A COMPLEX PICTURE

Part of the genetic revolution in movement disorders has come in understanding that for many disorders, a single gene acting in a purely dominant or recessive fashion will not explain the subtlety of the genetic picture. Huntington’s disease is the classic example of a purely genetic movement disorder, in which presence of an expanded huntingtin gene guarantees development of the disease, and absence precludes it. “The situation is quite different in dystonia and Parkinson’s disease,” noted Dr. Klein, of the Department of Neurology, University of Lübeck, Germany. “Monogenic forms can only be found in a minority of our patients.”

Despite a more complex genetic picture, correlations can often be made between genetics and clinical findings. Early-onset dystonia, characterized by onset in a limb and the tendency to generalize, is often hereditary. In contrast, adult-onset dystonia, which rarely involves the lower limbs and usually remains focal, is almost always sporadic.

“In Parkinson’s disease, however, the situation is not so clear,” Dr. Klein cautioned. Monogenic Parkinson’s disease is often indistinguishable from sporadic Parkinson’s disease. Given that the genetic status of most patients is unknown, and that most genetic contributors to the disease have yet to be discovered, “this raises the key question, What is idiopathic Parkinson’s disease?”

Indeed, one of the biggest changes brought on by the genetic explosion is to overturn the long-held concept that Parkinson’s disease is the “textbook example” of a “nongenetic” movement disorder, she said.

There are some common clues that raise suspicion of a familial movement disorder, including a positive family history, early age at onset, a specific clinical picture, and a specific ethnic origin. “We must keep in mind, however, that we may have to consider a genetic etiology even in the absence of a positive family history,” she said. Reasons may include nonpaternity, adoption, or early parental death, as well as the genetic phenomena of variable expressivity, reduced penetrance, anticipation, and a de novo mutation.

Conversely, Dr. Klein remarked, the family history may appear to be positive, even in the absence of a shared gene, due to the shared environment or common exposure to an infectious or toxic agent.

MOLECULAR DIAGNOSIS AN NEW DISEASES

The genetic diagnostic process has advanced considerably in recent years. The gold standard for investigating a gene mutation today is sequence analysis—looking for the specific mutation in the gene. Haplotype analysis—linking inheritance of a large DNA segment with disease in a family—was once the only way to predict disease in most cases. Today, it is reserved primarily for discovering the approximate location of new genes, which are then isolated for sequence analysis.

If the disease gene is known, is fairly small, and has only one or a few disease-causing mutations, sequence analysis is routine and usually easy, said Dr. Klein. Such is the case for DYT1 dystonia, and more recently, DYT8 dystonia. Genetic testing for repeat expansions, such as for Huntington’s disease or the spinocerebellar ataxias, is also relatively straightforward, and the results are typically unambiguous.

The situation is quite different for a large gene in which there are more than a handful of pathogenic mutations. Such is the case for LRRK2, the recently identified Parkinson’s disease gene, which has 51 exons and more than half a dozen significant mutations identified to date. In this kind of case, direct sequencing of the entire gene is impractical. Research groups typically restrict their focus to one exon and can provide a definitive molecular diagnosis only if a mutation is found within it.

“The situation for genetic testing becomes even more complicated,” said Dr. Klein, “when we turn to the genes causing early-onset parkinsonism,” such as parkin. This gene—an autosomal recessive responsible for a large minority of cases of early-onset Parkinson’s disease—has 12 exons, each of which is known to carry at least one pathogenic mutation. Dr. Klein’s group is moving to comprehensive mutation screening across all 12 exons, despite the labor, in order to avoid missing less common mutations.

New genetic diseases have also been discovered and confirmed with genetic methods, Dr. Klein noted. Perhaps the most famous is FXTAS, or fragile X–associated tremor/ataxia syndrome. FXTAS is due to an expansion of the same gene whose absence causes fragile X mental retardation.

IDENTIFYING AT-RISK INDIVIDUALS

Genetic advances have also made it clear that genes may play a role in many cases previously thought to be entirely sporadic. This is especially so in the still controversial issue of the role played by heterozygous mutations in early-onset, recessively inherited Parkinson’s disease. The classic mendelian view is that heterozygotes for a recessive trait manifest no signs of disease, because two copies are needed. But this simplification has significant exceptions.

“Heterozygous mutations are found frequently in early-onset Parkinson’s disease series,” noted Dr. Klein. Mutations in the parkin gene are the best-studied example. While a common objection is that perhaps the second mutation has been overlooked, or another gene is really the culprit, there is good evidence for an actual heterozygote effect, she said. In such series, there is an inverse correlation between the number of mutated alleles and the age at onset, with onset in heterozygotes 10 years later than in homozygotes. Furthermore, some offspring of parkin mutation carriers, in whom it is unlikely that a second mutation would be missed, display mild parkinsonian symptoms, or even full-blown Parkinson’s disease.

Even in those without overt clinical symptoms, the presence of a single mutated allele may have significant effects. “There is very clear-cut evidence that there are preclinical changes in asymptomatic heterozygotes,” Dr. Klein pointed out. Also, neuroimaging studies of carriers have indicated reduced fluorodopa uptake compared with controls. These individuals also have an increased gray matter volume that is negatively correlated with the uptake values, suggesting the occurrence of compensatory mechanisms in the brain in response to the loss of the parkin gene product.

TESTING

The wealth of new genetic information for movement disorders has brought the question of genetic testing—whether symptomatic, presymptomatic, or susceptibility testing—to the fore for a much wider set of diseases than in the past.

The benefits of genetic testing may be significant, said Dr. Klein, because a test can minimize further work-up, reduce uncertainty for the patient or family, clarify treatment approaches, and assist with future family planning. She stressed, however, that testing must be accompanied by both pretest and posttest education and counseling at a center that has experience in the issues that testing brings to the surface. The exemplar is Huntington’s disease, in which careful development of guidelines has been driven by extensive research into the psychosocial consequences of both positive and negative test results.

Again, however, the situation is much more complicated in Parkinson’s disease, she observed. There are many more genes, but each affects a far smaller proportion of the patient population, and most patients have no known genetic contribution to their disease.

THE PENETRANCE PROBLEM

Genetic testing is also complicated in diseases with reduced penetrance, Dr. Klein said. In DYT1 dystonia, for example, only about 30% of those with the DYT1 mutation will manifest the disease. A genetic test can determine presence of the mutation, but not whether the individual will become symptomatic.

Conversely, in myoclonic dystonia, reduced penetrance can not only be explained but can be predicted in about 90% of the carriers, based on genetic imprinting. Imprinting is the phenomenon in which an allele’s expression depends on which parent it is inherited from. In the case of the myoclonic dystonia gene, the maternal allele is silenced. If a child inherits a mutated allele from the father, she will develop symptoms in almost all cases, whereas if she inherits it from the mother, she will not. Thus, through testing to determine not only the presence but also the provenance of the allele, a confident prediction can be made in most cases.

TOWARD TREATMENT

Genetic testing may also be useful for guiding treatment decisions. For instance, psychiatric problems are a more significant concern in dopa-responsive and myoclonic dystonias than in other forms. To date, deep brain stimulation appears to be more effective in DYT1 dystonia than in other forms. Of course, if protective therapies can be developed, genetic testing will become a significant tool for identifying at-risk patients and starting them on the appropriate therapy, Dr. Klein remarked.

As the genetic revolution in movement disorders progresses, she continued, several key challenges remain. In addition to the need for guidelines for testing, there is also a need for improvements in the cost, quality control, and simplicity of the tests. At the same time, as the tests become more widely available, neurologists and pediatricians must be educated about the benefits and limitations of each new test so that they will be equipped to make recommendations and answer concerns of the patient and family.

Finally, Dr. Klein reminded the audience of the first principle of medicine. “Given all the uncertainties and problems, we need to be very careful. First, do no harm.” As the field advances, now is the time to work out important ethical, legal, and social issues inevitably raised by more widespread genetic testing, she said.

NR

—Richard Robinson

Suggested Reading
Klein C. Movement disorders: classifications. J Inherit Metab Dis. 2005;28:425-439.

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