Parkinson disease-18 is an autosomal dominant, adult-onset form of the disorder. It is phenotypically similar to idiopathic Parkinson disease (summary by Chartier-Harlin et al., 2011).
For a general phenotypic description and a discussion of genetic heterogeneity ... Parkinson disease-18 is an autosomal dominant, adult-onset form of the disorder. It is phenotypically similar to idiopathic Parkinson disease (summary by Chartier-Harlin et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600.
Chartier-Harlin et al. (2011) reported a large French family with classic late-onset Parkinson disease. The mean age at disease onset was 64 years, but there was a broad range (50 to 80 years). Affected individuals had insidious onset ... Chartier-Harlin et al. (2011) reported a large French family with classic late-onset Parkinson disease. The mean age at disease onset was 64 years, but there was a broad range (50 to 80 years). Affected individuals had insidious onset of asymmetric resting tremor or akinetic rigidity, and the parkinsonism followed a relatively long, mild course, with preserved cognition. Symptoms responded well to L-dopa treatment. Dopaminergic imaging in symptomatic patients was abnormal and asymmetric.
In affected members of a large French family with late-onset Parkinson disease, Chartier-Harlin et al. (2011) identified a heterozygous mutation in the EIF4G1 gene (R1205H; 600495.0001) by use of genomewide linkage analysis followed by direct sequencing. The EIF4G1 ... In affected members of a large French family with late-onset Parkinson disease, Chartier-Harlin et al. (2011) identified a heterozygous mutation in the EIF4G1 gene (R1205H; 600495.0001) by use of genomewide linkage analysis followed by direct sequencing. The EIF4G1 gene was subsequently sequenced in 95 probands with autosomal dominant parkinsonism and 130 pathologically-defined cases of Lewy body disease, which revealed 4 additional different missense mutations in 2 PD patients and 2 Lewy body disease cases. These 4 variants were then genotyped in a case-control series consisting of 4,483 individuals with idiopathic PD and 3,865 controls: 3 additional patients carried only 2 of the variants, 2 with A502V (600495.0002) and 1 with a G686C substitution. Coimmunoprecipitation studies indicated that the R1205H and A502V substitutions impaired formation of the larger translation initiation complex. The results were compatible with a dominant-negative loss of function and age-dependent neurodegeneration. Hydroperoxide treatment caused a profound loss of mitochondrial membrane potential in cells expressing the mutations compared to cells with wildtype protein. Chartier-Harlin et al. (2011) postulated that the mutations hindered the ability of cells to respond rapidly and dynamically to stress, presumably through changes in the translation of existing mRNAs essential to cell survival. The findings implicated defects in mRNA translation initiation in Parkinson disease.