The many faces of alpha‐synuclein mutations

Since the first description of alpha-synuclein (SNCA) mutations in 1997, this gene has probably become the most intensely investigated one associated with monogenic Parkinson disease (PD). Prompted by the finding of a novel SNCA mutation, H50Q, we systematically explored the 145 published SNCA mutation carriers for a possible mutation (type)-specific clinical expression, which appears to be rather unique to SNCA mutations compared with other PD genes. The A53T mutation is associated with an approximately 10-year earlier age at onset than the other 3 known missense mutations, including the new H50Q mutation. Similarly, SNCA triplication carriers have an approximately 10-year earlier onset and a more rapid disease course than duplication carriers, who, overall closely resemble patients with idiopathic PD. Furthermore, higher order SNCA multiplications are associated with additional neurologic features, such as myoclonus. For the nonmotor features, their mere frequency appears less striking than their severity, with an early age of onset of depression or dementia, suicidal ideation, and multimodal hallucinations. We conclude that, (1) although SNCA mutations are a rare cause of PD, it remains worth testing for new mutations in this gene; (2) a differential view of SNCA mutations and variants may allow important pathophysiologic inferences even beyond monogenic PD and is warranted in the context of clinical counseling.