Olfactory dysfunction in LRRK2 G2019S mutation carriers

Department of Neurology, Beth Israel Medical Center, 10 Union Square East, Suite 5J, New York, NY 10003, USA.
Neurology (Impact Factor: 8.29). 07/2011; 77(4):319-24. DOI: 10.1212/WNL.0b013e318227041c
Source: PubMed


Olfactory dysfunction is an established nonmotor feature of idiopathic Parkinson disease (PD), which may precede disease onset. Olfaction is likely disturbed in patients with PD with leucine-rich repeat kinase (LRRK2) G2019S mutations, although the degree of impairment is debated. It is also unclear whether mutation carriers who have not yet manifested with PD have olfactory disturbances.
Thirty-one subjects with LRRK2 G2019S mutation-related PD (PD-manifesting carriers [PD-MC]), 30 subjects with PD without mutations (PD noncarriers [PD-NC]), 28 mutation carrier family members (nonmanifesting carriers [NMC]), and 46 controls completed the University of Pennsylvania Smell Identification Test (UPSIT). Generalized estimating equations were applied to determine whether olfactory score was associated with PD and LRRK2 mutation status.
As expected, having PD was associated with impaired olfaction regardless of LRRK2 mutation status. More importantly, however, impaired olfaction was increased overall in LRRK2 carriers both with and without PD, though the impairment was only present in a subset of NMCs. Compared to controls, the mean score was lower among NMC (difference = -3.518, p = 0.006), MC (difference = -7.677, p < 0.0001), and idiopathic PD (PD-NC) (difference = -13.810, p < 0.0001). Olfaction was better among MC (PD-MC) than non-LRRK2 PD (PD-NC) (difference = 6.13, p = 0.0012). Group differences from the continuous analysis were maintained in dichotomous analysis stratifying at 15th percentile for age and gender.
Olfaction is impaired in LRRK2 G2019S-mutation related PD, although less overall than other PD. Further, olfaction is impaired in a subset of LRRK2 NMC, suggesting that olfaction may be a marker for development of PD in this group, and that longitudinal studies are warranted.

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Available from: Richard Lipton, Dec 12, 2013
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    • "The aim of this study was to determine whether o-α-syn is suitable biomarker for detecting PD at the early stages of the disease. Recently, abnormal PET changes and olfactory dysfunction were reported in LRRK2-H (Nandhagopal et al., 2008; Ruiz-Martínez et al., 2011; Saunders-Pullman et al., 2011). Therefore, healthy family members with LRRK2 mutations are an excellent population for validating surrogate biomarkers for early stages of PD. "
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    ABSTRACT: Mutations in the leucine-rich repeat kinase 2 gene are the most common cause of autosomal dominant Parkinson's disease (PD). To assess the cerebrospinal fluid (CSF) levels of α-synuclein oligomers in symptomatic and asymptomatic leucine-rich repeat kinase 2 mutation carriers, we used enzyme-linked immunosorbent assays (ELISA) to investigate total and oligomeric forms of α-synuclein in CSF samples. The CSF samples were collected from 33 Norwegian individuals with leucine-rich repeat kinase 2 mutations: 13 patients were clinically diagnosed with PD and 20 patients were healthy, asymptomatic leucine-rich repeat kinase 2 mutation carriers. We also included 35 patients with sporadic PD (sPD) and 42 age-matched healthy controls. Levels of CSF α-synuclein oligomers were significantly elevated in healthy asymptomatic individuals carrying leucine-rich repeat kinase 2 mutations (n = 20; P < 0.0079) and in sPD group (n = 35; P < 0.003) relative to healthy controls. Increased α-synuclein oligomers in asymptomatic leucine-rich repeat kinase 2 mutation carriers showed a sensitivity of 63.0% and a specificity of 74.0%, with an area under the curve of 0.66, and a sensitivity of 65.0% and a specificity of 83.0%, with an area under the curve of 0.74 for sPD cases. An inverse correlation between CSF levels of α- synuclein oligomers and disease severity and duration was observed. Our study suggests that quantification of α-synuclein oligomers in CSF has potential value as a tool for PD diagnosis and presymptomatic screening of high-risk individuals.
    Frontiers in Aging Neuroscience 09/2014; 6:248. DOI:10.3389/fnagi.2014.00248 · 4.00 Impact Factor
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    • "Overall, patients with LRRK2 mutations display late-onset PD with symptoms indistinguishable from those of sporadic PD. Some studies have observed a higher prevalence of postural/action tremor [3], or olfactory [4] and gait [5] disturbances in non-manifesting p.G2019S carriers compared to non-carriers, however no reliable clinical predictor of disease has been identified. Penetrance of disease in LRRK2 mutation carriers is incomplete and age-dependent, rising to almost 75% by age 80 years. "
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    ABSTRACT: The discovery of genes implicated in familial forms of Parkinson's disease (PD) has provided new insights into the molecular events leading to neurodegeneration. Clinically, patients with genetically determined PD can be difficult to distinguish from those with sporadic PD. Monogenic causes include autosomal dominantly (SNCA, LRRK2, VPS35, EIF4G1) as well as recessively (PARK2, PINK1, DJ-1) inherited mutations. Additional recessive forms of parkinsonism present with atypical signs, including very early disease onset, dystonia, dementia and pyramidal signs. New techniques in the search for phenotype-associated genes (next-generation sequencing, genome-wide association studies) have expanded the spectrum of both monogenic PD and variants that alter risk to develop PD. Examples of risk genes include the two lysosomal enzyme coding genes GBA and SMPD1, which are associated with a 5-fold and 9-fold increased risk of PD, respectively. It is hoped that further knowledge of the genetic makeup of PD will allow designing treatments that alter the course of the disease.
    Parkinsonism & Related Disorders 01/2014; 20S1:S35-S38. DOI:10.1016/S1353-8020(13)70011-7 · 3.97 Impact Factor
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    • "LRRK2 p.G2019S clinical features compared with iPD in literature are contradictory. Overall, the clinical presentation of iPD and LRRK2 parkinsonism are similar (Aasly et al., 2005; Gosal et al., 2005; Healy et al., 2008; Hulihan et al., 2008; Ishihara et al., 2006; Lesage et al., 2005; Saunders-Pullman et al., 2011). Pilot studies suggest some disparities in terms of motor and non-motor dysfunction. "
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    ABSTRACT: Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.
    Neurobiology of Aging 11/2013; DOI:10.1016/j.neurobiolaging.2013.11.015 · 5.01 Impact Factor
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