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Biomedical subjects

A Murgia

Publications and source records attributed to A Murgia.

At least 19 recordsLinked to original sources
PubMed2006

Periventricular heterotopia in fragile X syndrome.

The authors describe two unrelated individuals with fragile X syndrome (FXS) due to marked expansion and instability of the CGG trinucleotide repeats within the fragile X mental retardation 1 gene (FMR1) and periventricular heterotopia (PH). This observation suggests that the FMR1 gene is involved in neuronal migration and that abnormal neuronal migration, even beyond the resolution of MRI, contributes to the neurologic phenotype of FXS.

Adolescent↗
PubMed2005

Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: association with non-Hodgkin's lymphoma.

There is strong evidence that altered immunological function entails an increased risk of lymphoma, although the current knowledge of aetiological factors for lymphomas is limited. The CTLA4 gene encodes a receptor that provides a negative signal to the T-cell once an immune response is initiated and completed. We analysed the 2q33 chromosomal region harbouring CD28, CTLA4 and ICOS genes, which are closely linked and have related functions in immune regulation, for association in 100 non-Hodgkin's lymphoma (NHL) patients and in 128 healthy controls; both groups originated from Sardinia. There was a strong association of the CTLA4 49A and the 3'-untranslated region (AT)(82) alleles with NHL [odds ratio (OR) = 2, 95% confidence interval (CI) = 1.2-3.2, and OR = 1.6, 95% CI = 1.1-2.4 respectively]. CTLA4-318C:49A:(AT)(82) was the most represented haplotype in the studied population and was associated with NHL (P = 0.0029, OR = 1.76, 95% CI = 1.2-2.5). Strong linkage disequilibrium was detected between CD28, CTLA4 and ICOS and a 'common' haplotype was found very frequently among NHLs. However, no independent association between CD28, ICOS, D2S72 markers and NHL was observed. Our findings enable CTLA4 from adjacent functionally related genes as the true causative risk gene for NHL susceptibility at least in Sardinian patients.

Adult↗
PubMed2004

A genotype-phenotype correlation for GJB2 (connexin 26) deafness.

INTRODUCTION: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. OBJECTIVE: To assess a possible genotype-phenotype correlation for GJB2. DESIGN: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. SUBJECTS: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. RESULTS: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. CONCLUSIONS: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.

Adolescent↗
PubMed2003

Fine analysis of the short arm of chromosome 1 in sporadic and familial pheochromocytoma.

OBJECTIVE: Despite the very recent discovery that about 25% of apparently sporadic forms of pheochromocytoma are actually due to germline mutations of RET, VHL, SDHB or SDHD genes, the genetic bases of the tumourigenesis of this type of cancer are still incompletely understood. Recent studies provided evidence that a new tumour suppressor gene, mapping on the short arm of chromosome 1, could be involved in early tumourigenesis of pheochromocytoma. DESIGN: We have performed a fine analysis of loss of heterozygosity (LOH) of this region. In particular, we have analysed 31 highly polymorphic microsatellites distributed at 3.8 Mege base (Mb) mean intervals along the short arm of the chromosome 1 in paired samples of DNA extracted from peripheral blood lymphocytes and tumour tissues. PATIENTS: The study was carried out on 38 patients with pheochromocytoma that had been grouped, by careful clinical and molecular investigation, in the following classes: 21 sporadic, five multiple endocrine neoplasia type 2 (MEN2), two type 1 neurofibromatosis (NF1), five von Hippel-Lindau (VHL), one somatic VHL mutated and four nonsyndromic familial cases. RESULTS: In 12/21 sporadic cases (57.1%), in 4/5 MEN2 (80%), 2/4 non-syndromic familial cases (50%), and in 2/2 NF1 (100%), the entire short arm was deleted, while in 6/21 sporadic (28.6%) and 1/5 MEN2 (20%) cases a partial deletion was detected. On the other hand, none of the five cases due to VHL mutation (either germline or somatic) had LOH at chromosome 1. In total, complete or partial deletion of 1p was detected in 27/38 (71%) of the cases. The most frequently deleted marker was D1S2890, which maps at 1p32.1. This region, which spans from 50 to 62 Mb from telomere, was therefore further investigated with markers located at a mean interval of 1.3 Mb in the subset of cases that showed a partial deletion of 1p. This analysis showed that a small region between 55.1 and 59.0 Mb was most frequently missing, which could therefore contain a novel pheochromocytoma locus. CONCLUSIONS: The results presented here confirm that the short arm of chromosome 1 harbours one or more genes responsible for the development of pheochromocytoma and suggest that one of them could map in a 3.9-Mb fragment between 1p32.3 and 1p32.1.

Adrenal Gland Neoplasms↗
PubMed2000

Somatic mosaicism in von Hippel-Lindau Disease.

von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome predisposing to the development of retinal and central nervous system haemangioblastomas, pheochromocytomas, renal and pancreatic cancer. In the course of a molecular analysis conducted to detect germline mutations of this gene in von Hippel-Lindau patients and individuals affected by sporadic tumors, we have identified a case of somatic mosaicism in the asymptomatic mother of a VHL patient who was subsequently diagnosed with pheochromocytoma. This is the first report providing molecular evidence of somatic mosaicism in von Hippel-Lindau disease. Mosaicism could provide some genetic explanation for the clinical heterogeneity and variable severity of the VHL phenotype, and should be considered, as a possible event when evaluating sporadic cases of VHL or patients with isolated VHL-related tumors. Hum Mutat 15:114, 2000.

Adult↗
PubMed2000

Retinal abnormalities associated with a mutation of the nucleotide 683 in von Hippel-Lindau disease.

BACKGROUND: von Hippel-Lindau disease (VHL) is a hereditary cancer syndrome in which affected individuals are at risk of developing tumors in multiple organs, including eyes, cerebellum, spinal cord, kidneys, inner ear, adrenal glands and pancreas. METHODS: We performed a fundus examination and fluorescein and indocyanine green (ICG) angiography in both eyes of a young woman affected by VHL with bilateral pheochromocytoma, retinal angioma, retinal microaneurysms and unusual alterations of the deep retinal layers. A molecular analysis of the VHL gene was carried out. RESULTS: Ophthalmoscopy disclosed in her right eye a small retinal hemangioma, some microaneurysms in both eyes at the posterior pole and multiple, small, whitish, dome-shaped lesions scattered in the retinal pigment epithelium (RPE) of the posterior retina. Fluorescein angiograms revealed in the early phase multiple hyperfluorescent spots that showed progressive discoloration in the late phase of angiography. Some of these spots were ophthalmoscopically undetectable. The late phase of ICG angiography showed some small hyperfluorescent points located at the level of the RPE, and some of them corresponded to the hyperfluorescent spots seen on fluorescein angiography. The molecular analysis revealed the presence of a "missense" mutation of the VHL gene at nucleotide 683. CONCLUSIONS: Alterations in the RPE have never been observed in the VHL syndrome. We describe an unusual case of VHL with a capillary hemangioma associated to diffuse alterations with the RPE of the posterior retina. The possibility exists that these lesions form part of the eye modifications in VHL.

Adrenal Gland Neoplasms↗
PubMed1999

Molecular diagnosis of inherited diseases.

The importance of the interaction between basic science and clinical practice has long been known but it has become even more evident in the past few decades with the impressive rate of development in the field of molecular genetics. This short article reviews molecular diagnosis of two different diseases for which scientific progress has immediately been translated into a dramatic improvement of the quality of medical care: the Fragile X Syndrome, paradigm of the new mutational mechanism of the unstable triplet repeats, and von Hippel-Lindau disease, a recent acquisition in the growing number of familial cancer syndromes.

Fragile X Syndrome↗
PubMed1999

Spontaneous partial regression of low-grade glioma in children with neurofibromatosis-1: a real possibility.

At the age of 41 and 31 months, respectively, a boy and a girl affected by neurofibromatosis-1 were diagnosed with a visual pathway glioma during surveillance contrast-enhanced head magnetic resonance imaging (MRI). In the first child, the initial MRI showed that the entire optic chiasm, the intracranial tract of the left optic nerve, and hypothalamus were grossly enlarged and enhanced in the post-gadolinium T1-weighted images. Ten months later, the hypothalamic component of the lesion had regressed markedly and there were no more areas of contrast enhancement. In the second child, the initial MRI showed that the optic chiasm, the right optic tract, and geniculate body were enlarged and enhanced after gadolinium injection. At 6-month follow-up, the MRI showed that the right optic tract and the anterior aspect of the optic chiasm decreased in size and the contrast enhancement of the entire lesion was reduced dramatically. These findings, as indicated by other similar reports, confirm that spontaneous regression of visual pathway glioma is a rare but real possibility in children with neurofibromatosis-1. Therefore, clinicians need to be aware of visual pathway glioma's erratic behavior in children with neurofibromatosis-1 with special attention given to the importance of a very conservative attitude toward any type of treatment for such patients.

Child, Preschool↗
PubMed1999

Molecular genetics applied to clinical practice: the Cx26 hearing impairment.

Mutations in the Cx26/GJB2 gene account for a large proportion of pre-lingual hearing impairment with a prevalence up to 50% in autosomal recessive cases and a still undefined prevalence in sporadic cases. Ninety-four subjects affected by non-syndromal sensorineural hearing impairment (NSHI) were enrolled in the study. The patients had either a family history of childhood hearing deficit or represented sporadic cases. The risk of an acquired cause of the deficit has been carefully excluded. Audiological characteristics were investigated. Cx26 mutations were found in 50% of subjects. Seventy-three per cent of mutations in this gene were 35delG, with significant geographical variations. In 7% of the putative Cx26 alleles no mutations were detected either in the coding region or in the non-coding exon 1. Cx26 hearing impairment involves all frequencies, is of variable severity, and is very rarely progressive and most frequently symmetrical between the two ears. The high occurrence of this type of pre-lingual hearing impairment argues for modification of the protocols used to investigate the aetiology of childhood hearing impairment. Early screening for Cx26 mutations in all patients with non-syndromal familial and sporadic permanent childhood hearing impairment seems justified.

Adolescent↗
PubMed1999

Cx26 deafness: mutation analysis and clinical variability.

Mutations in the gap junction protein connexin 26 (Cx26) gene (GJB2) seem to account for many cases of congenital sensorineural hearing impairment, the reported prevalence being 34-50% in autosomal recessive cases and 10-37% in sporadic cases. The hearing impairment in these patients has been described as severe or profound. We have studied 53 unrelated subjects with congenital non-syndromic sensorineural hearing impairment in order to evaluate the prevalence and type of Cx26 mutations and establish better genotype-phenotype correlation. Mutations in the Cx26 gene were found in 53% of the subjects tested, 35.3% of the autosomal recessive and 60% of the sporadic cases in our series. Three new mutations were identified. The hearing deficit varied from mild to profound even in 35delG homozygotes within the same family. No evidence of progression of the impairment was found. Alterations of the Cx26 gene account for a large proportion of cases of congenital non-syndromic sensorineural deafness, so it seems appropriate to extend the molecular analysis even to subjects with mild or moderate prelingual hearing impairment of unknown cause.

Adolescent↗
PubMed1998

The guanine triphosphatase (GTPase) activating protein (GAP)-related domain of the neurofibromatosis type 1 gene is not mutated in neural crest-derived sporadic tumours.

We conducted a mutation analysis of the most conserved region of the neurofibromatosis type 1 (NF1) gene, the guanine triphosphatase (GTPase) activating protein (GAP)-related domain (NF1 GRD), to which the function of tumour suppressor is attributed. Sixty primary neuroectodermal tumours were analysed. The rationale for the study was based on the likelihood of finding structural alterations resulting in loss of function of this region in tumours of neuroepithelial tissues, where the activity of neurofibromin seems to be crucial in regulating the mechanisms of signal transduction and cell transformation mediated by p21 ras. Following analysis of the whole NF1 GRD sequence, no mutations were identified in the tumours analysed. We conclude that the loss of NF1 gene tumour suppressor function, that might lead or contribute to the development of malignancies in neuroectodermal tissues, is not due to structural abnormalities of the region of the gene which interacts with p21 ras.

Base Sequence↗
PubMed1997

Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region.

BACKGROUND: Diencephalic syndrome (DS) is a complex of signs and symptoms related to hypothalamic dysfunction; its main features are emaciation, despite a normal or slightly diminished caloric intake, and an alert appearance. DS has been almost exclusively described in association with space-occupying lesions of the hypothalamic-optic chiasm region, mainly juvenile pilocytic astrocytoma (JPA). A systematic diagnostic approach, including contrast-enhanced magnetic resonance imaging (MRI) of the child's head, is rapidly expanding our knowledge of this syndrome. METHODS: The MRI findings for three children affected by DS associated with biopsy-proven JPA, consecutively referred to the Pediatric Neuro-Oncology Program of the Department of Pediatrics at the University of Padua between September 1991 and January 1996, are presented in this article. The children were boys, ages 6, 7, and 18 months, respectively. RESULTS: In all three patients, the initial contrast-enhancing MRIs of the head showed evidence of tumor dissemination. This finding prompted a study of the spine, which in turn showed tumor deposits in all three subjects. Among the 43 patients younger than 16 years with low grade astroctyoma who consecutively entered the Neuro-Oncology Program during the study period, these 3 patients were the only ones who had disseminated tumors. CONCLUSIONS: In this study, the hypothesis was formulated that DS and disseminated hypothalamic-optic chiasm JPA tend to be more commonly associated than previously stated. This study suggests that the initial contrast-enhanced MRI of the head of a child affected by DS and hypothalamic JPA must be looked at carefully for evidence of tumor dissemination, and that the spine must also be examined if the findings are positive.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Antagonism of convulsions but failure to enhance GABA(A) receptor function by felbamate in mice tolerant to diazepam.

The transfer of tolerance between drugs may indicate a common mode of action. The development of cross-tolerance to the anticonvulsant effect of felbamate after long-term treatment of mice with diazepam, a positive modulator of gamma-aminobutyric acid (GABA)-mediated transmission, was therefore studied in order to clarify the mechanism of this action of felbamate. A challenge injection of felbamate, administered 36 h after the last dose of chronic diazepam treatment, antagonized convulsions elicited by administration of isoniazid. In contrast, felbamate had no effect on the isoniazid-induced increase in t-[35S]butylbicyclophosphorothionate binding to cerebral cortical membranes of diazepam-tolerant mice. These results suggest that the action of felbamate on GABAergic transmission is not required for the anticonvulsant effect of this drug. This conclusion is consistent with studies that have indicated that the antiepileptic activity of felbamate depends on its modulatory activity at excitatory amino acid receptors.

Animals↗