1.
Genotype–Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review
Balck, Alexander; Schaake, Susen; Kuhnke, Neele Sophie ...
Movement disorders,
November 2021, 2021-11-00, 20211101, Letnik:
36, Številka:
11
Journal Article
This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying ...
heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet‐derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet‐derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis‐regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one‐third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal‐dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype–phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 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
2.
A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism
Westenberger, Ana; Reyes, Charles Jourdan; Saranza, Gerard ...
Annals of neurology,
June 2019, Letnik:
85, Številka:
6
Journal Article
Objective
X‐linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE‐VNTR‐Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n ...
repeat within the SVA insertion has been reported as an age‐at‐onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP.
Methods
We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients.
Results
RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain.
Interpretation
The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN‐dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812–822.
več
Dostopno za:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
3.
ANO10‐Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series
Milovanović, Andona; Westenberger, Ana; Stanković, Iva ...
Movement disorders,
20/May , Letnik:
39, Številka:
5
Journal Article
Background
Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX‐ANO10).
Methods
Following the MDSGene protocol, we systematically investigated ...
genotype–phenotype relationships in ATX‐ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients.
Results
Most patients (>80%) had loss‐of‐function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14‐year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX‐ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX‐ANO10 diagnosis.
Conclusions
The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease‐modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 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
4.
Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism
Lüth, Theresa; Gabbert, Carolin; Koch, Sebastian ...
Movement disorders,
10/2023, Letnik:
38, Številka:
10
Journal Article
A mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk.
To investigate the impact of the MGS and ...
lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic PD (iPD).
We included N = 486 patients with LRRK2-PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP-PD), Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD-RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO.
Our derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10
). We observed that higher MGS was significantly associated with earlier AAO in LRRK2-PD (P = 0.047, β = -1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, β = 0.22). There was a correlation between MGS and AAO in LRRK2-PD patients of European descent (P = 0.049, r = -0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = -0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, β = -5.65) in LRRK2-PD and with tobacco use (P = 0.010, β = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non-smokers.
The MGS was more strongly associated with earlier AAO in LRRK2-PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2-PD. © 2023 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
5.
Prodromal X‐Linked Dystonia‐Parkinsonism is Characterized by a Subclinical Motor Phenotype
Steinhardt, Julia; Hanssen, Henrike; Heldmann, Marcus ...
Movement disorders,
July 2022, Letnik:
37, Številka:
7
Journal Article
Background
Early diagnosis in patients with neurodegenerative disorders is crucial to initiate disease‐modifying therapies at a time point where progressive neurodegeneration can still be modified.
...
Objectives
The objective of this study was to determine whether motor or non‐motor signs of the disease occur as indicators of a prodromal phase of X‐linked dystonia‐parkinsonism (XDP), a highly‐penetrant monogenic movement disorder with striking basal ganglia pathology.
Methods
In addition to a comprehensive clinical assessment, sensor‐based balance and gait analyses were performed in non‐manifesting mutation carriers (NMCs), healthy controls (HCs), and patients with XDP. Gradient‐boosted trees (GBT) methodology was utilized to classify groups of interest.
Results
There were no clinically overt disease manifestations in the NMCs. Balance analysis, however, revealed a classification accuracy of 90% for the comparison of NMC versus HC. For the gait analysis, the best‐performing GBT‐based model showed a balanced accuracy of 95% (NMC vs. HC; walking at maximum speed). Using a separate analysis of genetic modifiers, several gait parameters correlated strongly with the estimated age at disease onset in the NMC group.
Conclusions
Our study unraveled balance and gait abnormalities in NMCs that preceded the onset of XDP. These findings demonstrate prodromal motor changes among NMCs who will develop XDP with a very high likelihood in the future. Gait abnormalities had a predictive value for the estimated age at onset highlighting the impact of genetic modifiers in personalized treatment in monogenic neurodegenerative disorders. © 2022 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
6.
Stability of Mosaic Divergent Repeat Interruptions in X-Linked Dystonia-Parkinsonism
Laß, Joshua; Lüth, Theresa; Schlüter, Kathleen ...
Movement disorders,
04/2024
Journal Article
X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif ...
Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG 5'-SINE-VNTR-Alu(AGAGGG)
AGGG(AGAGGG)
mDRILS.
This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)
repeat length during transmission in parent-offspring pairs.
Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF).
When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 IQR: 0.066-0.076) was lower compared with children with retention or contraction (0.080 IQR: 0.073-0.083) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (β = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 IQR: 0.063-0.080 to 0.073 IQR: 0.069-0.078).
Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 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.
Vitamin D and the Risk of Depression: A Causal Relationship? Findings from a Mendelian Randomization Study
Libuda, Lars; Laabs, Björn-Hergen; Ludwig, Christine ...
Nutrients,
05/2019, Letnik:
11, Številka:
5
Journal Article
While observational studies show an association between 25(OH)vitamin D concentrations and depressive symptoms, intervention studies, which examine the preventive effects of vitamin D supplementation ...
on the development of depression, are lacking. To estimate the role of lowered 25(OH)vitamin D concentrations in the etiology of depressive disorders, we conducted a two-sample Mendelian randomization (MR) study on depression, i.e., "depressive symptoms" (DS,
= 161,460) and "broad depression" (BD,
= 113,769 cases and 208,811 controls). Six single nucleotide polymorphisms (SNPs), which were genome-wide significantly associated with 25(OH)vitamin D concentrations in 79,366 subjects from the SUNLIGHT genome-wide association study (GWAS), were used as an instrumental variable. None of the six SNPs was associated with DS or BD (all
> 0.05). MR analysis revealed no causal effects of 25(OH)vitamin D concentration, either on DS (inverse variance weighted (IVW); b = 0.025, SE = 0.038,
= 0.52) or on BD (IVW; b = 0.020, SE = 0.012,
= 0.10). Sensitivity analyses confirmed that 25(OH)vitamin D concentrations were not significantly associated with DS or BD. The findings from this MR study indicate no causal relationship between vitamin D concentrations and depressive symptoms, or broad depression. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.
več
Dostopno za:
NUK, UL, UM, UPUK, VSZLJ
8.
DNA Methylation as a Potential Molecular Mechanism in X‐linked Dystonia‐Parkinsonism
Krause, Christin; Schaake, Susen; Grütz, Karen ...
Movement disorders,
December 2020, 2020-12-00, 20201201, Letnik:
35, Številka:
12
Journal Article
ABSTRACT
Background
X‐linked dystonia‐parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation ...
of TAF1 expression. In X‐linked dystonia‐parkinsonism, 3 disease‐specific single‐nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation. Because transcriptional regulation tightly correlates with specific epigenetic marks, we investigated the role of DNA methylation in the pathogenesis of X‐linked dystonia‐parkinsonism.
Methods
DNA methylation at DSC12, DSC3, and DSC2 was quantified by bisulfite pyrosequencing in DNA from peripheral blood leukocytes, fibroblasts, induced pluripotent stem cell–derived cortical neurons and brain tissue from X‐linked dystonia‐parkinsonism patients and age‐ and sex‐matched healthy Filipino controls in a prospective study.
Results
Compared with controls, X‐linked dystonia‐parkinsonism patients showed striking differences in DNA methylation at the 3 investigated CpG sites. Using methylation‐sensitive luciferase reporter gene assays and immunoprecipitation, we demonstrated (1) that lack of DNA methylation because of DSC2 and DSC3 affects gene promoter activity and (2) that methylation at all 3 investigated CpG sites alters DNA–protein interaction. Interestingly, DSC3 decreased promoter activity per se compared with wild type, and promoter activity further decreased when methylation was present. Moreover, we identified specific binding of proteins to the investigated DSCs that are associated with splicing and RNA and DNA binding.
Conclusions
We identified altered DNA methylation in X‐linked dystonia‐parkinsonism patients as a possible additional mechanism modulating TAF1 expression and putative novel targets for future therapies using DNA methylation‐modifying agents. © 2020 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
9.
A mendelian randomization study on causal effects of 25(OH)vitamin D levels on attention deficit/hyperactivity disorder
Libuda, Lars; Naaresh, Roaa; Ludwig, Christine ...
European journal of nutrition,
08/2021, Letnik:
60, Številka:
5
Journal Article
Background
While observational studies revealed an inverse association between serum 25(OH)vitamin D (25(OH)D) and the risk of attention deficit/hyperactivity disorder (ADHD), the causality of this ...
relationship remains unclear.
Methods
We conducted a bidirectional two-sample Mendelian Randomization (MR) study to examine whether 25(OH)D has an effect on the risk to develop ADHD or vice versa. Information on single nucleotide polymorphisms (SNP) associated with serum 25(OH)D was obtained from a genome-wide association study (GWAS) considering phenotype data from 79,366 individuals of European ancestry. Data on risk for ADHD were derived from a GWAS analysis with 20,183 individuals diagnosed with ADHD and 35,191 controls. For our analysis, we considered effect sizes based on the European participants (19,099 cases and 34,194 controls).
Results
Single SNP analyses showed a causal effect of vitamin D on ADHD risk for only one SNP (rs12785878,
p
= 0.024). The overall MR estimates did not reveal a causal effect of 25(OH)D on risk for ADHD. In the reverse analysis, neither any single nor the multi-SNP MR analyses showed a causal effect of ADHD on 25(OH)D.
Conclusion
Results from this two-sample MR study did not confirm a causal effect of 25(OH)D on ADHD or vice versa. Accordingly, our study does not provide evidence that improving 25(OH)D via supplementation could reduce the risk of developing ADHD.
več
Dostopno za:
DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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