The Contursi Family 20 Years Later: Intrafamilial Phenotypic Variability of the SNCA p.A53T Mutation

The SNCA/alpha-synuclein p.A53T mutation segregating in the Contursi kindred was the first mutation ever described in inherited Parkinson’s disease (PD).1,2 We directly examined 10 subjects (4 PD patients and 6 asymptomatic relatives) of a branch of the Contursi kindred. We also collected data on 11 members affected by history, through interviews and inspection of available medical records. Nine had died in the fourth to seventh decade diagnosed with PD (plus psychiatric features in 3), whereas 2 were reported to have severe psychiatric disturbances and were unavailable for examination. After obtaining ethics approval and written informed consent, all subjects underwent a complete neurological examination (see Video 1) and SNCA p.A53T mutation testing. The 4 PD patients (age, 4269.8 years), and 2 unaffected individuals (age, 29.562.1 years) resulted as heterozygous for the mutation. Two affected (III:1, IV:1) and 2 unaffected (IV:2, IV:6) carriers also underwent extensive neuropsychological and psychiatric assessment, olfaction evaluation, and dopamine transporter imaging with single-photon emission computed tomography (DAT-SPECT); 3T brain MRI was performed in 3 subjects (III:1, IV:2, and IV:6; Fig. 1). Although the overall phenotype in the 4 patients was typical of SNCA-related PD with early, asymmetric onset, initial good response to dopaminergic therapy and early motor complications, 3 a relevant variability was observed in the combination and severity of motor symptoms (partially responding to levodopa and DBS in III-9) and nonmotor features (Table 1). Age at onset varied from 26 to 48 years (mean, 32.7610.5), with longer disease duration than previously reported (from 2 to 19 years; mean, 9.268.5). Cognitive deficits were present in all 4 patients, ranging from frank dementia in those with longer disease duration (III-8, III-9) to moderate cognitive impairment (III-1) or slight isolated executive dysfunction (IV-1) in those with a shorter one. Depression and anxiety were detected in 3 patients, behavioral disorders in 2, and dysautonomia in 2. Olfaction was impaired in both tested patients. Although the variable severity could depend on the different disease duration, the wide range of ages at onset among carriers of the same genetic mutation remains unexplained, suggesting the existence of yet unknown environmental, genetic, and/or epigenetic modifiers.4 Interestingly, 2 asymptomatic carriers, ages 31 and 28 years, were clinically unaffected. Their general cognitive functions were normal and they did not refer any sleep or mood disorder. However, the younger one (IV:2) presented an objective olfactory deficit and an abnormal DAT scan, suggesting an underlying, still subclinical, neurodegenerative process. The existence of SNCA mutation carriers who remain clinically asymptomatic at ages beyond the expected age of onset has been reported, implying reduced penetrance. 5 However, our carriers were still younger than the latest age of onset in the family; therefore, any conclusion would be merely speculative and further clinical follow-up is necessary. In conclusion, our data further highlight the relevant intrafamilial phenotypic variability in carriers of the SNCA p.A53T mutation, suggesting a role for yet unknown genetic or environmental modifiers. Follow-up studies are encouraged to better define the clinical spectrum of PD caused by SNCA gene mutations.