Background In the isolated population of Sardinia, a Mediterranean island, ∼25% of ALS cases carry either a p.A382T mutation of the TARDBP gene or a GGGGCC hexanucleotide repeat expansion in the first intron of the C9ORF72 gene.
Objective To describe the co-presence of two genetic mutations in two Sardinian ALS patients.
Methods We identified two index ALS cases carrying both the p.A382T missense mutation of TARDBP gene and the hexanucleotide repeat expansion of C9ORF72 gene.
Results The index case of Family A had bulbar ALS and frontemporal dementia (FTD) at 43. His father, who carried the hexanucleotide repeat expansion of C9ORF72 gene, had spinal ALS and FTD at 64 and his mother, who carried the TARDBP gene p.A382T missense mutation, had spinal ALS and FTD at 69. The index case of Family B developed spinal ALS without FTD at 35 and had a rapid course to respiratory failure. His parents are healthy at 62 and 63. The two patients share the known founder risk haplotypes across both the C9ORF72 9p21 locus and the TARDBP 1p36.22 locus.
Conclusions Our data show that in rare neurodegenerative causing genes can co-exist within the same individuals and are associated with a more severe disease course.
- Guillain–Barre syndrome
- movement disorders
- motor neuron disease
- HMSN (Charcot–Marie–Tooth)
- multiple sclerosis
- Alzheimer's disease
- genetic epidemiology
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Group information: Additional authors/Sardinian ALS (SARDINIALS) Consortium: Stefania Cammarosano, Antonio Ilardi, Anna Montuschi, Enrica Bersano (ALS Center, Department of Neuroscience, University of Torino and Azienda Ospedale-Università San Giovanni Battista, Torino, Italy); Antonino Cannas, Emanuela Costantino, Valeria Piras, Carla Pani (Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari, and University of Cagliari, Italy); Anna Ticca (Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy); Leslie D Parish, Paola Cossu (Department of Neuroscience, University of Sassari, Sassari, Italy); and Giuliana Solinas, Lucia Ulgheri (Department of Biomedical Sciences, University of Sassari, Italy).
Adriano Chiò, Gabriella Restagno, Bryan J Traynor, Giuseppe Borghero, *These authors have contributed equally to the paper.
Funding This work was supported by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02), the Packard Center for ALS Research at Hopkins, the ALS Association, Microsoft Research, Federazione Italiana Giuoco Calcio (grant 2010, #2) and European Community's Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. Dr. Traynor reports that a patent is pending based on the discovery of the hexanucleotide repeat expansion of C9ORF72.
Competing interests BJT has a patent pending based on the hexanucleotide repeat expansion of the C9ORF72 gene.
Ethics approval Approval provided by the ethical committees of San Giovanni Battista Hospital, Torino; Azienda Universitaria-Ospedaliera di Cagliari; and Azienda Ospedaliera di Sassari.
Provenance and peer review Not commissioned; externally peer reviewed.