Background 153 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. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was 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, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees.
Conclusions The authors 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 practice 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.
- Amyotrophic lateral sclerosis
- SOD1 mutation
- genetic counselling
- predictive testing
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Funding This project has been generously supported by the Kempe Foundations, the Swedish Brain Power Foundation, the Swedish Brain Research Foundation, the Hållstens Research Foundation, the Swedish Medical Society and the Björklund Foundation for ALS Research, the Ulla-Carin Lindquist Foundation and the Swedish Association for the Neurologically Disabled. We are also grateful to the Association Française contre les Myopathies and Association pour la Recherche contre la Sclérose Latérale Amyotrophique for their financial support.
Competing interest None.
Ethics approval Ethics approval was provided by the Medical Ethical Review boards at the universities in Umeå (Sweden), Ulm (Germany), Montpellier (France) and Montreal (Canada).
Provenance and peer review Not commissioned; externally peer reviewed.
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