Familial parkinsonism with synuclein pathology - Clinical and PET studies of A30P mutation carriers

Background: The authors identified the second known mutation in the alpha - synuclein (SNCA) gene, an alanine-to-proline exchange in amino acid positio n 30 (A30P), that cosegregates with the disease in one German family with a utosomal dominantly inherited parkinsonism (ADP). The authors studied carri ers of the A30P mutation to compare the phenotype of this mutation with idi opathic PD (:IPD) and to assess nigrostriatal dopaminergic function in symp tomatic and preclinical mutation carriers. Methods: The pedigree of the A30 P family spans five generations with five affected individuals. The authors performed detailed neurologic examinations followed by mutation analysis i n 11 living individuals. In three mutation carriers, two individuals with d efinite PD and one person at risk for PD, they used L-[(18)]F-fluoro-3,4-di hydroxyphenylalanine (F-DOPA), [(11)]C-raclopride (RAC), and [(18)]F-fluoro deoxyglucose (FDG) PET to investigate presynaptic dopaminergic function, do pamine D, receptors, and cerebral energy metabolism. The authors studied th e cognitive functions of carriers of the A30P mutation casing neuropsycholo gical screening. Results: PET studies revealed striatal presynaptic dopamin ergic alterations consistent with sporadic IPD in two affected family membe rs and no evidence for nigrostriatal dopaminergic dysfunction in one presym ptomatic mutation carrier. Neuropsychological testing in four mutation carr iers provided evidence for cognitive impairment as a frequent and early sym ptom of the A30P mutation; this is also supported by regional cerebral ener gy metabolism alterations in the clinically presymptomatic subject. Conclus ions: The phenotype of the A30P mutation in the SNCA gene is similar to tha t of sporadic IPD, including a high variability of the age at disease onset , ranging from 54 to 76 years. The follow-up of presymptomatic carriers of the A30P mutation may give insight into preclinical disease stages and earl y manifestations of PD.