Four familial ALS pedigrees discordant for two SOD1 mutations: Are all SOD1 mutations pathogenic?

Ansgar Felbecker (1) , William Camu (2) , Paul Valdmanis (3) , Anne-Dorte Sperfeld (1) , Stefan Waibel (1) , Peter Steinbach (4) , Guy A. Rouleau (3) , Albert C. Ludolph (4) , Peter Munch Andersen (5)

1 Neurology, University of Ulm
2 Neurology, Montpellier
3 Center of Excellence in Neuromics, University of Montreal
4 Universität Ulm - Ulm University [Ulm, Allemagne]
5 Umeå University

Background: One-hundred and fiftythree mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. We now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A and E100K SOD1 mutations in some but not all affected members. After re-collecting of DNA, the non-segregation of the SOD1 mutations with disease were confirmed by three independent laboratories using different PCR primers: While some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, we ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. Conclusions: We find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practise when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.

Mots clés: ALS; GENETICS

Ansgar Felbecker, William Camu, Paul Valdmanis, Anne-Dorte Sperfeld, Stefan Waibel, et al.. Four familial ALS pedigrees discordant for two SOD1 mutations: Are all SOD1 mutations pathogenic?. Journal of Neurology, Neurosurgery and Psychiatry, 2010, 81 (5), pp.572. ⟨10.1136/jnnp.2009.192310⟩. ⟨hal-00557419⟩