Biomedical subjects
Publications and source records attributed to V Bonifati.
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We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.
Parkinson's disease (PD) is a common degenerative neurologic disorder, which is pathologically characterized by a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta, and the presence of characteristic eosinophilic inclusions, known as Lewy-bodies in affected brain areas. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease. Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects and questioned earlier studies which had denied such influences. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically and in some cases also neuropathologically. Recently, a disease locus has been mapped to chromosome 4q21-22 in a large Mediterranean pedigree, in which disease expression is clinically and pathologically within the spectrum of sporadic PD; being atypical only for a relatively young mean age at onset of 46 years and rapid course of 10 years from onset to death. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding alpha-synuclein. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkinsonism was not linked to the 4q-locus and was not associated with the alpha-synuclein mutation (unpublished data). We describe a different genetic locus that appears to be involved in the development of parkinsonism closely resembling sporadic PD including a similar mean age of onset (59 years in the families, 59.7 years in sporadic PD; ref. 12). This locus was detected in a group of families of European origin. In two of these families, there is genetic evidence for a common founder. The penetrance of the mutation appears to be low, most likely below 40%. This is compatible with a possible role of this locus not only in familial, but also in typical (sporadic) PD.
The gene for autosomal recessive juvenile Parkinsonism (AR-JP) recently has been mapped to chromosome 6q25.2-27 in Japanese families. We have tested one Algerian and 10 European multiplex families with early-onset Parkinson disease for linkage to this locus, with marker D6S305. Homogeneity analysis provided a conditional probability in favor of linkage of >.9 in eight families, which were analyzed further with eight microsatellite markers spanning the 17-cM AR-JP region. Haplotype reconstruction for eight families and determination of the smallest region of homozygosity in two consanguineous families reduced the candidate interval to 11.3 cM. If the deletion of two microsatellite markers (D6S411 and D6S1550) that colocalize on the genetic map and that segregate with the disease in the Algerian family is taken into account, the candidate region would be reduced to <1 cM. These findings should facilitate identification of the corresponding gene. We have confirmed linkage of AR-JP, in European families and in an Algerian family, to the PARK2 locus. PARK2 appears to be an important locus for AR-JP in European patients. The clinical spectrum of the disease in our families, with age at onset <=58 years and the presence of painful dystonia in some patients, is broader than that reported previously.
A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha-synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.
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OBJECTIVE: To confirm whether a dinucleotide repeat sequence in an intron of the microtubule-associated protein tau is associated with progressive supranuclear palsy (PSP) in an independent study population and to establish an improved methodology for allelotyping. BACKGROUND: It has recently been reported that a genetic variant of tau, known as the A0 allele, was represented excessively in PSP patients when compared with control subjects. METHODS: In a multicenter study, the authors examined the allelic distribution of this dinucleotide repeat marker in a set of clinically ascertained PSP patients (n = 30), multiple system atrophy (MSA) patients (n = 35), and matched control subjects (n = 70). Individuals were allelotyped using automated analysis of fluorescently labeled PCR products. RESULTS: The A0 allele was significantly overrepresented in the PSP patients (93.3% versus 76.4%; p = 0.0067; odds ratio [OR] = 4.33; 95% confidence interval [CI], 1.36 to 13.60), but not in the MSA patients. Likewise, A0 homozygotes were overrepresented in the PSP group (86.7% versus 61.1%; p = 0.02; OR = 4.14; 95% CI, 1.19 to 14.48) compared with control subjects. CONCLUSIONS: The findings of this study, which is the largest to date, support those of a previous investigation that used pathologically confirmed PSP patients. These data provide additional strong evidence that genetic variation at or near the tau gene plays an important role in the pathogenesis of PSP.
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The aim of this study was to evaluate the effects of Tolcapone, a reversible, selective inhibitor of catechol-O-methyltransferase, on the cognitive function of eight patients with advanced Parkinson's disease. They underwent neuropsychological and motor assessment at baseline and were re-evaluated after 6 months. During this period, they received Tolcapone three times daily, while the L-dopa dosage was progressively reduced. Significant improvements were observed in the attentional task, auditory verbal short-term memory, visuo-spatial recall, constructional praxia and motor symptoms. These data suggest that treatment with Tolcapone, in combination with L-dopa therapy, may determine a significant improvement in cognitive resources of patients with advanced Parkinson's disease.
The frequency of the CYP2D6B allele of the gene for debrisoquine 4-hydroxylase was studied in 115 patients with sporadic idiopathic Parkinson's disease, 55 of their healthy siblings, 63 patients with familial Parkinson's disease, 55 unaffected relatives, and 92 patients with Alzheimer's disease and 73 age matched healthy controls. By contrast with several previous studies, no significant variation of allele frequencies could be found between any of the groups studied. The results argue against a significant role of the CYP2D6 gene in the aetiology of sporadic and familial idiopathic parkinsonism in this patient population.
OBJECTIVE: To study the frequency, clinical features and clinical genetics of familial Parkinson's disease (PD). METHODS: Family history for PD and tremors was studied in 100 consecutive PD cases. Spouses served as controls. Clinical features were compared between personally verified familial and sporadic PD cases, from the same consecutive clinical series. Clinical genetic analysis was performed in a larger group of non-consecutive multicase PD families. RESULTS: Family history for PD was positive in 24% of consecutive PD cases and in 6% of spouse controls (p < 0.001). When family history for isolated tremor is also considered, the number of positive cases rises to 43% compared with 9% in controls (p < 0.001). Nine of the consecutive cases had at least one living affected relative, for a total of 20 familial PD cases. These familial cases showed an earlier onset age when compared with sporadic ones from the same consecutive series. Within 22 non-consecutive PD families with at least two living and personally examined PD cases (total 52 PD cases), the crude segregation ratios were similar for parents and siblings and the lifetime cumulative risks approached 0.4 in siblings and tended to be comparable, but at later ages, in parents. Ancestral relatives were all unilaterally distributed. In some families, anticipation of onset age in new generations was observed. CONCLUSIONS: The frequency of positive family history for PD and for PD and tremor is higher among PD cases than controls. Familial and sporadic PD only differ in onset age. The clinical genetic analyses support autosomal dominant inheritance with strongly age-related penetrance as most likely in familial PD.
INTRODUCTION: The objective of the study was to estimate the prevalence of parkinsonism in the Province of Rome using antiparkinsonian prescription histories from 1986 to 1991. METHODS: A subject was defined as a case of parkinsonism if he/she had received "specific" and "consistent" antiparkinsonian therapy in the study period. RESULTS: In November 1990, 6,572 patients were defined as prevalent cases of parkinsonism. The crude prevalence ratio, for the total population of the Province of Rome, is 173.5 per 100,000 inhabitants (165.9 per 100,000 in men and 180.5 per 100,000 in women). The method was validated by record-linkage with clinical records of all patients visited during 1990 at the Department of Neurological Sciences of the University of Rome "La Sapienza". The sensitivity of the prevalence study was 83.6%. CONCLUSIONS: The use of a computerized data base of all prescription data, routinely collected for administrative purposes, enabled us to obtain a prevalence estimate based on a very large population, with low costs and in a relatively short time.
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We made a double-blind, crossover comparison of buspirone (10 mg orally, twice a day) and placebo in 10 patients with Parkinson's disease and levodopa-induced dyskinesias. The duration of the study was 3 weeks, for both buspirone and for placebo treatment. Chronic therapies remained unchanged. The extrapyramidal symptoms, dyskinesias, and anxious/depressive symptoms were evaluated at the beginning of the study and after the buspirone and placebo treatments. Seven patients concluded the trial. The extrapyramidal symptoms, evaluated in both the "off" and "on" states during an oral L-Dopa test, did not show any worsening during the trial. Buspirone significantly lessened the severity of levodopa-induced dyskinesias in five of the seven patients, whereas it proved ineffective in the two patients with the mildest dyskinesias. There were no changes in the mild anxious and depressive symptoms at any time during the study. The activities of buspirone on the serotonin and dopamine systems might have led to the antidyskinetic effect we observed. At daily dosages of 20 mg, buspirone might prove effective in reducing levodopa-induced dyskinesias without worsening of parkinsonism.
The mortality for multiple sclerosis in Italy was analyzed for the period 1969-1987. The age-adjusted (to Italian 1981 population) death rates decreased slightly during these years for both sexes. The average national female/male ratio of the age-adjusted rates is 1.33 and shows a north-south gradient, with values < 1 in the South-Islands area where multiple sclerosis cases are probably heavily underreported on the death certificates. A positive, significant correlation between the age-adjusted death rates and latitude of the 20 Italian regions exists for the period 1969-1975; in recent years (1981-1987), these parameters show a weaker, but not statistically significant positive correlation. Moreover, the 95% confidence intervals of the death rates in the 20 regions overlapped extensively in both periods studied (1969-1975 and 1981-1987). Death rates for multiple sclerosis are a weak index of the frequency of the disease and their utility is restricted to national surveys. The descriptive epidemiological data (incidence, prevalence, mortality) available at present in Italy do not seem to support a link between multiple sclerosis and latitude.
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