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V Bonifati

Publications and source records attributed to V Bonifati.

At least 37 records · Page 2Linked to original sources
PubMed2001

Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36.

Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.

Age of Onset↗
PubMed2001

Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family.

The authors describe a family of Sephardic Jews with progressive external ophthalmoparesis, skeletal muscle weakness, and parkinsonism. Autosomal recessive inheritance was suggested by many consanguineous marriages, although a dominant disorder could not be excluded. No linkage to known progressive external ophthalmoparesis locus was found. The presence of cytochrome c oxidase-negative ragged-red fibers, biochemically reduced respiratory chain complexes, and multiple mitochondrial DNA deletions in muscle biopsies from four patients suggested a new mitochondrial disorder of intergenomic communication.

Adult↗
PubMed2001

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects.

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Age of Onset↗
PubMed2001

Frontal lobe dysfunction in essential tremor: a preliminary study.

27 patients with essential tremor (ET) were studied to determine the cognitive feature of this condition. 15 familial cases and 12 cases with a family history Parkinson's disease (PD) were identified. Performances on frontal lobe tasks of ET patients were compared with those of 15 patients with PD and 15 healthy control subjects. The ET patients showed significant impairments both in attentional and conceptual thinking tasks, similar to those observed in the PD group. Despite the nosographic independence of the two conditions, data showed that the frontal lobe feature of ET was similar to those of PD, thus possibly suggesting a common dysregulation of dopamine pathways.

Aged↗
PubMed2001

The parkin gene and its phenotype. Italian PD Genetics Study Group, French PD Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.

Mutations of the parkin gene on chromosome 6 cause autosomal recessive, early onset parkinsonism. This is the most frequent form of monogenic parkinsonism so far identified. The associated phenotypical spectrum encompasses early onset, levodopa-responsive parkinsonism (average onset in the early 30s in Europe), and it overlaps with dopa-responsive dystonia in cases with the earliest onset, and with clinically typical Parkinson's disease in cases with later onset. Despite clinical features, Lewy bodies are not found at autopsy in brains of patients with parkin mutations. The parkin protein possesses ubiquitin ligase activity, which is abolished by the pathogenic mutations.

Age of Onset↗
PubMed2001

Epidemiology of multiple system atrophy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms.

Multiple system atrophy (MSA) is a form of atypical parkinsonism with unknown etiology. The epidemiological studies conducted up to now on this disease are scarce. The incidence rate is about 0.6 cases per 100,000 persons per year. The prevalence rates show 4-5 cases per 100,000 persons. In Italy, about 4,900 prevalent cases have been estimated. The mean onset age is about 54 years; the median survival is 7-9 years. Only one case-control study has been performed on this disease. This study showed an increased risk of MSA associated with occupational exposure to organic solvents, plastic monomers and additives, pesticides and metals. Smoking habits seem to be less frequent in MSA cases (as in Parkinson's disease cases) than in healthy controls. Quinn's clinical criteria and those of the Consensus Conference promoted by the American Academy of Neurology are in fair agreement. We have performed a case-control study on 73 MSA cases, 146 hospital controls and 73 population controls.

Age of Onset↗
PubMed2001

Epidemiology of progressive supranuclear palsy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms.

Progressive supranuclear palsy (PSP) is a rare form of parkinsonism. The incidence rates are about 0.3-1.1 cases per 100,000 persons. The only two case-control studies performed up to now show conflictual results as regards education and residence in rural areas. Recently, a cluster of PSP and atypical parkinsonism has been observed in French Antilles. The hypothesis is that a consumption of both tropical fruit and herbal tea may be associated with PSP onset. Some PSP families with a probably autosomal dominant transmission have been described. A high frequency of a tau haplotype (H1/H1) associated with PSP is reported by some authors. The significance of this association is still not clear. We have performed a case-control study on 58 PSP cases, 116 hospital controls and 58 population controls.

Age of Onset↗
PubMed2001

Donepezil in the treatment of progressive supranuclear palsy.

OBJECTIVES: To evaluate the effect of 3 month therapy with donepezil, a centrally acting cholinesterase inhibitor, on cognitive performances, motor function and daily living activities in progressive supranuclear palsy (PSP). MATERIALS AND METHODS: Six patients with a diagnosis of PSP were evaluated at baseline and after 3 months of treatment with donepezil, 10 mg given at bedtime. Cognitive functions, motor symptoms and daily activities were evaluated by means of appropriate rating scales. RESULTS: Donepezil was not effective on cognitive dysfunction and did not change ratings of daily living. Parkinsonian symptoms were unaffected by donepezil treatment. CONCLUSIONS: Cholinergic replacement therapy alone is not likely to improve symptoms in a disorder characterized by a more widespread impairment of monoaminergic systems. Larger studies may be necessary to confirm the lack of effect of donepezil in this disorder.

Aged↗
PubMed2001

Three parkin gene mutations in a sibship with autosomal recessive early onset parkinsonism.

The objective was to describe a family with autosomal recessive, early onset parkinsonism, with affected siblings carrying three different exon rearrangements in the parkin gene. The living affected siblings were personally examined. Molecular genetic analyses included exon dosage of the parkin gene using a semiquantitative multiplex polymerase chain reaction (PCR) protocol and haplotype analysis. The index case was a compound heterozygote with a deletion of exon 5 and a duplication of exon 3. His affected sister was a compound heterozygote for a deletion of exon 5 and a deletion of exons 3-9. Haplotype analysis confirmed the presence of three mutant alleles at the parkin locus. The phenotype was early onset parkinsonism with marked response to levodopa, and a very slow, prolonged course. In conclusion, the frequency of mutations in the parkin gene in certain populations might be high enough to cause allelic heterogeneity in the same sibship.

Aged↗
PubMed2000

Heart rate variability in Parkinson's disease patients treated with tolcapone.

Following the introduction of tolcapone, a potent, reversible Catechol-O-methyltransferase (COMT) inhibitor, it has been possible to optimise the management of Parkinson's disease (PD) patients in chronic Levodopa (L-dopa) therapy. The interaction between tolcapone and the endogenous metabolism of catecholamines points to a possible influence on autonomic cardiovascular function.Cardiovascular reflexes have been analysed in a group of seven PD patients (four males, three females; mean age 69.7years, mean disease duration 14.1years) by means of the heart rate variability (HRV) method using a continuous 24-h ECG (ECGD), before and after six months of treatment with tolcapone (in addition to L-dopa).We have observed no statistically significant differences in HRV parameters, nor any changes in the incidence of hyperkinetic and hypokinetic arrhythmias, which suggest that autonomic cardiovascular function in PD patients is not influenced by six months of treatment with tolcapone.

Journal Article↗
PubMed2000

Association between early-onset Parkinson's disease and mutations in the parkin gene.

BACKGROUND: Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. METHODS: We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. RESULTS: Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. CONCLUSIONS: Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.

Adolescent↗
PubMed2000

Smoking habits in multiple system atrophy and progressive supranuclear palsy. European Study Group on Atypical Parkinsonisms.

OBJECTIVE: To evaluate smoking habits in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) in a multicenter case-control study to determine whether these two forms of atypical parkinsonism share the inverse association with smoking previously found in PD. BACKGROUND: No epidemiologic studies have been performed on smoking habits in MSA. A previous investigation in PSP revealed no differences in smoking habits between patients and hospital control subjects. METHODS: Seventy-six MSA patients, 55 PSP patients, 140 PD patients, and 134 healthy control subjects were enrolled consecutively at seven neurologic clinics from January 1, 1994, to July 31, 1998. Detailed information on smoking habits was obtained using a structured questionnaire. RESULTS: The comparison between frequencies of never-smokers versus ever-smokers (ex-smokers/current smokers; adjusted odds ratio [ORadj], 0.56; 95% CI, 0.29 to 1.06) and a dose-response analysis for never-smokers, moderate smokers (ORadj, 0.64; 95% CI, 0.31 to 1.32), and heavy smokers (ORadj, 0.47; 95% CI, 0.21 to 1.05) suggest that MSA patients smoke less than population control subjects. By contrast, the comparison of frequencies of never-smokers versus ever-smokers (ORadj, 0.91; 95% CI, 0.42 to 1.98) and a dose-response analysis for never-smokers, moderate smokers (ORadj, 0.68; 95% CI, 0.27 to 1.69), and heavy smokers (ORadj, 1.24; CI 95%, 0.51 to 3.06) revealed no differences in smoking habits between PSP patients and population control subjects. CONCLUSIONS: The fact that the inverse association with smoking found previously in PD is shared by multiple system atrophy but not by progressive supranuclear palsy lends epidemiologic support to the notion that different smoking habits are associated with different groups of neurodegenerative disease.

Aged↗
PubMed1999

A study of five candidate genes in Parkinson's disease and related neurodegenerative disorders. European Study Group on Atypical Parkinsonism.

OBJECTIVE: To determine whether reported genetic association of polymorphisms in the CYP2D6, CYP1A1, N-acetyltransferase 2 (NAT2), DAT1, and glutathione s-transferase M1 (GSTM1) genes with PD were evident in a population of 176 unrelated patients with sporadic PD and to extend these findings to other disease groups (familial PD [n = 30], ALS [n = 50], multiple system atrophy [n = 38], progressive supranuclear palsy [n = 35], and AD [n = 23]). METHODS: A combination of allele-specific PCR and analysis of restriction fragment length polymorphisms were performed. RESULTS: We genotyped 1,131 individuals. After matching each patient with a control subject by age, sex, ethnicity, and geographic origin, there was no association of any allele/genotype with any of the six disease groups. There was an increased frequency of NAT2 slow acetylators in the ALS group compared with controls (70% versus 50%; OR 2.33 [95% CI, 1.03 to 5.30]), but this was not significant after adjusting for multiple testing. CONCLUSIONS: This is one of the most extensive candidate gene studies performed in PD and the first time that some of these loci have been studied in multiple system atrophy and progressive supranuclear palsy. In contrast with previous studies, we found no role for these polymorphisms in the etiology of PD, ALS, multiple system atrophy, progressive supranuclear palsy, or AD.

Aged↗
PubMed1999

The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases.

Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.

Aged↗
PubMed1999

The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease.

Recently an Ile93Met mutation in the ubiquitin-carboxy-terminal-hydrolase-L1 gene (UCH-L1) has been described in a German family with Parkinson's disease (PD). The authors showed that this mutation is responsible for an impaired proteolytic activity of the UCH-L1 protein and may lead to an abnormal aggregation of proteins in the brain. In order to determine the importance of this or any other mutation in the coding region of the UCH-L1 gene in PD, we performed mutation analysis on Caucasian families with at least two affected sibs. We did not detect any mutations in the UCH-L1 gene, however, we cannot exclude mutations in the regulatory or intronic regions of the UCH-L1 gene since these regions were not sequenced. We conclude that the UCH-L1 gene is not a major gene responsible for familial PD.

Aged↗
PubMed1999

New, selective catechol-O-methyltransferase inhibitors as therapeutic agents in Parkinson's disease.

Levodopa remains the most effective drug for Parkinson's disease (PD). However, its benefits are limited owing to extensive metabolism by catechol-O-methyltransferase (COMT), especially if levodopa is used in combination with peripheral dopa-decarboxylase inhibitors. A new generation of potent, orally active, selective, and reversible COMT inhibitors has become available recently. Among these, tolcapone and entacapone have been best characterised. Preclinical and clinical studies have shown that COMT inhibitors markedly enhance levodopa availability and prolong its plasma half-life. In recent large clinical trials they proved to be able to ameliorate motor fluctuations, reduce disability, and decrease levodopa requirements in PD patients. The tolerability profiles of entacapone and tolcapone are good. COMT inhibition promises to become an important means of extending the benefits of levodopa therapy in PD.

Animals↗
PubMed1999

A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. French Parkinson's Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson's Disease.

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias. The gene responsible for AR-JP was recently identified and designated parkin. We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point mutations (homozygous or heterozygous) were detected in eight families that included 20 patients. The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.

Binding Sites↗