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

Terminology and Genetic Categories of Parkinsonian Syndromes

Consensus statements for terminology and diagnostic criteria have been developed for several parkinsonian disorders,[1] and the umbrella term 'parkinsonism' was coined to broadly categorize this set of disorders. PD accounts for ~75% of cases of parkinsonism[2] and is clinically characterized by the cardinal features of bradykinesia, tremor, rigidity, postural instability, and responsiveness to dopaminergic therapy.[3,4] The diagnosis of 'IDIOPATHIC' PD usually refers to clinically typical, late-onset, nonheritable parkinsonism, which at autopsy reveals one of six stages of neuronal loss, astrocytic gliosis, and formation of hallmark inclusions in the brainstem and elsewhere (LEWY BODIES and dystrophic neurites); this type of PD is considered distinct from other parkinsonian syndromes.[2,5]

The differential diagnosis of parkinsonian disorders often poses clinical challenges, owing to phenotypic variance, associated comorbidities, and the general lack of validated and ubiquitously available biomarkers for individual subtypes. Parkinsonian disorders other than PD are often associated with atypical features and, together with idiopathic PD, are believed to be genetically distinct from monogenic forms of parkinsonism. The rare monogenic variants, however, which can be sporadic or familial and usually, but not always, present at an earlier age of onset (<20 years of age for the juvenile form and <40 years of age for the early form), are often clinically indistinguishable from idiopathic PD;[6,7,8,9] these monogenic variants can also appear pathologically indistinguishable.[10,11,12,13] For clarity and practical purposes, this review will focus on forms of parkinsonism that can mimic idiopathic PD clinically, and, therefore, the term PD is used. We consider this practical approach to be justified for two reasons: first, the general lack of molecular tools for gaining more accurate insight into the individual pathogenesis of each patient with PD seen in the clinic; and second, the persistent uncertainty surrounding the actual role of neural inclusions. These inclusions have served as diagnostic tools in post-mortem analysis for decades, but they might not represent an accurate surrogate marker for the actual mechanism that promotes the death of vulnerable neurons.

The identification of several PD-associated genes has resulted in a 'classification' of monogenic PD variants that represent an assortment of clinically and genetically heterogeneous parkinsonian conditions. In Table 1 , these conditions are listed in order of their first description. This growing list cannot, however, be recommended as a widely applicable categorization of parkinsonian syndromes, for several reasons.[14] First, the clinical phenotype of some variants differs markedly from that of idiopathic PD, as is the case with mutations in the PARK9 gene (KUFOR-RAKEB SYNDROME). Second, the true contributory role in PD pathogenesis of the described mutations in some genes (e.g. Ile93→Met in the UCHL1 gene product, previously known as PARK5) needs to be further established or the gene simply remains unknown (as in the case of the PARK3 locus). Third, in addition to the above-mentioned syndromes, mutations in various other genes have been linked to PD in individual cases or small numbers of families but have not yet been assigned a PARK locus number. Moreover, other movement disorder syndromes can occasionally present as a phenocopy of PD ( Table 2 ). Last, even seemingly 'objective' genetic data should be interpreted with caution, because errors in locus assignment or in the distinction of POLYMORPHISMS from genuine mutations might occasionally occur.