Clinical characterization of common pathogenic variants of SOD1-ALS in Germany

Abstract

Pathogenic variants in the Cu/Zn superoxide dismutase (SOD1) gene can be detected in approximately 2% of sporadic and 11% of familial amyotrophic lateral sclerosis (ALS) patients in Europe. We analyzed the clinical phenotypes of 83 SOD1-ALS patients focusing on patients carrying the most frequent (likely) pathogenic variants (R116G, D91A, L145F) in Germany. Moreover, we describe the effect of tofersen treatment on ten patients carrying these variants. R116G patients showed the most aggressive course of disease with a median survival of 22.0 months compared to 198.0 months in D91A and 87.0 months in L145F patients (HR 7.71, 95% CI 2.89-20.58 vs. D91A; p < 0.001 and HR 4.25, 95% CI 1.55-11.67 vs. L145F; p = 0.02). Moreover, R116G patients had the fastest median ALSFRS-R progression rate with 0.12 (IQR 0.07-0.20) points lost per month. Median diagnostic delay was 10.0 months (IQR 5.5-11.5) and therefore shorter compared to 57.5 months (IQR 14.0-83.0) in D91A (p < 0.001) and 21.5 months (IQR 5.8-38.8) in L145F (p = 0.21) carriers. As opposed to D91A carriers (50.0%), 96.2% of R116G (p < 0.001) and 100.0% of L145F (p = 0.04) patients reported a positive family history. During tofersen treatment, all patients showed a reduction of neurofilament light chain (NfL) serum levels, independent of the SOD1 variant. Patients with SOD1-ALS carrying R116G, D91A, or L145F variants show commonalities, but also differences in their clinical phenotype, including a faster progression rate with shorter survival in R116G, and a comparatively benign disease course in D91A carriers.

Keywords: SOD1; Amyotrophic lateral sclerosis; Clinical phenotype; Motor neuron disease; Tofersen.

Fig. 1

Clinical characteristics in R116G carriers vs. D91A carriers (homozygous and heterozygous) vs. L145F carriers. Boxplots show median (IQR; minimum–maximum). (a) age of onset (b) progression rate (c) diagnostic delay (d) ALSFRS-R at first visit. Experimental units n = number (a) R116G n = 22, D91A n = 10, p = 0.6814, R116G n = 22, L145F n = 6, p = 0.9239, D91A n = 10, L144F n = 6, p = 0.9798 (b) R116G n = 14, D91A n = 8, p = 0.0183, R116G n = 14, L145F n = 6, p = 0.2125, D91A n = 8, L145F n = 6, p = 0.3526 (c) R116G n = 13, D91A n = 6, p = 0.0008, R116G n = 13, L145F n = 4, p = 0.2723, D91A n = 6, L145F n = 4, p = 0.1286 (d) R116G n = 14, D91A n = 8, p = 0.0439, R116G n = 14, L145F n = 6, p = 0.08256, D91A n = 8, L145F n = 6, p = 0.4336. Mann–Whitney U test was used for two group comparison. A P-value of ≤ 0.05 was regarded as statistically significant. ALSFRS-R Amyotrophic lateral sclerosis functional rating scale revised

Fig. 2

Kaplan Meier Curves for survival in R116G carriers vs. D91A carriers (homozygous and heterozygous) vs. L145F carriers. Experimental units n = number, R116G n = 22, D91A n = 10, p = 0.0002, R116G n = 22, L145F n = 6, p = 0.02. Kaplan–Meier curves and Log-rank test were applied to determine the effect of demographic or clinical parameters on survival. A P-value of ≤ 0.05 was regarded as statistically significant

Fig. 3

ALSFRS-R and neurofilaments on individual level depending on SOD1 variants. Graphs show changes of ALSFRS-R and NfL levels (pg/ml) in serum prior to first administration of tofersen as well as after three and six months of therapy, and at last administration. (a) ALSFRS-R (b) NfL in serum (pg/ml). Time between first and last administration: R116G_1 11.5 months, R116G_2 7.7 months, R116G_3 10.3 months, R116G_4 1.9 months, D91A_1 11.4 months, D91A_2 11.6 months, D91A_3 8.9 months, L145F_1 12.1 months, L145F_2 3.1 months and L145F_3 2.8 months. Heterozygous allele genotype of D91A is shown in dashed lines. (a) ALSFRS-R after 3, 6, 9 months and 12 months (last visit) in patients with SOD1-ALS prior to initiation of the EAP is shown in x and dashed lines and was extrapolated from ALSFRS-R progression rate, calculated as median loss of points in ALSFRS-R/month between first and last visit, in patients with R116G (median time between first and last visit 8.0 months, IQR 5.5-27.0 months; n = 9), D91A (median 43.5 months, IQR 23.3-50.8 months; n = 6) and L145F (median 8.0 months, IQR 7.0–16.0 months; n = 3) until 2019. (b) Median NfL serum levels (pg/ml) of patients with SOD1-ALS from the German Early Access Program (EAP) are shown in a dashed black line (baseline n = 17, 3 months n = 17, 6 months n = 10, time between first and last administration median 6.0 months, IQR 2.5-10.5 months; n = 17). ALSFRS-R Amyotrophic lateral sclerosis functional rating scale revised, NfL neurofilament light chain (pg/ml).

Fig. 4

ALSFRS-R in R116G carriers, D91A carriers (homozygous and heterozygous) and L145F carriers on individual level. Graphs show ALSFRS-R values between onset of the disease and last visit. Retrospectively analyzed R116G carriers n = 14, R116G carriers treated with tofersen in the German Early Access Program (EAP) n = 4. Retrospectively analyzed D91A carriers n = 8 (n = 4 patients with homozygous and n = 4 patients with heterozygous allele genotype), D91A carriers treated with tofersen in the German EAP n = 3 (n = 2 patients with homozygous and n = 1 patient with heterozygous allele genotype). Heterozygous allele genotype of D91A is shown in dashed lines. Retrospectively analyzed L145F carriers n = 6, L145F carriers treated with tofersen in the German EAP n = 3. Patients treated with tofersen in the German EAP are highlighted with bold symbols, raw data of all patients is shown in Supplementary Table 1. ALSFRS-R Amyotrophic lateral sclerosis functional rating scale revised.