The Genetics of Parkinson Disease: Implications for Neurological Care

Christine Klein; Michael G. Schlossmacher


Nat Clin Pract Neurol. 2006;2(3):136 

In This Article

Summary and Introduction


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!').


During 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 (Figure 1). In the clinical setting, this evolution is reflected in an increasing demand for mutational analysis of PD-associated genes by doctors and well-informed patients. Recent advances in the molecular genetics of PD have markedly improved our conception of its etiology and pathophysiology; however, the identification of different forms of monogenic PD has revealed an unexpectedly large amount of clinical and genetic heterogeneity. Additional complexity is added by the existence of as yet unidentified PD genes, and by the still-incomplete picture of the scope of mutations in already identified genes.

Figure 1.

Frequency of heritable Parkinson disease. Estimated frequency of monogenic Parkinson disease variants in different groups separated by age at onset of disease. LRRK2, leucine-rich repeat kinase 2; PD, Parkinson disease; PINK1, phosphatase and tensin homolog (PTEN)-induced putative kinase 1; SNCA, α-synuclein.