Search

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research. [ABSTRACT FROM AUTHOR]

Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS.Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature.Results: We identified four sporadic ALS cases with de novo mutations in SOD1. They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1. We also encountered familial cases where de novo mutational events in recent generations may have been involved.Conclusions: De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy. [ABSTRACT FROM AUTHOR]

Objective: A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.Methods: A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.Results: The 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1WT in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1WT inclusions. Minute amounts of misSOD1WT inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1D90A mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.Conclusions and Relevance: Abundant inclusions containing misfolded SOD1WT are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1WT can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients. [ABSTRACT FROM AUTHOR]

Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The only identified cause of amyotrophic lateral sclerosis (ALS) are mutations in a number of genes found in familial cases but also in sporadic cases. De novo mutations occurring in a parental gonadal cell, in the zygote or postzygotic during embryonal development can result in an apparently sporadic/isolated case of ALS later in life. We searched for de novo mutations in SOD1 as a cause of ALS., Methods: We analysed peripheral-blood exome, genome and Sanger sequencing to identify deleterious mutations in SOD1 in 4000 ALS patients from Germany, South Korea and Sweden. Parental kinship was confirmed using highly polymorphic microsatellite markers across the genome. Medical genealogical and clinical data were reviewed and compared with the literature., Results: We identified four sporadic ALS cases with de novo mutations in SOD1 . They aggregate in hot-spot codons earlier found mutated in familial cases. Their phenotypes match closely what has earlier been reported in familial cases with pathogenic mutations in SOD1 . We also encountered familial cases where de novo mutational events in recent generations may have been involved., Conclusions: De novo mutations are a cause of sporadic ALS and may also be underpinning smaller families with few affected ALS cases. It was not possible to ascertain if the origin of the de novo mutations was parental germline, zygotic or postzygotic during embryonal development. All ALS patients should be offered genetic counselling and genetic screening, the challenges of variant interpretation do not outweigh the potential benefits including earlier confirmed diagnosis and possible bespoken therapy., Competing Interests: Competing interests: PMA serves on the scientific advisory boards of Biogen, Regeneron and Orphazyme A/S., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)