DYT16: Novel Dystonia-Parkinsonism Syndrome Described in 2 Families

Susan Jeffrey

February 12, 2008

February 12, 2008 — Researchers have described a novel, autosomal recessive young-onset dystonia parkinsonism syndrome in 2 Brazilian families, as well as the genetic mutation that appears to underlie the condition.

Corresponding author Andrew B. Singleton, PhD, from the Laboratory of Neurogenetics at the National Institute on Aging, in Bethesda, Maryland, told Medscape Neurology & Neurosurgery that clinically, this newly described disorder, dubbed DYT16, can present as a very young–onset dystonia, with signs and symptoms appearing in childhood and developing into generalized dystonia around age 20 years, while other affected people develop only mild dystonia, but with parkinsonism appearing in their 40s or 50s.

"It's quite a range of disease," he said. "Clearly, we don't understand why the disease can look so different across individuals, but that's interesting, too."

Their report, with first author Sarah Camargos, MD, and lead author Francisco Cardoso, MD, both from the Movement Disorders Clinic at the Federal University of Mias Gerais, Brazil, is published online February 1 in advance of the March issue of Lancet Neurology.

Single Common Ancestor

The current finding expands to 16 the number of genes associated with 14 forms of dystonia that have been described to date; the other mutations are DYT1 through DYT15.

Drs. Camargos and Cardoso in Brazil identified 2 apparently unrelated families with an autosomal recessive, young-onset generalized form of dystonia parkinsonism with shared features: affected individuals have progressive, early-onset dystonia with axial muscle involvement; oromandibular (sardonic smile), laryngeal dystonia; and in some cases, parkinsonian features. The condition is not responsive to levodopa therapy.

Using high-density genomewide single nucleotide polymorphism (SNP) genotyping arrays, they identified a genetic locus associated with the disease. Despite the families living hundreds of miles apart and being apparently unrelated, "the homozygous track of SNPs shared between all the mutation-positive samples clearly shows that this region is derived from a common ancestor," they write.

After complete sequence analysis of all coding regions within the locus, they found a single disease-segregating mutation, P222L, within the stress-response gene PRKRA.

They looked for but did not find this mutation in a variety of other populations, including 294 young-onset Parkinson's disease cases, 948 neurologically normal controls, and 738 other samples from diverse world populations, but they did find it in 3 of 14 probands with generalized dystonia in the Brazilian population, representing 21.4% of independent cases, they note.

"The P222L variant might not be pathogenic and could be in linkage disequilibrium with the actual disease-causing variant," they conclude. "However, the absence of the mutation in such a large series of controls and our inability to identify other mutations, despite screening all other genes in the identified region, clearly supports our assertion that mutation in PRKRA is the causative genetic mutation in DYT16."

Dr. Singleton said their group would continue to look for other mutations in this gene in other families with similar disease to try to confirm their findings and to discern more on the function of this gene. "We hope by understanding rare familial disorders that we can glean information about more common forms of similar diseases," he said.

"A New Twist on Familial Dystonia"

In a Reflection and Reaction article accompanying the paper, Christine Klein, MD, from the department of neurology at the University of Lübeck, in Germany, writes that Camargos and colleagues have identified a new, recessively inherited form of early-onset generalized dystonia associated with a homozygous missense mutation in PRKRA.

Affected members from unrelated Brazilian families have the same P222L mutation in PRKRA, inherited from a common founder and absent in almost 1000 neurologically healthy controls, Dr. Klein writes.

Advances in research often raise other lines of inquiry, she notes, "and accordingly, the finding of this mutation raises 3 important questions: what is the phenotype associated with mutations in PRKRA; what is the role of mutations in PRKRA in early-onset dystonia and related movement disorders; and what can mutations in PRKRA teach us about the pathophysiology of dystonia?"

Studies into the function of PRKRA will be a "natural extension of this work," Dr. Klein writes. "Likewise, mutational analyses of large samples of patients with dystonia who are from different ethnic backgrounds are needed to evaluate the frequency of mutations, the phenotypic and mutational spectrum, and more generally, the significance of DYT16 dystonia in clinical practice."

Dr. Singleton concurred that more work is needed to confirm their findings in other families. "We've clearly found this genetic region that contains a mutation, that we've put this mutation at PRKRA, but we really do have to find other families with this mutation to be 100% certain that this is what's causing the disease," he said. "It looks like it's the obvious candidate, but I think it still bears some follow-up work."

The study was supported in part by the intramural program of the National Institute on Aging, US National Institutes of Health, Department of Health and Human Services. The study authors declare no conflict of interest. Dr. Klein declares no conflict of interest.

Lancet Neurology 2008;7:207-215 Abstract, 192-193. Abstract