Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson's disease in Sardinia

Abstract

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson's disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51-79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD.

Fig. 1

Genetic findings and neuroimaging in a family with FTLD with parkinsonism and PD. a Pedigree of the family. b Electropherogram showing the heterozygous TARDBP p.Ala382Thr mutation. c DaTSCAN-SPECT in the SAR-403 patient showing severe defects at the level of the caudate nucleus and putamen, bilaterally

Fig. 2

DaTSCAN-SPECT images in PD patients with the TARDBP p.Ala382Thr mutation. In two patients carrying the TARDBP p.Ala382Thr mutation (a Sar-239, b Sar-104), the DaTSCAN-SPECT imaging shows asymmetric defects, predominantly at the level of the putamen, as typically observed in idiopathic PD