Genetic Testing in Parkinson Disease
When discussing genetic testing in PD, several important points need to be considered, including the primary indication for testing, concerns regarding the implications of symptomatic, presymptomatic and susceptibility testing, the available technical expertise, the feasibility of specific-PD-gene testing and its coverage by a health insurance provider, the mutation frequency in the gene of interest, the general lack of neuroprotective treatment options in PD, and the prognosis of the condition diagnosed (nonfatal in the case of PD). Other important issues include general clinical management decisions, such as the pursuit of further diagnostic work-up, the empiric treatment of a given parkinsonian syndrome because of its clinical resemblance to a treatable condition (e.g. chelation therapy in Wilson disease) or more confident planning for deep-brain stimulation in the future, and important patient-confidentiality concerns.
Several PD-associated genes are quite large (e.g. Parkin) or contain a sizable number of exons (e.g. LRRK2), and gene-dosage alterations have been found in many of them. Therefore, mutational analysis is technically demanding, labor-intense, and expensive. Importantly, a negative result does not fully exclude a mutation, because introns and promoter regions are not usually sequenced, and the sensitivity and specificity of many testing methods are less than 100%.
Factors associated with mutation frequencies have been studied most extensively in Parkin-associated PD. In such cases, the frequency of mutations appears to be highly correlated to a lower age of onset and a positive family history. The observed mutation rate in a given gene will be influenced by ethnic background, mode of patient ascertainment, the exclusion of mutations in known genes before testing of a novel gene, and the extent of the mutational analysis. It is important to note that for idiopathic, late-onset PD, data on the frequency and spectrum of mutations in the above-mentioned genes are currently scarce, limiting the extent to which genetic insights can be applied to clinical practice (Figure 1).
Symptomatic testing for PD is aimed at elucidating the origin of the present condition, whereas presymptomatic testing is usually performed on an individual with a clear-cut family history, who has no symptoms of PD at the time of testing. These approaches involve looking for genetic mutations that have a high penetrance, such as homozygous or compound heterozygous mutations in recessively inherited genes (e.g. Parkin, PINK1, and DJ1) or dominantly inherited SNCA or LRRK2 mutations. By contrast, susceptibility testing is employed to test for higher probability—rather than certainty—of developing signs of PD in the future. Susceptibility testing is more relevant to a much larger at-risk population, and obviously yields more-ambiguous information (e.g. when testing for heterozygous mutations in recessively inherited genes, such as Parkin, DJ1, PINK1 or GBA, or for polymorphisms in candidate genes). Because of this ambiguity, it is recommended that this approach should be confined to the research setting, rather than being applied to routine clinical practice.
Genetic testing for Parkin and PINK1 has become increasingly commercially available. In addition, testing of these two genes, as well as of SCNA, DJ1 and LRRK2, is performed at a number of research laboratories, some of which provide individual reports to the referring neurologist. In the absence of established guidelines for genetic testing in PD, however, genetic analysis should not be recommended lightly as a diagnostic test. Testing needs to be accompanied by proper pre-test and post-test education and counseling at an experienced center. This approach differs from that of genetic research studies, where test results are not communicated back to the patients, in accordance with most study designs and stipulations by ethics review boards. Moreover, in the management of essentially all monogenic PD cases, symptomatic treatment will not be affected. Furthermore, there is no widely accepted neuroprotective treatment regimen available in our standard-of-care options at the present time. In contrast to the usually highly informative results obtained in Huntington disease—historically the frontrunner in genetic testing for a neurodegenerative (but also fatal, in contrast to PD) disorder—the result of a genetic test in PD might be inconclusive.
It is important to stress that no formal guidelines have been established by the Movement Disorder Society or any other international PD alliance group. In our experience, to minimize further work-up, clarify treatment approaches, and to assist with future family planning, genetic testing will most frequently be considered in the following clinical scenarios affecting symptomatic subjects: juvenile-onset PD (age of onset <20 years) irrespective of family history; early-onset PD (age of onset 21-40 years) with a positive family history and/or atypical features (e.g. dystonia in the lower extremities); or onset of PD after age 40 years with a strongly positive family history (especially of early-onset PD). In addition, presymptomatic testing in carefully selected individuals with an identified mutation in a first-degree family member might be considered (Figure 1). The unknown clinical significance of heterozygous mutations in recessively inherited genes should, however, be strongly emphasized in predicted carriers of heterozygous mutations (Figure 4), and genetic testing for diagnostic purposes in lieu of a readily available and inexpensive biomarker of the disease state (e.g. [18F]fluoro-dopa PET scanning) should be strongly discouraged. When considering genetic testing in routine neurological practice, we should remind ourselves of the timeless mandate, 'Primum nil nocere!' ('First, do no harm!'): the academic curiosity of a knowledgeable practitioner has to be weighed against the actual benefit (or lack thereof) of genetic testing to the patient. Therefore, we strongly recommend involving an expert in movement disorders and genetic counseling when considering a genetic test for PD-linked genes.
Genetic testing: a case example. Inference of mutational status in a single pedigree with one identified carrier of homozygous mutations in a recessively inherited Parkinson disease gene (shaded in black). The two bars next to the pedigree symbols represent the two alleles of the respective genes. A mutation is indicated by the star symbol. With nonpaternity excluded, individuals I.1, I.2, and III.1 can be inferred to be carriers of heterozygous mutations on the basis of the pedigree structure, whereas the mutational status in individuals II.2, II.3, and II.4 is unknown. Confirmation of predicted heterozygous mutations should be discouraged because their clinical significance is still unresolved. The uncertainties associated with the (possible) finding of a heterozygous mutation in individuals II.2, II.3, and II.4 need to be carefully considered in pre-test and post-test counseling of these individuals.
Nat Clin Pract Neurol. 2006;2(3):136 © 2006 Nature Publishing Group
Cite this: The Genetics of Parkinson Disease: Implications for Neurological Care - Medscape - Mar 01, 2006.