Clinical and Genetic Features of Amyotrophic Lateral Sclerosis Patients with Mutations

An expansion of the GGGGCC hexanucleotide in the non-coding region of represents the most common cause of familial amyotrophic lateral sclerosis. The objective was to describe and analyse the clinical and genetic features of amyotrophic lateral sclerosis patients with mutations in a large population. Between November 2011 and December 2020, clinical and genetic characteristics of = 248 patients with amyotrophic lateral sclerosis carrying 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 = 84 patients with mutations and = 2178 sporadic patients without any known disease-related mutations. Patients with featured an almost balanced sex ratio with 48.4% ( = 120) women and 51.6% ( = 128) men. The rate of 33.9% patients ( = 63) with bulbar onset was significantly higher compared to sporadic (23.4%, = 0.002) and patients (3.1%, < 0.001). Of note, 56.3% ( = 138) of but only 16.1% of patients reported a negative family history ( < 0.001). The GGGGCC hexanucleotide repeat length did not influence the clinical phenotypes. Age of onset (58.0, interquartile range 52.0-63.8) was later compared to (50.0, interquartile range 41.0-58.0; < 0.001), but earlier compared to sporadic patients (61.0, interquartile range 52.0-69.0; = 0.01). Median survival was shorter (38.0 months) compared to (198.0 months, hazard ratio 1.97, 95% confidence interval 1.34-2.88; < 0.001) and sporadic patients (76.0 months, hazard ratio 2.34, 95% confidence interval 1.64-3.34; < 0.001). Phosphorylated neurofilament heavy chain levels in CSF (2880, interquartile range 1632-4638 pg/ml) were higher compared to sporadic patients (1382, interquartile range 458-2839 pg/ml; < 0.001). In neuropsychological screening, patients displayed abnormal results in memory, verbal fluency and executive functions, showing generally worse performances compared to and sporadic patients and a higher share with suspected frontotemporal dementia. In summary, clinical features of patients with mutations differ significantly from 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.