Clinical findings in a large family with a parkin ex3delta40 mutation

Objective To describe a large consanguineous family in which inheritance of a 438– to 477–base pair deletion in exon 3 (Ex3{Delta}40) in the parkin gene resulted in parkinsonism (age range at onset, 24-32 years). Design Fifty-two family members underwent genetic analysis. Main Outcome Measure Two clinical examiners blinded to genetic status evaluated 21 family members, including all mutation carriers (4 homozygous and 12 heterozygous individuals; 5 family members did not have the mutation). Results In this family, the parkin Ex3{Delta}40 mutation is recessive; only homozygotes manifest symptoms of early-onset levodopa-responsive parkinsonism, including resting tremor, dystonia, and slow progression, with the caveat that presymptomatic signs of dopaminergic loss in heterozygotes must be excluded by fluorodopa F 18 with positron emission tomography. This contrasts with the autosomal dominant pattern of inheritance of parkinsonism described in families with the same mutation. Conclusion In families with a dominant inheritance, an additional genetic or environmental cause must coexist with the Ex3{Delta}40 mutation.