Search PubMed⌕ Search

Biomedical subjects

E Fabrizio

Publications and source records attributed to E Fabrizio.

At least 19 recordsLinked to original sources
PubMed2005

Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.

OBJECTIVE: To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism. METHODS: The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases. RESULTS: Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later. CONCLUSIONS: PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.

Adolescent↗
PubMed2005

The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor.

BACKGROUND: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease. OBJECTIVE: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (<50 years) and late onset familial and sporadic Parkinson's disease. RESULTS: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation. The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p<0.002), and highest among probands with one affected parent (8.7%, 6/69) (p<0.001). There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease. Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected. None of the four mutations was found in Italian controls. Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder. The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years). CONCLUSIONS: G2019S is the most common genetic determinant of Parkinson's disease identified so far. It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases. These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.

Adult↗
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

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↗
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↗
PubMed1998

The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: a study of 230 European cases. European Consortium on Genetic Susceptibility in Parkinson's Disease.

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.

Adult↗
PubMed1998

A susceptibility locus for Parkinson's disease maps to chromosome 2p13.

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.

Adult↗
PubMed1997

Cognitive improvement during Tolcapone treatment in Parkinson's disease.

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.

Aged↗
PubMed1995

Familial Parkinson's disease: a clinical genetic analysis.

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.

Age of Onset↗
PubMed1994

Buspirone in levodopa-induced dyskinesias.

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.

Aged↗
PubMed1994

Parkinsonism after chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate).

Permanent parkinsonism was observed in a man with chronic exposure to the fungicide maneb (manganese ethylene-bis-dithiocarbamate). Symptoms developed at 37 years of age, two years after exposure had ceased. To our knowledge, this is the second report on parkinsonism associated with exposure to maneb. Manganese is a well-known parkinsonigen toxin in humans. More recently, it has been shown that dithiocarbamates can also induce extrapyramidal syndromes. The biochemical effects of manganese and dithiocarbamates are reviewed and their possible neurotoxic mechanisms are discussed. Both of these components may have played a role in this case.

Humans↗
PubMed1993

[Educational maladjustment: relational aspects].

Educational maladjustment is approached from a systemic point of view and the pupil's problems are therefore considered as the indication of a malfunction in the child-teacher-parent system. The possibilities of using psychotherapy are examined through the analysis of three case reports.

Adaptation, Psychological↗
PubMed1990

Hallucinations in Parkinson disease: neuropsychological study.

Hallucinations occur fairly frequently in the course of the pharmacological treatment of Parkinson disease. Our aim in this study was to assess first the relation between hallucinations and mental deterioration and second the correlation between the perception disorder and the profile on the Minnesota Multiphasic Personality Inventory (MMPI). Of 304 parkinsonian subjects followed as outpatients at our center 27 (8.88%) had had hallucinations and 17 of these presented marked cognitive deficits (Mini Mental State less than 18) (62.9%) compared with 32 of the other 277 patients (11.5%) (X2 = 55.16, p less than 0.0001). A group of 9 patients who had had hallucinations and 10 controls who had not, all free from marked cognitive deficits, were assessed on the Luria-Nebraska Neuropsychological Battery (LNNB) and on the MMPI. The two groups did not differ significantly in respect of the LNNB but did in respect of the MMPI scales. On this evidence the frequency of mental deterioration is significantly higher in patients who have hallucinated. We discuss the meaning of the MMPI differences both from the biochemical angle and from that of personality factors. These data suggest that the MMPI might be useful for predicting hallucinations in undeteriorated parkinsonian patients on pharmacological therapy.

Aged↗