Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 57
Filtrar
1.
Transl Stroke Res ; 13(1): 25-45, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34529262

RESUMO

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive spontaneous bilateral occlusion of the intracranial internal cerebral arteries (ICA) and their major branches with compensatory capillary collaterals resembling a "puff of smoke" (Japanese: Moyamoya) on cerebral angiography. These pathological alterations of the vessels are called Moyamoya arteriopathy or vasculopathy and a further distinction is made between primary and secondary MMD. Clinical presentation depends on age and population, with hemorrhage and ischemic infarcts in particular leading to severe neurological dysfunction or even death. Although the diagnostic suspicion can be posed by MRA or CTA, cerebral angiography is mandatory for diagnostic confirmation. Since no therapy to limit the stenotic lesions or the development of a collateral network is available, the only treatment established so far is surgical revascularization. The pathophysiology still remains unknown. Due to the early age of onset, familial cases and the variable incidence rate between different ethnic groups, the focus was put on genetic aspects early on. Several genetic risk loci as well as individual risk genes have been reported; however, few of them could be replicated in independent series. Linkage studies revealed linkage to the 17q25 locus. Multiple studies on the association of SNPs and MMD have been conducted, mainly focussing on the endothelium, smooth muscle cells, cytokines and growth factors. A variant of the RNF213 gene was shown to be strongly associated with MMD with a founder effect in the East Asian population. Although it is unknown how mutations in the RNF213 gene, encoding for a ubiquitously expressed 591 kDa cytosolic protein, lead to clinical features of MMD, RNF213 has been confirmed as a susceptibility gene in several studies with a gene dosage-dependent clinical phenotype, allowing preventive screening and possibly the  development of new therapeutic approaches. This review focuses on the genetic basis of primary MMD only.


Assuntos
Doença de Moyamoya , Adenosina Trifosfatases/genética , Predisposição Genética para Doença/genética , Humanos , Doença de Moyamoya/diagnóstico por imagem , Doença de Moyamoya/genética , Ubiquitina-Proteína Ligases/genética
2.
Ultrasound Obstet Gynecol ; 57(5): 783-789, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32515830

RESUMO

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.


Assuntos
Hemorragia Cerebral/embriologia , Hemorragia Cerebral/genética , Colágeno Tipo IV/genética , Malformações do Desenvolvimento Cortical/embriologia , Malformações do Desenvolvimento Cortical/genética , Adulto , Hemorragia Cerebral/diagnóstico , Feminino , Idade Gestacional , Humanos , Malformações do Desenvolvimento Cortical/diagnóstico , Mutação , Fenótipo , Porencefalia/diagnóstico , Porencefalia/embriologia , Porencefalia/genética , Gravidez , Resultado da Gravidez/genética , Diagnóstico Pré-Natal/métodos , Prevalência , Estudos Retrospectivos , Esquizencefalia/diagnóstico , Esquizencefalia/embriologia , Esquizencefalia/genética
3.
Rev Neurol (Paris) ; 176(3): 170-179, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31521395

RESUMO

INTRODUCTION: Leukoencephalopathy with calcifications and cysts (LCC) is a rare autosomal recessive cerebral angiomatous-like microangiopathy characterized by diffuse and asymmetric white-matter lesions associated with multiple calcifications and cysts. The disease is caused by SNORD118 mutations. The entire clinical spectrum of LCC is not yet fully determined. MATERIAL AND METHODS: To define the clinical spectrum of LCC, we analyzed data from recently diagnosed cases and from the litterature. Both clinical and imaging features from our five LCC cases harboring compound heterozygous SNORD118 mutations were presented and all cases reported in the litterature reviewed. RESULTS: Ninety-two LCC cases including our five patients were identified. Consanguinity was rare (4%), and 97% of cases were symptomatic. Mean age of first clinical manifestations was 16.1±16.1 years (range 1 month-71 years) and was earlier in men (10.3±14.3 years) than in women (20.2±22.8 years) (P=0.02). The main inaugural symptoms were seizures (36%; mean age at onset: 5.2±9.5 years) and progressive neurological symptoms including ataxia, dystonia and spasticity (26%; 27.8±23.6 years). Intracranial hypertension was less frequently observed (14%), mostly in adults (mean age 31.5±13.2 years). Ischemic or hemorrhagic strokes were inaugural symptoms in two adults (2%). During follow-up, most patients developed progressive extrapyramidal, cerebellar and pyramidal signs (83%), cognitive decline (56%), seizures (37%), intracranial hypertension (30%) or stroke (2%). CONCLUSION: In LCC, the clinical spectrum is largely heterogeneous and the course of the disease appears highly variable in contrast to other hereditary cerebral small vessel diseases.


Assuntos
Calcinose/complicações , Cistos do Sistema Nervoso Central/complicações , Leucoencefalopatias/complicações , RNA Nucleolar Pequeno/genética , Adolescente , Adulto , Idoso , Calcinose/diagnóstico , Calcinose/genética , Cistos do Sistema Nervoso Central/diagnóstico , Cistos do Sistema Nervoso Central/genética , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Doenças de Pequenos Vasos Cerebrais/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Adulto Jovem
4.
Rev Neurol (Paris) ; 175(3): 194-197, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30314744

RESUMO

Familial CCM is a rare entity associated with the mutation of three genes: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). We report here the first description of a Tunisian familial CCMs composed of six members. The father and two daughters were affected and symptomatic. The two other kindred were healthy. Surgical treatment was performed in only one affected patient. Molecular analysis of KRIT1, MGC4607 and PDCD10 genes identified a large KRIT1 deletion of the first ten exons. To the best of our knowledge, this large deletion has never been reported before.


Assuntos
Deleção de Genes , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteína KRIT1/genética , Adolescente , Pré-Escolar , Consanguinidade , Família , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tunísia
5.
Rev Neurol (Paris) ; 171(5): 445-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25843205

RESUMO

Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures.


Assuntos
Ataxia/genética , Neoplasias Encefálicas/genética , Calcinose/genética , Cistos do Sistema Nervoso Central/genética , Leucoencefalopatias/genética , Espasticidade Muscular/genética , Doenças Retinianas/genética , Convulsões/genética , Proteínas de Ligação a Telômeros/genética , Adolescente , Ataxia/fisiopatologia , Neoplasias Encefálicas/fisiopatologia , Calcinose/fisiopatologia , Cistos do Sistema Nervoso Central/fisiopatologia , Retardo do Crescimento Fetal/genética , Hemorragia Gastrointestinal/etiologia , Genes Recessivos/genética , Humanos , Leucoencefalopatias/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Espasticidade Muscular/fisiopatologia , Mutação/genética , Doenças Retinianas/fisiopatologia , Convulsões/fisiopatologia
6.
J Neurol Sci ; 350(1-2): 98-100, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25702150

RESUMO

BACKGROUND: Neurofibromatosis 1 (NF1) belongs to the autosomal dominant neurocutaneous disorders' group, which mainly includes NF1 and NF2, tuberous sclerosis, von Hippel-Lindau disease and Cerebral Cavernous Malformations (CCMs). NF1 has a major impact on the nervous system, eye, skin, bone or cardiovascular system. Cerebrovascular lesions have been reported in NF1 including aneurysm, pseudoaneurysm, arteriovenous malformations, vascular stenosis or occlusion and Moya moya syndrome. OBJECTIVE: To report a case of an NF1 patient with multiple CCMs. OBSERVATION: A 47-year-old man with café-au-lait skin lesions, countless cutaneous neurofibromas, short stature and scoliosis was admitted for progressive spinal cord compression due to histologically proven neurofibroma. Systematic cerebral MRI screening including gradient echo sequences showed multiple asymptomatic CCMs. Screening of CCM1, CCM2 and CCM3 genes was negative while a deleterious frameshift mutation was identified in NF1 gene. CONCLUSION: While single CCM can occur in NF1 patients following radiation exposure, they are only rarely reported in non-irradiated NF1 brain. Even if it could be a fortuitous association, plausible links and explanations exist. If cerebral MRI can be systematic in NF1 to detect asymptomatic gliomas, used protocols in neuroradiology do not usually include gradient echo sequences, the most sensitive test for CCM detection, leading possibly to failure to detect these vascular lesions. More reports having this combination and further investigations of NF1 families will certainly provide a better understanding of links between these 2 phakomatoses, as recently reported with "multiple meningiomas" phenotype associated with multiple CCMs in patients with CCM3 gene mutations or café-au-lait skin lesions in CCM1 mutation carriers.


Assuntos
Neoplasias Encefálicas/diagnóstico , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Neurofibromatose 1/diagnóstico , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Neurofibromatose 1/complicações
7.
Clin Genet ; 86(6): 585-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24251678

RESUMO

Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Proteínas Proto-Oncogênicas/genética , DNA Complementar , Feminino , Humanos , Íntrons , Proteína KRIT1 , Masculino , Linhagem
8.
Mol Syndromol ; 4(4): 165-72, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23801932

RESUMO

Mutations of CCM3/PDCD10 cause 10-15% of hereditary cerebral cavernous malformations. The phenotypic characterization of CCM3-mutated patients has been hampered by the limited number of patients harboring a mutation in this gene. This is the first report on molecular and clinical features of a large cohort of CCM3 patients. Molecular screening for point mutations and deletions was used to identify 54 CCM3-mutated index patients. Age at referral and clinical onset, type of inaugural events and presence of extra-axial lesions were investigated in these 54 index patients and 22 of their mutated relatives. Mean age at clinical onset was 23.0 ± 16 years. Clinical onset occurred before 10 years in 26% of the patients, and cerebral hemorrhage was the initial presentation in 72% of these patients. Multiple extra-axial, dural-based lesions were detected in 7 unrelated patients. These lesions proved to be meningiomas in 3 patients who underwent neurosurgery and pathological examination. This 'multiple meningiomas' phenotype is not associated with a specific CCM3 mutation. Hence, CCM3 mutations are associated with a high risk of early-onset cerebral hemorrhage and with the presence of multiple meningiomas.

9.
Clin Radiol ; 68(8): e453-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23663874

RESUMO

AIM: To elucidate the natural history of dot-like or "black spot" cavernomas. MATERIALS AND METHODS: Data of 18 children with black spot cavernomas were analysed retrospectively. RESULTS: Eleven boys and seven girls presented 187 black spot cavernomas during a mean observation period of 5.5 years. Mean and median age at diagnosis of the 187 cavernomas was 9.6 years. There were 70 de novo black spot cavernomas. Boys presented significantly more cavernomas than girls. There were three KRIT1 mutation carriers and four PDCD 10 mutation carriers. Children with a PDCD 10 mutation presented significantly more lesions than those children with a KRIT1 mutation (mean number of lesions per patient: 23.3 versus 3.3, respectively). There were 10 radiological haemorrhagic events caused by 10 black spot lesions. Two of these events were symptomatic. The haemorrhage rate of black spot cavernomas was 0.7% per lesion-year. CONCLUSIONS: A mean bleeding rate of 0.7% per lesion-year is lower than the overall haemorrhage rates provided in the literature. Nonetheless, black spot cavernomas are not purely benign lesions. Furthermore, genetic mutations may play a role in the natural history of black spot cavernomas.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Imageamento por Ressonância Magnética/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos
10.
Neuropediatrics ; 42(6): 227-33, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22134833

RESUMO

Intracranial calcification (ICC) is a relatively common radiological finding in children undergoing investigation for neurological disorders. Many causes are recognised, and ICC is often regarded as a non-specific sign.From an ongoing study of ICC, we identified 5 patients with characteristic radiological features, in whom a mutation in the COL4A1 gene was found.All patients had CT and MR imaging. MR images demonstrated features of periventricular leukomalacia with irregular dilatation of the lateral ventricles with or without porencephaly, loss of hemispheric white matter volume, and high signal on T2 and FLAIR sequences within periventricular and deep white matter. Calcification was apparent on MR in 4 patients. CT scans demonstrated spot and linear calcification in the subependymal region and around areas of porencephaly. Calcification was also visible in the deep cerebral white matter and basal ganglia. 1 patient showed calcification in the central pons.ICC occurs in COL4A1-related disease. The radiological features are distinct from other conditions demonstrating recognisable patterns of ICC, such as congenital cytomegalovirus infection and Aicardi-Goutiéres syndrome. In the absence of a known risk factor for periventricular leukomalacia, the presence of these radio-logical findings should suggest the possibility of COL4A1-related disease.


Assuntos
Encefalopatias/genética , Calcinose/genética , Ventrículos Cerebrais/fisiopatologia , Colágeno Tipo IV/genética , Mutação Puntual , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Leucomalácia Periventricular/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios X
11.
Arch Pediatr ; 18(12): 1297-1301, 2011 Dec.
Artigo em Francês | MEDLINE | ID: mdl-21963371

RESUMO

Genetic syndromes that mimic congenital infections must be recognized because of the associated risk of recurrence. We describe a male infant who was born with the association of intra-uterine growth retardation, microcephaly, intracranial calcifications, white matter abnormalities, microphtalmy, bilateral cataract, and hearing loss. Congenital cytomegalovirus (CMV) infection was suspected, but serologic CMV markers were not decisive (IgG+/IgM-). His half-sister (same father) presented a similar phenotype. Therefore, the diagnosis of congenital CMV infection was questioned and a genetic hypothesis was suggested. In 1983, Baraitser et al. first described two brothers with microcephaly and intracranial calcifications and negative TORCH analysis. Later, a number of authors reported children in whom detailed investigation failed to objectively confirm an intra-uterine infective agent. Clinical features include severe postnatal microcephaly, seizures, and pronounced developmental arrest. These cases have been considered to define a distinct autosomal recessive disorder first named pseudo-Torch syndrome. The family described herein is different from the cases previously described with a suspected autosomal dominant inheritance, severe ophtalmological abnormalities, and unusual brain imaging.


Assuntos
Anormalidades Múltiplas/genética , Doenças Autoimunes do Sistema Nervoso/congênito , Anormalidades Múltiplas/patologia , Adolescente , Doenças Autoimunes do Sistema Nervoso/genética , Encéfalo/anormalidades , Calcinose/genética , Catarata/genética , Pré-Escolar , Diagnóstico Diferencial , Feminino , Perda Auditiva/genética , Humanos , Masculino , Microcefalia/genética , Malformações do Sistema Nervoso/genética , Fatores de Risco , Convulsões/genética , Irmãos
12.
Neurology ; 75(11): 967-72, 2010 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-20837964

RESUMO

OBJECTIVE: Hemiplegic migraine (HM) is a rare subtype of migraine with aura that may occur as a familial (FHM) or sporadic condition (SHM). Screening of FHM genes in previous series of patients with SHM detected a very low proportion of mutated patients. In this study, we investigated the FHM genes in patients with an early onset sporadic form of HM (onset before 16 years). METHODS: Twenty-five patients were included. Each one and his or her 2 parents were blood sampled. Mean age at diagnosis was 14.7 ± 8.2 years and mean age at clinical onset was 7.7 ± 3.4 years. Sequencing of ATP1A2 and CACNA1A was conducted in each proband and all identified variants were looked for in both parents. SCN1A was screened in all patients without CACNA1A or ATP1A2 de novo mutation. RESULTS: Twenty-three different amino acid variants were identified in 23 of the 25 patients. The variants occurred de novo in 19 patients (76%), strongly in favor of their causal role. SCN1A analysis did not show any mutation. Among the 19 patients with a de novo mutation, 5 had a pure HM and 14 had associated neurologic signs such as ataxia, epilepsy, or intellectual disabilities. CONCLUSIONS: FHM genes are involved in early-onset SHM, in particular when associated with neurologic signs. Molecular analysis can be helpful in those cases. Our study identified 14 novel de novo mutations that will help to interpret genetic tests in molecular diagnosis practice.


Assuntos
Canais de Cálcio/genética , Hemiplegia/genética , Transtornos de Enxaqueca/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Adulto , Idade de Início , Criança , Biologia Computacional , DNA/genética , Feminino , Frequência do Gene , Hemiplegia/etiologia , Humanos , Masculino , Transtornos de Enxaqueca/complicações , Mutação/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.1 , Proteínas do Tecido Nervoso/genética , Testes Neuropsicológicos , Canais de Sódio/genética , Adulto Jovem
13.
Neurology ; 75(3): 259-64, 2010 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-20644152

RESUMO

OBJECTIVE: We report a detailed description of a family affected by a hereditary multisystem disorder associated with moyamoya syndrome. METHODS: In this family case report, we evaluated 9 members of the same family originating from Algeria. Investigations included neuroimaging, cardiologic and ophthalmologic evaluation, hormonal testing, hemoglobin electrophoresis, chromosomal karyotyping, muscle biopsy for morphology, immunohistochemistry and enzyme assays, mtDNA mutation screening, and haplotype analysis of 2 loci previously linked to moyamoya, on chromosomes 10 (ACTA2) and 17. RESULTS: Five males related through a maternal lineage were affected, suggesting an X-linked inheritance. Four of them had symptomatic moyamoya syndrome with an onset of acute neurologic manifestations between 4 and 32 years. Hypergonadotropic hypogonadism, azoospermia, short stature of postnatal onset (-2 to -4 SD in adulthood), premature graying of hair, and dysmorphism were present in all patients. The other features of the disease included early cataract in 4, dilated cardiomyopathy in 3, and partial growth hormone deficiency in 2 members. Muscle biopsy data did not reveal signs of a mitochondrial disorder. All conditions known to be associated with moyamoya syndrome such as Down syndrome, neurofibromatosis, and sickle cell disease were excluded. We also excluded linkage to the 2 loci previously reported to be involved in autosomal dominant syndromic and nonsyndromic moyamoya. Carrier females had normal phenotype and clinical history. CONCLUSIONS: These data strongly suggest that this family is affected by a hereditary moyamoya multisystem disorder with X-linked recessive pattern of inheritance.


Assuntos
Predisposição Genética para Doença , Doença de Moyamoya/genética , Doença de Moyamoya/fisiopatologia , Adolescente , Adulto , Argélia , Encéfalo/patologia , Artéria Carótida Interna/patologia , Criança , Saúde da Família , Feminino , Hormônio do Crescimento/metabolismo , Humanos , Hidrocortisona/metabolismo , Angiografia por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Doença de Moyamoya/diagnóstico , Fenótipo , Prolactina/metabolismo , Tireotropina/metabolismo , Adulto Jovem
15.
J Eur Acad Dermatol Venereol ; 23(9): 1066-72, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19453802

RESUMO

BACKGROUND: Familial cerebral cavernous malformations (FCCM) are vascular malformations inherited as an autosomal-dominant condition. Three genes (KRIT1/CCM1, MGC4607/CCM2, PDCD10/CCM3) have been identified so far. Extra-neurological manifestations include retinal and cutaneous vascular malformations. The cutaneous vascular malformation, which had been more specifically associated with FCCM, is hyperkeratotic cutaneous capillary venous malformation (HCCVM). OBJECTIVES: To define the frequency of cutaneous vascular malformations in patients with FCCM, to precise their different phenotypes, and to study the association of each cutaneous vascular malformation subtype with the different three mutated CCM genes. METHODS: Dermatological inquiry was systematically performed in a large series of consecutive FCCM patients. Cutaneous biopsies were reviewed when available. Cutaneous vascular malformations classification was based on predominant anomalous channels, using the current International Society for the Study of Vascular Anomalies classification. Molecular screening of CCM genes was performed. Results Four hundred seventeen consecutive FCCM patients from 182 unrelated families were included. 38 patients (9%) from 25 different families had cutaneous vascular malformations. In these 38 patients, cutaneous vascular malformations were classified as follows: 13 capillary malformations (CM), 15 HCCVM, 8 venous malformations (VM) and 2 unclassified lesions. All patients (92%), but one with CM had a KRIT1/CCM1 mutation. The last patient had no detectable mutation. All of the 15 patients with HCCVM had a KRIT1/CCM1 mutation; 86.7% of cutaneous vascular malformation patients (33 of 38) had a KRIT1/CCM1 mutation. CONCLUSION: Cutaneous vascular malformations are seen in 9% of FCCM patients. Three distinct major cutaneous vascular malformations phenotypes were identified: HCCVM (39%), CM (34%) and VM (21%). CCM1 is the most frequently mutated gene in cutaneous vascular malformations-FCCM patients.


Assuntos
Malformações Vasculares do Sistema Nervoso Central/complicações , Fenótipo , Dermatopatias Vasculares/epidemiologia , Dermatopatias Vasculares/patologia , Malformações Vasculares/epidemiologia , Malformações Vasculares/patologia , Proteínas Reguladoras de Apoptose/genética , Biópsia , Proteínas de Transporte/genética , Humanos , Proteína KRIT1 , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Mutação/genética , Prevalência , Estudos Prospectivos , Proteínas Proto-Oncogênicas/genética , Estudos Retrospectivos , Pele/irrigação sanguínea , Pele/patologia , Dermatopatias Vasculares/genética , Malformações Vasculares/genética
16.
Cephalalgia ; 28(7): 774-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18498390

RESUMO

We studied four members of a family suffering from typical attacks of familial hemiplegic migraine (FHM) caused by a new mutation, R548C, of ATP1A2 gene in exon 12. One individual had also childhood absence epilepsy and generalized tonic-clonic seizures (GTCS). GTCS were followed by a severe attack of hemiplegic migraine at four times. Sodium valproate enabled control of both the epileptic seizures and the most severe FHM attacks. This association of FHM and epileptic seizures and their control with the same treatment suggest similar pathophysiological mechanisms.


Assuntos
Epilepsia Tipo Ausência/genética , Epilepsia Tônico-Clônica/genética , Enxaqueca com Aura/genética , Mutação de Sentido Incorreto , ATPase Trocadora de Sódio-Potássio/genética , Adulto , Alelos , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tônico-Clônica/diagnóstico , Éxons/genética , Feminino , Humanos , Masculino , Enxaqueca com Aura/diagnóstico , Linhagem , Fenótipo
17.
Neurochirurgie ; 53(2-3 Pt 2): 136-40, 2007 Jun.
Artigo em Francês | MEDLINE | ID: mdl-17507048

RESUMO

In 20% of cases, central nervous system cavernomas are an autosomal dominant familial disease. In these cases, lesions are multiple and one or more parents suffer of the same affection. Three genes (CCM 1, 2 and 3) have been identified since 1999, two on chromosome 7 (one on each arm) and one on the short arm of chromosome 3. The role of these genes in normal cerebral angiogenesis is unknown today. In clinical practice, molecular tests may be useful in some situations: 1) in sporadic cases with a unique lesion, molecular test should not be performed since these cases are not genetic; 2) in patients with multiple lesions who have an affected relative, the genetic nature of the disease is obvious and molecular tests are useful only for genetic counseling; 3) in sporadic cases with multiple lesions and no known affected relative, molecular tests can establish the genetic nature of the disease and be useful for genetic counseling.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Biologia Molecular , Humanos
18.
Am J Hum Genet ; 76(1): 42-51, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15543491

RESUMO

Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and cerebral hemorrhages, which can result in focal neurological deficits. Three CCM loci have been mapped, and loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607 (CCM2) genes. We report herein the identification of PDCD10 (programmed cell death 10) as the CCM3 gene. The CCM3 locus has been previously mapped to 3q26-27 within a 22-cM interval that is bracketed by D3S1763 and D3S1262. We hypothesized that genomic deletions might occur at the CCM3 locus, as reported previously to occur at the CCM2 locus. Through high-density microsatellite genotyping of 20 families, we identified, in one family, null alleles that resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and D3S1614. This de novo deletion encompassed D3S1763, which strongly suggests that the CCM3 gene lies within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional distinct deleterious mutations within PDCD10, one of the five known genes mapped within this interval, were identified in seven families. Three of these mutations were nonsense mutations, and two led to an aberrant splicing of exon 9, with a frameshift and a longer open reading frame within exon 10. The last of the six mutations led to an aberrant splicing of exon 5, without frameshift. Three of these mutations occurred de novo. All of them cosegregated with the disease in the families and were not observed in 200 control chromosomes. PDCD10, also called "TFAR15," had been initially identified through a screening for genes differentially expressed during the induction of apoptosis in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and invertebrates. Its implication in cerebral cavernous malformations strongly suggests that it is a new player in vascular morphogenesis and/or remodeling.


Assuntos
Neoplasias Encefálicas/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas Reguladoras de Apoptose , Deleção Cromossômica , Mapeamento Cromossômico , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Proteínas de Membrana/genética , Repetições de Microssatélites , Mutação , Linhagem , Mutação Puntual , Proteínas Proto-Oncogênicas/genética
19.
Am J Hum Genet ; 74(2): 326-37, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14740320

RESUMO

Cerebral cavernous malformations (CCM) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and focal neurological deficits due to cerebral hemorrhages. CCM loci have already been assigned to chromosomes 7q (CCM1), 7p (CCM2), and 3q (CCM3) and have been identified in 40%, 20%, and 40%, respectively, of families with CCM. Loss-of-function mutations have been identified in CCM1/KRIT1, the sole CCM gene identified to date. We report here the identification of MGC4607 as the CCM2 gene. We first reduced the size of the CCM2 interval from 22 cM to 7.5 cM by genetic linkage analysis. We then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions, such as tuberous sclerosis or neurofibromatosis. We performed a high-density microsatellite genotyping of this 7.5-cM interval to search for putative null alleles in 30 unrelated families, and we identified, in 2 unrelated families, null alleles that were the result of deletions within a 350-kb interval flanked by markers D7S478 and D7S621. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these two distinct deletions overlapped and that both of the two deleted the first exon of MGC4607, a known gene of unknown function. In both families, one of the two MGC4607 transcripts was not detected. We then identified eight additional point mutations within MGC4607 in eight of the remaining families. One of them led to the alteration of the initiation codon and five of them to a premature termination codon, including one nonsense, one frameshift, and three splice-site mutations. All these mutations cosegregated with the disease in the families and were not observed in 192 control chromosomes. MGC4607 is so far unrelated to any known gene family. Its implication in CCMs strongly suggests that it is a new player in vascular morphogenesis.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/genética , Mutação Puntual , Feminino , Ligação Genética , Marcadores Genéticos , Genótipo , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Deleção de Sequência
20.
Arch Mal Coeur Vaiss ; 96(11): 1105-10, 2003 Nov.
Artigo em Francês | MEDLINE | ID: mdl-14694787

RESUMO

Ischaemic or haemorrhagic cerebral vascular accidents (CVA) are the second cause of premature death in Western countries. Their pathophysiological mechanisms are very heterogeneous and implicate environmental and genetic factors. The recent identification of several genes implicated in the rare monogenic forms of CVA, such as hereditary cerebral amyloid angiopathy, cerebral cavernous angioma or CADASIL, has had immediate diagnostic applications for patients and their relatives, and has opened new insights into the mechanisms governing angiogenesis and/or vascular homeostasis. In the multifactorial forms of CVA, by far the most frequent, the role of a genetic factor is much more moderate, making identification of the implicated genes difficult. A very great number of association studies have been performed in order to examine the possible implication of candidate genes due to their known or supposed functions, but very few genetic variants have been associated with an increased risk of CVA, this increase being modest moreover. Quite recently an approach combining genetic linkage analysis and a haplotypic association study has allowed the localisation and identification of a new gene, phosphodiesterase 4D, implicated in ischaemic CVA, and the localisation on chromosome 7 of a gene implicated in the occurrence of cerebral aneurysms, thus raising new hopes in these multifactorial form.


Assuntos
Isquemia Encefálica/fisiopatologia , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Proteínas Adaptadoras de Transdução de Sinal , Cromossomos Humanos Par 7/genética , Proteínas do Citoesqueleto , Ligação Genética , Humanos , Proteínas Musculares/genética , Proteínas Nucleares/genética , Acidente Vascular Cerebral/fisiopatologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA