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G Sebastio

Publications and source records attributed to G Sebastio.

At least 37 records · Page 2Linked to original sources
PubMed1998

Clinical aspects of cystathionine beta-synthase deficiency: how wide is the spectrum? The Italian Collaborative Study Group on Homocystinuria.

UNLABELLED: Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disease of sulphur amino acid metabolism. Major clinical manifestations include disorders of the eye, the skeleton, the central nervous system and the vascular system. A wide clinical spectrum of the disease has been reported. We discuss the role of genetic factors (e.g. different mutations of the CBS gene and a variable genetic background) and the importance of environmental factors (e.g. diet, vitamins, perinatal factors and drugs) in explaining the phenotypic variability observed in homocystinuria. CONCLUSION: Homocystinuria represents a good model to explain the clinical differences frequently observed among patients affected by monogenic diseases.

Cystathionine beta-Synthase↗
PubMed1997

Phenylketonuria in Italy: distinct distribution pattern of three mutations of the phenylalanine hydroxylase gene.

Phenylketonuria (PKU) is an autosomal recessive disease caused by the deficiency of a liver-specific enzyme, phenylalanine hydroxylase (PAH). The pattern of PAH mutations in Mediterranean populations appears to be different from that observed in northern Europe and Asia. Our aim was to study the molecular basis of PKU in Campania and Calabria, two regions of southern Italy. We studied 99 unrelated alleles, detecting 75.8% of the mutations. Our results show that 57% of all the PKU alleles are caused by three different mutations: IVS10nt-546, R261Q and L48S, which display significant differences in their relative distribution across Italy. A novel mutation, a G-to-T transversion at the codon 257 (G257C), was also identified. This mutation results in a Gly-to-Cys change in the catalytic domain of the protein.

Adolescent↗
PubMed1996

Congenital Alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs.

We report on two sisters affected by congenital alopecia, nail dystrophy, and a severe T-cell immunodeficiency, presumably inherited as an autosomal-recessive disorder. The T-cell defect was characterized by severe functional impairment, as shown by the lack of proliferative response and upregulation of activation markers following mitogen stimulation. The functional abnormality occurred in spite of the presence of phenotypically mature of the defect. This is the first observation reported on an ectodermal disorder, characterized by alopecia and nail dystrophy, observed at birth, in association with a primary immunodeficiency. The hypothesis that these two events may be casually related is discussed.

Alopecia↗
PubMed1996

Fragile X founder chromosomes in Italy: a few initial events and possible explanation for their heterogeneity.

A total of 137 fragile X and 235 control chromosomes from various regions of Italy were haplotyped by analyzing two neighbouring marker microsatellites, FRAXAC1 and DXS548. The number of CGG repeats at the 5' end of the FMR1 gene was also assessed in 141 control chromosomes and correlated with their haplotypes. Significant linkage disequilibrium between some "major" haplotypes and fragile X was observed, while other "minor" haplotypes may have originated by subsequent mutation at the marker microsatellite loci and/or recombination between them. Recent evidence suggests that the initial mechanism leading to CGG instability might consist of rare (10 (-6/-7)) CGG repeat slippage events and/or loss of a stabilizing AGG via A-to-C transversion. Also, the apparently high variety of fragile X chromosomes may be partly due to the relatively high mutation rate (10 (-4/-5)) of the microsatellite markers used in haplotyping. Our fragile X sample also showed a higher than expected heterozygosity when compared to the control sample and we suggest that this might be explained by the chance occurrence of the few founding events on different chromosomes, irrespective of their actual frequency in the population. Alternatively, a local mechanism could enhance the microsatellite mutation rate only on fragile X chromosomes, or fragile X mutations might occur more frequently on certain background haplotypes.

Alleles↗
PubMed1996

Molecular and cytogenetic characterization of a recurrent unbalanced translocation (4;21)(p16.3;q22.1): relevance to the Wolf-Hirschhorn and Down syndrome critical regions.

We report on an aneuploidy syndrome due to the unbalanced segregation of a familial translocation (4;21)(p16.3;q22.1) causing a partial 4p monosomy and a partial 21q trisomy. The three affected children presented with severe failure to thrive, short stature, microcephaly, profound hypotonia, and mental retardation. The face, very similar in the three children, is characterized by frontal bossing, upslanting of the palpebral fissures, short nose, and deep set ears, giving the overall appearance of the Down syndrome. The molecular study has defined the aneuploid segment on both 4p and 21q. Most of the Down syndrome critical region was found to the trisomic, while only part of the candidate Wolf-Hirschhorn syndrome critical region was deleted, suggesting that this region is not critical for the major malformations characteristic for WHS.

Abnormalities, Multiple↗
PubMed1996

Homocysteine response to methionine challenge in four obligate heterozygotes for homocystinuria and relationship with cystathionine beta-synthase mutations.

Fasting and post-methionine load plasma total homocysteine concentrations were investigated in the parents of two homocystinuric patients. Three genetic mutations in the cystathionine beta-synthase gene were found. In the patient of family 1, a frequent Caucasian mutation. T833C, was found on one allele, while the mutation on the other allele has not yet been defined. In the patient of family 2, a mutation C569T, recently described by Sperandeo and colleagues, was found on one allele, while a novel mutation, G346A, was characterized on the other allele. The frequent gene mutation T833C was detected in a heterozygous mother who, surprisingly, exhibited strictly normal fasting and post-methionine load homocysteinaemia. In contrast, in the other family, we found a novel mutation (G346A) in the mother located near Lys 119, the putative binding site of phosphopyridoxal phosphate. This mother exhibited increased fasting and post-methionine load homocysteinaemia. These observations could explain the conflicting results reported for vascular pathologies in parents of homocystinuric patients and direct the search for genetic mutations in these vascular pathologies.

Adolescent↗
PubMed1996

Molecular epidemiology of cystic fibrosis mutations and haplotypes in southern Italy evaluated with an improved semiautomated robotic procedure.

We screened for 22 cystic fibrosis (CF) mutations in DNA from a first cohort of 69 CF patients from southern Italy using a semiautomated allele specific oligonucleotide (ASO) dot blot procedure based on two multiplex PCR amplifications. Seven mutations (delta F508, N1303K, G542X, 1717-1 G-->A, W1282X, 1148T, and R553X) identified 77.6% of CF chromosomes. Detection reached 79.8% with the 2183 AA-->G mutation analysed with the restriction generating PCR method. Thus, we included the 2183 AA-->G mutation in the ASO protocol and set up the conditions to amplify the gene regions that include the eight mutations in a single multiplex PCR reaction. With this method we tested the DNA of the first cohort of 69 CF patients, a second cohort of 63 CF patients, and 300 carrier relatives; we also performed 12 prenatal diagnoses. The results from the 132 CF patients showed differences in the distribution of CF mutations between the south and north of Italy. The XV2c, KM19, and intron 8 VNDR haplotypes suggested the presence, in CF chromosomes bearing undetected mutations, of a limited number of unknown mutations typical of southern Italy. Finally, for six of the eight mutations, we compared the ASO procedure with the methods based on restriction enzymes; the results obtained with the two procedures were identical for all the 57 chromosomes compared.

Carrier State↗
PubMed1996

Early detection of lung involvement in lysinuric protein intolerance: role of high-resolution computed tomography and radioisotopic methods.

Pulmonary disease of unknown etiology is a potentially fatal complication in patients with lysinuric protein intolerance (LPI), an autosomal recessive disorder caused by the defective transport of cationic amino acids. Lung involvement was investigated in nine Italian LPI patients through pulmonary function tests and lung imaging studies consisting of conventional chest radiography, high-resolution computed tomography (HRCT), and perfusion and ventilation scintigraphy. One 10-yr-old patient died of severe respiratory insufficiency from alveolar proteinosis. All of the remaining patients were asymptomatic at the time of the study, although HRCT scans revealed signs of lung involvement defined by the presence of acinar nodules, inter- and/or intralobular thickening of the interstitial septa, and subpleural cysts in five of the patients. Radioisotope studies showed an uneven distribution of perfusion and ventilation, and confirmed the presence of segmental and/or diffuse pulmonary functional defects. No abnormalities of pulmonary function were evident, and answers to a questionnaire excluded primary coexisting lung disease. In patients with LPI, including those without clinical and functional impairment, HRCT and radioisotopic studies appear to be the most sensitive methods for the early diagnosis of lung disease and correct assessment of its progression.

Adult↗
PubMed1995

Analysis of the elastin gene in 60 patients with clinical diagnosis of Williams syndrome.

Williams syndrome (WS) is caused by deletion of the elastin (ELN) gene. We have analyzed an intragenic restriction fragment length polymorphism (RFLP) and the gene dosage of ELN using a new probe (FP4) in a series of 60 sporadic patients with a clinical diagnosis of WS. Deletion of the ELN gene was shown in 54 cases, while clinical revaluation of the 6 patients without the deletion did not confirm the diagnosis of WS. These results support the genetic homogeneity of WS, and the high accuracy of ELN molecular analysis, which can be confidenty used for providing genetic counselling to WS families.

Adolescent↗
PubMed1995

Lysinuric protein intolerance characterized by bone marrow abnormalities and severe clinical course.

STUDY OBJECTIVE: To evaluate phenotypic variability of lysinuric protein intolerance in a cohort of nine Italian patients. DESIGN: Retrospective analysis of patient records. SUBJECTS: Nine Italian patients (seven independent families), all originating from southern Italy, observed during the last 14 years. RESULTS: Some of the patients had unique clinical features, including bone marrow abnormalities featuring erythroblastophagocytosis (five patients) and clinical course and the outcome of the disease, have also been observed: respiratory involvement was present in five cases, with a lethal picture of "alveolar proteinosis" in one. Severe kidney involvement, with both glomerular and tubular damage and rapidly progressing to chronic renal failure, has been observed in one case. CONCLUSION: Lysinuric protein intolerance may cause severe multisystem involvement, which requires early and careful monitoring. Some peculiar clinical findings observed in Italian patients point to a genetic heterogeneity of lysinuric protein intolerance.

Adolescent↗
PubMed1995

Characterization of phenylketonuria alleles in the Italian population.

In order to identify the molecular basis of phenylketonuria (PKU) in Italy, we screened the entire coding sequence of the phenylalanine hydroxylase gene in 20 Italian PKU patients, whose origins are scattered throughout Italy. The frequency of each identified mutation and of 5 other European mutations was determined within a panel of 92 Italian PKU patients. This approach allowed us to identify 20 different PKU mutations and characterize 64% of the Italian PKU chromosomes. Eleven mutations (IVS10nt546, L48S, R158Q, R261Q, P281L, R261X, R252W, delta T55, IVS7nt1, IVS12nt1, Y414C) represent 55.4% of the Italian PKU alleles, the most common mutations being IVS10nt546 (12.4%) and L48S (9%). All the other mutations are very rare. These data confirm the great heterogeneity expected from previous RFLP haplotype studies. Genotype/phenotype correlation allowed for assessment of the clinical impact of the 20 identified mutations.

Alleles↗
PubMed1995

The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations.

Four new mutations in the cystathionine beta-synthase (CBS) gene have been identified in Italian patients with homocystinuria. The first mutation is a G-to-A transition at base 374 in exon 3, causing an arginine-to-glutamic acid substitution at position 125 of the protein (R125Q). This mutation has been found in homozygosity in a patient partially responsive to pyridoxine treatment. The second mutation is a C-to-T transition at base 770 in exon 7, causing a threonine-to-methionine substitution at amino acid 257 of the protein (T257M). This mutation has been observed in homozygosity in a patient nonresponsive to the cofactor treatment. The third mutation, found in heterozygosity in a patient responsive to pyridoxine treatment, is an insertion of 68 bp in exon 8 at base 844, which introduces a premature termination codon. The fourth mutation is C-to-T transition in exon 2 at base 262, causing a proline-to-serine substitution at position 88 of the protein (P88S). This mutation is carried on a single allele in three affected sisters responsive to the cofactor treatment. In addition, six previously reported mutations (A114V, E131D, P145L, I278T, G307S, and A1224-2C) have been tested in 14 independent Italian families. Mutations A114V and I278T are carried by three and by seven independent alleles, respectively. The other four mutations--including G307S and A1224-2C, common among northern European patients--have not been detected.

Adolescent↗