Parkinson Disease 22, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that heterozygous mutation in the CHCHD2 gene (616244) on chromosome 7p11.2 may be a rare cause of autosomal dominant Parkinson disease (PARK22).

Clinical Features

Funayama et al. (2015) identified a large 3-generation Japanese family in which a heterozygous mutation in the CHCHD2 gene cosegregated with autosomal dominant Parkinson disease (see MOLECULAR GENETICS). The mean age of onset among 8 affected members was 55.5 years (range, 48 to 61 years). Further screening of 340 index patients identified 3 additional patients with CHCHD2 variants. Among all families, most patients presented with typical parkinsonian features, including bradykinesia, rigidity, and gait disturbance. The mean age of onset among all 4 families was 56.2 years. A single patient presented as a child (age 10 years) and was 50 years old at the time of the report; his only symptoms were gait disturbance and upper limb essential tremor. All 8 patients tested had a clinical response to L-dopa; 3 of those had that response wear off. One person had depression and smell disturbance. Nine of 12 patients had asymmetry at onset of symptoms.

Molecular Genetics

Using linkage analysis, exome sequencing, and whole-genome sequencing, Funayama et al. (2015) identified a heterozygous thr61-to-ile mutation (T61I; 616244.0001) in 8 affected members of a Japanese family with autosomal dominant Parkinson disease (PARK22). Screening of 340 further index cases with autosomal dominant Parkinson disease by Sanger sequencing detected another patient with the T61I variant as well as an arg145 to gln (R145Q; 616244.0002) and c.300+5G-A (616244.0003) mutation in 1 patient each. To investigate whether CHCHD2 might be a susceptibility gene for sporadic Parkinson disease, Funayama et al. (2015) sequenced all CHCHD2 exons, including splice junctions, in 517 patients with sporadic Parkinson disease and 559 controls. They identified 2 SNPs with significantly different frequencies between cases and controls: -9T-G (OR 2.51, 95% CI 1.48-4.24, p = 0.0004) and 5C-T (OR 4.69, 95% CI 1.59-13.83, p = 0.0025). To confirm the link between CHCHD2 variants and the risk of sporadic Parkinson disease, Funayama et al. (2015) examined a previously reported genomewide association study on Parkinson disease in Japanese people (Satake et al., 2009). Although 1 SNP, rs816411, was found in an intron of CHCHD2, there was no significant difference in its frequency between patients and controls in that study.

In response to the report of Funayama et al. (2015), several groups independently investigated the pathogenicity of CHCHD2 variants in Parkinson disease and achieved results that called the findings of Funayama et al. (2015) into question. See 616244 for a discussion of these further reports.