Purpose of reviewAmyotrophic lateral sclerosis (ALS) is an incurable, devastating neurodegenerative disease. Still, the diagnosis is mainly based on clinical symptoms, and the treatment options are strongly limited. However, the pipeline of potential treatments currently tested in clinical trials is promising. This review will discuss developments in ALS biomarker research and applications within the last 2 years and suggest future directions and needs.Recent findingsThe diagnostic and prognostic utility of neurofilaments, a general marker for axoneuronal degeneration, has been confirmed by further studies in patients with ALS, and neurofilaments are finding their way into routine diagnostic and clinical trials. Additionally, there have been advancements in developing and implementing disease-specific biomarkers, especially in patients with a genetic variant, such as SOD1 or C9orf72. Here, biomarkers have already been used as target markers and outcome parameters for novel treatment approaches. In addition, several novel biomarkers have shown encouraging results but should be discussed in the context of their early stage of assay and clinical establishment.SummaryThe first biomarkers have found their way into clinical routine in ALS. In light of an increasing pipeline of potential treatments, further progress in discovering and implementing novel and existing biomarkers is crucial.

An expansion of the GGGGCC hexanucleotide in the non-coding region of C9orf72 represents the most common cause of familial amyotrophic lateral sclerosis. The objective was to describe and analyze the clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations in a large population. Between 11/2011 and 12/2020, clinical and genetic characteristics of n = 248 patients with amyotrophic lateral sclerosis carrying C9orf72 mutations were collected from the clinical and scientific network of German motoneuron disease centres. Clinical parameters included age of onset, diagnostic delay, family history, neuropsychological examination, progression rate, phosphorylated neurofilament heavy chain levels in CSF, and survival. The number of repeats was correlated with the clinical phenotype. The clinical phenotype was compared to n = 84 patients with SOD1 mutations and n = 2178 sporadic patients without any known disease-related mutations. Patients with C9orf72 featured an almost balanced sex ratio with 48.4% (n = 120) women and 51.6% (n = 128) men. The rate of 33.9% patients (n = 63) with bulbar onset was significantly higher compared to sporadic (23.4%, P = 0.002) and SOD1 patients (3.1%, P < 0.001). Of note, 56.3% (n = 138) of C9orf72, but only 16.1% of SOD1 patients reported a negative family history (P < 0.001). The GGGGCC hexanucleotide repeat length did not influence the clinical phenotypes. Age of onset (58.0, IQR 52.0-63.8) was later compared to SOD1 (50.0, IQR 41.0-58.0; P < 0.001), but earlier compared to sporadic patients (61.0, IQR 52.0-69.0; P = 0.01). Median survival was shorter (38.0 months) compared to SOD1 (198.0 months, HR 1.97, 95% CI 1.34-2.88; P < 0.001) and sporadic patients (76.0 months, HR 2.34, 95% CI 1.64-3.34; P < 0.001). Phosphorylated neurofilament heavy chain levels in CSF (2880, IQR 1632-4638 pg/ml) were higher compared to sporadic patients (1382, IQR 458-2839 pg/ml; P < 0.001). In neuropsychological screening, C9orf72 patients displayed abnormal results in memory, verbal fluency, and executive functions, showing generally worse performances compared to SOD1 and sporadic patients and a higher share with suspected frontotemporal dementia. In summary, clinical features of patients with C9orf72 mutations differ significantly from SOD1 and sporadic patients. Specifically, they feature a more frequent bulbar onset, a higher share of female patients, and shorter survival. Interestingly, we found a high proportion of patients with negative family history and no evidence of a relationship between repeat lengths and disease severity.

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