Sporadic Idiopathic Parkinson's Disease Research Articles

Expanding the genetics of huntingtonism

The lines defining many clinical syndromes have become blurred. A patient presenting with what appears to be Parkinson disease may in fact have one of several genetic mutations (e.g., LRRK2 , parkin ), an atypical parkinsonian syndrome (e.g., multisystem atrophy, progressive supranuclear palsy), sporadic idiopathic Parkinson disease, or a number of other conditions. Conversely, known genetic mutations may have classical presentations, but they may also present with widely varying signs and symptoms.

Emerging parkinsonian phenotypes

There is no unique way to define Parkinson's disease (PD) clinically. "Classical parkinsonian features" can be found not only in sporadic idiopathic PD patients, but also in other parkinsonian disorders, such as genetic forms associated with mutations in PARK or in other genes. The present review will describe the parkinsonian phenotypes emerging from the new Mendelian genes which have been linked to PD (such as PARK9 and PARK14), the associated dystonia-parkinsonism disorders (such as the syndromes of neurodegeneration with brain iron accumulation) and the emerging data on heterozygous variants of genes which could influence the risk to develop PD and the PD phenotypes (like PD associated with glucose cerebrosidase mutations).

No association between common POLG1 variants and sporadic idiopathic Parkinson's disease

No association between common <i>POLG1</i> variants and sporadic idiopathic Parkinson's disease

Is the common LRRK2 G2019S mutation related to dyskinesias in North African Parkinson disease?

Parkinson disease (PD) is a progressive neurodegenerative disorder that mainly affects the elderly. The majority of cases are sporadic; only 10 to 15% are familial. Recently, mutations in the leucine-rich repeat kinase 2 (LRRK2) were associated with autosomal dominant, late-onset parkinsonism.1,2 The most common mutation, G2019S (c.6055 G>A), was detected in up to 5–6% of several European PD populations and 1–2% of patients with sporadic late-onset disease,3 but ∼40% in patients with PD from North Africa.4 Here we report the screening of the LRRK2 G2019S mutation in a new independent series of 136 North African patients with PD, and in ethnically matched healthy controls. We found that dyskinesias were significantly more frequent in patients with the G2019S mutation than in noncarriers. ### Methods. A new series of 136 unrelated patients with PD from Algeria (n = 114), Morocco (n = 10), Tunisia (n = 7), France (n = 4), and Libya (n = 1) (74 men, 62 women; mean age at onset, 54.7 ± 12.4 years, range 12–78) were compared with 66 healthy Algerian controls (32 men, 34 women; mean age at examination, 55.9 ± 11.0 years, range 39–84). The clinical diagnosis of PD was established as previously reported.4 A total of 119 patients (88%), 31 of whom had consanguinity, were diagnosed with sporadic idiopathic PD, 17 patients reported family histories of PD. …

Alpha‐synuclein immunohistochemistry in two cases of co‐occurring idiopathic Parkinson's disease and motor neuron disease

We report on two cases of sporadic idiopathic Parkinson's disease with motor neuron disease co-occurring in the same individuals. Pathological analysis revealed the presence of Lewy bodies in brainstem nuclei and basal forebrain consistent with Lewy body disease (LBD), as well as motor neuron degeneration and argyrophilic grain disease. We compared our two cases to all previously published pathological cases of combined LBD and motor neuron degeneration.

Genes in familial parkinsonism and their role in sporadic Parkinson?s disease

For several decades there has been a controversy on the contribution of genetic factors to the pathogenesis of sporadic idiopathic Parkinson's disease (PD). The identification of families in which typical parkinsonism is inherited as an autosomal dominant or recessive trait sheds light on genes that cause phenotypes resembling sporadic PD. These genes are involved in molecular pathways leading to neurodegeneration and dysfunction of the nigrostriatal system. The present article gives insight into molecular pathways to neurodegeneration deciphered by the functional characterization of five genes identified in inherited forms of typical levodopa-responsive parkinsonism. There is increasing evidence that genes involved in monogenic forms of the disease may act as susceptibility factors also in the common sporadic form of PD. Transgenic animal models based on disease genes identified in monogenic forms of typical parkinsonism replicate important features of PD including protein aggregation and progressive motor symptoms. This implicates novel perspectives for neuroprotective therapeutic approaches that might be beneficial also to sporadic PD.

The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease.

The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 - patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 - patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT(L) as well as high activity ones, i.e. MAOB allele G and COMT(H), were determined using PCR-RFLP method. No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT(L/L) homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). The results of the study suggest that patients with COMT(L/L) genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.

Genetic study of Apolipoprotein E gene, alpha‐1 antichymotrypsin gene in sporadic Parkinson disease

Several lines of evidence have suggested some common genetic risk factors for Alzheimer disease (AD) and Parkinson disease (PD) because there are some overlapping pathologies in these two neurodegenerative diseases. In the present study, we investigated the role of Apolipoprotein E gene polymorphism and the signal peptide polymorphism in alpha-1 antichymotrypsin (ACT) gene in idiopathic sporadic PD. The study was performed in a sample consisting of 68 PD cases and 160 healthy subjects in Shanghai China. We found no significant differences of ACT gene polymorphic distribution between PD cases and controls. The ApoE gene epsilon2/epsilon4 genotype was significantly more frequent in PD subjects (chi2 = 7.126, df = 1, P = 0.008) and conferred a 12.70 times susceptibility for PD (OR = 12.62, 95% CI: 1.445-110.17, chi2 = 5.259, P < 0.05, AF = 4.59%). No interaction of ApoE and ACT genes was detected in PD. Therefore, our data suggested that the ApoE epsilon2/epsilon4 genotype might be a susceptibility variant of moderate effect for sporadic idiopathic PD in our samples, whereas the ACT gene signal peptide polymorphism might not.

Motor unit changes in sporadic idiopathic Parkinson's disease.

We studied motor unit changes in 20 patients with Parkinson's disease (PD) and 20 age-matched control subjects to look for evidence of motorneuron degeneration in sporadic idiopathic PD. Patients and control subjects were screened by clinical criteria and nerve conduction studies to exclude those with peripheral neuropathic processes. Changes in motor unit morphology were investigated with subjective and computerized quantitative electromyography (QEMG) of the anterior tibialis (AT) and first dorsal interosseous. Multivariate comparisons showed a significant difference in the QEMG analysis for motor unit enlargement in patients with PD versus control subjects. Some of the univariate comparisons for both the subjective and QEMG analyses of the AT were also significant. These results demonstrate that motorneuron drop-out with reinnervation occurs in sporadic idiopathic PD. In summary, our findings provide evidence that clinically silent motorneuron disease occurs in typical cases of sporadic idiopathic PD, suggesting that it may be a normal part of the pathologic picture of PD. Any hypothesis concerning the pathogenic mechanism of PD would need to take into account such a finding.

Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to Parkinson's disease

Toxicologists have thought that the paraoxonase (PON) enzyme polymorphism might contribute to effects of pollutants and other environmental chemicals on susceptibility to cancer, birth defects and Parkinson's disease (PD). We studied a biallelic PON1 polymorphism at codon 192 (A and B alleles) in 166 patients with sporadic idiopathic PD. The frequency of the B (Arg) allele of PON1 was significantly increased in patients with PD than in healthy controls ( χ 2=8.75, df=1, P<0.005). The relative risk of PD in homozygotes for the B allele was 1.60 fold higher than individuals with the A (Gln) allele ( χ 2=7.38, df=1, P<0.01). Our data suggest that environmental neurotoxins metabolized by PON1 might be responsible for neurodegeneration with aging and that the B (Arg) allele form might have genetic susceptibility to PD.

Lack of Relation Between Genetic Polymorphism of Cytochrome P-450IID6 and Sporadic Idiopathic Parkinson's Disease

We investigated genetic polymorphism of the cytochrome P-450 CYP2D6 gene from white patients with idiopathic Parkinson's disease (IPD). The mutations of the CYP2D6 gene associated with the poor metabolizer (PM) phenotype of the debrisoquine/sparteine polymorphism were analyzed in DNA of 130 IPD patients by a polymerase chain reaction (PCR)-based DNA amplification combined with Xba I restriction fragment length polymorphism (RFLP) analysis in 105 patients. Another mutation located in exon 6 was analyzed by Hha I RFLP in 94 IPD patients. The frequencies of the different CYP2D6 gene mutations were compared to the frequencies in sex- and age-matched white control population with chronic bronchitis. The rate of genotypically defined PM and the frequencies of the different mutations were not significantly different in IPD patients and controls. These results fail to confirm the previously reported results concerning CYP2D6 gene mutations in IPD. These equivocal results might be related to methodologic problems. However, other hypotheses have been suggested: impairment of neuronal CYP 2D6 expression, transient modification of CYP 2D6 phenotype, or linkage of CYP2D6 gene to the candidate gene locus directly involved in IPD.