Association study between the LINGO1 gene and Parkinson's disease in the Italian population.

Some studies have suggested an overlap of clinical and genetic findings between essential tremor (ET) and Parkinson's disease (PD). The first genome-wide association study in ET showed a significant association with the rs9652490 SNP of the leucine-rich repeat and Ig domain containing 1 (LINGO1) gene. Since patients with PD have higher LINGO1 expression levels compared to healthy controls, and animal models of PD show elevated LINGO1 protein levels after experimentally induced damage in the striatum, it can be inferred that LINGO1 is probably involved in PD pathophysiology. In this study, we performed a genetic association analysis of the rs9652490 and rs11856808 SNPs in Italian PD patients and controls to assess the role of these variants in our population. A total of 567 patients with PD and 468 control subjects were enrolled in five Movement Disorder centers located in Central-Southern Italy. Both variants were significantly associated with PD under a recessive model of inheritance before applying the Bonferroni correction. The GG genotype of rs9652490 and the TT genotype of rs11856808 were less frequent in patients than in controls, suggesting a protective effect against the disease. However, after stringent correction, only the P-values obtained from allele and genotype comparisons of the rs11856808 SNP remained significant. Our findings suggest that LINGO1 plays a certain role in the development of PD in the Italian population and represents an interesting candidate gene responsible for PD, due to its involvement in neurological processes.

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.

Hyperhomocysteinemia in L-dopa treated Parkinson's disease patients: effect of cobalamin and folate administration.

Homocysteine (Hcy) is a risk factor for vascular diseases, cognitive impairment and dementia. L-dopa treatment may represent an acquired cause of hyperhomocysteinemia (HHcy), as evidenced by studies in rats as well as in Parkinson's disease (PD) patients. Folate and cobalamin status also seems to influence the effects of L-dopa on plasma Hcy levels; therefore B-vitamins supplementation has been proposed to reduce the HHcy in L-dopa treated PD patients. Plasma Hcy, folate, and cobalamin levels were evaluated in 20 PD patients treated with L-dopa in the baseline condition and following a 5-week period of treatment with cobalamin and folate; results were compared with 35 controls. Analysis of data revealed that Hcy levels were higher in L-dopa treated PD patients when compared with age- and sex-matched controls and that supplementation of the diet with cobalamin and folate is effective in reducing Hcy concentrations; these findings may have important implications in the treatment of PD patients who are potentially at risk for vascular diseases and cognitive impairment or dementia.

Plasma homocysteine levels in Parkinson's disease: role of antiparkinsonian medications.

Elevated plasma homocysteine (Hcy) concentrations have been reported in L-dopa treated Parkinson's disease (PD) patients, suggesting that L-dopa treatment is an acquired cause of hyperhomocysteinemia. Aim of this study is to evaluate the effects of different antiparkinsonian drugs on Hcy concentrations. We compared Hcy, B(12) and folate levels in 45 PD patients (15 treated with dopamine-agonists, 15 with L-dopa and 15 with L-dopa plus a catechol-O-methyltransferase-inhibitor (COMT-I) and in 15 controls. Analysis of data revealed that L-dopa administration significantly increases Hcy concentrations and that the addition of COMT-I effectively reduces the homocysteinemia.

Fatigue in Parkinson's disease.

Fatigue is a recognized problem in Parkinson's disease and other clinical conditions. We characterized this symptom in 19 patients and 19 age- and sex-matched controls, using the Multidimensional Fatigue Inventory (MFI) and the Geriatric Depression Scale. Fatigue may be an independent symptom in Parkinson's disease, frequently associated with depression. Our analysis showed the usefulness of the MFI in discriminating between different dimensions of fatigue for a better therapeutic approach.

Natural history and clinical features of progressive supranuclear palsy: a clinical study.

Progressive supranuclear palsy (PSP or Steele-Richardson-Olszewski syndrome) is one of the most-common types of atypical parkinsonism. To characterize the natural history and the clinical features of PSP, we reviewed the records of 25 patients followed in our clinic since 1991, with a clinical diagnosis of PSP according to NINDS and Golbe criteria. Progressive onset of early bilateral bradykinesia and postural instability with falls during the 5th decade strongly support the diagnosis of PSP in our patients. Pseudobulbar symptoms are very common at onset and during the course of the illness.

Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7.

Autosomal recessive, early onset parkinsonism (AREP) is genetically heterogeneous. Mutations in the parkin gene (PARK2 locus, chromosome 6q) account for up to 50% of AREP families. The parkin protein displays ubiquitin-ligase activity for different targets, which accumulate in the brain of patients with parkin defect and might cause neurodegeneration. Two new AREP loci (PARK6 and PARK7) have been recently mapped on chromosome 1p and confirmed in independent datasets, suggesting that both might be frequent. The three AREP forms display similar clinical phenotypes. Recruiting new families will help cloning the defective genes at PARK6 and PARK7 loci. This will contribute to unraveling the pathogenesis of AREP, and it is also expected to foster our understanding of molecular events underlying classic Parkinson's disease.

Frequency of apraxia of eyelid opening in the general population and in patients with extrapyramidal disorders.

We ascertained the prevalence of apraxia of eyelid opening (AEO) in a community located in Puglia, a region of southern Italy. The crude prevalence rate was 59 per million (95% confidence interval, 24-173). AEO coexisted with adult onset blepharospasm in 75% of cases, with atypical parkinsonism in 25% of cases. Among the overall patient population seen at our movement disorders clinic from 1987 to 1997, AEO was isolated in 10 otherwise healthy individuals, associated with adult-onset dystonia in 13 cases, and associated with a parkinsonian syndrome in 9 cases. The frequency of AEO was 10.8% in the dystonia group, and 2.1% in the overall parkinsonian group (Parkinson's disease, 0.7%; progressive supranuclear palsy, 33.3%). In two patients with possible progressive supranuclear palsy, AEO worsened after increasing levodopa dosage or acute apomorphine challenge and disappeared following levodopa discontinuation. AEO developing in the setting of a parkinsonian syndrome may be either disease- or drug-related.

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.

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.

Paroxysmal dystonia with thalamic lesion in multiple sclerosis.

Paroxysmal dystonia (PD) is a usually painful, unilateral dystonic posture, precipitated by voluntary movement, tactile stimulation, startling noise or hyperventilation. We describe two cases of paroxysmal dystonia in multiple sclerosis, both with a critically localized lesion in the thalamus, contralateral to the paroxysmal symptoms. Only one other case of paroxysmal dystonia with a demyelinated lesion of the thalamus has been reported previously.

Parkinsonism in a patient with AIDS and cerebral opportunistic granulomatous lesions.

The localization of opportunistic infections in the basal ganglia in patients with acquired immunodeficiency syndrome (AIDS) can cause movement disorders, such as choreoathetosis, dystonia, hemiballism and, more rarely, parkinsonism. We describe the case of an AIDS patient who developed cerebral opportunistic granulomatous lesions and, subsequently, a parkinsonian akinetic-rigid syndrome. In agreement with cases reported in the literature, the parkinsonian syndrome developed only when the lesions bilaterally involved basal ganglia. The critical localization of the opportunistic lesions in the direct and indirect strio-pallidal pathways possibly associated with the HIV-related neurotoxicity might have contributed to determine this clinical picture.

Post-vaccinic opsoclonus-myoclonus syndrome: a case report.

The opsoclonus-myoclonus syndrome is a pathological condition characterized mainly by involuntary myoclonic movements involving ocular, trunk and limb muscles associated with ataxia and other neurological signs.We describe the case of a 30-year-old woman who developed this syndrome 15days after anti-Rubella vaccination. This case suggests a possible autoimmune post-vaccinic etiopathogenesis of opsoclonus-myoclonus syndrome, rarely described in the literature.

Isinglass/collagen: denaturation and functionality.

Isinglass is widely used commercially to clarify alcoholic beverages by aggregation of the yeast and other insoluble particles. It is derived from swim bladders of tropical fish by solubilisation in organic acids and consists predominantly of the protein collagen. The low content of intermolecular cross-links allows ready dissolution of swim bladder compared to bovine hide which is cross-linked by a high proportion of stable bonds and requires enzymic digestion to solubilise. Isinglass is no longer effective as a clarifying agent if thermally denatured hence the collagenous triple helical structure must be maintained. Thermal denaturation of isinglass occurs at 29 degrees C, compared to 40-41 degrees C for mammalian collagens, primarily due to the lower hydroxyproline content. The hydroxyproline is essential for the formation of H-bonded water-bridges through the hydroxyl group and the peptide chain thereby stabilising the triple helix. Based on the lower enthalpy determined by differential scanning calorimetry we have calculated that the thermally labile domain of the isinglass molecule was 41 residues compared to 66 for mammalian collagen. The fining efficiency was unaffected by pH, chelating agents, detergents and removal of surface proteins from yeast cells. Studies on the mechanism of action of isinglass have shown that higher molecular weight aggregates that increase the length of the collagen molecules (trimers, tetramers, etc.) increase efficiency and that their surface charge are important in the clarification process. By chemical modification, we have shown that blocking positively charged groups had no effect on the fining process, whilst negative charges are clearly essential and that increasing the negative charge by succinylation increases its efficacy. Solutions of bovine hide collagen were shown to be equally effective in refining beers and standard yeast preparations. The higher thermal denaturation temperature, ready availability and reproducibility of bovine collagen preparations gives it considerable advantages over isinglass.

Usefulness of proton magnetic resonance spectroscopy in differentiating parkinsonian syndromes.

Proton magnetic resonance spectroscopy ((1)H-MRS) was performed in patients with a clinical diagnosis of idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA) or progressive supranuclear palsy (PSP) in order to assess metabolic differences between the three groups of patients. Single-volume (1)H-MRS, localized to the lentiform nucleus, was carried out in 19 IPD patients, 14 MSA patients, 11 PSP patients and 12 age-matched healthy subjects. The signals of N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine-phosphocreatine (Cr) were evaluated as peak area ratios. The NAA/Cho peak ratio was significantly reduced in MSA and in PSP patients compared to IPD patients and to controls. The NAA/Cr peak ratio was significantly reduced in MSA, in PSP and in IPD patients compared to controls, but only in MSA compared to IPD patients. The NAA reduction in the basal ganglia of MSA and PSP patients may reflect a neuronal loss or damage. Single-volume (1)H-MRS may be a useful tool in differentiating MSA and PSP from IPD patients.

"Apraxia of eyelid opening" induced by levodopa therapy and apomorphine in atypical parkinsonism (possible progressive supranuclear palsy): a case report.

We report a female patient in whom so-called apraxia of eyelid opening (AEO) developed after the onset of possible progressive supranuclear palsy (National Institute of Neurological Disorders and Stroke criteria) and the introduction of antiparkinsonian medications including levodopa. Although parkinsonian symptoms responded poorly to levodopa, AEO worsened after increasing levodopa dosage and disappeared when levodopa was discontinued. Later, a dose of apomorphine widely accepted for acute tests had no significant effect on limb motor activity but induced AEO. Overall, these observations are grounds for thinking that AEO developing in the course of parkinsonism may be either disease- or drug-related. The possibility of manipulating dopaminergic treatment should always be considered when dealing with AEO associated with parkinsonism.

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.

Direct genetic evidence for involvement of tau in progressive supranuclear palsy. European Study Group on Atypical Parkinsonism Consortium.

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.