Objective: A systematic review of autosomal recessive parkinsonism using DJ-1 as an example.

Background: MDGene is a genotype-phenotype database for rare mutations in movement disorders and will be launched in June 2016. MDGene summarizes genetic and phenotypic information on mutation-positive individuals from the literature and thereby facilitates a synopsis of the available data in the field.

Methods: A systematic literature screen for DJ-1 in PubMed yielded 499 original articles. We identified 27 articles that reported at least one mutation-positive individual with parkinsonism and/or provided clinical information on mutation carriers. Mutations were included if they had a minor allele frequency <1% (based on the ExAC Browser, dbSNP or unaffected control individuals screened in the publication). We extracted data for 90 genetic and phenotypic features for affected and unaffected mutation carriers.

Results: Sixty-eight mutation-positive individuals affected or unaffected with parkinsonism from 37 families were included in our review. They carried 29 different DJ-1 mutations among which missense changes were the most common mutation type. We identified 19 homozygous (40%) and 2 compound-heterozygous (4%) patients. While DJ-1 mutations commonly segregate with PD following an autosomal recessive inheritance model, 58% (26/45) of all reported heterozygous individuals were also clinically affected. The presence of tremor, bradykinesia and rigidity was reported in the majority of homozygous patients while postural instability was only described in 37%. However, the percentage of missing data was large across the four symptoms (32% to 53%). The median age of onset in homozygous patients was 27.5 years (interquartile range = 34.0-22.5). Information on the effect of levodopa was given for 63% (12/19) of homozygous patients and 67% (8/12) responded to medication. Availability of data was low (11 to 26%) for anxiety, depression, psychotic symptoms and cognitive deficits.

Conclusions: Homozygous DJ-1 mutations lead to early-onset levodopa-responsive parkinsonism, and a substantial fraction of heterozygotes are also clinically affected suggesting that penetrance of DJ-1 mutations is influenced by other (epi)genetic or non-genetic factors. Our review revealed several data gaps in the literature, especially for non-motor symptoms. MDGene is a useful tool for the review of genotype-phenotype data in autosomal recessive parkinsonism.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/systematic-review-of-autosomal-recessive-parkinsonism-using-the-mdgene-database-protocol/