Objective: To systematically review information regarding genotype, phenotype, and biochemistry in dopa-responsive dystonia (DRD).

Background: To date, five causative genes (GCH1, TH, SPR, PTS, and QDPR), all encoding enzymes involved in the biosynthesis of dopamine/BH4, have been associated with DRD with variable phenotypic characteristics, impacting early diagnosis and treatment. The Movement Disorder Society Genetic mutation database (www.mdsgene.org) provides an overview of published genetic and phenotypic data on monogenic movement disorders.

Method: We performed a systematic literature search using PubMed and analyzed individual genetic, clinical, and histochemical data of 735 patients from 205 articles. Inclusion criteria were presence of a movement disorder and a clearly indicated, rare and at least possibly pathogenic genetic variant in one of the five genes. Cases with variants in more than one gene were excluded as well as carriers of single heterozygous variants in recessive disease genes.

Results: Besides an overall excellent response to L-Dopa, multiple significant differences were found across genes. While heterozygous DYT/PARK-GCH1 often starts in childhood, all other DRDs showed a median infantile onset. Dystonia was the most prominent motor sign except for DYT/PARK-PTS (38% dystonia but 67% hypotonia). Dystonia was typically complex and accompanied by cognitive impairment and global developmental delay in all forms but heterozygous DYT/PARK-GCH1, who often showed isolated (68%) or combined dystonia (17%). Parkinsonism (DYT/PARK-GCH1) and hypotonia (DYT/PARK-TH, DYT/PARK-SPR, DYT/PARK-QDPR) were the second most common motor feature after dystonia. Most frequent initial signs were hypotonia (DYT/PARK-TH, DYT/PARK-SPR, DYT/PARK-PTS), global developmental delay (DYT/PARK-QDPR), and foot dystonia (DYT/PARK-GCH1). Biochemically, DYT/PARK-GCH1 showed reduced neopterin and biopterin values in CSF and urine, whereas these metabolites were increased in carriers of mutations in others DRD genes. Prolactin blood values were elevated in all DRDs except for DYT/PARK-GCH1.

Conclusion: Our review provides a comprehensive overview of the current knowledge of DRD. Especially in the rare forms of DRD, our understanding is based on very small numbers of patients calling for detailed and systematic databases like MDSGene to assist with clinical diagnosis and genetic counseling.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mdsgene-systematic-review-on-dopa-responsive-dystonia-caused-by-mutations-in-gch1-th-spr-pts-or-qdpr/