Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology
SOD1 mutations are a frequent cause of autosomal dominant familial amyotrophic lateral sclerosis (fALS).1 The D91A SOD1 variant is unique in its association with an atypical form of autosomal recessive fALS in Scandinavia. ALS has also been described in heterozygous D91A carriers,2 but it remains un...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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American Academy of Neurology
2020
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| _version_ | 1826304988950822912 |
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| author | Feneberg, E Turner, MR Ansorge, O Talbot, K |
| author_facet | Feneberg, E Turner, MR Ansorge, O Talbot, K |
| author_sort | Feneberg, E |
| collection | OXFORD |
| description | SOD1 mutations are a frequent cause of autosomal dominant familial amyotrophic lateral sclerosis (fALS).1 The D91A SOD1 variant is unique in its association with an atypical form of autosomal recessive fALS in Scandinavia. ALS has also been described in heterozygous D91A carriers,2 but it remains uncertain whether this is pathogenic, given that the D91A carrier state exists in European populations with an allele frequency of 0.007 (gnomad.broadinstitute.org/), and the observation that ALS does not co-segregate with the heterozygous carrier status in D91A-associated fALS.3 It is generally accepted that dominant SOD1 cases are neuropathologically distinct from sporadic ALS, because of the absence of the TDP-43 proteinopathy found in 97% of all ALS cases, suggesting that different pathogenic mechanisms are involved.4 With the advent of trials of antisense oligonucleotides in SOD1-related ALS it is critical to establish if D91A SOD1 is pathogenic in the heterozygous state, to ensure appropriate recruitment of patients to clinical trials. Here we report a case of corticobulbar ALS in an individual heterozygous for the D91A variant, with autopsy findings of widespread TDP-43 proteinopathy typical of sporadic ALS (figure). |
| first_indexed | 2024-03-07T06:26:04Z |
| format | Journal article |
| id | oxford-uuid:f45644de-154e-4485-9fb2-cd6ca3b7597e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:26:04Z |
| publishDate | 2020 |
| publisher | American Academy of Neurology |
| record_format | dspace |
| spelling | oxford-uuid:f45644de-154e-4485-9fb2-cd6ca3b7597e2022-03-27T12:19:05ZAmyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathologyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f45644de-154e-4485-9fb2-cd6ca3b7597eEnglishSymplectic ElementsAmerican Academy of Neurology2020Feneberg, ETurner, MRAnsorge, OTalbot, KSOD1 mutations are a frequent cause of autosomal dominant familial amyotrophic lateral sclerosis (fALS).1 The D91A SOD1 variant is unique in its association with an atypical form of autosomal recessive fALS in Scandinavia. ALS has also been described in heterozygous D91A carriers,2 but it remains uncertain whether this is pathogenic, given that the D91A carrier state exists in European populations with an allele frequency of 0.007 (gnomad.broadinstitute.org/), and the observation that ALS does not co-segregate with the heterozygous carrier status in D91A-associated fALS.3 It is generally accepted that dominant SOD1 cases are neuropathologically distinct from sporadic ALS, because of the absence of the TDP-43 proteinopathy found in 97% of all ALS cases, suggesting that different pathogenic mechanisms are involved.4 With the advent of trials of antisense oligonucleotides in SOD1-related ALS it is critical to establish if D91A SOD1 is pathogenic in the heterozygous state, to ensure appropriate recruitment of patients to clinical trials. Here we report a case of corticobulbar ALS in an individual heterozygous for the D91A variant, with autopsy findings of widespread TDP-43 proteinopathy typical of sporadic ALS (figure). |
| spellingShingle | Feneberg, E Turner, MR Ansorge, O Talbot, K Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology |
| title | Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology |
| title_full | Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology |
| title_fullStr | Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology |
| title_full_unstemmed | Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology |
| title_short | Amyotrophic lateral sclerosis with a heterozygous D91A SOD1 variant and classical ALS-TDP neuropathology |
| title_sort | amyotrophic lateral sclerosis with a heterozygous d91a sod1 variant and classical als tdp neuropathology |
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