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BMC Medical Genetics Aug 2014Almost one-third of congenital cataracts are primarily autosomal dominant disorders, which are also called autosomal dominant congenital cataract, resulting in blindness...
BACKGROUND
Almost one-third of congenital cataracts are primarily autosomal dominant disorders, which are also called autosomal dominant congenital cataract, resulting in blindness and clouding of the lens. The purpose of this study was to identify the disease-causing mutation in a Chinese family affected by bilateral, autosomal dominant congenital cataract.
METHODS
The detection of candidate gene mutation and the linkage analysis of microsatellite markers were performed for the known candidate genes. Molecular mapping and cloning of candidate genes were used in all affected family members to screen for potential genetic mutations and the mutation was confirmed by single enzyme digestion.
RESULTS
The proband was diagnosed with isolated, congenital cataract without the typical clinical manifestations of cataract, which include diabetes, porencephaly, sporadic intracerebral hemorrhage, and glomerulopathy. A novel mutation, c.2345 G > C (Gly782Ala), in exon 31 of the collagen type IV αlpha1 (COL4A1) gene, which encodes the collagen alpha-1(IV) chain, was found to be associated with autosomal dominant congenital cataract in a Chinese family. This mutation was not found in unaffected family members or in 200 unrelated controls. Sequence analysis confirmed that the Gly782 amino acid residue is highly conserved.
CONCLUSIONS
The novel mutation (c.2345 G > C) of the COL4A1 gene is the first report of a non-syndromic, autosomal dominant congenital cataract, thereby highlighting the important role of type IV collagen in the physiological and optical properties of the lens.
Topics: Asian People; Cataract; Chromosomes, Human, Pair 13; Collagen Type IV; Evolution, Molecular; Exons; Female; Genetic Variation; Humans; Linkage Disequilibrium; Male; Microsatellite Repeats; Pedigree; Sequence Analysis
PubMed: 25124159
DOI: 10.1186/s12881-014-0097-2 -
Journal of Neurosciences in Rural... Jul 2014Pycnodysostosis is a rare autosomal recessive disorder caused by mutations in the cysteine protease Cathepsin K gene located on chromosome 1q21. It has a well...
Pycnodysostosis is a rare autosomal recessive disorder caused by mutations in the cysteine protease Cathepsin K gene located on chromosome 1q21. It has a well characterized skeletal phenotype which include short stature, generalized increased bone density with propensity of fractures, open calvarial sutures and fontanelle, dental abnormalities, obtuse mandibular angle, resorption of lateral end of clavicle, acro-osteolysis, and in some cases visceromegaly. Central nervous system involvement is very rare and porencephalic cysts has been reported only once, the cause being hypothesised to be an imbalance between the growing brain, its vascular supply and intraventricular fluid pressure. We had a patient with bilateral frontal lobe porencephalic cysts; the patient presenting with complex partial seizures. Cathepsins have been found to be involved in neurological diseases and role of proteases has been well established in gliosis.
PubMed: 25002775
DOI: 10.4103/0976-3147.133606 -
Orphanet Journal of Rare Diseases May 2014Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the...
BACKGROUND
Oral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder.
METHODS
A cohort of 117 molecularly diagnosed OFD type I patients was screened for the presence of neurological symptoms and/or cognitive/behavioral abnormalities on the basis of the available information supplied by the collaborating clinicians. Seventy-one cases showing CNS involvement were further investigated through neuroimaging studies and neuropsychological testing.
RESULTS
Seventeen patients were molecularly diagnosed in the course of this study and five of these represent new mutations never reported before. Among patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, we identified brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed brain structural anomalies included agenesis of the corpus callosum and neuronal migration/organisation disorders as well as intracerebral cysts, porencephaly and cerebellar malformations.
CONCLUSIONS
Our results support recent published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Our findings correlate well with the kind of brain developmental anomalies described in other ciliopathies. Interestingly, we also described specific neuropsychological aspects such as reduced ability in processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions.
Topics: Central Nervous System Diseases; Cohort Studies; Female; Humans; Magnetic Resonance Imaging; Mutation; Neuropsychological Tests; Orofaciodigital Syndromes
PubMed: 24884629
DOI: 10.1186/1750-1172-9-74 -
Pediatrics and Neonatology Dec 2016We report our experience with a preterm infant with severe hemolytic jaundice who required exchange transfusion just after birth. The patient was negative for alloimmune...
We report our experience with a preterm infant with severe hemolytic jaundice who required exchange transfusion just after birth. The patient was negative for alloimmune hemolysis as a result of maternal-fetal blood type incompatibility, and tests for inherited defects in erythrocyte metabolism, membrane function, and hemoglobin synthesis were normal. We also performed a bone marrow examination, but could not identify the cause of hemolysis. The patient had several other complications, including porencephaly, epilepsy, elevated serum levels of creatine kinase, and persistent microscopic hematuria. Later, we detected a genetic mutation in COL4A1, which was recently found to be associated with hemolytic anemia. We therefore believe that all of the patient's clinical features, including hemolytic anemia, were due to the mutation in COL4A1. Genetic testing for COL4A1 mutations is recommended in neonates who exhibit hemolytic disease of unknown etiology, especially when other complications compatible with COL4A1-related disorders are present.
Topics: Blood Group Incompatibility; Collagen Type IV; Humans; Infant, Newborn; Jaundice; Male; Mutation
PubMed: 24861536
DOI: 10.1016/j.pedneo.2014.04.001 -
Revista de Neurologia Mar 2014The surgical treatment of hydrocephalus is one of the most commonly procedures of modern pediatric neurosurgical practice, and cerebrospinal fluid shunts are the main...
INTRODUCTION
The surgical treatment of hydrocephalus is one of the most commonly procedures of modern pediatric neurosurgical practice, and cerebrospinal fluid shunts are the main means of treatment of hydrocephalus, being independent of site of obstruction and ventricular shunt complications are frequent, especially in children. The most common complications are shunt obstructions, mechanical disconnections, overdrainage and infection.
CASE REPORT
A 7.5-year-old girl with ventriculoperitoneal shunt presented with intermittent headache. A head computed tomography scan revealed a cyst located in right temporal lobe. After ventriculoperitoneal shunt revision, a gradual resolution of the cyst was demonstrated on computed tomography.
CONCLUSIONS
Cerebrospinal fluid porencephaly is a rare postoperative complication of a ventricular shunt that results from dysfunction of the distal catheter, especially in children with taut ventricles.
Topics: Central Nervous System Cysts; Child; Female; Humans; Hydrocephalus; Ventriculoperitoneal Shunt
PubMed: 24610692
DOI: No ID Found -
PloS One 2013The Bluetongue virus serotype 8 (BTV-8) strain, which emerged in Europe in 2006, had an unusually high ability to cause foetal infection in pregnant ruminants. Other...
The Bluetongue virus serotype 8 (BTV-8) strain, which emerged in Europe in 2006, had an unusually high ability to cause foetal infection in pregnant ruminants. Other serotypes of BTV had already been present in Europe for more than a decade, but transplacental transmission of these strains had never been demonstrated. To determine whether transplacental transmission is a unique feature of BTV-8 we compared the incidence and pathological consequences of transplacental transmission of BTV-8 to that of BTV-1. Nine pregnant ewes were infected with either BTV-8 or BTV-1. The BTV strains used for the infection were field strains isolated on embryonated chicken eggs and passaged twice on mammalian cells. Blood samples were taken to monitor the viraemia in the ewes. Four weeks after the infection, the foetuses were examined for pathological changes and for the presence of BTV. BTV-8 could be demonstrated in 12 foetuses (43%) from 5 ewes (56%). %). BTV-1 was detected in 14 foetuses (82%) from 6 ewes (67%). Pathological changes were mainly found in the central nervous system. In the BTV-8 group, lympho-histiocytic infiltrates, gliosis and slight vacuolation of the neuropil were found. BTV-1 infection induced a severe necrotizing encephalopathy and severe meningitis, with macroscopic hydranencephaly or porencephaly in 8 foetuses. In our experimental setting, using low passaged virus strains, BTV-1 was able to induce transplacental transmission to a higher incidence compared to BTV-8, causing more severe pathology.
Topics: Animals; Bluetongue; Bluetongue virus; Female; Incidence; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Serotyping; Sheep; Sheep, Domestic
PubMed: 24358112
DOI: 10.1371/journal.pone.0081429 -
Human Molecular Genetics Jan 2014Haemorrhagic stroke accounts for ∼20% of stroke cases and porencephaly is a clinical consequence of perinatal cerebral haemorrhaging. Here, we report the...
Chemical chaperone treatment reduces intracellular accumulation of mutant collagen IV and ameliorates the cellular phenotype of a COL4A2 mutation that causes haemorrhagic stroke.
Haemorrhagic stroke accounts for ∼20% of stroke cases and porencephaly is a clinical consequence of perinatal cerebral haemorrhaging. Here, we report the identification of a novel dominant G702D mutation in the collagen domain of COL4A2 (collagen IV alpha chain 2) in a family displaying porencephaly with reduced penetrance. COL4A2 is the obligatory protein partner of COL4A1 but in contrast to most COL4A1 mutations, the COL4A2 mutation does not lead to eye or kidney disease. Analysis of dermal biopsies from a patient and his unaffected father, who also carries the mutation, revealed that both display basement membrane (BM) defects. Intriguingly, defective collagen IV incorporation into the dermal BM was observed in the patient only and was associated with endoplasmic reticulum (ER) retention of COL4A2 in primary dermal fibroblasts. This intracellular accumulation led to ER stress, unfolded protein response activation, reduced cell proliferation and increased apoptosis. Interestingly, the absence of ER retention of COL4A2 and ER stress in cells from the unaffected father indicate that accumulation and/or clearance of mutant COL4A2 from the ER may be a critical modifier for disease development. Our analysis also revealed that mutant collagen IV is degraded via the proteasome. Importantly, treatment of patient cells with a chemical chaperone decreased intracellular COL4A2 levels, ER stress and apoptosis, demonstrating that reducing intracellular collagen accumulation can ameliorate the cellular phenotype of COL4A2 mutations. Importantly, these data highlight that manipulation of chaperone levels, intracellular collagen accumulation and ER stress are potential therapeutic options for collagen IV diseases including haemorrhagic stroke.
Topics: Apoptosis; Basement Membrane; Brain Diseases; Cell Proliferation; Cells, Cultured; Collagen Type IV; Endoplasmic Reticulum Stress; Female; Hemiplegia; Humans; Intracranial Hemorrhages; Male; Mutation; Phenotype; Phenylbutyrates; Porencephaly; Proteasome Endopeptidase Complex; Stroke
PubMed: 24001601
DOI: 10.1093/hmg/ddt418 -
Journal of the American Veterinary... Jun 2013
Topics: Animals; Brain; Brain Diseases; Cat Diseases; Cats; Male; Seizures
PubMed: 23725423
DOI: 10.2460/javma.242.12.1641 -
Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host.PLoS Pathogens Jan 2013Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its...
Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and "synthetic" SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV.
Topics: Amino Acid Sequence; Animals; Base Sequence; Bunyaviridae Infections; Cattle; Cell Line; Cerebellar Diseases; Cerebral Cortex; Disease Models, Animal; Disease Progression; Endothelium, Vascular; Host-Pathogen Interactions; Immunity, Innate; Mice; Molecular Sequence Data; Neurons; Orthobunyavirus; Sequence Deletion; Sheep; Spinal Cord; Survival Rate; Vacuoles; Viral Tropism; Virulence; Virus Cultivation; Virus Replication
PubMed: 23326235
DOI: 10.1371/journal.ppat.1003133 -
BMC Veterinary Research Dec 2012Seizures are a common problem in small animal neurology and it may be related to underlying diseases. Porencephaly is an extremely rare disorder, and in Veterinary...
BACKGROUND
Seizures are a common problem in small animal neurology and it may be related to underlying diseases. Porencephaly is an extremely rare disorder, and in Veterinary Medicine it affects more often ruminants, with only few reports in dogs.
CASE PRESENTATION
A one-year-old intact male Shih-Tzu dog was referred to Veterinary University Hospital with history of abnormal gait and generalized tonic-clonic seizures. Signs included hypermetria, abnormal nystagmus and increased myotatic reflexes. At necropsy, during the brain analysis, a cleft was observed in the left parietal and occipital lobes, creating a communication between the subarachnoid space and the left lateral ventricle, consistent with porencephaly; and also a focal atrophy of the caudal paravermal and vermal portions of the cerebellum. Furthermore, the histological examination showed cortical and cerebellar neuronal dysplasia.
CONCLUSIONS
Reports of seizures due to porencephaly are rare in dogs. In this case, the dog presented a group of brain abnormalities which per se or in assemblage could result in seizure manifestation.
Topics: Animals; Brain Diseases; Dog Diseases; Dogs; Male; Malformations of Cortical Development; Seizures
PubMed: 23269021
DOI: 10.1186/1746-6148-8-246