| 1. |
- Heckman, Michael G., et al.
(author)
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Population-specific Frequencies for LRRK2 Susceptibility Variants in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium
- 2013
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 28:12, s. 1740-1744
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Journal article (peer-reviewed)abstract
- BackgroundVariants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. ConclusionsEstablishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. (c) 2013 International Parkinson and Movement Disorder Society
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| 2. |
- Ross, Owen A., et al.
(author)
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Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study
- 2011
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In: Lancet Neurology. - 1474-4465. ; 10:10, s. 898-908
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Journal article (peer-reviewed)abstract
- Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. Methods LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0.5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. Findings 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1.43, 95% CI 1.15-1.78; p=0.0012) and Asian individuals (A419V, 2.27, 1.35-3.83; p=0.0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0.82, 0.72-0.94; p=0.0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1.73, 1.20-2.49; p=0.0026), but no association was noted for R1628P (0.62, 0.36-1.07; p=0.087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4.48, 133-15.09; p=0.012). Interpretation The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. Funding Michael J Fox Foundation and National Institutes of Health.
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| 3. |
- Chung, Sun Ju, et al.
(author)
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Alpha-Synuclein Repeat Variants and Survival in Parkinson's Disease
- 2014
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 29:8, s. 1053-1057
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Journal article (peer-reviewed)abstract
- Objectives: To determine whether alpha-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD). Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival. Results: Twenty-one sites contributed data for 6,154 cases. There was no significant association between alpha-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value = 0.01). Conclusions: In our large consortium study, alpha-synuclein REP1 genotypes were not associated with survival in PD. Further studies of alpha-synuclein's role in disease progression and long-term outcomes are needed. (C) 2014 International Parkinson and Movement Disorder Society
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| 4. |
- Elbaz, Alexis, et al.
(author)
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Independent and Joint Effects of the MAPT and SNCA Genes in Parkinson Disease
- 2011
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 69:5, s. 778-792
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Journal article (peer-reviewed)abstract
- Objective: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium. Methods: Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach. Results: Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 30 end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale. Interpretation: This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects. ANN NEUROL 2011; 69: 778-792
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| 5. |
- Fujioka, Shinsuke, et al.
(author)
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Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics.
- 2013
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In: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 8
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Research review (peer-reviewed)abstract
- Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.
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| 6. |
- Krüger, Rejko, et al.
(author)
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A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease
- 2011
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 32:3, s. 9-548
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Journal article (peer-reviewed)abstract
- High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
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| 7. |
- Puschmann, Andreas, et al.
(author)
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An African-American family with dystonia.
- 2011
-
In: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 17, s. 547-550
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Journal article (peer-reviewed)abstract
- The genetic cause of late-onset focal and segmental dystonia remains unknown in most individuals. Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6 dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians. We are not aware of any previous descriptions of familial dystonia in African-Americans or reports of THAP1 mutations in African-Americans. Herein, we characterize an African-American (AA) kindred with late-onset primary dystonia, clinically and genetically. The clinical phenotype included cervical, laryngeal and hand-forearm dystonia. Symptoms were severe and disabling for several family members, whereas others only displayed mild signs. There were no accompanying motor or cognitive signs. In this kindred, age of onset ranged from 45 to 50 years and onset was frequently sudden, with symptoms developing within weeks or months. DYT1 was excluded as the cause of dystonia in this kindred. The entire genomic region of THAP1, including non-coding regions, was sequenced. We identified 13 sequence variants in THAP1, although none co-segregated with dystonia. A novel THAP1 variant (c.-237-3G>T/A) was found in 3/84 AA dystonia patient alleles and 3/212 AA control alleles, but not in 5870 Caucasian alleles. In summary, although previously unreported, familial primary dystonia does occur in African-Americans. Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African-Americans. Therefore, genetic testing for dystonia and future studies of candidate genes must take genetic background into consideration.
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| 8. |
- Puschmann, Andreas, et al.
(author)
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Diagnosis and Treatment of Common Forms of Tremor
- 2011
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In: Seminars in Neurology. - : Georg Thieme Verlag KG. - 0271-8235 .- 1098-9021. ; 31:1, s. 65-77
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Journal article (peer-reviewed)abstract
- Tremor is the most common movement disorder presenting to an outpatient neurology practice and is defined as a rhythmical, involuntary oscillatory movement of a body part. The authors review the clinical examination, classification, and diagnosis of tremor. The pathophysiology of the more common forms of tremor is outlined, and treatment options are discussed. Essential tremor is characterized primarily by postural and action tremors, may be a neurodegenerative disorder with pathologic changes in the cerebellum, and can be treated with a wide range of pharmacologic and nonpharmacologic methods. Tremor at rest is typical for Parkinson's disease, but may arise independently of a dopaminergic deficit. Enhanced physiologic tremor, intention tremor, and dystonic tremor are discussed. Further differential diagnoses described in this review include drug- or toxin-induced tremor, neuropathic tremor, psychogenic tremor, orthostatic tremor, palatal tremor, tremor in Wilson's disease, and tremor secondary to cerebral lesions, such as Holmes' tremor ( midbrain tremor). An individualized approach to treatment of tremor patients is important, taking into account the degree of disability, including social embarrassment, which the tremor causes in the patient's life.
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| 9. |
- Puschmann, Andreas, et al.
(author)
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First neuropathological description of a patient with Parkinson's disease and LRRK2 p.N1437H mutation.
- 2012
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In: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 18:4, s. 332-338
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Journal article (peer-reviewed)abstract
- The c.4309A>C mutation in the LRRK2 gene (LRRK2 p.N1437H) has recently been reported as the seventh pathogenic LRRK2 mutation causing monogenic Parkinson's disease (PD). So far, only two families worldwide have been identified with this mutation. By screening DNA from seven brains of PD patients, we found one individual with seemingly sporadic PD and LRRK2 p.N1437H mutation. Clinically, the patient had levodopa-responsive PD with tremor, and developed severe motor fluctuations during a disease duration of 19 years. There was severe and painful ON-dystonia, and severe depression with suicidal thoughts during OFF. In the advanced stage, cognition was slow during motor OFF, but there was no noticeable cognitive decline. There were no signs of autonomic nervous system dysfunction. Bilateral deep brain stimulation of the subthalamic nucleus had unsatisfactory results on motor symptoms. The patient committed suicide. Neuropathological examination revealed marked cell loss and moderate alpha-synuclein positive Lewy body pathology in the brainstem. There was sparse Lewy pathology in the cortex. A striking finding was very pronounced ubiquitin-positive pathology in the brainstem, temporolimbic regions and neocortex. Ubiquitin positivity was most pronounced in the white matter, and was out of proportion to the comparatively weaker alpha-synuclein immunoreactivity. Immunostaining for tau was mildly positive, revealing non-specific changes, but staining for TDP-43 and FUS was entirely negative. The distribution and shape of ubiquitin-positive lesions in this patient differed from the few previously described patients with LRRK2 mutations and ubiquitin pathology, and the ubiquitinated protein substrate remains undefined.
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| 10. |
- Puschmann, Andreas, et al.
(author)
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Genotype-Phenotype Correlations in Parkinson Disease
- 2014
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In: Movement Disorders: Genetics and Models, 2nd Edition. - 9780124051959 - 9780124055162 ; , s. 259-285
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Book chapter (peer-reviewed)abstract
- Mutations in four autosomal dominant (SNCA, LRRK2, VPS35, EIF4G1) and three recessive genes (PARK2, PINK1, PARK7/DJ1) are known to cause Parkinson disease (PD). This chapter describes the clinical and pathological phenotypes associated with mutations in these genes. We systematically reviewed the phenotypes associated with all known pathogenic mutations in the dominant genes. SNCA point mutations and genomic multiplications cause a disorder with akinetic-rigid Parkinsonism, dysautonomia, cognitive decline, myoclonus, and pronounced alpha-synuclein pathology. LRRK2 mutations cause tremor-dominant or akinetic-rigid Parkinsonism with variable pathology. Our knowledge about the newly described genes VPS35 and EIF4G1 is still limited. Homozygous or compound heterozygous mutations in the recessive PD genes cause Parkinsonism with an early or very-early onset, but many different mutations are found in these genes and genotype-phenotype correlations are based on low numbers of patients per mutation. Homozygous mutations in GBA may cause Parkinsonism, usually in patients who have Gaucher disease, whereas heterozygous GBA mutations are genetic risk factors for PD. The monogenic forms of PD represent distinct subtypes of this heterogeneous disorder.
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| 11. |
- Puschmann, Andreas, et al.
(author)
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Human leukocyte antigen variation and Parkinson's disease.
- 2011
-
In: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 17, s. 376-378
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Journal article (peer-reviewed)abstract
- A role for the immune system in the pathogenesis of Parkinson's Disease (PD) has previously been suggested. A recent genome-wide association (GWA) study identified an association between one single nucleotide polymorphism (SNP) in the human leucocyte antigen (HLA) region (HLA-DRA rs3129882) and PD in a population of American patients with European ancestry. In that study, the minor rs3129882 allele (G) was associated with an increased risk of PD under an additive model. Due to the increased likelihood of obtaining false positive results in GWA studies compared to studies conducted based on a hypothesis-driven approach, repeated validation of findings from GWA studies are necessary. Herein, we evaluated the association between rs3129882 and PD in three different Caucasian patient-control series (combined 1313 patients and 1305 controls) from the US, Ireland, and Poland. We observed no association (OR: 0.96, P = 0.50) between rs3129882 and PD when analyzing our data under an additive or dominant model. In contrast, when examined under a recessive model, the GG genotype was observed to be protective in the Irish (OR: 0.55, P = 0.008), Polish (OR: 0.67, P = 0.040) and combined (OR: 0.75, P = 0.006) patient-control series. In view of these diverging results, the exact role of genetic variation at the HLA region and susceptibility to PD remains to be resolved.
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| 12. |
- Puschmann, Andreas J., et al.
(author)
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Familial late-onset focal dystonia in an African American family
- 2010
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 68:Suppl. S14, s. 69-69
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Conference paper (peer-reviewed)abstract
- Recent studies of THAP1 (DYT6) have pointed out that late-onset focal dystonia can have a genetic basis. Familial late-onset primary dystonia has not been described in African- Americans. Six members of an African American family were affected by focal or segmental dystonia with a mean age at onset of 47 years (range, 45-50). Two additional individuals with milder clinical signs were classified as probably affected. Clinical phenotypes included cervical, laryngeal and handforearm (writer's cramp) dystonia, following an autosomal dominant mode of inheritance. TOR1A (DYT1) and THAP1 (DYT6) were screened for sequence variants. There were no abnormalities in TOR1A. A novel THAP1 sequence variant (c.-237-3G>T) was found in both affected and unaffected family members and did not co-segregate with dystonia. This variant was also found in 1/212 African American control alleles. Another variant at the same site (c.-237-3G>A) was found in 2/212 African American control alleles and one African American subject with laryngeal dystonia (1/84 alleles). Therefore, these variants are unlikely to be pathogenic. Familial late-onset primary dystonia does occur in non-Caucasian populations. Future studies of THAP1 and other dystonia genes must take genetic background into consideration.
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| 13. |
- Puschmann, Andreas, et al.
(author)
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Olfactory Dysfunction.
- 2013
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In: Parkinson's Disease and Nonmotor Dysfunction. - 9781607614296 - 9781607614289 ; , s. 335-348
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Book chapter (peer-reviewed)abstract
- Olfactory dysfunction is well documented as an early nonmotor manifestation of Parkinson’s disease (PD). This chapter outlines the anatomy and physiology of the olfactory system and summarizes the pathological changes in the olfactory system in PD. We review the occurrence of olfactory dysfunction in parkinsonian syndromes and familial parkinsonism. Different methods to assess olfactory function are presented. Their usefulness in routine clinical situations is limited to special diagnostic situations. However, these methods have provided important insights into the pathophysiology of parkinsonism and can help to identify at-risk groups for future neuroprotective trials. Several lines of evidence now suggest that olfactory disturbance reflects Lewy pathology more closely than it reflects striatonigral dopamine deficiency.
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| 14. |
- Rademakers, Rosa, et al.
(author)
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Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:2, s. 200-5
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Journal article (peer-reviewed)abstract
- Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
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| 15. |
- Sharma, Manu, et al.
(author)
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Large-scale replication and heterogeneity in Parkinson disease genetic loci
- 2012
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In: Neurology. - 1526-632X. ; 79:7, s. 67-659
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.METHODS: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.RESULTS: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.CONCLUSION: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
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| 16. |
- Sundal, Christina, et al.
(author)
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Autosomal dominant Parkinson's disease.
- 2012
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In: Parkinsonism & related disorders. - 1873-5126. ; 18 Suppl 1
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Research review (peer-reviewed)abstract
- Over the past two decades the understanding and classification of Parkinson's disease (PD) has been revolutionized by genetic research. Currently, sixteen PARK loci have been identified with autosomal dominant genes such as SNCA, and LRRK2, and autosomal recessive genes such as PRKN, DJ-1, and PINK1. Among these genes, LRRK2 is the most prevalent. Additionally, susceptibility variants located on some of these genes are widely recognized as risk factors for PD in certain ethnic populations. Alpha synuclein Lewy body (LB) pathology, the hallmark of sporadic PD, is predominantly seen in carriers of SNCA and LRRK2. Recently two new autosomal dominant PD genes have been discovered, eukaryotic translation initiation factor 4-gamma (EIF4G1) and vacuolar protein sorting 35 (VPS35). EIF4G1 is associated with LB pathology; however, only limited data currently exists on pathology of the VPS35. Thus, it remains to be seen if LB pathology can be identified on autopsy examination of carriers of VPS35 gene. The mechanism behind the cause of PD has yet to be elucidated; however, genetic studies on autosomal dominant PD have provided novel insights into the potential etiology of PD. Thus, paving the way for future targeted therapies aimed at disease prevention and cure.
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| 17. |
- Sundal, Christina, et al.
(author)
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Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): A misdiagnosed disease entity
- 2012
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In: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X .- 1878-5883. ; 314, s. 130-137
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Journal article (peer-reviewed)abstract
- Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindreds and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US. We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS. HDLS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis. © 2011 Elsevier B.V. All rights reserved.
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| 18. |
- Sundal, Christina, et al.
(author)
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MRI characteristics and scoring in HDLS due to CSF1R gene mutations.
- 2012
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In: Neurology. - 1526-632X. ; 79:6, s. 566-74
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Journal article (peer-reviewed)abstract
- To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.
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| 19. |
- Vemula, Satya R, et al.
(author)
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GNAL mutations cause adult-onset primary dystonia
- 2013
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In: Neurology. - 0028-3878. ; 80:1
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Conference paper (peer-reviewed)abstract
- OBJECTIVE: Identification of the causal mutation in an African-American family with adult-onset primary dystonia. BACKGROUND: The vast majority of patients with dystonia are adults with primary focal or segmental anatomical distributions. Familial and sporadic dystonia appear to share the same genetic etiological background. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large pedigrees suited for linkage analysis are uncommon. In previous work, we excluded THAP1 and TOR1A mutations in an African-American family with clinical phenotypes that included cervical, laryngeal and hand-forearm dystonia. DESIGN/METHODS: Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in order to identify the causal mutation (GNAL, c.913G>T) in our African-American family with dystonia. High resolution melting and Sanger sequencing were used to screen 768 additional subjects with primary cervical or segmental dystonia for sequence variants in GNAL. RESULTS: The missense mutation in GNAL (c.913G>T, p.V305F) was found to co-segregate with dystonia in our African-American pedigree. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) is highly expressed in the olfactory bulb, striatum and cerebellar Purkinje cells. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. Screening identified two additional pedigrees with GNAL mutations (c.822-823insA [p.R275T∗13] and c.964C>T [p.R322∗]). None of these sequence variants were found in 760 controls. CONCLUSIONS: Mutations in GNAL are causally-associated with adult-onset primary cervical and segmental dystonia. The prominent expression of Gα(olf) in striatum and cerebellar Purkinje cells points to potential sites of functional pathology in primary dystonia.
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| 20. |
- Vemula, Satya R, et al.
(author)
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Role of Gα(olf) in Familial and Sporadic Adult-Onset Primary Dystonia.
- 2013
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:12, s. 2510-2519
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Journal article (peer-reviewed)abstract
- The vast majority of patients with primary dystonia are adults with focal or segmental distribution of involuntary movements. Although approximately 10% of probands have at least one first- or second-degree relative with dystonia, large families suited for linkage analysis are exceptional. After excluding mutations in known primary dystonia genes (TOR1A, THAP1, and CIZ1), whole-exome sequencing identified a GNAL missense mutation (c.682G>T, p.V228F) in an African-American pedigree with clinical phenotypes that include cervical, laryngeal and hand-forearm dystonia. Screening of 760 subjects with familial and sporadic primary dystonia identified 3 Caucasian pedigrees with GNAL mutations (c.591dupA [p.R198Tfs*13]; c.733C>T [p.R245*]; and c.3G>A [p.M1?]). These mutations show incomplete penetrance. Our findings corroborate those of a recent study which used whole exome sequencing to identify missense and nonsense GNAL mutations in Caucasian pedigrees of mixed European ancestry with mainly adult-onset cervical and segmental dystonia. GNAL encodes guanine nucleotide-binding protein G(olf), subunit alpha [Gα(olf)]. Gα(olf) plays a role in olfaction, coupling D1 and A2a receptors to adenylyl cyclase, and histone H3 phosphorylation. African-American subjects harboring the p.V228F mutation exhibited microsmia. Lymphoblastoid cell lines from subjects with the p.V228F mutation showed up-regulation of genes involved in cell cycle control and development. Consistent with known sites of network pathology in dystonia, immunohistochemical studies indicated that Gα(olf) is highly expressed in the striatum and cerebellar Purkinje cells, and co-localized with corticotropin-releasing hormone receptors in the latter.
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| 21. |
- Vilarino-Gueell, Carles, et al.
(author)
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VPS35 Mutations in Parkinson Disease
- 2011
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 89:1, s. 162-167
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Journal article (peer-reviewed)abstract
- The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 +/- 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.
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| 22. |
- Wray, Selina, et al.
(author)
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Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research
- 2012
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Journal article (peer-reviewed)abstract
- Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
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