1.
GBA-associated Parkinson's disease: Reduced survival and more rapid progression in a prospective longitudinal study
Brockmann, Kathrin; Srulijes, Karin; Pflederer, Sylvia ...
Movement disorders,
March 2015, Letnik:
30, Številka:
3
Journal Article
Background
Parkinson's disease (PD) patients with GBA mutations show an earlier age at onset and more severe non‐motor symptoms compared with PD patients without GBA mutations.
Objective
This study ...
was undertaken to evaluate progression of motor and non‐motor symptoms in sporadic PD patients depending on the mutational GBA status.
Methods
We used regression analysis to evaluate independent effects of the mutational GBA status, age at onset, age at examination, and disease duration on motor (Unified Parkinson's Disease Rating Scale UPDRS‐III, Hoehn and Yahr H&Y stage, Levodopa l‐dopa‐equivalent‐dosage) and non‐motor characteristics (cognition and mood). Disease progression was assessed prospectively over 3 years.
Results
The GBA‐associated PD patients compared with non‐mutation PD patients, although younger and with an earlier age at onset, show (1) a more rapid disease progression of motor impairment and cognitive decline and (2) reduced survival rates.
Conclusions
The mutational GBA status, rather than older age and age at onset, presents an important predictor for disease progression in this specific subgroup of PD patients. © 2014 International Parkinson and Movement Disorder Society
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
2.
A Novel SNCA A30G Mutation Causes Familial Parkinsonʼs Disease
Liu, Hui; Koros, Christos; Strohäker, Timo ...
Movement disorders,
July 2021, Letnik:
36, Številka:
7
Journal Article
ABSTRACT
Background
The SNCA gene encoding α‐synuclein (αSyn) is the first gene identified to cause autosomal‐dominant Parkinsonʼs disease (PD).
Objective
We report the identification of a novel ...
heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences.
Methods
Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn.
Results
We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co‐segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation.
Conclusion
Based on the identification of A30G co‐segregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
3.
Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles
Lerche, Stefanie; Wurster, Isabel; Roeben, Benjamin ...
Movement disorders,
March 2020, 2020-03-00, 20200301, Letnik:
35, Številka:
3
Journal Article
Background
Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha‐synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As ...
disease‐modifying treatment options such as alpha‐synuclein lowering compounds are under way, patient stratification according to alpha‐synuclein‐specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite.
Objective
Are GBA1 mutations associated with a CSF alpha‐synuclein profile in PD?
Methods
Screening of the GBA1 gene and analysis of CSF levels of total alpha‐synuclein were performed in 80 PDGBA, 80 PDGBA_wildtype and 39 healthy controls cross‐sectionally. Subgroup analyses based on mutation severity was done for PDGBA.
Results
Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha‐synuclein.
Conclusion
The effects of GBA1 mutations on CSF alpha‐synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
4.
The longevity gene Klotho and its cerebrospinal fluid protein profiles as a modifier for Parkinson´s disease
Zimmermann, Milan; Köhler, Leonie; Kovarova, Marketa ...
European journal of neurology,
20/May , Letnik:
28, Številka:
5
Journal Article
Background
Parkinson´s disease (PD) has a large phenotypic variability, which may, at least partly, be genetically driven including alterations of gene products. Candidates might not only be proteins ...
associated with disease risk but also pathways that play a role in aging.
Objective
To evaluate phenotype‐modifying effects of genetic variants in Klotho, a longevity gene.
Methods
We analyzed two longitudinal cohorts: one local cohort comprising 459 PD patients who underwent genotyping for the KL‐VS haplotype in Klotho including a subgroup of 125 PD patients and 50 healthy controls who underwent biochemical cerebrospinal fluid (CSF) analyses of Klotho and fibroblast growth factor 23 as well as vitamin D metabolites. The second cohort comprised 297 patients from the Parkinsonʼs Progression Markers Initiative (PPMI) for validation of genetic−clinical findings.
Results
PD patients carrying the KL‐VS haplotype demonstrated a shorter interval between PD onset and onset of cognitive impairment (both cohorts) and higher Unified Parkinson´s Disease Rating Scale part III (UPDRS III) scores (PPMI). CSF protein levels of Klotho and fibroblast growth factor 23 were lower in PD patients irrespective of gender compared to controls. Moreover, low CSF levels of Klotho were associated with higher scores in the UPDRS III and Hoehn and Yahr Scale.
Conclusions
Our results indicate that genetic variants in Klotho together with its corresponding CSF protein profiles are associated with aspects of disease severity in PD. These findings suggest that pathways associated with aging might be targets for future biomarker research in PD.
Low CSF levels of the longevity protein Klotho were associated with higher scores in Unified Parkinson's Disease Rating scale part II (UPDRS III). Patients with Parkinson's disease (PD) carrying the genetic “KL‐VS”‐variant demonstrated a shorter interval between PD onset and onset of cognitive impairment and higher UPDRS III scores. Genetic variants in Klotho along with its corresponding CSF protein profiles are associated with aspects of disease severity in PD.
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
5.
The Mutation Matters: CSF Profiles of GCase, Sphingolipids, α‐Synuclein in PDGBA
Lerche, Stefanie; Schulte, Claudia; Wurster, Isabel ...
Movement disorders,
20/May , Letnik:
36, Številka:
5
Journal Article
ABSTRACT
Background
With pathway‐specific trials in PD associated with variants in the glucocerebrosidase gene (PDGBA) under way, we need markers that confirm the impact of genetic variants in ...
patient‐derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read‐out for target engagement.
Objective
To explore GBA‐pathway‐specific biomarker profiles cross‐sectionally (TUEPAC‐MIGAP, PPMI) and longitudinally (PPMI).
Methods
We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by‐products) and CSF levels of total α‐synuclein in PDGBA patients compared to PDGBA_wildtype patients.
Results
Cross‐sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PDGBA compared to PDGBA_wildtype. (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PDGBA compared to PDGBA_wildtype. (3) CSF levels of total α‐synuclein were lower in PDGBA compared to PDGBA_wildtype. All of these findings were most pronounced in PDGBA with severe mutations (PDGBA_severe). Cross‐sectionally in TUEPAC‐MIGAP and longitudinally in PPMI, CSF levels of downstream‐products (ceramides) were higher in PDGBA_severe. Cross‐sectionally in TUEPAC‐MIGAP by‐products sphinganine and sphingosine‐1‐phosphate and longitudinally in PPMI species of by‐products lactosylceramides and sphingomyelin were higher in PDGBA_severe.
Interpretation
These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PDGBA with severe variants. © 2021 International Parkinson and Movement Disorder Society
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
6.
CSF Protein Level of Neurotransmitter Secretion, Synaptic Plasticity, and Autophagy in PD and DLB
Lerche, Stefanie; Sjödin, Simon; Brinkmalm, Ann ...
Movement disorders,
November 2021, Letnik:
36, Številka:
11
Journal Article
Background
Molecular pathways associated with α‐synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin‐proteasome system, mitochondrial ...
homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids.
Objective
The objective of this study was to evaluate CSF protein profiles of pathways related to α‐synuclein proteostasis.
Methods
We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α‐synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α‐synuclein pathology with pronounced clinical trajectories.
Results
(1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α‐synuclein, with lower levels of proteostasis proteins related to lower levels of total α‐synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α‐synuclein longitudinally compared with PD patients with a normal proteostasis profile.
Conclusion
CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α‐synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
7.
Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile
Lerche, Stefanie; Machetanz, Gerrit; Wurster, Isabel ...
Movement disorders,
July 2019, 2019-07-00, 20190701, Letnik:
34, Številka:
7
Journal Article
Background
Patients with dementia with Lewy bodies reveal a variable pathology including alpha‐synuclein, amyloid‐beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. ...
PD patients with GBA1 mutations show reduced CSF levels of total alpha‐synuclein.
Objective
Whether GBA1 mutations are associated with a CSF alpha‐synuclein profile in dementia with Lewy bodies.
Methods
Screening of the GBA1 gene and single‐nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha‐synuclein, amyloid‐beta1‐42, total‐Tau, phospho‐Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross‐sectionally.
Results
Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha‐synuclein were lowest in DLBGBA_pathogenic compared to DLBGBA_mild and DLBGBA_wildtype.
Conclusion
Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha‐synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha‐synuclein–lowering compounds. © 2019 International Parkinson and Movement Disorder Society
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
8.
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
9.
HPCA confirmed as a genetic cause of DYT2‐like dystonia phenotype
Atasu, Burcu; Hanagasi, Hasmet; Bilgic, Basar ...
Movement disorders,
August 2018, 2018-08-00, 20180801, Letnik:
33, Številka:
8
Journal Article
Background: HPCA (hippocalcin) is one of the underlying genetic causes of autosomal‐recessively inherited forms of dystonia. Here, we describe two consanguineous Turkish DYT‐HPCA families carrying ...
the novel HPCA mutations.
Methods: After detailed clinical and neurological examination, whole‐exome sequencing was performed.
Results: Whole‐exome sequencing analysis revealed two homozygous novel truncating mutations (p.W103* and p.P10PfsTer80) in the HPCA gene in two unrelated Turkish dystonia families presenting with complex dystonia.
Conclusions: After identification of HPCA as a genetic cause of DYT‐HPCA‐like dystonia by Charlesworth et al, this is the second report in the scientific literature that describes dystonia families harboring HPCA mutations. Our findings confirm that HPCA leads to recessively inherited dystonia. © 2018 International Parkinson and Movement Disorder Society
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
10.
Plasma ceramide and glucosylceramide metabolism is altered in sporadic Parkinson's disease and associated with cognitive impairment: a pilot study
Mielke, Michelle M; Maetzler, Walter; Haughey, Norman J ...
PloS one,
09/2013, Letnik:
8, Številka:
9
Journal Article
Mutations in the gene coding for glucocerebrosidase (GBA), which metabolizes glucosylceramide (a monohexosylceramide) into glucose and ceramide, is the most common genetic risk factor for sporadic ...
Parkinson's disease (PD). GBA mutation carriers are more likely to have an earlier age of onset and to develop cognitive impairment and dementia. We hypothesized that plasma levels of lipids involved in ceramide metabolism would also be altered in PD non-GBA mutation carriers and associated with worse cognition.
Plasma ceramide, monohexosylceramide, and lactosylceramide levels in 26 cognitively normal PD patients, 26 PD patients with cognitive impairment or dementia, and 5 cognitively normal non-PD controls were determined by LC/ESI/MS/MS.
Levels of all lipid species were higher in PD patients versus controls. Among PD patients, levels of ceramide C16:0, C18:0, C20:0, C22:0, and C24:1 and monohexosylceramide C16:0, C20:0 and C24:0 species were higher (all P<0.05) in those with versus without cognitive impairment.
These results suggest that plasma ceramide and monohexosylceramide metabolism is altered in PD non-GBA mutation carriers and that higher levels are associated with worse cognition. Additional studies with larger sample sizes, including cognitively normal controls, are needed to confirm these findings.
več
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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