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Observational Study
. 2022 Nov 12;13(1):6901.
doi: 10.1038/s41467-022-34620-y.

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Sarah Opie-Martin #  1 , Alfredo Iacoangeli #  1   2   3 , Simon D Topp  1 , Olubunmi Abel  4 , Keith Mayl  1 , Puja R Mehta  1 , Aleksey Shatunov  1   5   6 , Isabella Fogh  1 , Harry Bowles  1 , Naomi Limbachiya  1 , Thomas P Spargo  1 , Ahmad Al-Khleifat  1 , Kelly L Williams  7 , Jennifer Jockel-Balsarotti  8 , Taha Bali  8 , Wade Self  8 , Lyndal Henden  7 , Garth A Nicholson  7   9 , Nicola Ticozzi  10   11 , Diane McKenna-Yasek  12 , Lu Tang  13 , Pamela J Shaw  14 , Adriano Chio  15   16 , Albert Ludolph  17   18 , Jochen H Weishaupt  19   20 , John E Landers  12 , Jonathan D Glass  21 , Jesus S Mora  22 , Wim Robberecht  23 , Philip Van Damme  23   24 , Russell McLaughlin  25 , Orla Hardiman  26 , Leonard van den Berg  27 , Jan H Veldink  27 , Phillippe Corcia  28   29 , Zorica Stevic  30 , Nailah Siddique  31 , Vincenzo Silani  10   11 , Ian P Blair  7 , Dong-Sheng Fan  13 , Florence Esselin  32 , Elisa de la Cruz  32 , William Camu  32 , Nazli A Basak  33 , Teepu Siddique  31 , Timothy Miller  8 , Robert H Brown  12 , Ammar Al-Chalabi  1 , Christopher E Shaw  34   35
Affiliations
Observational Study

The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration

Sarah Opie-Martin et al. Nat Commun. .

Erratum in

  • Author Correction: The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration.
    Opie-Martin S, Iacoangeli A, Topp SD, Abel O, Mayl K, Mehta PR, Shatunov A, Fogh I, Bowles H, Limbachiya N, Spargo TP, Al-Khleifat A, Williams KL, Jockel-Balsarotti J, Bali T, Self W, Henden L, Nicholson GA, Ticozzi N, McKenna-Yasek D, Tang L, Shaw PJ, Chio A, Ludolph A, Weishaupt JH, Landers JE, Glass JD, Mora JS, Robberecht W, Damme PV, McLaughlin R, Hardiman O, van den Berg L, Veldink JH, Corcia P, Stevic Z, Siddique N, Silani V, Blair IP, Fan DS, Esselin F, de la Cruz E, Camu W, Basak NA, Siddique T, Miller T, Brown RH, Al-Chalabi A, Shaw CE. Opie-Martin S, et al. Nat Commun. 2024 Jul 2;15(1):5560. doi: 10.1038/s41467-024-49938-y. Nat Commun. 2024. PMID: 38956107 Free PMC article. No abstract available.

Abstract

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.

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Conflict of interest statement

J.H.V. reports to have sponsored research agreements with Biogen. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”. Several authors of this publication (A.C., A.L., J.W., L.B., O.H., V.S.) are members of the European Reference Network for Rare Neuromuscular Diseases (ERN-NMD). The remaining authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Modified CONSORT diagram of datasets included in analysis.
The diagram shows the number of records identified from the following sources: ALS online Database, Project MinE, ALS Clinic databases, STRENGTH and the US population dataset. Records were excluded for missing or spurious data, or because of the diagnostic phenotype.
Fig. 2
Fig. 2. Box plots of age of onset and disease duration by variant.
Information is displayed for those variants where there were >9 cases. The centre value is the median and boxes represent interquartile range with whiskers representing the minima and maxima values associated with each variant. A Box plot showing age of symptom onset by variant, n = 976. B Box plot of lg survival by variant, n = 809. C Selected box plots of log survival faceted by codon to highlight differences and similarities in survival distribution, n = 415. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Forest plots of variants associated with age of onset.
The centre of the Forest plot represents the hazard ratio of the Cox proportional hazards model, the error bars are two-sided 95% confidence intervals. All models were adjusted for site of symptom onset and gender. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Forest plots of variants associated with disease duration.
The centre of the Forest plot represents the hazard ratio of the Cox proportional hazards model, the error bars are two-sided 95% confidence intervals. All models were adjusted for site of symptoms onset, gender and age of symptom onset. Source data are provided as a Source Data file.
Fig. 5
Fig. 5. Variants associated with age of onset plotted onto a wild-type SOD1 dimer representation.
Variants associated with a younger age of onset compared to the non-SOD1 ALS population using Cox proportional hazards regression plotted onto PDB structure 2c9v. Codon numbers refer to genomic location.
Fig. 6
Fig. 6. Variants associated with disease duration plotted onto a wild-type SOD1 dimer representati on.
Variants associated with a distinct survival compared to the non-SOD1 ALS population using Cox proportional hazards regression plotted onto PDB structure 2c9v. Codon numbers refer to genomic location.
See this image and copyright information in PMC

References

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