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Supplemental material, sj-docx-1-taj-10.1177_20406223221109480 for Relaxation-weighted 23Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis by Hans-Peter Müller, Armin M. Nagel, Franziska Keidel, Arthur Wunderlich, Annemarie Hübers, Lena V. Gast, Albert C. Ludolph, Meinrad Beer and Jan Kassubek in Therapeutic Advances in Chronic Disease

Supplemental material, sj-docx-1-taj-10.1177_20406223221109480 for Relaxation-weighted 23Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis by Hans-Peter Müller, Armin M. Nagel, Franziska Keidel, Arthur Wunderlich, Annemarie Hübers, Lena V. Gast, Albert C. Ludolph, Meinrad Beer and Jan Kassubek in Therapeutic Advances in Chronic Disease

Supplemental material, sj-docx-2-taj-10.1177_20406223221109480 for Relaxation-weighted 23Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis by Hans-Peter Müller, Armin M. Nagel, Franziska Keidel, Arthur Wunderlich, Annemarie Hübers, Lena V. Gast, Albert C. Ludolph, Meinrad Beer and Jan Kassubek in Therapeutic Advances in Chronic Disease

Supplemental material, sj-docx-2-taj-10.1177_20406223221109480 for Relaxation-weighted 23Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis by Hans-Peter Müller, Armin M. Nagel, Franziska Keidel, Arthur Wunderlich, Annemarie Hübers, Lena V. Gast, Albert C. Ludolph, Meinrad Beer and Jan Kassubek in Therapeutic Advances in Chronic Disease

In the version of this article initially published, the label along the right margin of the top row in Fig. 2d (SO1DG93A) was incorrect. The correct label is ‘SOD1G93A’. The error has been corrected in the HTML and PDF versions of the article.

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts., Swiss Medical Weekly, 151, ISSN:1424-7860, ISSN:1424-3997

Background: Changes of cerebral diffusivity detected by magnetic resonance imaging (MRI) have been reported in epilepsy. Diffusion weighted imaging (DWI) detects changes in the distribution of water molecules by measuring the apparent diffusion coefficient (ADC) and is mainly used in the diagnosis of ischemic stroke. DWI changes in epilepsy were reported in status epilepticus (SE) or series of seizures. It remains unclear whether this phenomenon also occurs after single seizures. Accordingly, possible pathomechanisms have only been discussed on the presumed basis of ongoing epileptic brain activity. Methods: In this retrospective study, we systematically analyzed DWI alterations related to epileptic seizures in 454 patients who received MRI scanning within the first 24 h after seizure onset. Results: DWI restrictions not classified as ischemic stroke were observed in 18 patients (4%). We found DWI restrictions in 19% of patients with SE/seizure series and in 3% of patients after single focal and 2.5% after single generalized seizures. 17 patients with DWI alterations were diagnosed with a structural epilepsy. DWI signal decreased in the majority of patients within the first days and could not be detected in follow-up imaging >3 months. In all patients except one, DWI alterations were detected in the same hemisphere as the lesion. In the case of seizure series or SE, DWI restrictions mostly presented with a typical “garland-like” pattern alongside the cortical band or on the border of a defined lesion, while in isolated seizures, the restrictions were often rather subtle and small. Discussion: We show that DWI restrictions can be observed in patients after single epileptic seizures. As the vast majority of these patients was diagnosed with an epilepsy due to structural cerebral pathology, DWI restriction may reflect a higher vulnerability in these regions. This might also explain the fact that diffusivity changes were observed after single focal seizures as well as after multiple seizures or SE. The occurence itself on one side as well as the spatial pattern of this phenomenon on the other may thus not only be related to the duration of ictal activity, but to structural pathology.

ObjectivesRecent 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.MethodsHere 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.Results49% 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.ConclusionsWe 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.

Brenner et al. show that mutations in a C-terminal hotspot of kinesin-5A (KIF5A) can cause a classical ALS phenotype. Experiments using patient-derived cell lines suggest haploinsufficiency as the molecular genetic mechanism. This underlines the relevance of intracellular transport processes for ALS, and is important for clinico-genetic diagnosis and counselling., 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 × 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 × 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.

Brain : a journal of neurology 141(3), 688-697 (2018). doi:10.1093/brain/awx370, Published by Oxford Univ. Press, Oxford