Genetically isolated populations are an important resource for finding genetic determinants of human diseases. As a result of a limited number of founder alleles, prolonged geographical isolation, and genetic drift, the genetic architecture of disease is expected to be simpler in the genetic isolates than in the general populations, thereby facilitating the identification of the disease-causing or disease-predisposing alleles . The population of Sardinia is one of the most extensively studied genetic isolates, which has yielded founder mutations and risk alleles in several disorders ([18, 19, 23, 26] and references therein).
The recent identification of the founder TARDBP p.Ala382Thr mutation as the cause of a large percentage of ALS cases in this island is not only another example of the power of this approach. It is also a proof of principle that large etiological fractions of common neurodegenerative diseases can be underlain by rare mutations of large effects. A similar scenario has been delineated for the founder p.Gly2019Ser mutation in the LRRK2 gene as a cause of PD among patients of North African and Middle Eastern ancestries (reviewed in ).
The fact that all the three apparently healthy controls included in our study, who carried the p.Ala382Thr mutation, have developed ALS or dementia themselves or among their close relatives is a clear confirmation of the strong association between this mutation and the motoneuron disease–frontotemporal dementia spectrum. Furthermore, one control individual remains free from neurodegenerative signs and symptoms at the age of 79 years, illustrating the age-related, incomplete penetrance, already reported for this and other TARDBP mutations. A penetrance of 60% by age 70 has been recently estimated for the p.Ala382Thr mutation . The incomplete penetrance is also in keeping with the frequent occurrence of this founder mutation among patients with sporadic disease presentation.
While TARDBP mutations have been detected in several patients with familial and sporadic ALS (approximately 2–3% of cases in large studies), to our knowledge, an association between TARDBP mutations and FTLD has been reported so far in only eight unrelated cases [4–6, 28, 29]. In two of these patients, the FTLD phenotype (familial in one and sporadic in the other case) was followed by the development of MND within 2 years ; in another three cases with familial ALS (and carrying the p.Ala382Thr mutation), the MND was the presenting phenotype, which was followed soon by an FTLD . In the remaining three patients, sporadic FTLD presented as an isolated syndrome, without the development of MND within the follow-up period [4, 6, 28]. Of note, none of these cases presented parkinsonism.
Only three of the recently reported Sardinian ALS patients who carried the p.Ala382Thr mutation developed akinetic parkinsonism after the onset of ALS . Therefore, our family with FTLD and parkinsonism (Fig. 1) represents already a further expansion of the clinical spectrum associated with TARDBP mutations, by showing two patients with FTLD and prominent parkinsonism without MND, and a third with pure, l-dopa-responsive parkinsonism, in the absence of cognitive or motoneuron disturbances.
However, the most important finding of this study is the association between the p.Ala382Thr mutation and PD within our consecutive large Sardinian series. This points to a broader clinical expressivity of this mutation than earlier realized.
To our knowledge, only one systematic study of the entire TARDBP coding region in 125 PD patients of French–Canadian ancestry has been published, with negative results . It is interesting to note that none of our eight PD patients who carry the mutation reported a family history for PD, ALS, or dementia, providing further evidence for the incomplete penetrance of this mutation.
Unfortunately, pathological studies are not available to verify whether Lewy bodies, TDP-43-positive inclusions, or both, are present in the brain of these patients. This remains a very important objective for follow-up studies. However, all these eight cases fulfill the widely accepted clinical diagnostic criteria for definite PD, including several supporting features (asymmetric onset, good and prolonged l-dopa response, presence of resting tremor, progressive course with the absence of atypical signs for more than 5 years). In two patients carrying the TARDBP p.Ala382Thr mutation, the DaTSCAN-SPECT imaging showed asymmetric defects, predominantly at the level of the putamen, as typically observed in idiopathic PD (Fig. 2). Apart from a slightly (and non-significantly) later onset age of PD symptoms, these cases were clinically indistinguishable from the other patients in our study.
The reasons of the broad variability in the clinical expression of this mutation remain to be found. It is possible that the severity and the rapid progression of the ALS hamper the detection of extrapyramidal signs. However, three patients who carried the p.Ala382Thr mutation described in one of the previous studies developed extrapyramidal symptoms several years after their initial presentation with motoneuron disease . On the other hand, it is possible that the clinical signs of PD interfere with the detection of initial motoneuron disease signs. Nevertheless, none of our PD mutation carriers nor any of their close relatives developed clinical signs of the ALS spectrum.
It is likely that additional genetic (or non-genetic) factors modify the effects of the primary mutation (p.Ala382Thr), thereby leading to different clinical outcomes: ALS, FTLD, or parkinsonism, alone or in combination. For example, patients who manifest PD, or FTLD, as the resulting isolated clinical phenotype might carry mutations or polymorphisms in other loci that prevent (or delay) the onset of motoneuron disease and lead to the appearance of extrapyramidal or cognitive signs as the earliest clinical expression of the disease. Further work remains therefore ahead to identify the modifier(s) of this mutation, and genetic isolates (such as the Sardinian population) represent once more an ideal resource in this endeavor.
Following the initial association with the pathological hallmark inclusions in patients with FTLD, ALS, and ALS-MND, the TDP-43 protein has also been detected in the pathological lesions in relevant percentages of brains of patients with Lewy body disorders, ranging from 7% of PD cases to 19% of PD with dementia in one study , and to more than 50% of the brains with diffuse Lewy body disease in another study . Moreover, pathological lesions containing the TDP-43 protein were reported in proximity of small blood vessels in the brain of one patient with familial Lewy body disease caused by the p.Ala53Thr mutation in the alpha-synuclein (SNCA) gene . Taken together, these findings provide evidences of important intersections between the pathogenesis of the TDP-43 proteinopathies and the alpha-synucleinopathies, supporting the contention that TARDBP mutations might underlie prominent parkinsonism in patients with FTLD and also present as isolated PD.
In conclusion, our data provide a first direct link between the TARDBP mutation and PD, supporting an involvement of the TDP-43 protein in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD, but also PD. Further analyses of the whole TARDBP coding region in large series of familial and sporadic PD patients are warranted.