| 1. |
- Giorgio, Elisa, et al.
(författare)
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Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele-Specific Expression
- 2013
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:8, s. 1160-1171
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
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| 2. |
- Plotnik, Meir, et al.
(författare)
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Differential gait adaptation patterns in Parkinson's disease – a split belt treadmill pilot study
- 2023
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Ingår i: BMC Neurology. - : BioMed Central (BMC). - 1471-2377. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interventions using split belt treadmills (SBTM) aim to improve gait symmetry (GA) in Parkinson's disease (PD). Comparative effects in conjugated SBTM conditions were not studied systematically despite potentially affecting intervention outcomes. We compared gait adaptation effects instigated by SBTM walking with respect to the type (increased\decreased speed) and the side (more/less affected) of the manipulated belt in PD.Methods: Eight individuals with PD performed four trials of SBTM walking, each consisted of baseline tied belt configuration, followed by split belt setting – either WS or BS belt's speed increased or decreased by 50% from baseline, and final tied belt configuration. Based on the disease's motor symptoms, a 'worst' side (WS) and a 'best' side (BS) were defined for each participant.Results: SB initial change in GA was significant regardless of condition (p ≤ 0.02). This change was however more pronounced for BS-decrease compared with its matching condition WS-increase (p = 0.016). Similarly, the same was observed for WS-decrease compared to BS-increase (p = 0.013). Upon returning to tied belt condition, both BS-decrease and WS-increased resulted in a significant change in GA (p = 0.04). Upper limb asymmetry followed a similar trend of GA reversal, although non-significant.Conclusions: Stronger effects on GA were obtained by decreasing the BS belt’s speed of the best side, rather than increasing the speed of the worst side. Albeit a small sample size, which limits the generalisability of these results, we propose that future clinical studies would benefit from considering such methodological planning of SBTM intervention, for maximising of intervention outcomes. Larger samples may reveal arm swinging asymmetries alterations to match SBTM adaptation patterns. Finally, further research is warranted to study post-adaption effects in order to define optimal adaptation schemes to maximise the therapeutic effect of SBTM based interventions.
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| 3. |
- Schuster, Jens, et al.
(författare)
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Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms
- 2011
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Ingår i: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6745 .- 1364-6753. ; 12:1, s. 65-72
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Tidskriftsartikel (refereegranskat)abstract
- Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.
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