| 1. |
- Alix, James J. P., et al.
(författare)
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Assessment of the reliability of the motor unit size index (MUSIX) in single subject "round-robin" and multi-centre settings
- 2019
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Ingår i: Clinical Neurophysiology. - : ELSEVIER IRELAND LTD. - 1388-2457 .- 1872-8952. ; 130:5, s. 666-674
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The motor unit size index (MUSIX) is incorporated into the motor unit number index (MUNIX). Our objective was to assess the intra-/inter-rater reliability of MUSIX in healthy volunteers across single subject "round robin" and multi-centre settings.Methods: Data were obtained from (i) a round-robin assessment in which 12 raters (6 with prior experience and 6 without) assessed six muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis and abductor hallucis) and (ii) a multi-centre study with 6 centres studying the same muscles in 66 healthy volunteers. Intrafinter-rater data were provided by 5 centres, 1 centre provided only intra-rater data. Intrafinter-rater variability was assessed using the coefficient of variation (COV), Bland-Altman plots, bias and 95% limits of agreement.Results: In the round-robin assessment intra-rater COVs for MUSIX ranged from 7.8% to 28.4%. Inter-rater variability was between 7.8% and 16.2%. Prior experience did not impact on MUSIX values. In the multi-centre study MUSIX was more consistent than the MUNIX. Abductor hallucis was the least reliable muscle.Conclusions: The MUSIX is a reliable neurophysiological biomarker of reinnervation.Significance: MUSIX could provide insights into the pathophysiology of a range of neuromuscular disorders, providing a quantitative biomarker of reinnervation.
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| 2. |
- Brenner, David, et al.
(författare)
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Hot-spot KIF5A mutations cause familial ALS
- 2018
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 688-697
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Tidskriftsartikel (refereegranskat)abstract
- Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
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| 3. |
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| 4. |
- Chan, Young, et al.
(författare)
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Reinnervation as measured by the motor unit size index is associated with preservation of muscle strength in amyotrophic lateral sclerosis, but not all muscles reinnervate
- 2022
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Ingår i: Muscle and Nerve. - : John Wiley & Sons. - 0148-639X .- 1097-4598. ; 65:2, s. 203-210
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Tidskriftsartikel (refereegranskat)abstract
- Introduction/Aims: The motor unit size index (MUSIX) may provide insight into reinnervation patterns in diseases such as amyotrophic lateral sclerosis (ALS). However, it is not known whether MUSIX detects clinically relevant changes in reinnervation, or if all muscles manifest changes in MUSIX in response to reinnervation after motor unit loss.Methods: Fifty-seven patients with ALS were assessed at 3-month intervals for 12 months in four centers. Muscles examined were abductor pollicis brevis, abductor digiti minimi, biceps brachii, and tibialis anterior. Results were split into two groups: muscles with increases in MUSIX and those without increases. Longitudinal changes in MUSIX, motor unit number index (MUNIX), compound muscle action potential amplitude, and Medical Research Council strength score were investigated.Results: One hundred thirty-three muscles were examined. Fifty-nine percent of the muscles exhibited an increase in MUSIX during the study. Muscles with MUSIX increases lost more motor units (58% decline in MUNIX at 12 months, P <.001) than muscles that did not increase MUSIX (34.6% decline in MUNIX at 12 months, P <.001). However, longitudinal changes in muscle strength were similar. When motor unit loss was similar, the absence of a MUSIX increase was associated with a significantly greater loss of muscle strength (P =.002).Discussion: MUSIX increases are associated with greater motor unit loss but relative preservation of muscle strength. Thus, MUSIX appears to be measuring a clinically relevant response that can provide a quantitative outcome measure of reinnervation in clinical trials. Furthermore, MUSIX suggests that reinnervation may play a major role in determining the progression of weakness.
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| 6. |
- Neuwirth, Christoph, et al.
(författare)
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Motor Unit Number Index (MUNIX) : A novel neurophysiological marker for neuromuscular disorders; test-retest reliability in healthy volunteers
- 2011
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Ingår i: Clinical Neurophysiology. - : Elsevier BV. - 1388-2457 .- 1872-8952. ; 122:9, s. 1867-1872
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the intra-rater and inter-rater test-retest reliability of the Motor Unit Number Index (MUNIX) in healthy subjects in a multicentre setting. Methods: Six study centres applied the MUNIX technique in 66 healthy subjects. Five to six muscles (biceps brachii, BB; abductor digiti minimi, ADM; abductor pollicis brevis, APB; tibialis anterior, TA; extensor digitorum brevis, EDB and abductor hallucis, AH) were measured in each volunteer four times by two independent examiners. Results: The method was easy to perform and well tolerated. The intraclass correlation coefficient (ICC) varied between centres and muscles. Intra-rater reliability was greatest for the AH (ICC 0.83) and EDB (ICC 0.81). Inter-rater reliability was greatest for the AH (ICC 0.69) and ADM muscles (ICC 0.69). The most critical muscle was the APB muscle (ICC 0.52, total variability). This was mostly due to variability in the compound muscle action potential (CMAP) measurements. MUNIX values of the APB, ADM and TA fell into the same range as in other motor unit number estimation (MUNE) studies. Conclusion: MUNIX measurements in multiple muscles show good inter- and intra-rater reliability in healthy subjects. CMAP amplitude must be controlled to optimize reliability. Significance: Results suggest that MUNIX could serve as a reliable marker for motor neuron loss in diseases like amyotrophic lateral sclerosis. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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| 7. |
- Neuwirth, Christoph, et al.
(författare)
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Motor Unit Number Index (MUNIX) detects motor neuron loss in pre-symptomatic muscles in Amyotrophic Lateral Sclerosis
- 2017
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Ingår i: Clinical Neurophysiology. - : ELSEVIER IRELAND LTD. - 1388-2457 .- 1872-8952. ; 128:3, s. 495-500
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Motor Unit Number Index (MUNIX) is a quantitative neurophysiological measure that provides an index of the number of lower motor neurons supplying a muscle. It reflects the loss of motor neurons in patients with Amyotrophic Lateral Sclerosis (ALS). However, it is unclear whether MUNIX also detects motor unit loss in strong, non-wasted muscles. Methods: Three centres measured MUNIX in 49 ALS patients every three months in six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor digitorum brevis, abductor hallucis) on the less affected side. The decline of MUNIX in initially non-wasted, clinically strong muscles (manual muscle testing, MMT grade 5) was analysed before and after onset of weakness. Results: In 49 subjects, 151 clinically strong muscles developed weakness and were included for analysis. The average monthly relative loss of MUNIX was 5.0% before and 5.6% after onset of weakness. This rate of change was significantly higher compared to ALS functional rating scale (ALSFRS-R) and compound muscle action potential (CMAP) change over 12 months prior to the onset of muscle weakness (p = 0.024). Conclusion: MUNIX is an electrophysiological marker that detects lower motor neuron loss in ALS, before clinical weakness becomes apparent by manual muscle testing. Significance: This makes MUNIX a good biomarker candidate for disease progression and possibly pharmacodynamics responds.
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| 8. |
- Neuwirth, Christoph, et al.
(författare)
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Tracking motor neuron loss in a set of six muscles in amyotrophic lateral sclerosis using the Motor Unit Number Index (MUNIX) : a 15-month longitudinal multicentre trial
- 2015
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 86:11, s. 1172-1179
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Tidskriftsartikel (refereegranskat)abstract
- Background Motor Unit Number Index (MUNIX) is a novel neurophysiological measure that provides an index of the number of functional lower motor neurons in a given muscle. So far its performance across centres in patients with amyotrophic lateral sclerosis (ALS) has not been investigated. Objective To perform longitudinal MUNIX recordings in a set of muscles in a multicentre setting in order to evaluate its value as a marker of disease progression. Methods Three centres applied MUNIX in 51 ALS patients over 15 months. Six different muscles (abductor pollicis brevis, abductor digiti minimi, biceps brachii, tibialis anterior, extensor dig. brevis, abductor hallucis) were measured every 3 months on the less affected side. The decline between MUNIX and ALSFRS-R was compared. Results 31 participants reached month 12. For all participants, ALSFRS-R declined at a rate of 2.3%/month. Using the total score of all muscles, MUNIX declined significantly faster by 3.2%/month (p <= 0.02). MUNIX in individual muscles declined between 2.4% and 4.2%, which differed from ASLFRS-R decline starting from month 3 (p <= 0.05 to 0.002). Subgroups with bulbar, lower and upper limb onset showed different decline rates of ALSFRS-R between 1.9% and 2.8%/month, while MUNIX total scores showed similar decline rates over all subgroups. Mean intraclass correlation coefficient for MUNIX intra-rater reliability was 0.89 and for inter-rater reliability 0.80. Conclusion MUNIX is a reliable electrophysiological biomarker to track lower motor neuron loss in ALS.
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| 9. |
- Nordin, Angelica, et al.
(författare)
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Sequence variations in C9orf72 downstream of the hexanucleotide repeat region and its effect on repeat-primed PCR interpretation : a large multinational screening study
- 2017
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Informa UK Limited. - 2167-8421 .- 2167-9223. ; 18:3-4, s. 256-264
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Tidskriftsartikel (refereegranskat)abstract
- A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele. In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.
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| 10. |
- Tazelaar, Gijs H.P., et al.
(författare)
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Whole genome sequencing analysis reveals post-zygotic mutation variability in monozygotic twins discordant for amyotrophic lateral sclerosis
- 2023
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 122, s. 76-87
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.
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