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Arch Neurol. 2004;61:1006.

In 1940, Mount and Reback¹ described familial paroxysmal choreoathetosis in a report in the ARCHIVES, more than 60 years ago. Known also as paroxysmal dystonic choreoathetosis (PDC) (Mendelian Inheritance in Man No. 11880) and paroxysmal nonkinesigenic dyskinesia, it is a movement disorder in which episodes of dystonia, chorea, and athetosis begin in childhood through early adulthood; involve the extremities, trunk, and face; and may be associated with dysarthria and dysphagia. These episodes are of varying lengths—from minutes to an hour—and may recur several times a day. Paroxysmal movements may occur spontaneously while at rest or may be precipitated by alcohol or caffeine use, fatigue, hunger, or emotional stress.

Fink et al^2-3 mapped this disorder on chromosome 2q in 1996, and in 1997 they described the essential issues involved in its pathophysiologic features. Now in this issue of the ARCHIVES, Rainier et al⁴ report the identification of the PDC gene. It represents a major step forward in the molecular characterization of the genetic basis of movement disorders and is a tribute to the tenacity and dedication of John Fink, MD, and his able collaborators.

These authors analyzed 2 unrelated PDC kindreds and found 2 disease-specific missense mutations in the myofibrillogenesis regulator 1 gene (MR-1): an exchange of valine for alanine at amino acids 7 and 9 in affected subjects in 2 kindreds, PDC-Pa and PDC-Det. Of note, they find that these MR-1 mutations disrupt an interspecies conserved residue, disrupt the predicted amino-terminal helix, segregate completely with the disorder in each family, and most important, are absent in DNA samples from unaffected family members and 105 unrelated control subjects. They also show that the MR-1 exon containing these mutations (exon 1) is expressed only in the brain, thus providing the basis for its being a neurologic disorder.

The authors propose that the MR-1 gene plays a role in myofibril development through the regulation of calcium or possibly other ion sequestration. Thus, they view PDC as resulting from abnormal ion localization, similar to other episodic neurologic disorders. The finding of MR-1 as the gene that causes PDC is an important neurogenetic event. This finding will be an impetus for studies to explain the effect of alcohol and caffeine on triggering paroxysmal movement attacks and, more centrally and specifically, why MR-1 mutations cause episodic extrapyramidal involuntary movements.

The question is often asked regarding whether or not the Human Genome Project (http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml; http://www.ncbi.nlm.nih.gov/genome/guide/human/) has clearly benefited human neurogenetics by advancing the understanding of clinical neurogenetic disorders. The article by Rainier et al⁴ provides a clear affirmative. Dr Fink and his colleagues physically mapped the PDC locus interval using 22 overlapping bacterial artificial chromosome elements. Subsequently, as they point out, the Human Genome Project created overlapping contigs spanning 2.4 Mb that included this locus and for which DNA sequences were available. These data made it possible to identify 116 potential candidate genes for PDC and finally, as elegantly described in their article, the MR-1 gene and missense mutations that cause this disorder. It is a triumph of intense and brilliant research and also a stunning example of the translational power and precision that the Human Genome Project is bringing to clinical neurogenetics.

AUTHOR INFORMATION
This article was corrected online on 7/19/2004.

Roger N. Rosenberg, MD, Editor

REFERENCES
1. Mount LA, Reback S. Familial paroxysmal choreoathetosis: preliminary report on a hitherto undescribed clinical syndrome. Arch Neurol Psychiatry. 1940;44:841-847. FREE FULL TEXT 2. Fink JK, Rainier S, Wilkowski J, et al. Paroxysmal dystonia choreoathetosis: tight linkage to chromosome 2q. Am J Hum Genet. 1996;59:140-145. ISI | PUBMED 3. Fink JK, Hedera P, Albin RL, Mathay JG. Paroxysmal dystonia choreoathetosis: clincial and genetic analysis and proposed pathophysiology. Neurology. 1997;49:177-183. FREE FULL TEXT 4. Rainier S, Thomas D, Tokarz D, et al. Myofibrillogenesis regulator 1 gene mutations cause paroxysmal dystonic choreoathetosis. Arch Neurol. 2004;61:1025-1029. FREE FULL TEXT

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Myofibrillogenesis Regulator 1 Gene Mutations Cause Paroxysmal Dystonic Choreoathetosis
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