In this current paper, we provided an exhaustive clinical description, neurophysiological, neuropsychological and neuroimaging data for a patient that we previously identified as carrying the p.A382T missense pathogenic variant of the TARDBP
gene (Chiò et al, 2011
). Highlighting the unique clinical aspects of this case may facilitate the identification of similar cases by other neurologists. The index case is affected by a predominant upper motor neuron ALS (Gordon et al, 2009
; Sabatelli et al, 2009), associated with a motor and vocal tic syndrome since childhood, extrapyramidal features consistent with a rigid-akinetic parkinsonism, and a mild FTD. None of his relatives, who also carry the same p.A382T missense mutation of the TARDBP
gene, albeit heterozygous, have clinical features of ALS, with the exception of his paternal grandfather, who developed of ALS and dementia and died 17 years after the onset of ALS. The patient’s father and one of his maternal aunts had FTD, while one of his paternal uncles has a motor and vocal tic syndrome from childhood and later-onset FTD. It is not clear whether the tic syndrome identified in the index case and in one of his paternal uncles is related to the p.A382T missense mutation of the TARDBP
gene. To the best of our knowledge, TARDBP
mutations have not been assessed in patients with tic syndrome.
mutations have been described as being related to typical ALS (Sreedharan et al, 2008
), ALS with FTD (Chiò et al, 2010
), ALS with extrapyramidal symptoms (Chiò et al, 2011
), ALS and supranuclear palsy (Chiò et al, 2011
), supranuclear palsy, FTD and chorea (Kovacs et al, 2009
), and FTD without motor neuron disease (Borroni et al, 2009
). In this family we have found that the same mutation can manifest with broadly different neurological phenotypes. Interestingly, the index case, who carries a homozygous mutation, has a clinical syndrome summarizing all the constellation of symptoms found in his family, but nevertheless he has a relatively mild ALS, with relatively slow progression over a four year period. Our previously published data demonstrated the founder nature of the p.A382T mutation in the Sardinian population (Chiò et al, 2011
). Thus, it is highly likely that the p.A382T mutation in both the maternal and paternal sides of the kindred shared the same common ancestor.
As already observed in our previous paper (Chiò et al, 2010
), the penetrance of this mutation is not complete, since the 82 years-old mother of the index case, who carries the p.A382T TARDBP
missense mutation, is neurologically healthy.
encodes for the TDP-43 protein, which has been found to be deposited in neurons in several neurological disorders, such as ALS, FTD with or without ALS, Parkinson’s disease and Alzheimer’s disease (Geser et al, 2009
), conditions that are now grouped under the general heading of multisystem TDP-43 proteinopaties. Moreover, post-mortem analysis of ALS cases shows the diffusion of TDP-43 pathology beyond the motor system to involve the nigro-striatal system, the neocortical and allocortical area and the cerebellum (Geser et al, 2008
). Therefore, the heterogeneity of clinical features associated to TARDBP
missense mutations may not be surprising. It is perhaps more surprising the presence of a marked phenotypic heterogeneity in members of same family, all carrying the same missense mutation. This finding indicates that other factors influence the phenotype related to TARDBP
mutations. While these factors remains unknown, it can be hypothesized that these can be genetic, epigenetic, post-translational, or environmental in nature (Simpson & Al Chalabi, 2006
). The unveiling of the mechanisms underlying the variability of the clinical phenotype in patients carrying pathogenic mutations may be of importance for identifying new pathways for targeted therapeutic interventions in ALS.