; Gastrointestinal Microbiome; Gene Expression Regulation; Humans; Immunity, Innate; Intestines; Muscular Diseases; Mutation
PubMed: 26363084
DOI: 10.1016/j.matbio.2015.09.002 -
Prenatal Diagnosis Dec 2016The primary objective of our study was to evaluate the long-term neurodevelopment outcome after laser surgery for twin-twin transfusion syndrome (TTTS). The secondary...
OBJECTIVE
The primary objective of our study was to evaluate the long-term neurodevelopment outcome after laser surgery for twin-twin transfusion syndrome (TTTS). The secondary objective was to identify perinatal prognostic factors associated with neurodevelopmental impairment.
METHOD
This was a single-center cohort prospective study carried out in pregnancies complicated by TTTS and treated by laser. Neurodevleopmental assesment included the administration of Ages and Stages Questionnaires® (ASQ), for the infants between 2 and 5 years of age.
RESULTS
A total of 187 patients underwent a laser for TTTS between 2004 and 2013. Significant brain lesions were detected in eight (2.9%) cases by ultrasound and/or magnetic resonance imaging including intraventricular hemorrhage, periventricular leukomalacia, and porencephaly. Questionnaires were administered to 126 children (50.4%) at 24 months or older at the moment of testing. There were 13.5% of those infants who had an abnormal ASQ (established as one area or more scoring < 2 SD) at 3.6 years ±1.3 follow-up. There was a higher rate of abnormal ASQ among the infants with a birth weight below the fifth percentile (p = 0.036).
CONCLUSION
Twin-twin transfusion syndrome is associated with a risk of abnormal neurological development, even in case of laser surgery. Further studies are necessary to identify the risk factors for neurological impairment. © 2016 John Wiley & Sons, Ltd.
Topics: Adult; Brain; Cerebral Hemorrhage; Cerebral Ventricles; Child, Preschool; Cohort Studies; Echoencephalography; Female; Fetal Therapies; Fetofetal Transfusion; Humans; Laser Therapy; Leukomalacia, Periventricular; Magnetic Resonance Imaging; Neurodevelopmental Disorders; Porencephaly; Pregnancy; Prospective Studies; Surveys and Questionnaires; Twins, Monozygotic; Young Adult
PubMed: 27764900
DOI: 10.1002/pd.4950 -
Developmental Medicine and Child... Mar 2022This is a case series of six children with unilateral cerebral palsy and hemispheric encephaloclastic lesions who were evaluated for epilepsy surgery. Seizure onset was...
This is a case series of six children with unilateral cerebral palsy and hemispheric encephaloclastic lesions who were evaluated for epilepsy surgery. Seizure onset was in the neonatal period in three children, at 17 months in two, and at 5 years in one. Their ictal and interictal electroencephalogram (EEG) abnormalities showed paradoxical lateralization to the incorrect/'normal' hemisphere or showed bilateral abnormalities. After cautious discussion regarding the discordant electroclinical profile and implications for outcome, they proceeded to a functional hemispherectomy (between ages 4-11y) with good outcomes (at 1-10y follow-up). Their clinical details, EEG findings, electrocorticography, neuroimaging, and histology are reported. Possible surgical candidacy should be evaluated early in children with refractory epilepsy, even those with complex profiles and discordant data from the different investigations. Contralateral or bilateral EEG abnormalities should not preclude consideration of hemispherectomy in children with refractory epilepsy, hemiparesis, and uniclastic lesions.
Topics: Cerebral Palsy; Child; Child, Preschool; Drug Resistant Epilepsy; Electroencephalography; Female; Follow-Up Studies; Hemispherectomy; Humans; Male; Outcome Assessment, Health Care; Paresis; Porencephaly
PubMed: 34495552
DOI: 10.1111/dmcn.15047 -
American Journal of Medical Genetics.... Jan 2015COL4A1-associated disorders encompass a wide range of hereditary vasculopathy, including porencephaly and HANAC (adult-onset hemorrhagic stroke with cerebral aneurysm...
COL4A1-associated disorders encompass a wide range of hereditary vasculopathy, including porencephaly and HANAC (adult-onset hemorrhagic stroke with cerebral aneurysm and retinal arterial tortuosity, renal cysts, and thenar muscle cramp). It remains elusive whether or not porencephaly and HANAC are molecularly distinctive disorders due to different classes of mutations. We report on a girl with porencephaly and an episode of microangiopathic hemolysis in infancy and her father with HANAC, both of whom had a heterozygous missense mutation of COL4A1 (c.3715G>A, p.G1239R). The current observation implies phenotypic diversities of COL4A1 mutations.
Topics: Adult; Base Sequence; Collagen Type IV; Fathers; Female; Fetus; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Molecular Sequence Data; Muscle Cramp; Mutation; Pedigree; Porencephaly; Pregnancy; Raynaud Disease; Young Adult
PubMed: 25425218
DOI: 10.1002/ajmg.a.36823 -
Disease Models & Mechanisms Apr 2021Collagen type IV alpha 1 and alpha 2 (COL4A1 and COL4A2) are major components of almost all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder...
Collagen type IV alpha 1 and alpha 2 (COL4A1 and COL4A2) are major components of almost all basement membranes. COL4A1 and COL4A2 mutations cause a multisystem disorder that can affect any organ but typically involves the cerebral vasculature, eyes, kidneys and skeletal muscles. In recent years, patient advocacy and family support groups have united under the name of Gould syndrome. The manifestations of Gould syndrome are highly variable, and animal studies suggest that allelic heterogeneity and genetic context contribute to the clinical variability. We previously characterized a mouse model of Gould syndrome caused by a Col4a1 mutation in which the severities of ocular anterior segment dysgenesis (ASD), myopathy and intracerebral hemorrhage (ICH) were dependent on genetic background. Here, we performed a genetic modifier screen to provide insight into the mechanisms contributing to Gould syndrome pathogenesis and identified a single locus [modifier of Gould syndrome 1 (MoGS1)] on Chromosome 1 that suppressed ASD. A separate screen showed that the same locus ameliorated myopathy. Interestingly, MoGS1 had no effect on ICH, suggesting that this phenotype could be mechanistically distinct. We refined the MoGS1 locus to a 4.3 Mb interval containing 18 protein-coding genes, including Fn1, which encodes the extracellular matrix component fibronectin 1. Molecular analysis showed that the MoGS1 locus increased Fn1 expression, raising the possibility that suppression is achieved through a compensatory extracellular mechanism. Furthermore, we found evidence of increased integrin-linked kinase levels and focal adhesion kinase phosphorylation in Col4a1 mutant mice that is partially restored by the MoGS1 locus, implicating the involvement of integrin signaling. Taken together, our results suggest that tissue-specific mechanistic heterogeneity contributes to the variable expressivity of Gould syndrome and that perturbations in integrin signaling may play a role in ocular and muscular manifestations.
Topics: Abnormalities, Multiple; Animals; Cerebral Hemorrhage; Chromosome Mapping; Chromosomes, Mammalian; Collagen Type IV; Eye Abnormalities; Fibronectins; Genes, Modifier; Genes, Suppressor; Genetic Loci; Integrins; Mice, Mutant Strains; Muscular Diseases; Porencephaly; Signal Transduction; Syndrome; Mice
PubMed: 34424299
DOI: 10.1242/dmm.048231 -
Veterinary Microbiology Nov 2017Schmallenberg virus (SBV) is an emerging virus responsible for congenital malformations in the offspring of domestic ruminants. It is speculated that infection of...
Schmallenberg virus (SBV) is an emerging virus responsible for congenital malformations in the offspring of domestic ruminants. It is speculated that infection of pregnant dams may also lead to a significant number of unrecognized fetal losses during the early period of gestation. To assess the pathogenic effects of SBV infection of goats in early pregnancy, we inoculated dams at day 28 or 42 of gestation and followed the animals until day 55 of gestation. Viremia in the absence of clinical signs was detected in all virus-inoculated goats. Fetal deaths were observed in several goats infected at day 28 or 42 of gestation and were invariably associated with the presence of viral genomic RNA in the affected fetuses. Among the viable fetuses, two displayed lesions in the central nervous system (porencephaly) in the presence of viral genome and antigen. All fetuses from goats infected at day 42 and the majority of fetuses from goats infected at day 28 of gestation contained viral genomic RNA. Viral genome was widely distributed in these fetuses and their respective placentas, and infectious virus could be isolated from several organs and placentomes of the viable fetuses. Our results show that fetuses of pregnant goats are susceptible to vertical SBV infection during early pregnancy spanning at least the period between day 28 and 42 of gestation. The outcomes of experimental SBV infection assessed at day 55 of gestation include fetal mortalities, viable fetuses displaying lesions of the central nervous system, as well as viable fetuses without any detectable lesion.
Topics: Animals; Bunyaviridae Infections; Female; Fetus; Goat Diseases; Goats; Orthobunyavirus; Placenta; Pregnancy; Viremia
PubMed: 29102110
DOI: 10.1016/j.vetmic.2017.10.011 -
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 -
Child's Nervous System : ChNS :... Apr 2018Porencephalic cysts and cerebrospinal fluid (CSF) edema around the intracranial shuntcatheter are rare complications of ventriculoperitoneal shunt (VPS) surgery.... (Review)
Review
INTRODUCTION
Porencephalic cysts and cerebrospinal fluid (CSF) edema around the intracranial shuntcatheter are rare complications of ventriculoperitoneal shunt (VPS) surgery. Possible mechanisms leading to a porencephalic cyst formation in a patient with a VPS include taut ventricle, dysfunction of distalcatheters, and irreversible damage to the brain parenchyma caused by shunt insertion, chemotherapy, or radiation. Most of the previous reports were due to shunt malfunction and treatment consisted of shunt revision or removal.
CASE REPORT
We present a case of porencephalic cyst formation in a 6-year-old female as a result ofcerebrospinal fluid under-drainage that was promptly improved with shunt valve adjustment.
COCLUSIONS
A heightened index of suspicion is required to prevent misdiagnosis of porencephalic cysts astumors or abscesses that may lead to unnecessary surgical explorations. Further research is needed toelucidate the pathophysiological mechanism that causes a porencephalic cyst formation.
Topics: Cerebrospinal Fluid; Child; Cysts; Female; Humans; Porencephaly; Ventriculoperitoneal Shunt
PubMed: 29380111
DOI: 10.1007/s00381-018-3725-x