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Andersen, Peter M.
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Publications (10 of 166) Show all publications
Brockmann, S. J., Freischmidt, A., Oeckl, P., Müller, K., Ponna, S. K., Helferich, A. M., . . . Weishaupt, J. H. (2018). CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency. Human Molecular Genetics, 27(4), 706-715
Open this publication in new window or tab >>CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 4, p. 706-715Article in journal (Refereed) Published
Abstract [en]

Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.

Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-145134 (URN)10.1093/hmg/ddx436 (DOI)000424137500011 ()29315381 (PubMedID)
Available from: 2018-03-05 Created: 2018-03-05 Last updated: 2018-06-09Bibliographically approved
Mueller, K., Brenner, D., Weydt, P., Meyer, T., Grehl, T., Petri, S., . . . Weishaupt, J. H. (2018). Comprehensive analysis of the mutation spectrum in 301 German ALS families. Journal of Neurology, Neurosurgery and Psychiatry, 89(8), 817-827
Open this publication in new window or tab >>Comprehensive analysis of the mutation spectrum in 301 German ALS families
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2018 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 89, no 8, p. 817-827Article in journal (Refereed) Published
Abstract [en]

Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.

Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.

Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.

Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-151563 (URN)10.1136/jnnp-2017-317611 (DOI)000442475000013 ()29650794 (PubMedID)
Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2018-09-10Bibliographically approved
Volk, A. E., Weishaupt, J. H., Andersen, P. M., Ludolph, A. C. & Kubisch, C. (2018). Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis. Medizinische Genetik, 30(2), 252-258
Open this publication in new window or tab >>Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis
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2018 (English)In: Medizinische Genetik, ISSN 1863-5490, Vol. 30, no 2, p. 252-258Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5-8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2-3 years after onset.

Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS.

Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone.

Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i.aEuro<overline>e., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2018
Keywords
Motor neuron disease, Genetic heterogeneity, C9orf72, Oligogenic inheritance, Predictive testing
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-152232 (URN)10.1007/s11825-018-0185-3 (DOI)000443457600005 ()30220791 (PubMedID)
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-25Bibliographically approved
Gromicho, M., Pinto, S., Gisca, E., Pronto-Laborinho, A. C., Andersen, P. M. & de Carvalho, M. (2018). Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis. Neurobiology of Aging, 70, Article ID 325.e7.
Open this publication in new window or tab >>Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis
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2018 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 70, article id 325.e7Article in journal (Refereed) Published
Abstract [en]

Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS) erelated genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p. Ala152Pro (c. 457G>C). The C9orf72 hexanucleotide repeat expansion was the commonest abnormality, accounting for 4.6% of sporadic ALS and 37.5% of FALS; in these patients, Frontotemporal Dementia was prevalent. This first report on the frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese ALS patients reiterate that the genetic architecture of ALS varies among different geographic regions. The mutations incidence in ALS patients (w10%) and associated phenotypes suggest that genetic tests should be offered to more patients, and other genes should be investigated in our population. 

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Amyotrophic lateral sclerosis, C9orf72 hexanucleotide repeat expansion, SOD1, Mutation, Phenotype, Frontotemporal dementia
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-151518 (URN)10.1016/j.neurobiolaging.2018.05.009 (DOI)000442879100034 ()29861044 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved
Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., . . . Landers, J. E. (2018). Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268-1283.e6
Open this publication in new window or tab >>Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
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2018 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 97, no 6, p. 1268-1283.e6Article in journal (Refereed) Published
Abstract [en]

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Place, publisher, year, edition, pages
Cell Press, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-146567 (URN)10.1016/j.neuron.2018.02.027 (DOI)000428235400013 ()29566793 (PubMedID)
Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-06-09Bibliographically approved
Brenner, D., Yilmaz, R., Müller, K., Grehl, T., Petri, S., Meyer, T., . . . Weishaupt, J. H. (2018). Hot-spot KIF5A mutations cause familial ALS. Brain, 141, 688-697
Open this publication in new window or tab >>Hot-spot KIF5A mutations cause familial ALS
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2018 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, p. 688-697Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keywords
ALS, KIF5A mutations, axonal transport, whole exome sequencing
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-146237 (URN)10.1093/brain/awx370 (DOI)000426813600016 ()29342275 (PubMedID)
Available from: 2018-04-09 Created: 2018-04-09 Last updated: 2018-06-09Bibliographically approved
Higelin, J., Catanese, A., Semelink-Sedlacek, L. L., Oeztuerk, S., Lutz, A.-K., Bausinger, J., . . . Boeckers, T. M. (2018). NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons. Stem Cell Research, 30, 150-162
Open this publication in new window or tab >>NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons
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2018 (English)In: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 30, p. 150-162Article in journal (Refereed) Published
Abstract [en]

Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contributes to the development of novel therapeutic strategies to reduce DNA damage accumulation in neurodegenerative diseases and ALS.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
hiPSC, ALS, NEK1, neurodegeneration, DNA damage
National Category
Medical Genetics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-150372 (URN)10.1016/j.scr.2018.06.005 (DOI)000438786600020 ()29929116 (PubMedID)2-s2.0-85048705749 (Scopus ID)
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
Benatar, M., Wuu, J., Andersen, P. M., Lombardi, V. & Malaspina, A. (2018). Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. Annals of Neurology, 84(1), 130-139
Open this publication in new window or tab >>Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion
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2018 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 84, no 1, p. 130-139Article in journal (Refereed) Published
Abstract [en]

Objective: To evaluate neurofilament light (NfL) as a biomarker of the presymptomatic phase of amyotrophic lateral sclerosis (ALS).

Methods: The study population includes 84 individuals at risk for developing ALS, 34 controls, 17 ALS patients, and 10 phenoconverters (at-risk individuals observed both before and after the emergence of clinically manifest disease). At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation (in SOD1, C9orf72, TARDBP, FUS, VCP, etc), but who, at the time of enrollment, demonstrated no clinical symptoms or signs (including electromyographic evidence) of manifest disease. NfL in serum and cerebrospinal fluid (CSF) were quantified using an electrochemiluminescence immunoassay.

Results: Serum and CSF NfL are substantially higher in ALS patients compared to controls and at-risk individuals and remain relatively stable over time. Among phenoconverters, however, NfL levels were elevated (ie, above the range observed in controls) as far back as approximate to 12 months preceding the emergence of the earliest clinical symptoms or signs of disease.

Interpretation: Serum (and CSF) NfL are informative biomarkers of presymptomatic ALS, providing a new tool to quantify presymptomatic disease progression and to potentially predict the timing of clinical phenoconversion. As such, quantification of NfL may aid the design and implementation of early therapeutic intervention for affected individuals and/or disease prevention trials for individuals at short-term risk of developing ALS. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-151797 (URN)10.1002/ana.25276 (DOI)000443302300012 ()30014505 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilThe Swedish Brain Foundation
Available from: 2018-09-14 Created: 2018-09-14 Last updated: 2018-09-14Bibliographically approved
Benatar, M., Wuu, J., Andersen, P. M., Atassi, N., David, W., Cudkowicz, M. & Schoenfeld, D. (2018). Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology, 90(7), E565-E574
Open this publication in new window or tab >>Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS
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2018 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90, no 7, p. E565-E574Article in journal (Refereed) Published
Abstract [en]

ObjectiveTo examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS).

MethodsThis was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS).

ResultsThirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32-1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI -0.63 to 1.63) and 1.24 percent predicted/month (95% CI -2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol.

ConclusionsThis study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol.

Clinicaltrials.gov identifierNCT00706147.

Classification of evidenceThis study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-146584 (URN)10.1212/WNL.0000000000004960 (DOI)000427813200004 ()29367439 (PubMedID)
Available from: 2018-04-17 Created: 2018-04-17 Last updated: 2018-06-09Bibliographically approved
Van Der Spek, R. A., Van Rheenen, W., Pulit, S. L., Kenna, K. P., Ticozzi, N., Kooyman, M., . . . Veldink, J. H. (2018). Reconsidering the causality of TIA1 mutations in ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 19(1-2), 1-3
Open this publication in new window or tab >>Reconsidering the causality of TIA1 mutations in ALS
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2018 (English)In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 19, no 1-2, p. 1-3Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-145803 (URN)10.1080/21678421.2017.1413118 (DOI)000425671500001 ()29235362 (PubMedID)2-s2.0-85038017115 (Scopus ID)
Available from: 2018-08-14 Created: 2018-08-14 Last updated: 2018-08-14Bibliographically approved
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