ALS/FTD phenotype in two Sardinian families carrying bothC9ORF72andTARDBPmutations

Abstract

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.

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

“…Further studies are needed to determine if the co-occurrence of ATXN2 and C9orf72 expansions could influence age at onset or survival in addition to the ALS/FTD phenotype. The C9orf72 expansion has also been described in association with TARDBP, FUS, and SOD1 mutations [109][110][111][112][113][114][115][116] in patients with ALS, with PGRN, MAPT, PSEN-2, and SQSTM1 mutations in FTD patients [75,[117][118][119][120], and with variants in other minor genes, such as ANG, PRPH, OPTN, DAO, UBQLN2, VAPB, CHMP2B, SETX, ALS2, SPG11, and DCTN1 [20,[110][111][112][113]121]. Double mutations have also been described in patients without C9orf72 mutations.…”

Neuroimaging features inC9orf72andTARDBPdouble mutation with FTD phenotype

“…In our family, it was not possible to analyze the parents. Therefore, we cannot demonstrate the paternal and maternal genetic contribution to the pathogenesis of the disorder, although the family history is suggestive of dual inheritance similar to that reported by Chiò et al (2012).…”

“…A similar hypometabolic pattern has been also found in three Italian families with familial ALS and TARDBP gene mutations (Chiò et al, 2012). The TARDBP p. N267S mutation was described in a woman with bvFTD, without motor neuron disease, with onset in late seventies.…”

“…To the best of our knowledge, no other neuroimaging findings in such patients have been reported, nor there is any FDG-PET data available in the bvFTD presentation of TARDBP patients. Chiò et al (2012) described a patient with ALS-FTD who carried C9orf72 expansion, inherited from the father, and p. A382T in the TARDBP gene, inherited from the mother, demonstrating that these mutations can coexist, but neuroimaging findings were not available. In our family, it was not possible to analyze the parents.…”

“…Neuropathology studies in patients with the C9orf72 mutation showed the presence of TDP-43 inclusions in many cerebral regions, thus including these patients in the TDP-43 phenotypic spectrum. Moreover, the evidence for an oligogenic basis for ALS and FTD has been recently highlighted by reports of patients carrying mutations in either causative gene (Chiò et al, 2012). In a small number of FTD/ALS cases, coexistent mutations have been found in GRN, TARDBP, and MAPT.…”