RESUMO
Skeletal overgrowth accompanied by de novo heterozygous activating mutations in PDGFRB (platelet-derived growth factor receptor beta), that is, p.Pro584Arg and p.Trp566Arg, defines Kosaki overgrowth syndrome (OMIM #616592). Emerging evidence suggests a role of PDGFRB in the genesis of cerebral aneurysms. The delineation of the range and progression of the vascular phenotype of Kosaki overgrowth syndrome is urgently needed. Herein, we conducted subsequent analyses of serial neurovascular imaging studies of two original patients with a de novo heterozygous mutation in PDGFRB, that is, p.Pro584Arg. The analysis showed the progressive dilation of basilar and vertebral arteries and coronary arteries commencing during the teenage years and early 20s. The radiographic appearance of the basilar vertebral aneurysms showed signs of arterial wall dilation, compatible with the known vascular pathology of vascular-type Ehlers-Danlos syndrome and Loeys-Dietz syndrome. The dolichoectasia in cerebrovascular arteries can lead to fatal complications, even with neurosurgical interventions. To prevent the progression of artery dilation, preventative and therapeutic medical measures using tyrosine kinase inhibitors may be necessary in addition to optimal control of the systemic blood pressure. Kosaki overgrowth syndrome is a clinically recognizable syndrome that can exhibit progressive dilatory and tortuous vascular changes in basilar/vertebral and coronary arteries as early as in the teenage years. We recommend careful counseling regarding the risk of future vascular complications, optimal blood pressure control, and regular systemic vascular screening during follow-up examinations.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Aneurisma Coronário/genética , Mutação com Ganho de Função , Aneurisma Intracraniano/genética , Mutação de Sentido Incorreto , Mutação Puntual , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Insuficiência Vertebrobasilar/genética , Adolescente , Idade de Início , Substituição de Aminoácidos , Aneurisma/genética , Cegueira/etiologia , Calcinose/etiologia , Doenças das Artérias Carótidas/genética , Aneurisma Coronário/diagnóstico por imagem , Progressão da Doença , Feminino , Perda Auditiva Unilateral/etiologia , Humanos , Aneurisma Intracraniano/diagnóstico por imagem , Receptor beta de Fator de Crescimento Derivado de Plaquetas/fisiologia , Síndrome , Insuficiência Vertebrobasilar/diagnóstico por imagemRESUMO
Developmental dolichoectasia of the intracranial vessels is a rare occurrence. The authors report 2 sibling pediatric patients who were born with 6p25.3 deletion, associated with carotid and vertebrobasilar dolichoectasia. MRI imaging of both children showed asymptomatic elongation and dilation of the vertebrobasilar system and "kissing" carotid arteries. A microarray analysis was also performed for both patients, which identified a 1.5-Mb deletion of 6p25.3 covering 15 genes including FOXC1, which has been implicated in defects in vascular morphogenesis.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Deficiências do Desenvolvimento/genética , Insuficiência Vertebrobasilar/genética , Adolescente , Artéria Basilar/patologia , Artérias Carótidas/patologia , Criança , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Análise em Microsséries , Fenótipo , Insuficiência Vertebrobasilar/diagnóstico por imagemRESUMO
BACKGROUND: RNF213 rare variant-p.R4810K (rs112735431) was significantly associated with intracranial artery stenosis/occlusion disease (ICASO) in Japan and Korea and to a lesser degree in China. Considering the allelic heterogeneity, we performed target exome sequencing of RNF213 with the aim to identify the rare variants spectrum and their association with ICASO in a Chinese population and further to explore whether the rare variants carrier patients present specific clinical phenotype. METHODS: Target exome sequencing of RNF213 was performed in 250 ICASO patients using FastTarget sequencing technology. Various filtering process were used to select the candidate variants. Control individuals were obtain from 1000 Genome Project (208 Chinese samples) and GeneSky in-house database (1007 samples). Gene-based association analyses were conducted to identify the association between RNF213 rare variants and ICASO. The clinical characteristics of rare variant carriers and non-carriers were compared using Chi-squared test or Fisher's exact test. RESULTS: After filtration, 18 rare variants were identified in 39 patients. Gene-based association test showed that rare variants of RNF213 were significantly associated with ICASO (Minor allele frequency < 0.05, WSS p = 4.88 × 10- 10; SKAT p = 9.68 × 10- 6; SKAT-O p = 3.42 × 10- 9). There were no significant clinical characteristic differences other than the diagnosis age which was older in the carriers than the non-carriers (60.5 ± 6.2 vs 57.3 ± 8.9 years old, p = 0.028). CONCLUSION: Rare variants of RNF213 are associated with ICASO in Chinese. However, there are limited genetic diagnosis values of the gene due to no specific phenotypic presentation in the carriers and non carrier patients.
Assuntos
Adenosina Trifosfatases/genética , Povo Asiático/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Ubiquitina-Proteína Ligases/genética , Insuficiência Vertebrobasilar/genética , Adulto , Idoso , Estudos de Casos e Controles , China , Exoma , Feminino , Testes Genéticos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNA/métodosRESUMO
BACKGROUND AND PURPOSE: Vetebrobasilar dolichoectasia is characterized by arterial elongation, dilation, and tortuosity and leads to high risks of ischemic stroke. Our aim was to investigate the differential susceptibility to elastase-induced vertebrobasilar dolichoectasia induction in 2 different mouse strains. MATERIALS AND METHODS: Elastase (25 mU) was injected into the cisterna magna in C57BL/6J (n = 36) and 129/SvEv (SV129) (n = 36) mice. Control animals were injected with heat-inactivated elastase (n = 12 for each strain). At 3, 7, 14, and 28 days after elastase injection, MICROFIL polymer perfusion was performed. The arterial tortuosity index and the percentage increase in diameter were calculated for the basilar artery. Arterial samples were processed for conventional histologic examination, immunostaining, and matrix metalloproteinase expression. A ≥50% increase in diameter and a tortuosity index of ≥10 for the basilar artery were used to indicate success in achieving vertebrobasilar dolichoectasia. RESULTS: Successful vertebrobasilar dolichoectasia induction was noted in 67% (18 of 27) of the C57BL/6J strain versus 0% (0 of 19) of the SV129 strain (P < .001). Vertebrobasilar dolichoectasia was not observed in sham-operated controls. Both the tortuosity index and diameter increase for the basilar artery were greater in the C57BL/6J strain compared with the SV129 strain (56.3% ± 16.4% versus 21.1% ± 21.6% for diameter, P < .001; 17.4 ± 7.6 versus 10.4 ± 3.8 for tortuosity index, P < .001). Expression of pro-matrix metalloproteinase-2 and pro- and active matrix metalloproteinase-9 was increased in elastase-injected C57BL/6J animals compared with elastase-injected SV129 animals (P = .029, 0.029, and 0.029, respectively). Inflammation scores were significantly higher in C57BL/6J animals versus SV129 animals (P < .001). C57BL/6J subjects demonstrated arterial wall dilation and elongation characterized by internal elastic lamina disruption, muscular layer discontinuity, inflammatory cell infiltration, and high matrix metalloproteinase expression in the media. CONCLUSIONS: C57BL/6J mice demonstrated greater susceptibility to vertebrobasilar dolichoectasia induction than SV129 mice.
Assuntos
Insuficiência Vertebrobasilar/genética , Animais , Artéria Basilar/patologia , Cisterna Magna , Feminino , Imuno-Histoquímica , Inflamação/genética , Inflamação/patologia , Metaloproteinases da Matriz/biossíntese , Metaloproteinases da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Elastase Pancreática , Especificidade da Espécie , Insuficiência Vertebrobasilar/induzido quimicamente , Insuficiência Vertebrobasilar/patologiaRESUMO
The role of platelet receptor gain-of-function single nucleotide polymorphisms (SNP) in cardiovascular disease is controversial. We hypothesised that certain SNPs may accelerate the development of carotid artery stenosis. The intronic PAR-1 receptor intervening sequence-14 A/T (IVSn-14 A/T) polymorphism and three additional platelet receptor polymorphisms, i.e. GPIa (807C/T), GPIbα (5T/C) and HPA-1a/HPA-1b (Pl (A1/A2)) of GPIIIa were studied. The interaction of SNPs with conventional risk factors including male gender, hypertension, high cholesterol, diabetes, advanced age and smoking were investigated. The hypothesis was tested in 114 well-characterised patients with symptomatic carotid or vertebral stenosis from the British CAVATAS population and compared the results with 97 unrelated controls. The allele frequency of the platelet gain-of-function SNP was not significantly different in the CAVATAS population as compared to controls (PAR-1A/T (P = 0.13), GPIa C/T (P = 0.25), GPIIIa HPA-1a/HPA-1b (PlA1/A2) (P = 0.66) and GPIb T/C (P = 0.20)). In the subgroup of smokers, however, the prothrombotic GPIbα C mutated allele was found in a significantly higher frequency in the patient as compared to the control group (P = 0.04). Contrary to the primary hypothesis, the PAR-1A/T SNP as well as the other SNPs tested were not over- or underrepresented in the CAVATAS population. However, a significantly increased prevalence of GPIb-α (5C/T) was found in the subgroup of smokers and may represent an important cofactor in this patient group of our hypothesis-generating study.
Assuntos
Estenose das Carótidas/genética , Epistasia Genética , Glicoproteínas da Membrana de Plaquetas/genética , Polimorfismo de Nucleotídeo Único , Insuficiência Vertebrobasilar/genética , Fatores Etários , Idoso , Estenose das Carótidas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Reino Unido , Insuficiência Vertebrobasilar/terapiaRESUMO
OBJECTIVES: To determine the influence of global cerebral ischemia on the activation of extracellular-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) in optic nerves of rats exposed to different reperfusion periods. MATERIALS AND METHODS: Transient global cerebral ischemia (20-min duration) was induced by the four-vessel occlusion method. After different reperfusion periods (5 and 10 min; 1; 6 and 12 h after ischemia), optic nerves were extracted and ERK and JNK activation signals were determined by Western immunoblot analyses. RESULTS: The activation signals of ERK and JNK were detected within first 10 min of reperfusion, but striking activation for both enzymes was found 1 h after ischemia. After a transient decrease, the activation of ERK returned to peak level after 12 h of reperfusion in the second wave of kinase activation. In that period, a slight increase of JNK activation was registered. CONCLUSION: Our results demonstrated for the first time that ERK and JNK were activated in rat optic nerves during early and later periods of reperfusion, suggesting their potential active role in the response of cerebral white matter tissue to ischemic injury.
Assuntos
Isquemia Encefálica/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Nervo Óptico/irrigação sanguínea , Traumatismo por Reperfusão/genética , Animais , Western Blotting , Encéfalo/patologia , Isquemia Encefálica/patologia , Ativação Enzimática/genética , Técnicas Imunoenzimáticas , Nervo Óptico/patologia , Ratos , Ratos Wistar/genética , Traumatismo por Reperfusão/patologia , Insuficiência Vertebrobasilar/genética , Insuficiência Vertebrobasilar/patologiaRESUMO
Intravenous tissue plasminogen activator (t-PA) is currently approved by the US Food and Drug Administration (FDA) for the treatment of ischemic stroke in patients > 18 years of age who present within 3 hours of stroke onset and meet certain criteria. We report a case of a 16-year-old, previously healthy female who presented with a basilar artery occlusion and pontine ischemic stroke. She was treated with intravenous t-PA approximately 4 hours after the onset of symptoms. The patient demonstrated a remarkable recovery 6 hours after onset of her symptoms and had minimal deficits on discharge from the hospital 1 week later. She was found to have a lupus anticoagulant and was heterozygous for the prothrombin gene G2010A mutation. These were likely contributing causes for her stroke. She was also homozygous for plasminogen activator inhibitor 1 (PAI-1) 4G/4G, which at present is a controversial stroke risk factor.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/complicações , Transtornos Herdados da Coagulação Sanguínea/genética , Predisposição Genética para Doença/genética , Ativador de Plasminogênio Tecidual/administração & dosagem , Insuficiência Vertebrobasilar/tratamento farmacológico , Insuficiência Vertebrobasilar/genética , Adolescente , Artéria Basilar/efeitos dos fármacos , Artéria Basilar/patologia , Artéria Basilar/fisiopatologia , Transtornos Herdados da Coagulação Sanguínea/fisiopatologia , Infartos do Tronco Encefálico/tratamento farmacológico , Infartos do Tronco Encefálico/genética , Infartos do Tronco Encefálico/fisiopatologia , Doença de Crohn , Análise Mutacional de DNA , Feminino , Fibrinolíticos/administração & dosagem , Testes Genéticos , Genótipo , Humanos , Inibidor de Coagulação do Lúpus/sangue , Inibidor de Coagulação do Lúpus/genética , Mutação/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Protrombina/genética , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Insuficiência Vertebrobasilar/fisiopatologiaRESUMO
Intracranial vascular malformations are rare but tend to appear more frequently than usual in patients with type I neurofibromatosis (NFI). Aneurysms of the basilar artery have been described four times so far. We report two cases of 51- and 62-year-old patients with type I neurofibromatosis who showed long fusiform dilation of the basilar artery. Clinically both patients presented with locked-in syndrome and died 15 and 11 days after admission. The diagnosis was confirmed by autopsy. These are the first published cases of locked-in syndrome following thrombosis of a megadolichobasilar artery in association with neurofibromatosis I. Our results show that cerebral vascular malformations are found more frequently than random chance would predict in patients with NF I.
Assuntos
Aneurisma Intracraniano/diagnóstico , Neurofibromatose 1/diagnóstico , Insuficiência Vertebrobasilar/diagnóstico , Artéria Basilar/patologia , Infartos do Tronco Encefálico/diagnóstico , Infartos do Tronco Encefálico/genética , Angiografia Cerebral , Aberrações Cromossômicas , Evolução Fatal , Humanos , Aneurisma Intracraniano/genética , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurofibromatose 1/genética , Exame Neurológico , Ponte/patologia , Tomografia Computadorizada por Raios X , Insuficiência Vertebrobasilar/genéticaRESUMO
We describe an 11-year-old boy with facial dysmorphism consisting of a round and flat face, hypertelorism, short nose, and down turned corners of the mouth. In addition, he had severe mental retardation, short stature, imperforate anus, and basilar artery dolichoectasia. Cytogenetic evaluation revealed an unbalanced paternally inherited translocation t(18;20)(p11.2q13.3), resulting in partial monosomy 18p and partial trisomy 20q. The combination of deletion 18pduplication 20q has not been previously described and we suggest that the unusual finding of basilar artery dolichoectasia may be a feature of one of the imbalances.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 20/genética , Insuficiência Vertebrobasilar/genética , Criança , Bandeamento Cromossômico , Anormalidades Craniofaciais/genética , Humanos , Deficiência Intelectual/genética , Cariotipagem , Imageamento por Ressonância Magnética , Masculino , Fenótipo , Translocação GenéticaRESUMO
OBJECT: The cellular events leading to cerebral vasospasm after subarachnoid haemorrhages (SAH) involve a number of members of the protein kinase C (PKC) family. However, whereas calcium is thought to play a number of major roles in the pathophysiology of SAH, a number of PKCs function independently of calcium. We recently emphasized the potential role of the calcium-binding S100 proteins in a 'double haemorrhage' rat model of SAH-induced vasospasm. A number of S100 proteins are known to interfere directly with PKC, or indirectly with PKC substrates. We therefore investigated whether specific S100 proteins and PKCs are co-expressed/co-located in a rat model of SAH-induced vasospasm. METHODS AND RESULTS: SAH-induced vasospasm in rats (by means of a double cisternal injection of autologous blood from a rat femoral artery) distinctly modified the expression levels of calcium-dependent PKC-alpha and PKC-beta and calcium-independent PKC-eta and PKC-zeta in endothelial and smooth-muscle cells. The RNA levels of these four PKC isotypes were determined by quantitative RT-PCR. The present study reveals that, in endothelial cells, the S100B expression/location correlate well with those of PKC-eta, and those of S100A1 with PKC-beta. In smooth-muscle cells S100A2 expression/location correlate with those of PKC-eta, and those of S100B with PKC-zeta. CONCLUSION: The present data argue in favour of a joint action of the S100 protein network and the PKC signalling pathway during cerebral vasospasm.
Assuntos
Proteínas de Ligação ao Cálcio/genética , Fatores de Crescimento Neural/genética , Proteína Quinase C/genética , Proteínas S100/genética , Vasoespasmo Intracraniano/genética , Vasoespasmo Intracraniano/metabolismo , Insuficiência Vertebrobasilar/genética , Insuficiência Vertebrobasilar/metabolismo , Animais , Artéria Basilar/fisiologia , Western Blotting , Proteínas de Ligação ao Cálcio/metabolismo , Fatores Quimiotáticos/genética , Fatores Quimiotáticos/metabolismo , Modelos Animais de Doenças , Fatores de Crescimento Neural/metabolismo , Proteína Quinase C/metabolismo , Proteína Quinase C beta , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismo , RNA Mensageiro/análise , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subunidade beta da Proteína Ligante de Cálcio S100 , Proteínas S100/metabolismo , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/fisiopatologia , Vasoespasmo Intracraniano/fisiopatologia , Insuficiência Vertebrobasilar/fisiopatologiaRESUMO
We describe a case of Pseudoxanthoma elasticum (PXE) in a 14-year-old girl. This case is especially rare because of its association with carotid rete mirabile (CRM). Only three cases have been reported previously in the literature. Although the relation between P. elasticum and carotid rete mirabile is unclear, both disorders are believed to be major risk factors for cerebrovascular disease.