Background: Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary movements that occur spontaneously while at rest and following caffeine or alcohol consumption. Previously, we and others identified a locus for autosomal dominant PDC on chromosome 2q33-2q35.

Objective: To identify the PDC gene.

Design: Analysis of PDC positional candidate genes by exon sequencing and reverse transcription-polymerase chain reaction.

Setting: Outpatient clinical and molecular genetic laboratory at a university hospital. Patients Affected (n = 12) and unaffected (n = 26) subjects from 2 unrelated families with PDC and 105 unrelated control subjects.

Results: We identified missense mutations in the myofibrillogenesis regulator gene (MR-1) in affected subjects in 2 unrelated PDC kindreds. These mutations were absent in control subjects and caused substitutions of valine for alanine at amino acid positions 7 and 9. The substitutions disturb interspecies conserved residues and are predicted to alter the MR-1 gene's amino-terminal alpha helix. The MR-1 exon containing these mutations (exon 1) was expressed only in the brain, a finding that explains the brain-specific symptoms of subjects with these mutations.

Conclusions: Although MR-1 gene function is unknown, the precedence of ion channel disturbance in other episodic neurologic disorders suggests that the pathophysiologic features of PDC also involve abnormal ion localization. The discovery that MR-1 mutations underlie PDC provides opportunities to explore this condition's pathophysiologic characteristics and may provide insight into the causes of other paroxysmal neurologic disorders as well as the neurophysiologic mechanisms of alcohol and caffeine, which frequently precipitate PDC attacks.