Peter Vieregge

Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinsons disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.

Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia.

A novel neurological syndrome has recently been described to be associated with an expanded polyglutamine domain. The expansion results from partial duplication within the TATA-binding protein (TBP). By investigation of 604 sporadic and familial cases with various forms of neurological syndromes and 157 unaffected individuals, we found repeat expansions in the TBP in four patients of two families with autosomal dominant inheritance of ataxia, dystonia, and intellectual decline. Two different genotypes for the repetitive sequence could be demonstrated which led to elongated polyglutamine stretches between 50 and 55 residues, whereas normal alleles with 27 to a maximum of 44 glutamine residues were found in this study. The expansion to 50 or more glutamine residues results in a pathological phenotype and confirms the report of a new polyglutamine disease.

A study of five candidate genes in Parkinson’s disease and related neurodegenerative disorders

OBJECTIVE To determine whether reported genetic association of polymorphisms in the CYP2D6, CYP1A1, N-acetyltransferase 2 (NAT2), DAT1, and glutathione s-transferase M1 (GSTM1) genes with PD were evident in a population of 176 unrelated patients with sporadic PD and to extend these findings to other disease groups (familial PD [n = 30], ALS [n = 50], multiple system atrophy [n = 38], progressive supranuclear palsy [n = 35], and AD [n = 23]). METHODS A combination of allele-specific PCR and analysis of restriction fragment length polymorphisms were performed. RESULTS We genotyped 1,131 individuals. After matching each patient with a control subject by age, sex, ethnicity, and geographic origin, there was no association of any allele/genotype with any of the six disease groups. There was an increased frequency of NAT2 slow acetylators in the ALS group compared with controls (70% versus 50%; OR 2.33 [95% CI, 1.03 to 5.30]), but this was not significant after adjusting for multiple testing. CONCLUSIONS This is one of the most extensive candidate gene studies performed in PD and the first time that some of these loci have been studied in multiple system atrophy and progressive supranuclear palsy. In contrast with previous studies, we found no role for these polymorphisms in the etiology of PD, ALS, multiple system atrophy, progressive supranuclear palsy, or AD.

Genes associated with Parkinson syndrome

Genetic findings have changed our views on Parkinson’s disease (PD) and parkinsonism, which will be collectively referred to as Parkinsonian Syndrome (PS) in the present manuscript. Mutations in several genes are found to cause monogenic forms of the disorder. Point mutations, duplications and triplications in the α-synuclein gene cause a rare dominant form of PS in families. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as a much more common cause for dominant PS, especially in certain ethnic groups, while mutations in the parkin gene, in DJ-1, PINK1 and ATP13A2 cause autosomal recessive parkinsonism of early onset. The monogenic variants are important tools in identifying cellular pathways that also shed light on the molecular pathogenesis of sporadic PS and some of these genes may play a role in the etiology of the common sporadic form of PS. Here we add recent findings to a greatly challenging puzzle.

Direct genetic evidence for involvement of tau in progressive supranuclear palsy

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.

Smoking habits in multiple system atrophy and progressive supranuclear palsy

Objective: To evaluate smoking habits in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) in a multicenter case–control study to determine whether these two forms of atypical parkinsonism share the inverse association with smoking previously found in PD. Background: No epidemiologic studies have been performed on smoking habits in MSA. A previous investigation in PSP revealed no differences in smoking habits between patients and hospital control subjects. Methods: Seventy-six MSA patients, 55 PSP patients, 140 PD patients, and 134 healthy control subjects were enrolled consecutively at seven neurologic clinics from January 1, 1994, to July 31, 1998. Detailed information on smoking habits was obtained using a structured questionnaire. Results: The comparison between frequencies of never-smokers versus ever-smokers (ex-smokers/current smokers; adjusted odds ratio [ORadj], 0.56; 95% CI, 0.29 to 1.06) and a dose–response analysis for never-smokers, moderate smokers (ORadj, 0.64; 95% CI, 0.31 to 1.32), and heavy smokers (ORadj, 0.47; 95% CI, 0.21 to 1.05) suggest that MSA patients smoke less than population control subjects. By contrast, the comparison of frequencies of never-smokers versus ever-smokers (ORadj, 0.91; 95% CI, 0.42 to 1.98) and a dose–response analysis for never-smokers, moderate smokers (ORadj, 0.68; 95% CI, 0.27 to 1.69), and heavy smokers (ORadj, 1.24; CI 95%, 0.51 to 3.06) revealed no differences in smoking habits between PSP patients and population control subjects. Conclusions: The fact that the inverse association with smoking found previously in PD is shared by multiple system atrophy but not by progressive supranuclear palsy lends epidemiologic support to the notion that different smoking habits are associated with different groups of neurodegenerative disease.

Parkinson's disease in twins

Among nine monozygotic (MZ) and 12 dizygotic (DZ) twin pairs in which an index case had typical Parkinsons disease (PD) or PD with associated dementia, three MZ and three DZ pairs were concordant. Three of the six affected co-twins were first diagnosed during the study. Occurrence of PD in families of MZ and DZ index cases was more frequent than expected from population prevalence rates. The study underlines the need for personal examination using defined criteria in a cross-sectional twin study on PD. Although the study did not establish a major genetic impact in the etiology of PD, a genetic predisposition for the disease cannot be ruled out for some individuals.

Sexuality in young patients with Parkinson's disease: a population based comparison with healthy controls

Answers from a multiple choice questionnaire on the opinions about public sexual attitudes, on emotion from personal sexual practice, on personal sexual function, and on general health perception were compared between 121 patients with Parkinsons disease (mean age 45 years) and 126 age and sex matched community derived controls. Patients were more dissatisfied with their present sexual functioning and relationship, and perceived their general health as poorer than the controls, whereas opinions about public sexual attitudes were only marginally different. No differences were found for sexual function. Further analysis showed that the perception of sexual functioning and general health in younger patients with Parkinsons disease is considerably influenced by depression and state of unemployment.

MDR1 variants and risk of Parkinson disease

The multidrug resistance protein 1 (MDR1 or ABCB1) gene encodes a P-glycoprotein that protects the brain against neurotoxicants. Certain MDR1 genetic variants are known to compromise the function of this transporter and may thus be associated with Parkinson disease (PD). We therefore conducted a large case-control study investigating the potential relationship between MDR1 variants and PD. We determined the frequency of three MDR1 variants in 599 European PD patients and controls and further stratified the population by ethnicity, age at onset, and exposure to pesticides. We detected no relevant association in either the entire sample, or when separately investigating by ethnic origin or age at onset. However, the distribution of c.3435C/T differed significantly between PD patients exposed to pesticides compared to those non-exposed (odds ratio = 4.74; confidence interval = [1.009; 22.306]); p = 0.047), suggesting that common MDR1 variants might influence the risk to develop PD in conjunction with exposure to pesticides.

Role of ethnicity on the association of MAPT H1 haplotypes and subhaplotypes in Parkinson's disease

An association of the H1 haplotype and subhaplotypes in the microtubule-associated protein Tau (MAPT) gene with Parkinsons disease (PD) has been reported. To further evaluate their role in PD, we genotyped a sample set of 765 cases and controls consisting of two large European subgroups of German (n=418) and Serbian (n=347) origin for the MAPT haplotypes H1 and H2. The H1/H1 carriers were tested for three additional MAPT polymorphisms. In the Serbian sample, there was significant evidence (P=0.0108) of an association of the H1/H1 genotype and PD. Surprisingly, in the German sample, we did not find significant differences in genotype or haplotype frequencies between patients and controls. These results suggest that the role of H1 haplotypes in the etiology of PD may be ethnically dependent.