Clinical and pathological features of a parkinsonian syndrome in a family with an Ala53Thr alpha-synuclein mutation

We describe an Australian family of Greek origin with a parkinsonian syndro me and an Ala53Thr alpha -synuclein gene mutation. Five of 9 siblings were affected, the average age of onset was 45 years, and the initial symptoms w ere variable, including resting tremor, bradykinesia, and gait disturbance, as previously described in families with the same point mutation. Affected family members responded well to levodopa, developed progressive cognitive impairment, and had a disease duration of 5 to 16 years. Pathologic featur es typical of idiopathic Parkinson's disease were found at autopsy. However , there were several additional features not previously reported in familie s with this gene mutation. These features included severe central hypoventi lation, orthostatic hypotension, prominent myoclonus, and urinary incontine nce. An abundance of alpha -synuclein-immunoreactive Lewy neurites were fou nd in the brainstem pigmented nuclei, hippocampus, and temporal neocortex. The Lewy neurites were associated with temporal lobe vacuolation. Subcortic al basal ganglia cell loss and gliosis were seen. These additional clinical and pathological features suggest that the Ala53Thr alpha -synuclein mutat ion can produce a more widespread disorder than found in typical idiopathic Parkinson's disease.