Motor phenotypes and neurofilament light chain in genetic amyotrophic lateral sclerosis-results from a multicenter screening program

Abstract

Objective: In genetic amyotrophic lateral sclerosis (ALS), the clinical phenotypes, disease progression and neurofilament light chain (NfL) levels are incompletely characterized.

Methods: In a total cohort of 1988 ALS patients, a subcohort of genetic ALS linked to C9orf72 (n = 137), SOD1 (n = 54), TARDBP (n = 27), and FUS (n = 19) was investigated. The phenotypes of onset region, propagation and motor neuron involvement were analyzed according to the OPM classification. Serum NfL (sNfL) was measured and related to ALS progression (ALSPR, monthly change of ALS Functional Rating Scale-Revised). To quantify NfL elevation relative to ALSPR, the logNfL(index), the log-transformed ratio of sNfL to ALSPR was calculated.

Results: C9orf72-associated ALS showed frequent bulbar onset (n = 42.6%), higher ALSPR (0.95, SD 0.84), highest NfL (116.3, SD 72.7 pg/mL) and logNfL(index) (5.02, SD 0.88). SOD1-ALS had mostly limb onset (n = 96.1%), slower ALSPR (0.57, SD 0.60), high NfL (76.1, SD 61.4 pg/mL) and a comparably high logNfL(index) (4.94, SD 1.03). FUS-ALS exhibited mostly limb onset (82.4%), lower motor neuron dysfunction (70.6%), a wide range of faster (22.2%) to slower ALSPR (55.6%), lower NfL (66.2, SD 32.9) and logNfL(4.65, SD 0.9). TARDBP-ALS displayed the lowest ALSPR (0.53, SD 0.52), the lowest NfL (43.3, SD 31.8 pg/mL) and the lowest logNfL(index) (4.40, SD 0.7).

Conclusion: In C9orf72-ALS, the phenotype and NfL profile are close to typical ALS. The finding of distinct phenotypes and NfL patterns in SOD1-, FUS- and TARDBP-associated ALS underscores the relevance of genetic ALS for prognostic counseling, clinical trial design, treatment expectations and unraveling of pathogenic mechanisms in ALS.

Keywords: ALS progression; Genetic ALS; Neurofilament; Phenotype.

Fig. 1

Studied cohort. n = number of ALS patients with genetic variants. C5, pathogenic (class 5) variant; C4, likely pathogenic (class 4) variant; C3, variant of uncertain significance (class 3) according to the guidelines of the American College of Medical Genetics and Genomics (ACMG); HRE: number of hexanucleotide repeat expansion. Only symptomatic carriers had been analyzed further

Fig. 2

Gender and age distribution across ALS-associated gene mutations. A The percentage of male and female patients is displayed for each mutation: C9orf72 (76 male, 55.5%; 61 female, 44.5%), SOD1 (24 male, 44.4%; 30 female, 55.6%), TARDBP (15 male, 55.6%; 12 female, 44.4%), and FUS (11 male, 57.9%; 8 female, 42.1%). Differences in the group and between the groups are not statistically significant (n.s., Chi-Square-Test). B Results of the ANOVA test comparing mean ages of patients with mutations C9orf72 (59.0 ± SD 9.2 years, n = 137), SOD1 (50.8 ± SD 11.0 years, n = 54), TARDBP (61.9 ± SD 10.2 years, n = 27), and FUS (57.0 ± SD 13.9 years, n = 19). Data are presented as mean age at disease onset for each subgroup with standard deviations. ns  not significant

Fig. 3

Distribution of clinical phenotypes and motor neuron involvement. A Proportional distribution of region onset localization (limb, head region, trunk) across the genetic subgroups C9orf72 (57.4% limb, 42.6% head region, 0% trunk, n = 122), SOD1 (96.1% limb, 2.0% head region, 2.0% trunk, n = 51), TARDBP (95.8% limb, 4.2% head region, 0% trunk, n = 24), and FUS (82.4% limb, 11.8% head region, 5.9% trunk, n = 17). B Distribution of propagation of motor symptoms for arm onset and earlier propagation, leg onset and earlier propagation, arm onset with later propagation (“flail arm syndrome”) and leg onset with later propagation (“flail leg syndrome”) are shown for C9orf72 (39.7%, 53.0%, 2.9%, 4.4%, n = 68), SOD1 (16.3%, 55.1%, 8.2%, 20.4%, n = 49), TARDBP (47.8%, 34.8%, 13.0%, 4.3%, n = 23), and FUS (15.4%, 23.1%, 38.4%, 23.1%, n = 13). C Distribution of motor neuron dysfunction of patients with balanced UMN and LMN dysfunction, predominant LMN dysfunction, predominant UMN dysfunction and dissociated motor neuron dysfunction is shown for C9orf72 (74.4%, 8.8%, 14.4%, 2.4%, n = 122), SOD1 (52.9%, 39.2%, 7.8%, 0%, n = 51), TARDBP (45.8%, 29.2%, 8.3%, 16.7%, n = 24) and FUS (23.5%, 70.6%, 0%, 5.9%, n = 17). D Proportion of flail variants compared to all phenotypes including non-limb are shown for C9orf72 (4.1%), SOD1 (27.5%), TARDBP (16.7%) and FUS (47.1%)

Fig. 4

Disease activity displayed by sNfL and progression rate. A Shown are sNFL levels as mean values and standard deviation: C9orf72 group (116.3 ± SD 72.7 pg/mL, n = 129); SOD1 (76.1 ± SD 61.4 pg/mL, n = 46); TARDBP (43.3 ± SD 31.8 pg/mL, n = 25); and FUS (66.2 ± SD 32.9 pg/mL, n = 17). B Mean progression rates of the ALS-FR-R. The mean values are as follows: C9orf72 (0.95 ± 0.84, n = 133); SOD1 (0.57 ± 0.6, n = 51); TARDBP (0.53 ± 0.52, n = 23); and FUS (0.84 ± 0.85, n = 18). C Distribution of progression groups among C9orf72 (33.1% slower, 37.6% intermediate, 29.3% faster), SOD1 (66.7% slower, 11.8% intermediate, 21.6% faster), TARDBP (69.6% slower, 21.8% intermediate, 8.7% faster), and FUS (55.6% slower, 22.2% intermediate, 22.2% faster)