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.
In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease‐modifying therapies. X‐linked dystonia‐parkinsonism is a hereditary ...neurodegenerative movement disorder characterized by severe adult‐onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long‐lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X‐linked dystonia‐parkinsonism, structural and iron‐sensitive magnetic resonance imaging (MRI) was performed in 10 non‐manifesting carriers and 24 healthy controls in a double‐blind fashion. Seventeen patients with X‐linked dystonia‐parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non‐manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single‐nucleotide polymorphisms associated with age at onset. Voxel‐based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non‐manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non‐manifesting carriers. Susceptibility‐weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non‐manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X‐linked dystonia‐parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X‐linked dystonia‐parkinsonism. ANN NEUROL 2023;93:999–1011
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.
Abstract
While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease ...caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions.
Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs.
In addition to the canonical pure SINE-VNTR-Alu-5′-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG 5′-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n, similar to the pure tract, followed by AGGG 5′-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n, at median frequencies of 0.425 (IQR: 0.42–0.43) and 0.128 (IQR: 0.12–0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = −3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = −41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = −161.09, P = 3.44 × 10−5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = −92.46430, P = 0.079).
We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.
While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. Trinh et al. identify a novel somatic divergent repeat interruption within the TAF1 repeat expansion that influences repeat stability, and indirectly the age at onset of X-linked dystonia parkinsonism.
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