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ARTICLES: A. S. Chen-Plotkin, W. Yuan, C. Anderson, E. McCarty Wood, H. I. Hurtig, C. M. Clark, B. L. Miller, V. M.-Y. Lee, J. Q. Trojanowski, M. Grossman, and V. M. Van Deerlin Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations Neurology 2008; 70: 521-527 [Abstract] [Full text] [PDF]

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Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations

Owen A. Ross, PhD, Mathias Toft, MD, PhD, (Oslo Norway), Kristoffer Haugarvoll, MD   (24 January 2008)

Reply from the authors

Alice Chen-Plotkin, Wuxing Yuan, Chivon Anderson, Elisabeth McCarty Wood, Howard I. Hurtig, Christopher Clark, Bruce L. Miller, Virginia M.-Y. Lee, John Q. Trojanowski, Murray Grossman, and Vivianna M. Van Deerlin   (24 January 2008)

Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations 24 January 2008
Owen A. Ross, PhD, Mayo Clinic 4500 San Pablo Road South, Jacksonville, FL 32224, Mathias Toft, MD, PhD, (Oslo Norway), Kristoffer Haugarvoll, MD Send Correspondence to journal: Re: Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations ross.owen{at}mayo.edu Owen A. Ross, PhD, et al.	Several recent articles in Neurology discuss mutations in the leucine- rich repeat kinase 2 (LRRK2) gene and their relevance to Parkinson’s disease (PD).[1-4] Pathogenic mutations in LRRK2 were first identified by linkage studies in large kindreds with autosomal dominant PD. However, an increasing number of novel LRRK2 variants are being identified in single patients or small families with PD, and pathogenicity for these variants thus remains equivocal. [2,4] Goldstein et al. describe neurocirculatory and nigrostriatal abnormalities reminiscent of sporadic PD in a patient harboring a LRRK2 p.T2356I substitution. [3] The p.T2356I variant was originally identified in one small family with incomplete segregation. Therefore pathogenicity of this variant is undetermined and it seems premature to attribute disease to LRRK2 p.T2356I in the examined patient. Given this background, Goldstein et al. may be reporting a patient with ‘idiopathic’ PD rather than LRRK2-associated disease. This uncertainty also applies to several novel LRRK2 mutations recently identified. [2,4] Chen-Plotkin et al. report their LRRK2 mutation screening in a series of 434 patients with neurodegenerative disorders. [2] Two patients carried the LRRK2 p.R793M substitution, one with a diagnosis of primary progressive aphasia (PPA) and the other with PD. We identified this variant in two healthy controls (n=587) and no parkinsonian patients (n=433) from the Norwegian population, which strongly indicates that p.R793M is not pathogenic and probably a rare variant. [5] Given these findings and the absence of dementia in other p.R793M carriers, there is no evidence that PPA is related to LRRK2 mutations as reported. Over 50 LRRK2 variants have been reported and in the recent review by Klein and Schlossmacher, it is claimed that at least sixteen “appear to be clearly pathogenic”. [1] The pathogenicity of a mutation is generally assumed if it segregates with disease in families or significantly associates with disease. In our opinion, five LRRK2 mutations segregates with PD in families (p.R1441C, p.R1441G, p.Y1699C, p.G2019S and p.I2020T), and only these are definitively proven pathogenic. In addition the p.G2385R variant is consistently associated with an increased risk for PD in Asian populations. Evaluation of pathogenicity for each individual LRRK2 mutation is critical when assessing its role in PD. Manifestation of disease should not always be attributed to LRRK2 due to the presence of a mutation, even one considered putatively pathogenic. Symptomatic attribution or diagnostic genetic testing is only meaningful for LRRK2 mutations that are definitively proven to be pathogenic. References 1. Klein C, Schlossmacher MG. Parkinson disease, 10 years after its genetic revolution. Multiple clues to a complex disorder. Neurology 2007:Aug 29; [Epub ahead of print]. 2. Chen-Plotkin AS, Yuan W, Anderson C, et al. Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations. Neurology 2007:Oct 3; [Epub ahead of print]. 3. Goldstein DS, Imrich R, Peckham E, et al. Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation. Neurology 2007;69:1580-1584. 4. Nichols WC, Elsaesser VE, Pankratz N, et al. LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. Neurology 2007;69:1737-1744. 5. Toft M, Haugarvoll K, Ross OA, Farrer MJ, Aasly JO. LRRK2 and Parkinson's disease in Norway. Acta Neurol Scand Suppl 2007;187:72-75. Klein et al and Goldstein et al were offered the opportunity to respond but declined. The authors report no conflicts of interest.
Reply from the authors 24 January 2008
Alice Chen-Plotkin, University of Pennsylvania 3600 Spruce St., Philadelphia, PA, Wuxing Yuan, Chivon Anderson, Elisabeth McCarty Wood, Howard I. Hurtig, Christopher Clark, Bruce L. Miller, Virginia M.-Y. Lee, John Q. Trojanowski, Murray Grossman, and Vivianna M. Van Deerlin Send Correspondence to journal: Re: Reply from the authors alicechenplotkin{at}gmail.com Alice Chen-Plotkin, et al.	We thank Drs. Ross et al for their comments and agree that caution is needed in attributing pathogenicity to genetic variants. In our article, the LRRK2 p.R793M variant is considered only a change of putative pathogenicity which had previously been reported in two familial PD cases, one sporadic PD case, and one control individual. [6] We agree that at this point p.R793M is not a definitively pathogenic mutation, but it may confer risk of neurodegeneration. Our point was that LRRK2 mutations, which have previously been considered to manifest clinically as parkinsonism, may exhibit cognitive phenotypes. As other screens for LRRK2 mutations have been carried out primarily in patients with movement disorders, the assumption that LRRK2 mutations uniformly exhibit parkinsonian clinical phenotypes may be premature. References 6. Berg D, Schweitzer KJ, Leitner P, et al. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson’s disease. Brain 2005;128:3000-3011. Disclosure: The authors report no conflicts of interest.