Hereditary parkinsonism: Parkinson disease look‐alikes—An algorithm for clinicians to “PARK” genes and beyond

Abstract

In the past decade, a number of genetic causes of parkinsonism have been identified. As a consequence, clinicians have to consider an increasing range of differential diagnoses when confronted with a patient with parkinsonism with a positive family history. While well-established monogenic forms with PARK acronyms have been reviewed extensively, less emphasis has been placed on other inherited conditions that may also present with signs of parkinsonism or even mimic idiopathic Parkinson's disease clinically. In this review, we focus on three different scenarios in patients with an overall early age of onset of parkinsonism: (i) atypical features in patients with mutations in one of the "PARK" genes; (ii) classical parkinsonism due to mutations in "other than-PARK" genes or yet other genes where parkinsonism may be a well-recognized, concomitant, or even an isolated feature; (iii) atypical parkinsonism in other genetic disorders which are, however, typically characterized by features other than parkinsonism. Atypical features in patients from Group I include, for example, a slower disease course (PARK2, PARK6, PARK7) or dementia (PARK1/4, PARK14). Conditions in Group II have been designated by a DYT or SCA acronym (for example, DYT5 or SCA3) and also include patients with heterozygous GBA mutations, mitochondrial gene mutations. Group III comprises mutations in the FMR1, MAPT, GRN, ATP7B, PANK2, FBXO7, CHAC, FTL1, Huntingtin, JPH3 genes, and a number of even rarer, miscellaneous conditions.

Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management

“…Many of these are classified as young-onset (,40 yr) or juvenile-onset PD (,21 yr) (Schrag and Schott 2006). A number of levodopa-responsive parkinsonian syndromes have been described and linked to a specific locus or gene in the last few years, and some of them have been classified as PARK syndromes (Gasser 2007;Klein et al 2009). Some of these denote true PD, whereas others represent more complex phenotypes and dissimilar diseases.…”

The role of α-synuclein in neurodegeneration — An update

“…So far, 18 PARK loci have been described, and 10 genes have been linked to PD [35,196,198,[201][202][203][204][205][206] (Figure 3): Autosomaldominant (ad) parkinsonism is caused by the genes encoding AS or LRRK2 (leucine-rich repeat kinase 2, dardarin/PARK 8), clinically comparable to sporadic (s) PD [207][208][209], but with variable neuropathology [210,211], suggesting an upstream role of LRRK2 in protein aggregation [212]. Mutations in the LRRK2 gene, being the most common form of fPD in the world, cause impairment of protein degradation pathways, in particular autophagy, which can lead to accumulation of AS and unbiquitinated proteins, accumulation of oxidized proteins, inflammatory response, and increased apoptosis [213] (Figure 4).…”

“…DJ-1 (PARK7) or ATP13A2 (PARK9), and PARK2, which encodes E ubiquitin in the UPS [223] disrupting this ligase activity and mitochondrial function [224][225][226], lead to arPD, but also to sPD [198]. The characteristics and molecular biology of PARK1-18 and of other genes associated with PD have recently been summarized [196,204].…”

The entity of parkinsonism and associated lipomatosis

“…Parkinson disease (PD) is usually a sporadic disorder; however, in approximately 5% of the cases, it can be familial. 1 In some genetic forms of PD, the phenotype may closely resemble sporadic PD; however, in others, the syndrome is more complicated and includes neurologic or systemic features that are unusual for sporadic PD. 1 We describe a new association of parkinsonism clinically resembling PD with multiple lipomatosis.…”

“…Giant-cell arteritis (GCA) is the most common systemic vasculitis of the elderly, with a lifetime risk of 1% in women and 0.5% in men. 1 Failure to identify the early signs of GCA can result in treatment delay, predisposing patients to a number of potentially disabling and life-threatening complications, including anterior ischemic optic neuropathy, stroke, aortic aneurysm, and dissection. 2 We present a case of biopsy-negative GCA in which PET-CT revealed evidence of extensive largevessel vasculitis.…”