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The genetics of Parkinson disease: implications for neurological care

Nature Clinical Practice Neurology volume 2, pages 136–146 (2006)Cite this article

Abstract

The identification of single genes linked to heritable forms of Parkinson disease (PD) has challenged the previously held view of a nongenetic etiology for this progressive movement disorder. Detailed analyses of individuals with mutations in SNCA, Parkin, PINK1, DJ1 or LRRK2 have greatly advanced our knowledge of preclinical and clinical, morphological, and pathological changes in PD. These genetic breakthroughs have had profound implications for scientists, neurologists and patients alike. Such advances have provided unique opportunities to pursue the mechanisms of neuronal degeneration in models of PD pathogenesis, thereby reinforcing the significance of oxidative stress and mitochondrial dysfunction. With emerging clues from familial variants, researchers have begun to explore factors that lead to the expression of the more common, sporadic disease phenotype (idiopathic PD), including interactions between various genes, modifying effects of susceptibility alleles and epigenetic factors, and the influence of environmental agents and aging on the expression of PD-linked genes. These genetic leads have added to the urgency of developing translational drug treatments, and neurologists and their patients are confronting considerations relating to DNA testing. In this article, we summarize recent progress in establishing a neurogenetic component of PD, emphasize the need for developing PD biomarkers to improve diagnostic accuracy (in both clinical practice and therapeutic trials), and discuss scenarios in which specific DNA tests might be considered for diagnostic purposes. In the absence of consensus guidelines for DNA testing in PD and of any neuroprotective treatment for this nonfatal disorder, we remind ourselves of the omnipresent mandate, 'Primum nil nocere!' ('First, do no harm!').

Key Points

  • Over the past decade, Parkinson disease (PD) has evolved from a textbook example of a mostly nonhereditary disease to a complex disorder with a well-established genetic component in a considerable subset of patients

  • PD is clinically characterized by the cardinal features of bradykinesia, tremor, rigidity, postural instability, and responsiveness to dopaminergic therapy

  • Disease phenotypes associated with the PARK1–9 chromosomal loci follow a typical Mendelian pattern of inheritance, but PARK10 and PARK11 represent susceptibility loci with an as yet undefined mode of transmission

  • Monogenic PD accounts for a minority of cases; most of the other cases are probably caused by complex interactions between several genes, modifying effects of susceptibility alleles and epigenetic factors, and effects on PD-linked-gene expression that are attributable to environmental agents and aging

  • When considering genetic testing in routine PD practice, the academic curiosity of a knowledgeable practitioner has to be weighed against the actual benefit of genetic testing to the subject

  • The PD field now enjoys an embarrassment of riches in genetic leads that also represent a mandate for translational research success

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Figure 1: Frequency of heritable Parkinson disease.
Figure 2: Examples of pedigrees, to illustrate mode of inheritance in monogenic Parkinson disease (PD).
Figure 3: Parkinson disease (PD) as a complex disorder.
Figure 4: Genetic testing: a case example.

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Acknowledgements

We thank our patients and their families for encouragement and support. The authors wish to express their gratitude to their colleagues M Farrer, A Lang and L Sudarsky for critical comments on earlier versions of the manuscript. CK received support through a Lichtenberg Grant from the Volkswagen Foundation, the Deutsche Forschungsgemeinschaft, and a Research Grant from the University of Lübeck; MGS received support from the National Institute of Neurological Disorders and Stroke/National Institutes of Health, Michael J Fox Foundation, and Multiple System Atrophy Fund at Brigham and Women's Hospital.

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Authors and Affiliations

  1. Lichtenberg Professor of Clinical and Molecular Neurogenetics at the Department of Neurology at Lübeck University, Lübeck, Germany

    Christine Klein

  2. assistant professor of neurology at Harvard Medical School, Boston, MA, USA

    Michael G Schlossmacher

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Correspondence to Christine Klein.

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Klein, C., Schlossmacher, M. The genetics of Parkinson disease: implications for neurological care. Nat Rev Neurol 2, 136–146 (2006). https://doi.org/10.1038/ncpneuro0126

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