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1.
Neurogenetics ; 19(3): 179-187, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29971521

RESUMO

TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.


Assuntos
Mutação de Sentido Incorreto , Distrofias Neuroaxonais/genética , Proteínas/genética , Adulto , Substituição de Aminoácidos/genética , Arginina/genética , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Consanguinidade , Cisteína/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Irmãos , Paraplegia Espástica Hereditária/genética
2.
Reprod Fertil Dev ; 29(8): 1545-1555, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27623773

RESUMO

MicroRNAs (miRNAs) are known to control several reproductive functions, including oocyte maturation, implantation and early embryonic development. Recent advances in deep sequencing have allowed the analysis of all miRNAs of a sample. However, when working with embryos, due to the low RNA content, miRNA profiling is challenging because of the relatively large amount of total RNA required for library preparation protocols. In the present study we compared three different procedures for RNA extraction and prepared libraries using pools of 30 bovine blastocysts. In total, 14 of the 15 most abundantly expressed miRNAs were common to all three procedures. Furthermore, using miRDeep discovery and annotation software (Max Delbrück Center), we identified 1363 miRNA sequences, of which bta-miR-10b and bta-miR-378 were the most abundant. Most of the 179 genes identified as experimentally validated (86.6%) or predicted targets (13.4%) were associated with cancer canonical pathways. We conclude that reliable analysis of bovine blastocyst miRNAs can be achieved using the procedures described herein. The repeatability of the results across different procedures and independent replicates, as well as their consistency with results obtained in other species, support the biological relevance of these miRNAs and of the gene pathways they modulate in early embryogenesis.


Assuntos
Blastocisto/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica no Desenvolvimento , Sequenciamento de Nucleotídeos em Larga Escala , MicroRNAs/metabolismo , Animais , Bovinos , Epigênese Genética , Feminino , MicroRNAs/genética , Gravidez
3.
Eur J Neurol ; 23(10): 1580-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27444738

RESUMO

BACKGROUND AND PURPOSE: The term hereditary spastic paraplegia (HSP) covers a spectrum of genetically heterogeneous disorders in which lower limb spasticity is the common clinical feature. Many patients with childhood-onset HSP are mistakenly diagnosed with cerebral palsy (CP). METHODS: A group of as yet molecularly undiagnosed HSP patients were analyzed using SpastoPlex, a customized target re-sequencing panel able to investigate the coding regions of 72 genes linked to HSP, spastic ataxias or related motor diseases. RESULTS: Our investigations identified loss-of-function mutations in AP4S1/SPG52 in four children (three families) who had previously received a diagnosis of diplegic/quadriplegic CP. The patients presented spastic paraparesis, mild facial dysmorphisms, moderate-to-severe intellectual disability and severe speech delay. Two patients manifested febrile seizures and childhood-onset focal seizures. In all the patients, brain magnetic resonance imaging (MRI) showed a peculiar hypoplastic posterior corpus callosum, often associated with ventriculomegaly, white matter loss and cerebral atrophy. CONCLUSION: Adaptor protein 4 (AP-4) deficiency disorders should be suspected in children with spastic paraparesis, cognitive deficit and absent speech accompanied by suggestive MRI features. Seizures might be amongst the clinical manifestations of the syndrome.


Assuntos
Complexo 4 de Proteínas Adaptadoras/genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Adolescente , Paralisia Cerebral/diagnóstico , Pré-Escolar , Erros de Diagnóstico , Feminino , Humanos , Masculino , Mutação , Linhagem
4.
Seizure ; 120: 135-141, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38991296

RESUMO

Familial hyperlysinemia is a rare autosomal recessive disorder due to defects of the AASS (α-aminoadipate δ-semialdehyde synthase) gene, which encodes for a bifunctional enzyme. Two types of hyperlysinemia have been identified namely type 1, due to the deficit of the alfa-ketoglutarate activity, and type 2, due to the deficit of the saccharopine dehydrogenase activity. METHODS: To better characterize the phenotypic spectrum of familial hyperlysinemia type 1, we conducted a systematic review of cases in the literature following PRISMA guidelines. We selected 16 articles describing 23 patients with hyperlysinemia type 1, twelve of whom with homozygous or compound heterozygous mutations in AASS gene. We also included a novel patient with a homozygous c.799C>T; p.(Arg267Cys) mutation in AASS gene. We collected genetic, clinical, brain imaging and electroencephalogram (EEG) features when available. RESULTS: The phenotype of this disease is heterogeneous, ranging from more severe forms with spastic tetraparesis, intellectual disability and epilepsy and mild-moderate forms with only intellectual disability or behavioural problem and/or epilepsy to normal clinical conditions. Only our patient has neuropathy unrelated to infectious event. CONCLUSIONS: We described the heterogeneous phenotypic spectrum of familial hyperlysinemia type 1 and we identified a new symptom, axonal neuropathy, never before described in this condition.


Assuntos
Hiperlisinemias , Humanos , Hiperlisinemias/genética
5.
Theriogenology ; 145: 77-85, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32004821

RESUMO

Developmental competence determines the oocyte capacity to support initial embryo growth, but the molecular mechanisms underlying this phenomenon are still ill-defined. Changes in microRNA (miRNA) expression pattern have been described during follicular growth in several species. Therefore, aim of this study was to investigate whether miRNA expression pattern in cow oocyte and follicular fluid (FF) is associated with the acquisition of developmental competence. Samples were collected from ovaries with more than, or fewer than, 10 mid-antral follicles (H- and L-ovaries) because previous studies demonstrated that this parameter is a reliable predictor of oocyte competence. After miRNA deep sequencing and bioinformatic data analysis, we identified 58 miRNAs in FF and 6 in the oocyte that were differentially expressed between H- and L-ovaries. Overall, our results indicate that miRNA levels both in FF and in the ooplasm must remain within specific thresholds and that changes in either direction compromising oocyte competence. Some of the miRNAs found in FF (miR-769, miR-1343, miR-450a, miR-204, miR-1271 and miR-451) where already known to regulate follicle growth and their expression pattern indicate that they are also involved in the acquisition of developmental competence. Some miRNAs were differentially expressed in both compartments but with opposite patterns, suggesting that miRNAs do not flow freely between FF and oocyte. Gene Ontology analysis showed that the predicted gene targets of most differentially expressed miRNAs are part of a few signalling pathways. Regulation of maternal mRNA storage and mitochondrial activity seem to be the processes more functionally relevant in determining oocyte quality. In conclusion, our data identified a few miRNAs in the follicular fluid and in the ooplasm that modulate the oocyte developmental competence. This provides new insights that could help with the management of cattle reproductive efficiency.


Assuntos
Bovinos , Líquido Folicular/química , MicroRNAs/metabolismo , Oócitos/metabolismo , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética
6.
AJNR Am J Neuroradiol ; 37(5): 917-23, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26659337

RESUMO

BACKGROUND AND PURPOSE: Advances in MR imaging modeling have improved the feasibility of reconstructing crossing fibers, with increasing benefits in delineating angulated tracts such as cerebellar tracts by using tractography. We hypothesized that constrained spherical deconvolution-based probabilistic tractography could successfully reconstruct cerebellar tracts in children with cerebellar hypoplasia/atrophy and that diffusion scalars of the reconstructed tracts could differentiate pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia, and progressive cerebellar atrophy. MATERIALS AND METHODS: Fifteen children with cerebellar ataxia and pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia or progressive cerebellar atrophy and 7 controls were included in this study. Cerebellar and corticospinal tracts were reconstructed by using constrained spherical deconvolution. Scalar measures (fractional anisotropy and mean, axial and radial diffusivity) were calculated. A general linear model was used to determine differences among groups for diffusion MR imaging scalar measures, and post hoc pair-wise comparisons were performed. RESULTS: Cerebellar and corticospinal tracts were successfully reconstructed in all subjects. Significant differences in diffusion MR imaging scalars were found among groups, with fractional anisotropy explaining the highest variability. All groups with cerebellar pathologies showed lower fractional anisotropy compared with controls, with the exception of cerebellar hypoplasia. CONCLUSIONS: This study shows the feasibility of constrained spherical deconvolution to reconstruct cerebellar and corticospinal tracts in children with morphologic cerebellar pathologies. In addition, the preliminary results show the potential utility of quantitative analysis of scalars of the cerebellar white matter tracts in children with cerebellar pathologies such as cerebellar hypoplasia and atrophy. Further studies with larger cohorts of patients are needed to validate the clinical significance of our preliminary results.


Assuntos
Cerebelo/anormalidades , Imagem de Tensor de Difusão/métodos , Interpretação de Imagem Assistida por Computador/métodos , Malformações do Sistema Nervoso/diagnóstico por imagem , Biomarcadores/análise , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Criança , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Masculino , Malformações do Sistema Nervoso/patologia , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
7.
Radiol Med ; 112(5): 763-75, 2007 Aug.
Artigo em Inglês, Italiano | MEDLINE | ID: mdl-17673955

RESUMO

PURPOSE: This study was performed to evaluate the accuracy of multidetector computed tomography (MDCT) in detecting parathyroid lesions in patients with primary hyperparathyroidism. MATERIALS AND METHODS: We included 60 patients with primary hyperparathyroidism. Preoperative first-line examinations revealed negative and doubtful ultrasound (US) findings in 34 and 26 cases, respectively, and negative, doubtful and positive scintigraphic findings in 19, 20 and 21 cases, respectively. CT findings were compared with the surgical results. RESULTS: CT examination was positive in 35 cases, negative in 15 cases and doubtful in ten cases. Forty out of 60 patients underwent surgery, and 39 lesions (37 adenomas, two primary hyperplasias) were identified. Surgery was negative in two cases. In eight cases, lesions had ectopic location. Surgery confirmed the CT findings in 23 positive cases. In 8/10 doubtful cases, surgery confirmed the location of the lesion in five cases, identified the ectopic location of lesions in two cases, and was negative in one case. In 9/15 cases with negative CT findings, surgery identified the lesion in eight cases. Sensitivity, specificity and diagnostic accuracy values were 78%, 25% and 73%, respectively. CONCLUSIONS: MDCT is an accurate second-line diagnostic technique in the detection of parathyroid lesions, allowing exploration of the entire cervical and mediastinal regions.


Assuntos
Hiperparatireoidismo Primário/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Meios de Contraste , Diagnóstico Diferencial , Feminino , Humanos , Hiperparatireoidismo Primário/cirurgia , Iopamidol/análogos & derivados , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade
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