Frequency of C9orf72 and SOD1 mutations in 302 sporadic ALS patients from three German ALS centers

Abstract

Background: ALS patients with a negative family history (sporadic ALS, SALS) represent more than 90% of all ALS cases. In light of the gene-specific therapies that are currently in development for ALS, knowledge about the genetic landscape of SALS in Germany is urgently needed. Objectives: We aimed to determine the frequency of C9orf72 hexanucleotide repeat expansion (HRE) and SOD1 mutations among patients in Germany with a diagnosis of sporadic or idiopathic ALS. Methods: We genotyped SALS patients from three German ALS centers. Sanger sequencing, fragment length analysis, and repeat-primed PCR technologies were used to detect mutations in SOD1 and C9orf72 HRE. Pathological C9orf72 HRE results were confirmed in an independent laboratory. Results: In 302 patients with SALS, 27 (8.9%) patients with a C9orf72 HRE mutation were detected. Moreover, we identified two patients with a pathogenic SOD1 mutation, one patient with a heterozygous p.D91A mutation in SOD1, and three additional patients with rare SOD1 variants not predicted to change the amino acid sequence. Conclusions: According to our data, the proportion of SALS patients with SOD1 mutations is in the expected range, whereas that with C9orf72 HRE is higher, suggesting a reduced penetrance. A considerable number of SALS patients can be amenable to gene-specific therapies.

Keywords:

• Amyotrophic lateral sclerosis
• neurodegeneration
• sporadic ALS
• motor neuron disease
• neurogenetics

Acknowledgements

We are indebted to the patients and their families for their participation in this project. We are thankful to Helena Alstermark for her technical assistance and our study nurse Antje Knehr. We thank Dr. Rosanna Parlato for the discussions and critical reading of the manuscript.

Declaration of interest

There are no relevant financial or non-financial competing interests to report.

Additional information

Funding

RY is supported German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) Walter Benjamin Programme (YI 209/1-1, AOBJ 680080).