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Giuseppe Meco

Publications and source records attributed to Giuseppe Meco.

At least 19 recordsLinked to original sources
PubMed2007

Biological effects of the PINK1 c.1366C>T mutation: implications in Parkinson disease pathogenesis.

PINK1 gene mutations are a cause of recessively inherited, early-onset Parkinson's disease. In some patients, a single heterozygous mutation has been identified, including the recurrent c.1366C>T transition. The interpretation of this finding remains controversial. Furthermore, the c.1366C>T mutation is associated with lower levels of PINK1 transcript, raising the question of whether mRNA levels correlate with the clinical status. We sequenced genomic DNA and copy DNA (cDNA) from 20 subjects carrying the c.1366C>T mutation in the homozygous (n = 5) or heterozygous (n = 15) state. In 17 mutation carriers, messenger RNA (mRNA) was quantified by real-time PCR using four different assays (PINK1 exon 5-6 or exon 7-8 relative to control genes SDHA or YWHAZ). Genomic sequencing confirmed the presence and zygosity of PINK1 mutations. cDNA sequencing in heterozygous mutation carriers revealed a strong wild-type and a much weaker or almost absent mutant signal, whereas in the homozygous patients, only the mutant signal was detected. Homozygous and heterozygous carriers showed PINK1 mRNA levels relative to a reference gene in the range of 0.1-0.2 and 0.5-0.6, respectively, compared with values of 0.9-1.0 in mutation-negative individuals. Treatment of lymphoblasts from a heterozygous mutation carrier with cycloheximide markedly increased the mutant transcript signal. We conclude that the recurrent PINK1 c.1366C>T mutation exerts a major effect at the mRNA level (80-90% reduction), most likely via nonsense-mediated mRNA decay. The absence of correlation between PINK1 mRNA levels and clinical status in heterozygous mutation carriers suggests that other genetic or environmental factors play a role in determining the phenotypic variability associated with the c.1366C>T mutation.

Base Sequence↗
PubMed2006

Health-related quality of life in multiple system atrophy.

Although multiple system atrophy (MSA) is a neurodegenerative disorder leading to progressive disability and decreased life expectancy, little is known about patients' own evaluation of their illness and factors associated with poor health-related quality of life (Hr-QoL). We, therefore, assessed Hr-QoL and its determinants in MSA. The following scales were applied to 115 patients in the European MSA-Study Group (EMSA-SG) Natural History Study: Medical Outcome Study Short Form (SF-36), EQ-5D, Beck Depression Inventory (BDI), Mini-Mental state examination (MMSE), Unified MSA Rating Scale (UMSARS), Hoehn & Yahr (H&Y) Parkinson's disease staging scale, Composite Autonomic Symptom Scale (COMPASS), and Parkinson's Disease Sleep Scale (PDSS). Forty-six percent of patients had moderate to severe depression (BDI > or = 17); Hr-QoL scores on the SF-36 and EQ-5D were significantly impaired. Pain, the only domain with similar scores in MSA and published PD patients, was reported more frequently in patients with MSA-P (predominantly parkinsonian motor subtype) than MSA-C (predominantly cerebellar motor subtype; 76% vs. 50%; P = 0.005). Hr-QoL scores correlated most strongly with UMSARS motor, COMPASS, and BDI scores but not with MMSE scores, age at onset, or disease duration. The COMPASS and UMSARS activities of daily living scores were moderate-to-strong predictors for the SF-36 physical summary score and the BDI and UMSARS motor scores for the SF-36 mental summary score. This report is the first study to show that Hr-QoL is significantly impaired in MSA. Although not all possible factors related to impaired Hr-QoL in MSA could be assessed, autonomic dysfunction, motor impairment, and depression were most closely associated with poor Hr-QoL, and therapeutic management, therefore, should concentrate upon these aspects of the disease.

Anxiety↗
PubMed2006

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease.

Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

Adult↗
PubMed2005

Prevalence and clinical features of hedonistic homeostatic dysregulation in Parkinson's disease.

Hedonistic homeostatic dysregulation (HHD) is a neuropsychiatric disorder recently described in Parkinson's disease (PD), which is characterized by self-medication and addiction to dopaminergic drugs. To understand the prevalence of this disorder, we screened 202 PD patients attending our movement disorder unit for HHD. The clinical features of the patients identified as affected by this syndrome were then compared with those of control PD patients in an attempt to ascertain the possible risk factors for HHD. Results showed 7 subjects who fulfilled the HHD criteria. The analysis of a case-control study showed a significant correlation between HHD and a previous history of mood disorders, and the use of dopamine agonists, either in monotherapy or in combination. The prevalence of HHD in our study is similar to the one reported in the United Kingdom by the authors who first described this syndrome in PD. Of interest, our patients showed a somewhat different pattern of the disorder, suggesting that cultural and environmental factors may play a role in the phenomenology of HHD.

Adult↗
PubMed2005

Case-control study of multiple system atrophy.

The epidemiology of multiple system atrophy (MSA) is scarcely known, and risk factors have not been definitely identified. We investigated the effect of family history for neurodegenerative diseases and environmental factors on MSA risk in a multicentric case-control study. A total of 73 MSA patients (42 men, 31 women; age, 64.3 +/- 8.1 years; disease duration, 4.8 +/- 3.9 years), 146 hospital controls (84 men, 62 women; age, 64.9 +/- 8.4 years), and 73 population controls (42 men, 31 women; age, 63.7 +/- 8.9 years) matched for sex, age (+/-3 years), and province of residence were enrolled consecutively at seven neurological centers from 1 January 1994 to 31 July 1998. The following variables were investigated: family history of neurodegenerative diseases, education, smoking habits, hobbies, and occupational history. Occupational history of farming was significantly more frequent among MSA cases than controls (OR adj = 2.52; 95% CI, 1.25 to 5.07, MSA vs. hospital controls; OR adj = 4.53; 95% CI, 1.68 to12.2, MSA cases vs. population controls). A dose-response analysis for years of farming corroborated this association. We recently found that smoking is significantly less frequent among MSA cases than controls (Vanacore et al. [2000] Neurology 54:114-119). Here, we report that the effects of farming and smoking on MSA risk do not interact. Our results suggest that occupational history of farming is a risk factor for MSA. Smoking and farming seem to influence MSA risk independently. Further epidemiological studies might provide clues on the etiopathogenesis of MSA.

Aged↗
PubMed2005

Novel parkin mutations detected in patients with early-onset Parkinson's disease.

A multiethnic series of patients with early-onset Parkinson's disease (EOP) was studied to assess the frequency and nature of parkin/PARK2 gene mutations and to investigate phenotype-genotype relationships. Forty-six EOP probands with an onset age of < 45 years, and 14 affected relatives were ascertained from Italy, Brazil, Cuba, and Turkey. The genetic screening included direct sequencing and exon dosage using a new, cost-effective, real-time polymerase chain reaction method. Mutations were found in 33% of the indexes overall, and in 53% of those with family history compatible with autosomal recessive inheritance. Fifteen parkin alterations (10 exon deletions and five point mutations) were identified, including four novel mutations: Arg402Cys, Cys418Arg, IVS11-3C > G, and exon 8-9-10 deletion. Homozygous mutations, two heterozygous mutations, and a single heterozygous mutation were found in 8, 6, and 1 patient, respectively. Heterozygous exon deletions represented 28% of the mutant alleles. The patients with parkin mutations showed significantly earlier onset, longer disease duration, more frequently symmetric onset, and slower disease progression than the patients without mutations, in agreement with previous studies. This study confirms the frequent involvement of parkin and the importance of genetic testing in the diagnostic work-up of EOP.

Adolescent↗
PubMed2005

PARK11 is not linked with Parkinson's disease in European families.

Parkinson's disease (PD) is a genetically heterogeneous disease. Recently, significant linkage has been reported to a 39.5 cM region on the long arm of chromosome 2 (2q36-37; PARK11) in North American Parkinson families under an autosomal dominant model of inheritance. We have performed a replication study to confirm linkage to this region in a European population. Linkage analysis in 153 individuals from 45 European families with a strong family history of PD did not show any significant LOD score in this region. Therefore, PARK11 does not seem to play a major role for familial PD in the European population.

Chromosomes, Human, Pair 2↗
PubMed2003

How much phenotypic variation can be attributed to parkin genotype?

To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.

Adolescent↗
PubMed2002

Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism.

The DJ-1 gene encodes a ubiquitous, highly conserved protein. Here, we show that DJ-1 mutations are associated with PARK7, a monogenic form of human parkinsonism. The function of the DJ-1 protein remains unknown, but evidence suggests its involvement in the oxidative stress response. Our findings indicate that loss of DJ-1 function leads to neurodegeneration. Elucidating the physiological role of DJ-1 protein may promote understanding of the mechanisms of brain neuronal maintenance and pathogenesis of Parkinson's disease.

Alleles↗
PubMed2002

Localization of autosomal recessive early-onset parkinsonism to chromosome 1p36 (PARK7) in an independent dataset.

Two new loci, PARK6 and PARK7, for autosomal recessive early-onset parkinsonism have recently been identified on chromosome 1p, in single large pedigrees. Among 4 autosomal recessive early-onset families analyzed here, 2 supported linkage to PARK7, 1 with conclusive evidence. These data confirm localization of autosomal recessive early-onset parkinsonism to PARK7, suggesting it to be a frequent locus. Assignment of families to either PARK6 or PARK7 might be difficult because of the proximity of the two loci on chromosome 1p.

Adult↗
PubMed2002

Excessive daytime sleepiness in de novo and treated Parkinson's disease.

Excessive daytime sleepiness (EDS) in Parkinson's disease (PD) is due to either treatment-related factors or the disease itself. The study of this disturbing phenomenon in de novo parkinsonian patients may contribute to a better understanding of its pathophysiology. We conducted a case control study in which we compared 25 PD patients who had never been treated before with dopaminergic drugs (de novo PD), 50 PD patients being treated with dopaminergic drugs (treated PD), and 25 healthy control subjects, all of whom were matched for age and gender. EDS was measured by means of the Epworth Sleepiness Scale (ESS) and quality of sleep by means of the Pittsburgh Sleep Quality Index (PSQI). ESS and PSQI scores were not statistically different between de novo PD patients and controls, whereas they were significantly higher in treated PD. Differences in ESS score variability were best explained by the treatment effect, whereas there was no clear correlation between PSQI and any of the clinical variables considered.

Disorders of Excessive Somnolence↗
PubMed2002

PARK6-linked parkinsonism occurs in several European families.

The Parkin gene on 6q25.2-27 is responsible for about 50% of autosomal recessive juvenile parkinsonism and less than 20% of sporadic early-onset cases. We recently mapped a novel locus for early-onset parkinsonism (PARK6) on chromosome 1p35-p36 in a large family from Sicily. We now confirm linkage to PARK6 in eight additional families with Parkin-negative autosomal recessive juvenile parkinsonism from four different European countries. The maximum cumulative pairwise LOD score was 5.39 for marker D1S478. Multipoint linkage analysis gave the highest cumulative LOD score of 6.29 for marker D1S478. Haplotype construction and determination of the smallest region of homozygosity in one consanguineous family has reduced the candidate interval to a 9cM region between markers D1S483 and D1S2674. No common haplotype could be detected, excluding a common founder effect. These families share some clinical features with the phenotype reported for European Parkin-positive cases, with a wide range of ages at onset (up to 68 yrs) and slow progression. However, features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6-linked families, thus making the clinical presentation of late-onset cases indistinguishable from idiopathic Parkinson's disease. PARK6 appears to be an important locus for early-onset parkinsonism in European Parkin-negative patients.

Adult↗
PubMedDate not supplied

A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease.

Mutations in the LRRK2 gene have been identified in families with autosomal dominant parkinsonism. We amplified and sequenced the coding region of LRRK2 from genomic DNA by PCR, and identified a heterozygous mutation (Gly2019 ser) present in four of 61 (6.6%) unrelated families with Parkinson's disease and autosomal dominant inheritance. The families originated from Italy, Portugal, and Brazil, indicating the presence of the mutation in different populations. The associated phenotype was broad, including early and late disease onset. These findings confirm the association of LRRK2 with neurodegeneration, and identify a common mutation associated with dominantly inherited Parkinson's disease.

Adult↗
PubMedDate not supplied

Mirtazapine in L-dopa-induced dyskinesias.

Mirtazapine is a novel antidepressant with a pharmacologic profile (alpha-2 antagonist, 5HT-(1A) agonist, and 5HT-(2) antagonist) that renders it potentially useful for l-dopa-induced dyskinesias. Drugs with 5HT-(1A) agonistic activity, such as buspirone and tandospirone, have been reported to be effective in reducing l-dopa-induced dyskinesias. Furthermore, 5HT-(2) antagonism may, by reducing substantia nigra pars reticulata hyperactivity, play a role in the improvement of Parkinsonian symptoms and l-dopa-induced dyskinesias, as has been observed with ritanserin, a 5HT-(2) antagonist. Alpha-2 antagonists, such as idazoxan, have recently also been reported to improve l-dopa-induced dyskinesias. The authors investigated the antidyskinetic properties of mirtazapine by designing an open-label study of 20 Parkinsonian patients with l-dopa-induced dyskinesias. Mirtazapine proved to be moderately effective in reducing l-dopa-induced dyskinesias, either alone or in association with amantadine. Mirtazapine may be of use in patients who do not respond or are intolerant to amantadine.

Aged↗
PubMedDate not supplied

Levetiracetam in tardive dyskinesia.

OBJECTIVES: The aim of this study was to evaluate the effect of levetiracetam on tardive dyskinesia (TD), which is known to be a major limitation of chronic antipsychotic drug therapy, particularly with conventional antipsychotics. METHODS: Sixteen patients suffering from chronic psychosis with TD were enrolled consecutively. Levetiracetam was given in gradually increasing doses, starting with 125 twice a day until the best clinical benefit was achieved (mean dosage, 2,290 mg; range, 1,000-3,000 mg). Tardive dyskinesia was assessed using the Abnormal Involuntary Movement Scale at baseline and after 1 month and 3 months of treatment with levetiracetam. RESULTS: Compared with baseline, there was a significant improvement in the Abnormal Involuntary Movement Scale score after 1 month still present after 3 months (P < 0.001). All patients well tolerated levetiracetam, except one who dropped out of the trial after the first 2 weeks owing to excessive drowsiness. CONCLUSIONS: The results of this open-label observational study suggest that levetiracetam is a well-tolerated drug and effectively controls TD.

Aged↗