RESUMO
BACKGROUND: Cell survival critically depends on the integrity of mitochondria, which play a pivotal role during apoptosis. Extensive mitochondrial damage promotes release of pro-apoptotic factors from the intermembrane space of mitochondria. Released mitochondrial proteins include Smac/DIABLO and HTRA2/Omi, which inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of apoptosis proteins. AIMS: Here we investigated the cause of extreme hypertonia at birth, alternating with hypotonia, with the subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, intractable seizures and early death in four patients from two unrelated families. The patients showed lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, evolving brain atrophy and disturbed cristae structure in muscle mitochondria. METHODS AND RESULTS: Using whole-exome sequencing, we identified missplicing mutation and a 5â bp deletion in HTRA2, encoding HTRA2/Omi. This protein was completely absent from the patients' fibroblasts, whose growth was impaired and which were hypersensitive to apoptosis. Expression of HtrA2/Omi or of the proteolytically inactive HTRA2/Omi protein restored the cells' apoptotic resistance. However, cell growth was only restored by the proteolytically active protein. CONCLUSIONS: This is the first report of recessive deleterious mutations in HTRA2 in human. The clinical phenotype, the increased apoptotic susceptibility and the impaired cell growth recapitulate those observed in the Htra2 knockout mice and in mutant mice with proteolytically inactive HTRA2/Omi. Together, they underscore the importance of both chaperone and proteolytic activities of HTRA2/Omi for balanced apoptosis sensitivity and for brain development. Absence of HTRA2/Omi is associated with severe neurodegenerative disorder of infancy, abnormal mitochondria, 3-methylglutaconic aciduria and increased sensitivity to apoptosis.
Assuntos
Apoptose , Erros Inatos do Metabolismo/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Mutação , Doenças Neurodegenerativas/metabolismo , Serina Endopeptidases/genética , Animais , Análise Mutacional de DNA , Exoma , Evolução Fatal , Feminino , Serina Peptidase 2 de Requerimento de Alta Temperatura A , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/patologia , Erros Inatos do Metabolismo/fisiopatologia , Camundongos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Linhagem , SíndromeRESUMO
Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.
Assuntos
Cerebelo/anormalidades , Quinase 5 Dependente de Ciclina/genética , Lisencefalia/genética , Malformações do Sistema Nervoso/genética , Sequência de Bases , Células Cultivadas , Cerebelo/enzimologia , Consanguinidade , Análise Mutacional de DNA , Deficiências do Desenvolvimento/enzimologia , Deficiências do Desenvolvimento/genética , Feminino , Genes Recessivos , Estudos de Associação Genética , Teste de Complementação Genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Lisencefalia/enzimologia , Masculino , Mutação de Sentido Incorreto , Malformações do Sistema Nervoso/enzimologia , LinhagemRESUMO
3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the disease MEGDHEL syndrome.
Assuntos
Anormalidades Múltiplas/genética , Hidrolases de Éster Carboxílico/genética , Perda Auditiva Neurossensorial/genética , Doença de Leigh/genética , Hepatopatias/genética , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Mutação , Anormalidades Múltiplas/diagnóstico , Encéfalo/patologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Perda Auditiva Neurossensorial/diagnóstico , Homozigoto , Humanos , Recém-Nascido , Doença de Leigh/diagnóstico , Fígado/patologia , Fígado/ultraestrutura , Hepatopatias/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Erros Inatos do Metabolismo/diagnóstico , Repetições de Microssatélites/genética , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/diagnóstico , Linhagem , Polimorfismo de Nucleotídeo Único , SíndromeRESUMO
Magnetic resonance imaging (MRI) is one of the most powerful tools in diagnostic imaging. With the growing rates of orthodontic treatment, there are increasing chances of post-orthodontic treatment patients permanently wearing fixed retainers who shall undergo MRI examination.Three adolescent patients were referred for craniofacial MRI examination. All the patients had completed full orthodontic treatment with a retention protocol of permanently wearing bonded gold solder-filled wire fixed retainers. In the first 2 cases, the MRI examination was performed on a 1.5-T system and in the last case on a 3-T system.All the images achieved were of good quality and high resolution. No adverse effects were reported by the first 2 patients including no complaint of heat sensation or any other discomfort in the anterior teeth area. The third patient complained of a headache during the MRI examination.Radiologists and technicians may consider allowing performance of MRI examination using 1.5-T systems when a gold solder-filled wire fixed retainer is involved with no concern regarding the patient's health or the accuracy of the MRI scans.
Assuntos
Imageamento por Ressonância Magnética , Contenções Ortodônticas , Fios Ortodônticos , Acidentes de Trânsito , Adolescente , Traumatismos Craniocerebrais/diagnóstico , Feminino , Ouro , Cefaleia/diagnóstico , Humanos , Neurofibromatoses/diagnósticoRESUMO
Hypomyelinating leukodystrophies (HMLs) are disorders involving aberrant myelin formation. The prototype of primary HMLs is the X-linked Pelizaeus-Merzbacher disease (PMD) caused by mutations in PLP1. Recently, homozygous mutations in GJA12 encoding connexin 47 were found in patients with autosomal-recessive Pelizaeus-Merzbacher-like disease (PMLD). However, many patients of both genders with PMLD carry neither PLP1 nor GJA12 mutations. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD, in which linkage to PLP1 and GJA12 was excluded. Using homozygosity mapping and mutation analysis, we have identified a homozygous missense mutation (D29G) not previously described in HSPD1, encoding the mitochondrial heat-shock protein 60 (Hsp60) in all affected individuals. The D29G mutation completely segregates with the disease-associated phenotype. The pathogenic effect of D29G on Hsp60-chaperonin activity was verified by an in vivo E. coli complementation assay, which demonstrated compromised ability of the D29G-Hsp60 mutant protein to support E. coli survival, especially at high temperatures. The disorder, which we have termed MitCHAP-60 disease, can be distinguished from spastic paraplegia 13 (SPG13), another Hsp60-associated autosomal-dominant neurodegenerative disorder, by its autosomal-recessive inheritance pattern, as well as by its early-onset, profound cerebral involvement and lethality. Our findings suggest that Hsp60 defects can cause neurodegenerative pathologies of varying severity, not previously suspected on the basis of the SPG13 phenotype. These findings should help to clarify the important role of Hsp60 in myelinogenesis and neurodegeneration.
Assuntos
Chaperonina 60/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Proteínas Mitocondriais/genética , Doenças Neurodegenerativas/genética , Sequência de Aminoácidos , Estudos de Casos e Controles , Chaperonina 60/análise , Chaperonina 60/química , Chaperonina 60/metabolismo , Cromossomos Humanos Par 2 , Consanguinidade , Sequência Conservada , Análise Mutacional de DNA , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Feminino , Genes Letais , Genes Recessivos , Ligação Genética , Marcadores Genéticos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/fisiopatologia , Humanos , Lactente , Masculino , Repetições de Microssatélites , Dados de Sequência Molecular , Mutação , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Linhagem , Mapeamento Físico do Cromossomo , Polimorfismo de Fragmento de Restrição , Radiografia , Homologia de Sequência de AminoácidosRESUMO
OBJECTIVE: To draw attention to a rare, life threatening complication of a rather common procedure, namely medullary injury following adenoidectomy and local anesthetic infiltration of the operative bed. DESIGN: Case report. SETTING: A tertiary pediatric critical care unit. PATIENT: A healthy 7-year-old girl underwent adenoidectomy and local anesthetic infiltration of the adenoid bed with lidocaine and adrenaline. In the recovery room, nystagmus, dysarthria, dyspnea, inability to cough and right hemiparesis were noticed. Because of her inability to remove secretions tracheal intubation was performed, followed by severe, life threatening respiratory failure. INTERVENTIONS: Tracheal intubation, hemodynamic support, prolonged mechanical ventilation, nitric oxide, and tracheostomy. CONCLUSION: In children, local anesthetic infiltration of the adenoid bed may cause life-threatening medullary injury and its routine use should be re-considered.
Assuntos
Adenoidectomia/efeitos adversos , Anestésicos Locais/administração & dosagem , Lidocaína/administração & dosagem , Bulbo/lesões , Criança , Feminino , Humanos , Hemorragias Intracranianas/etiologia , Intubação Intratraqueal , Paresia/etiologia , Respiração Artificial , Insuficiência Respiratória/etiologia , Resultado do TratamentoRESUMO
Sixty-five years old patient suffering from acute stroke was treated by rTPA intravenously. TCD monitoring of both middle cerebral arteries (MCA) was carried out simultaneously with administration of rTPA. Seven microemboli were found in right and four in left MCA. Duplex ultrasound, CT angiography and digital subtractional angiography revealed occlusion of left common carotid artery (CCA) and moderate to severe stenosis of right internal carotid artery (ICA). The case presented here is, to the best of our knowledge, the first description of MCA microemboli signals in patient with occlusion of ipsilateral CCA. This location of occlusion eliminates the possibility of microemboli passage from carotid bulb proximally to the site of occlusion through the ipsilateral external carotid artery or from the distal stump of occluded ICA. The possibility of emboli from contralateral stenosed ICA through the patent anterior communicating artery (ACoA) or from the distal stump of occluded CCA seems to be the most probable explanation.
Assuntos
Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/etiologia , Artéria Cerebral Média/diagnóstico por imagem , Idoso , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/patologia , Estenose das Carótidas/patologia , Angiografia Cerebral , Círculo Arterial do Cérebro/diagnóstico por imagem , Círculo Arterial do Cérebro/patologia , Círculo Arterial do Cérebro/fisiopatologia , Fibrinolíticos/uso terapêutico , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Masculino , Artéria Cerebral Média/patologia , Artéria Cerebral Média/fisiopatologia , Stents , Ativador de Plasminogênio Tecidual/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ultrassonografia , Procedimentos Cirúrgicos VascularesRESUMO
Gelastic seizures comprise a very rare form of epilepsy. They present with recurrent bursts of laughter voices without mirth and are most commonly associated with the evolution of a hypothalamic hamartoma. The purpose of this article is to describe the second reported ictal fluorodeoxyglucose-positron emission tomography study in a unique case of an infant with intractable gelastic seizures since the neonatal period associated with a hypothalamic hamartoma. The patient presented at 4 months old with recurrent, almost persistent, gelastic seizures consisting of laughter bouts without mirth. The seizures were noticeable at the first week of life and increased in frequency to last up to 12 hours, namely status gelasticus. These gelastic fits were accompanied with focal motor seizures, including unilateral right-eye blinking and mouth twitching. Developmental mile-stones were intact for age. Magnetic resonance imaging of the cortex demonstrated a large hypothalamic hamartoma within the third ventricle, hampering cerebrovascular fluid drainage of the lateral ventricles. An electroencephalography was nondiagnostic. Ictal fluorodeoxyglucose-positron emission tomography demonstrated a large circumscribed hypermetabolic region within the location of the hypothalamic hamartoma, representing localized intense epileptiform activity. The infant became instantly free of all seizure types given minute doses of oral benzodiazepine (clonazepam) and remains completely controlled after 12 months. Her overall development remains intact. This ictal fluorodeoxyglucose-positron emission tomography is the second reported study verifying that the main source of the epileptic activity inducing gelastic seizures originates from the hypothalamic hamartoma itself; therefore, a complementary fluorodeoxyglucose-positron emission tomography study should be considered in any patient presenting with intractable gelastic seizures, especially in those associated with hypothalamic hamartoma, in order to localize the region of epileptiform activity amenable to surgical resection if intensive drug therapy fails.
Assuntos
Anticonvulsivantes/uso terapêutico , Clonazepam/uso terapêutico , Epilepsias Parciais/patologia , Hamartoma/patologia , Neoplasias Hipotalâmicas/patologia , Convulsões/patologia , Eletroencefalografia , Epilepsias Parciais/etiologia , Feminino , Hamartoma/complicações , Humanos , Neoplasias Hipotalâmicas/complicações , Lactente , Tomografia por Emissão de Pósitrons , Convulsões/etiologia , Resultado do TratamentoRESUMO
Tumor necrosis factor (TNF) blockade has been used successfully to treat a number of rheumatic disorders that have a substantial burden of illness. In children, the TNF antagonists are used mainly for the treatment of juvenile idiopathic arthritis (JIA). There are, however, a variety of rare systemic inflammatory diseases, in which TNF blockade appears promising. Preliminary data in adults suggest that several forms of vasculitis appear to be responsive to TNF antagonists-Behcet's disease, polyarteritis nodosa, Wegener granulomatosis, among others. Some of them respond better to infliximab, a chimeric monoclonal anti-TNF antibody, than to etanercept, a recombinant p75 TNF receptor. We describe our limited experience with infliximab in the treatment of three children with rare vasculitic conditions.
Assuntos
Febre Familiar do Mediterrâneo/terapia , Poliarterite Nodosa/terapia , Sarcoidose/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Artrite Juvenil/terapia , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/metabolismo , Feminino , Humanos , Masculino , Poliarterite Nodosa/metabolismo , Sarcoidose/metabolismo , Resultado do Tratamento , Vasculite/terapiaRESUMO
Dilated cardiomyopathy (DCM) is a life-threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4-30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients' fibroblasts and PPP1R13L-knocked down human fibroblasts presented higher expression levels of pro-inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l-knocked down murine cardiomyocytes and hearts of Ppp1r13l-deficient mice. The hypersensitivity to lipopolysaccharide was NF-κB-dependent, and its inducible binding activity to promoters of pro-inflammatory cytokine genes was elevated in patients' fibroblasts. RNA sequencing of Ppp1r13l-knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13l-deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomal-recessive cardio-cutaneous syndrome in humans and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors.
Assuntos
Códon sem Sentido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome LEOPARD/genética , Síndrome LEOPARD/patologia , Proteínas Repressoras/genética , Animais , Células Cultivadas , Pré-Escolar , Citocinas/metabolismo , Feminino , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Lactente , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismoRESUMO
BACKGROUND AND PURPOSE: Different definitions have been proposed to define the ischemic penumbra from perfusion-CT (PCT) data, based on parameters and thresholds tested only in small pilot studies. The purpose of this study was to perform a systematic evaluation of all PCT parameters (cerebral blood flow, volume [CBV], mean transit time [MTT], time-to-peak) in a large series of acute stroke patients, to determine which (combination of) parameters most accurately predicts infarct and penumbra. METHODS: One hundred and thirty patients with symptoms suggesting hemispheric stroke < or =12 hours from onset were enrolled in a prospective multicenter trial. They all underwent admission PCT and follow-up diffusion-weighted imaging/fluid-attenuated inversion recovery (DWI/FLAIR); 25 patients also underwent admission DWI/FLAIR. PCT maps were assessed for absolute and relative reduced CBV, reduced cerebral blood flow, increased MTT, and increased time-to-peak. Receiver-operating characteristic curve analysis was performed to determine the most accurate PCT parameter, and the optimal threshold for each parameter, using DWI/FLAIR as the gold standard. RESULTS: The PCT parameter that most accurately describes the tissue at risk of infarction in case of persistent arterial occlusion is the relative MTT (area under the curve=0.962), with an optimal threshold of 145%. The PCT parameter that most accurately describes the infarct core on admission is the absolute CBV (area under the curve=0.927), with an optimal threshold at 2.0 ml x 100 g(-1). CONCLUSIONS: In a large series of 130 patients, the optimal approach to define the infarct and the penumbra is a combined approach using 2 PCT parameters: relative MTT and absolute CBV, with dedicated thresholds.
Assuntos
Encéfalo/diagnóstico por imagem , Infarto Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Volume Sanguíneo , Infarto Cerebral/diagnóstico , Circulação Cerebrovascular , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Acidente Vascular Cerebral/diagnóstico , Fatores de TempoRESUMO
OBJECTIVES: Patent foramen ovale (PFO) is considered as an important risk factor for cerebrovascular diseases. Nevertheless, the relationship between the distribution of high-intensity transient signals (HITS), resulting from injection of air mixed with saline and detected by transcranial Doppler (TCD), and clinical cerebrovascular syndromes in these patients has not been investigated. METHODS: Using TCD, we screened 40 patients with stroke or transient ischemic attack (TIA), in whom PFO was proven by transesophageal echocariography (TEE). Of these, 30 patients (75%) with artificially produced HITS either in the middle cerebral artery (MCA) or the basilar artery (BA) were included in the analysis. RESULTS: Nineteen patients had a stroke or TIA in the carotid territory and 11 patients in the vertebro-basilar territory. HITS were found in the MCA in all 30 patients and in 21 of the 30 patients in the BA. Of the latter, ten patients were in the carotid group and 11 patients were in the veretebro-basilar group, p = 0.011. CONCLUSION: There is a significant association between the distribution of artificial HITS and the clinical cerebrovascular syndromes.
Assuntos
Comunicação Interatrial/complicações , Embolia Intracraniana/etiologia , Acidente Vascular Cerebral/complicações , Ultrassonografia Doppler Transcraniana , Adulto , Artéria Basilar/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Feminino , Comunicação Interatrial/diagnóstico por imagem , Humanos , Embolia Intracraniana/diagnóstico por imagem , Ataque Isquêmico Transitório/diagnóstico por imagem , Ataque Isquêmico Transitório/etiologia , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/diagnóstico por imagem , Estudos Prospectivos , Fatores de Risco , Sensibilidade e Especificidade , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
There is no information about the physical behavior of microemboli en route from their source to the cerebral vessels. Microemboli could abide to a certain laminae, and have a consistent velocity, or wander between different laminae, and keep changing their velocity. Two hundred and seventy four microemboli were recorded by transcranial Doppler (TCD) in six patients with artificial valves, and 119 microemboli were recorded in response to i.v. injection of saline agitated with air in eight patent foramen ovale (PFO) patients. Transit time of microemboli, calculated based on their arrival time at the cerebral vessel (site of monitoring) was explored as a possible function of their measured velocity at the detection point. In the PFO group, the relation between embolus velocity and transit time was: embolus velocityPFO = -41.8 * transit time + 100.6, whereas for the artificial heart valve group it was: embolus velocityValve = -22.6 * transit time + 67.1. Transit time, in both clinical groups, was inversely related to velocity (p < 0.001), thus, early appearing emboli had higher velocity and vice versa. The inverse relation between transit time and measured terminal velocity implies a consistent velocity per microemboli en route, in both groups. Thus, a flow abided to a certain laminae seems to characterize microemboli.
Assuntos
Cardiopatias/fisiopatologia , Comunicação Interatrial/fisiopatologia , Embolia e Trombose Intracraniana/diagnóstico por imagem , Artéria Cerebral Média/fisiologia , Ultrassonografia Doppler Transcraniana/métodos , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular , Cardiopatias/diagnóstico por imagem , Comunicação Interatrial/complicações , Próteses Valvulares Cardíacas/efeitos adversos , Humanos , Pessoa de Meia-Idade , Cintilografia , Sensibilidade e Especificidade , Fatores de TempoRESUMO
BACKGROUND: Features of Goldenhar syndrome include several craniofacial anomalies of structures derived from the first and second pharyngeal arches, as well as vertebral, cardiac and renal systems abnormalities. In addition, Goldenhar patients were reported to manifest a variety of central nervous system anomalies and several types of neoplasias. CASE HISTORY AND DISCUSSION: The first case of medulloblastoma in a patient with Goldenhar syndrome is presented here. There is no clear association between these two pathologies. We speculate that aberrant events during the migration of neural crest cells in early stages of development could be the basis of an association between medulloblastoma and Goldenhar syndrome. The case history suggests other possible etiological contributing factors to the development of medulloblastoma, such as patient's history of trauma and/or early childhood exposure to ionizing radiation.
Assuntos
Neoplasias Cerebelares/diagnóstico , Síndrome de Goldenhar/diagnóstico , Meduloblastoma/diagnóstico , Neoplasias Cerebelares/genética , Cromossomos Humanos Par 17/genética , Feminino , Seguimentos , Quarto Ventrículo/patologia , Síndrome de Goldenhar/genética , Humanos , Hidrocefalia/etiologia , Recém-Nascido , Isocromossomos/genética , Perda de Heterozigosidade/genética , Meduloblastoma/genéticaRESUMO
C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotype-phenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment.
Assuntos
Estudos de Associação Genética , Proteínas Mitocondriais/genética , Mutação , Fatores de Terminação de Peptídeos/genética , Fenótipo , Adolescente , Adulto , Processamento Alternativo , Sequência de Aminoácidos , Encéfalo/patologia , Criança , Consanguinidade , Análise Mutacional de DNA , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Óptica/genética , Linhagem , Adulto JovemRESUMO
OBJECTIVE: Ovarian adrenal rest tumors (OARTs) are rare in contrast to testicular adrenal rest tumors. We report a case of OART in a patient with congenital adrenal hyperplasia who developed Nelson's syndrome after bilateral adrenalectomy. METHODS: We describe the clinical, imaging, and laboratory findings of the patient and review the relevant literature regarding OART and the possible interaction between ACTH and brown adipose tissue. RESULTS: An 18-year-old female with congenital adrenal hyperplasia, who had undergone bilateral adrenalectomy at the age of 10 years, presented with severe hyperpigmentation and hirsutism. Rectal ultrasonography showed a mass in the right ovary. (18)F-fluorodeoxyglucose PET/CT revealed intense uptake both in this mass and in brown adipose tissue located in typical supradiaphragmatic sites. Laparoscopic removal of the ovarian mass confirmed the diagnosis of OART. A systematic review revealed 9 documented cases of OART. As in our case, all presented with elevated ACTH levels. CONCLUSIONS: Common to all documented cases of OART are sustained high ACTH levels that activate the adrenal anlagen tissue in the ovaries.