Publications by authors named "Jochen Weishaupt"
Genetic alterations in the ERCC4 gene typically cause Xeroderma pigmentosum and other nucleotide excision repair disorders. Neurologic symptoms are present in some of these patients. In rare cases, ERCC4-mutations can manifest with prominent neurologic symptoms.
View Article and Find Full Text PDFAmyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases.
View Article and Find Full Text PDFgene screening in ALS - frequency of mutations, patients' attitudes to genetic information and transition to tofersen treatment in a multi-center program.
Amyotroph Lateral Scler Frontotemporal Degener
September 2024
Article Synopsis
- A study was conducted at 11 ALS centers in Germany from October 2021 to February 2024 to evaluate the frequency of pathogenic gene variants in ALS patients and their transition to an expanded access program for tofersen treatment.
- Out of 1935 patients screened, 48.8% chose to be informed about genetic variants related to tofersen, revealing that 1.8% had (likely) pathogenic variants, 0.9% had other pathogenic variants, and 7.0% showed hexanucleotide repeat expansion.
- The transition to tofersen treatment from genetic testing averaged 94 days, with a notable 74.0% of patients with certain variants opting for the therapy, highlighting the importance of comprehensive
Article Synopsis
- The introduction of the antisense oligonucleotide tofersen for treating ALS caused by SOD1 mutations emphasizes the need to clarify the impact of over 230 SOD1 variants, particularly the debated p.D91A variant common in Europe.
- A study involving 11 ALS patients treated with tofersen for up to 16 months shows that it significantly reduces serum neurofilament light chain (sNfL) levels, which are linked to ALS progression, in both homozygous and heterozygous SOD1 patients.
- These findings support the role of mono- and bi-allelic SOD1 variants as relevant targets for treatment, offering a new perspective for assessing causality based on biomarker responses in clinical
Article Synopsis
- This multicenter study evaluated tofersen treatment for patients with SOD1-ALS, focusing on clinical outcomes and patient-reported outcomes (PRO) after at least 6 months of treatment.
- Results showed a 25% reduction in ALS progression rate, stable lung capacity, and a significant decrease in serum neurofilament light chain levels, indicating a positive response to the drug.
- Patients reported high satisfaction with tofersen treatment, showing improved symptom severity and a strong willingness to recommend the drug to others.
Article Synopsis
- The study aimed to evaluate the relationship between serum neurofilament light chain (sNfL) levels and different clinical forms of amyotrophic lateral sclerosis (ALS) in nearly 3000 patients across Germany and Austria.
- Results indicated that sNfL levels varied significantly across ALS phenotypes, with higher levels associated with faster disease progression and bulbar onset, while primary lateral sclerosis (PLS) and some other phenotypes showed lower levels.
- The findings suggest that understanding these phenotypes is crucial for interpreting sNfL results and could influence clinical trials and practice in ALS management.
Article Synopsis
- Inclusion body myositis (IBM) is a common inflammatory muscle disease in older adults that currently has no effective treatment and presents a mix of inflammatory and degenerative characteristics.
- Researchers used advanced sequencing techniques to analyze muscle biopsies from IBM patients, finding unique patterns of cellular changes compared to other muscle diseases and non-inflammatory muscles.
- Key findings reveal a loss of specific muscle fibers, increased immune cell presence, and markers of cell stress and protein degradation, highlighting potential mechanisms behind muscle degeneration in IBM and pointing to vulnerabilities in type 2 muscle fibers.
Article Synopsis
- MicroRNAs (miRNAs) are small RNA molecules that help regulate gene expression, and changes in their levels can affect key biological functions, contributing to diseases like Amyotrophic lateral sclerosis (ALS).
- ALS is characterized by the degeneration of motor neurons in the brain and spinal cord, but the exact mechanisms linking RNA metabolism and miRNA dysregulation to ALS are not well understood.
- In this study, researchers found that certain miRNAs are upregulated in motor neuron samples from SOD1-ALS patients, influencing mRNA expression and potentially playing critical roles in neuron development and survival, contrasting with TDP-43-linked ALS.
Article Synopsis
- Heterozygous mutations in the TBK1 gene are linked to neurodegenerative diseases like ALS and FTD, with most patients carrying harmful loss-of-expression mutations.
- The study focused on the p.E696K missense variant of TBK1, which doesn't completely stop protein expression but disrupts its interaction with the autophagy protein optineurin.
- Research showed that this mutation leads to early dysfunction in neuron recycling processes, resulting in damaged lysosomes and eventually causing a progressive motor neuron disease, highlighting potential therapeutic targets for treatment.
Disease-associated variants of (alpha-tubulin 4A) have recently been identified in familial ALS. Interestingly, a downregulation of TUBA4A protein expression was observed in familial as well as sporadic ALS brain tissue. To investigate whether a decreased TUBA4A expression could be a driving factor in ALS pathogenesis, we assessed whether knockdown in zebrafish could recapitulate an ALS-like phenotype.
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- - In April 2023, tofersen, an antisense oligonucleotide, was FDA-approved for treating ALS after it significantly reduced levels of neurofilament light chain (NfL), a marker of neurodegeneration.
- - A follow-up study involving 24 ALS patients in Germany showed that while ALS functional scores declined, there was a notable reduction in both serum NfL and phosphorylated neurofilament heavy chain (pNfH) levels in the cerebrospinal fluid (CSF).
- - The therapy was considered safe, with no ongoing symptoms, despite some patients showing signs of immune response in the CSF, pointing to potential autoimmune reactions.
Article Synopsis
- A 2016 study tested the effectiveness of 1 mg rasagiline per day as an additional treatment for 252 ALS patients, aiming to identify which subgroups may benefit most from the drug.
- New analyses revealed that ALS patients with very slow disease progression showed better survival rates without treatment, while those with intermediate to fast progression benefited from rasagiline, showing increased survival at 6 and 12 months.
- The study found no clear link between genetic variations in the MAOB and DRD2 genes and rasagiline's treatment effects, emphasizing the importance of factoring in individual disease progression in future ALS research.
Article Synopsis
- * Investigation into TDP-43 peptides as potential antigenic triggers for T-cell activation revealed weak responses in both ALS patients and healthy controls.
- * The findings imply that while there is a general increase in activated T cells in ALS, TDP-43 appears to function as a weak autoantigen, with no significant change in levels of auto-antibodies against it.
Background: ALS is a heterogeneous disease in which different factors such as mitochondrial phenotypes act in combination with a genetic predisposition. This study addresses the question of whether homoplasmic (total mitochondrial genome of a sample is affected) and/or heteroplasmic mutations (wildtype and mutant mitochondrial DNA molecules coexist) might play a role in familial ALS. Blood was drawn from familial ALS patients with a possible maternal pattern of inheritance according to their pedigrees, which was compared to blood of ALS patients without maternal association as well as age-matched controls.
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- Primary familial brain calcification (PFBC) and early-onset Alzheimer's disease (EOAD) may have shared genetic causes, as seen in a patient with both conditions.
- A specific mutation in the SLC20A2 gene was linked to brain calcifications, while another mutation in the PSEN1 gene was connected to early-onset dementia symptoms.
- The study suggests that the effects of these two genetic mutations appear to add to each other rather than interact in a more complex way, and emphasizes the importance of neuropsychological assessments and amyloid PET scans for diagnosing these disorders.
Article Synopsis
- New intrathecal antisense oligonucleotide therapies are being developed for motoneuron diseases like familial amyotrophic lateral sclerosis, prompting a study of sporadic cases to identify genetic mutations.
- Researchers screened 2,340 patients for variants in 36 ALS-associated genes, completing genetic analysis on 2,267 patients and identifying 79 likely pathogenic and 10 pathogenic variants.
- The study found that around 13% of the cohort could be genetically resolved, suggesting the presence of both known and novel variants and shedding light on the complexities of genetic factors contributing to ALS outcomes.
Article Synopsis
- ALS is a neurodegenerative disorder influenced by both genetic and epigenetic factors, leading to changes in how genes are expressed.
- Researchers identified an epigenetic signature related to ALS, called 'epiChromALS', by analyzing chromatin accessibility in blood cells of ALS patients, revealing connections to neuronal pathways.
- The study used advanced techniques to show that epigenetic changes in ALS can be observed not only in the brain but also in peripheral blood cells, indicating a potential link between these changes and the disease's progression.
Article Synopsis
- * Six SOD1-ALS patients were monitored for changes in NfL levels in cerebrospinal fluid and serum, alongside ALS progression rates and functionality scores, revealing a decrease in NfL levels in all participants despite varying progression rates.
- * The results indicate that tofersen may have disease-modifying effects, as the significant decline in NfL levels correlates with ALS progression, reinforcing the potential of NfL as a response biomarker in ALS treatments
Article Synopsis
- Researchers studied presymptomatic ALS gene mutation carriers to identify metabolic changes that may serve as biomarkers for early treatment before motor symptoms appear.* -
- The study involved 60 mutation carriers and 73 controls from the same families, focusing on various body composition metrics and metabolic rates using bioimpedance and calorimetry.* -
- Findings revealed a decrease in metabolically active body components in carriers, such as lean body mass and cell percentage, while neurofilament light chain levels in serum were similar between groups, indicating metabolic alterations may precede typical ALS biomarkers.*
Background And Purpose: The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV).
Methods: A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale.
Clinical testing panels for ALS: global distribution, consistency, and challenges.
Amyotroph Lateral Scler Frontotemporal Degener
August 2023
: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS.
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- Superoxide dismutase-1 (SOD1) is an important antioxidant enzyme, and mutations in its gene can lead to amyotrophic lateral sclerosis (ALS) by causing toxic protein aggregation.
- Researchers studied eight children with a specific mutation (p.C112Wfs*11) that resulted in SOD1 deficiency, finding that they experienced progressive motor neuron dysfunction and brain atrophy starting around 8 months of age.
- Despite motor system deterioration, other organs showed normal integrity and resilience, indicating a unique vulnerability of the motor system to changes in SOD1 function.