LETTERTOTHEEDITOR SOD1 mutation can mask C9orf72 abnormal expansion P. Corcia a,b,c , H. Blasco b , G. Besson d , J.-P. Camdessanch e e , V. Pautot f , S. Beltran a,c , P. Couratier c,g , C. Andres b , W. Camu h and P. Vourc’h b a Centre de Ressources et de Comp etences SLA, CHU Tours, Tours, b Inserm Unit UMR U930, Tours, c F ed eration des Centres de Ressources et de Comp etences de Tours et Limoges, LITORALS, Limoges, d Service de Neurologie, CHU Grenoble, Grenoble, e Centre de Ressources et de Comp etences SLA, CHU St Etienne, Saint-Etienne, f Centre de Ressources et de Comp etences SLA, CHU Angers, Angers, g Centre de Ressources et de Comp etences SLA, CHU Limoges, Limoges, and h Centre de Ressources et de Comp etences SLA, CHU Montpellier, Montpellier, France Correspondence: P. Corcia, CRCSLA Tours, CHRU Bretonneau, 2 Boulevard Tonnelle, 37044 Tours Cedex 1, France (tel.: +33247473724; fax: +33218370809; e-mail: corcia@med.univ-tours.fr). Keywords: C9orf72 gene, FALS, genetic and inherited disorders, motor neuron disease, neurological disorders, neuromuscular diseases, SOD1 gene doi:10.1111/ene.13257 Received: 1 November 2016 Accepted: 11 January 2017 To date, the pathogenicity of several mutations in the SOD1 gene remains uncertain due to the lack of evidence demonstrating the damage to motor neurons. This is the case for the N19S mutation for which no familial linkage has been shown [1,2]. However, the expression of this mutation in neural cell cultures leads to enhanced susceptibility to degeneration of these neural cells [3]. Given the weak evidence supporting the pathogenicity of the N19S mutation and the key genetic influence of the C9orf72 gene in amyotrophic lateral scle- rosis (ALS), we screened this gene in four patients with ALS (two familial and two sporadic cases) and six controls (the daughter of one familial ALS and five relatives of sporadic ALS) with the N19S mutation. Abnormal GGGGCC repeat expansion (>30) was only found in the two familial ALS cases; the remaining cases had <30 repeats. If one study supported a potential toxic effect of N19S on the survival of motor neurons and suggested it could be causative, more evidence is required to support a pathogenic role for this mutation due to the absence of co-seg- regation with the disease, as already suggested, and the lack of functional studies [1,3,4]. In view of the high pro- portion of C9orf72-linked ALS added to the growing literature supporting oli- gogenic inheritance, we considered it essential to screen the C9orf72 gene in our sample [5,6]. This revealed that the familial ALS cases of our series were linked to C9orf72 (Table 1). This result strengthened the theory that the N19S mutation is non-causative but possibly modulates the phenotype of the disease as evidenced by the young age of onset in three out of the four cases. Cur- rently, we have not found other cases with the N19S mutation amongst our cohort of 90 ALS patients with C9orf72 abnormal expansion screened in our laboratory. This result appears of key importance in daily medical practice and particularly in the field of pre-symptomatic coun- selling. The development of new genetic technologies such as next generation sequencing will lead clinicians to be con- fronted with several mutations. Clinicians must underpin the results of their analy- sis with further information in order to determine the causative mutations; there- fore, they must extend the analysis to rel- atives and have a robust knowledge of genotypeÀphenotype correlation. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest. References 1. Mayeux V, Corcia P, Besson G, et al. N19S, a new superoxide dismutase gene mutation in sporadic amyotrophic lateral sclerosis: no evidence for disease causation. Ann Neurol 2003; 53: 815–818. 2. Vela A, Gakan L, Valencia C, et al. SOD1- N19S mutation in a family with amy- otrophic lateral sclerosis. Neurologia 2012; 27: 11–15. 3. Obata Y, Niikura T, Kanekura K, et al. Expression of N19S-SOD1, an SOD1 mutant found in sporadic amyotrophic lat- eral sclerosis patients, induces low-grade motoneuronal toxicity. J Neurosci Res 2005; 81: 720–729. 4. Restagno G, Gomez A, Lombardo F, et al. The IVS1+319 t>a of SOD1 gene is not an ALS causing mutation. Amyotroph Lateral Scler Other Motor Neuron Disord 2005; 6: 45–49. 5. Millecamps S, Boill ee S, Le Ber I, et al. Phenotype difference between ALS patients with expanded repeats in C9orf72 and patients with mutations in other ALS- related genes. J Med Genet 2012; 49: 258– 263. 6. Cady J, Allred P, Bali T, et al. Amy- otrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Ann Neurol 2015; 77: 100–113. Table 1 Clinical data of the four ALS cases with N19S mutation Name FALS/ SALS Gender AOO (years) SOO ALS duration (months) N19S c9orf72 ALS1- 1 FALS F 69 Bulbar 27 + + ALS2 FALS F 42 LL 72 + + ALS3 SALS F 42 UL 162 + À ALS4 SALS M 32 LL 36 + À FALS, familial ALS; SALS, sporadic ALS; F, female; M, male; AOO, age of onset; UL, upper limb; LL, lower limb; SOO, site of onset; C9orf72+, GGGGCC repeats >30; C9orf72À, GGGGCC repeats <30. EUROPEANJOURNALOFNEUROLOGY LETTERTOTHEEDITOR © 2017 EAN e24