Background: Dystonia and parkinsonism may present as part of the same genetic disorder. Identification of the genetic mutations that underlie these diseases may help to shed light on the aetiological processes involved.
Methods: We identified two unrelated families with members with an apparent autosomal recessive, novel, young-onset, generalised form of dystonia parkinsonism. We did autozygosity mapping and candidate gene sequencing in these families.
Findings: High-density genome-wide SNP genotyping revealed a disease-segregating region containing 277 homozygous markers identical by state across all affected members from both families. This novel disease locus, designated DYT16, covers 1.2 Mb at chromosome 2q31.2. The crucial interval contains 11 genes or predicted transcripts. Sequence analysis of every exon of all of these transcripts revealed a single disease-segregating mutation, c.665C>T (P222L), in the stress-response gene PRKRA, which encodes the protein kinase, interferon-inducible double-stranded RNA-dependent activator.
Interpretation: We describe a mutation within the gene PRKRA that segregates with a novel, autosomal recessive, dystonia parkinsonism syndrome. These patients have progressive, generalised, early-onset dystonia with axial muscle involvement, oromandibular (sardonic smile), laryngeal dystonia and, in some cases, parkinsonian features, and do not respond to levodopa therapy.