Familial parkinsonism: Study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes

Hasegawa, Kazuko; Stoessl, A. Jon; Yokoyama, Teruo; Kowa, Hisayuki; Wszołek, Zbigniew K.; Yagishita, Saburo

doi:10.1016/j.parkreldis.2008.07.010

Cited by 103 publications

(77 citation statements)

References 21 publications

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“…On the basis of these results, the phenotypes of our patients seemed to be different from those of iPD patients with Lewy pathology. Pathologic findings in PD patients with LRRK2 mutations are very variable despite them exhibiting a relatively uniform clinical phenotype of parkinsonism (Cookson et al, 2008; Hasegawa et al, 2009; Ross et al, 2006; Ujiie et al, 2012; Zimplich et al, 2004). A clinicopathological study of patients with the p.G2019S mutation revealed no correlation between Lewy pathology and clinical phenotypes, including dementia and psychiatric symptoms (Ross et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease

Hatano

Funayama

Kubo

et al. 2014

Neurobiology of Aging

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Leucine-rich repeat kinase 2 (LRRK2) is a causative gene of autosomal dominant familial Parkinson’s disease (PD). We screened for LRRK2 mutations in 3 frequently reported exons (31, 41, and 48) in our cohort of 871 Japanese patients with PD (430 with sporadic PD and 441 probands with familial PD). Direct sequencing analysis of LRRK2 revealed 1 proband (0.11%) with a p.R1441G mutation, identified for the first time in Asian countries, besides frequently reported substitutions including, the p.G2019S mutation (0.11%) and p.G2385R variant (11.37%). Several studies have suggested that the LRRK2 p.R1441G mutation, which is highly prevalent in the Basque country, is extremely rare outside of northern Spain. Further analysis of family members of the proband with the p.R1441G mutation revealed that her mother and first cousin shared the same mutation and parkinsonism. Haplotype analysis revealed a different haplotype from that of the original Spanish families. Our patients demonstrated levodopa-responsive parkinsonism with intrafamilial clinical heterogeneity. This is the first report of familial PD because of the LRRK2 p.R1441G mutation in Asia.

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Section: Discussionmentioning

confidence: 99%

Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease

Hatano

Funayama

Kubo

et al. 2014

Neurobiology of Aging

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“…While a number of mutations have been described, only seven have been linked to disease with the G2019S mutation being the most common (reviewed in Dachsel and Farrer 2010). Individuals with familial LRRK2 mutations present with typical parkinsonism and often reveal typical Lewy body pathology, although this is not always the case (Khan et al 2005; Gaig et al 2007; Healy et al 2008; Perry et al 2008; Hasegawa et al 2009; Poulopoulos et al 2012). LRRK2 encodes a 2527-amino acid protein with both kinase and GTPase activity.…”

Section: Etiologymentioning

confidence: 99%

Parkinson’s Disease

Mhyre¹,

Boyd²,

Hamill³

et al. 2012

Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease

314

203

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Parkinson’s disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800’s by James Parkinson as the ‘Shaking Palsy’. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, α-synuclein. The presence of toxic aggregated forms of α-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of α-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded α-synuclein.

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“…1 ) [2,3] . Most patients from the Sagamihara family with the Lrrk2 p.I2020T mutation had 'pure' nigral degeneration (n = 6); however, one patient had MSA pathology and another one BLBD [16] . …”

Section: Neuropathology Of Lrrk2 Mutation Carriersmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 Gene-Associated Disease: Redefining Genotype-Phenotype Correlation

2010

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Background: Leucine-rich repeat kinase 2 (LRRK2) has emerged as the most prevalent genetic cause of Parkinson’s disease (PD) among Caucasians. Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families. Methods: Herein, we review available clinical and pathologic data on patients with an LRRK2 mutation who have come to autopsy. Results: Thirty-eight patients have been reported who presented clinically with PD; parkinsonism with resistance to levodopa, supranuclear gaze palsy, or autonomic dysfunction; or tremor and dementia. Pathology showed typical PD-type Lewy body disease (LBD) in most patients, whereas in others there was ‘pure’ nigral degeneration (one with TDP-43-positive inclusions), diffuse LBD, or tau-, α-synuclein- or ubiquitin-positive pathology reminiscent of progressive supranuclear gaze palsy, multisystem atrophy, and frontotemporal dementia with ubiquitin-positive inclusions. Conclusions: Such clinical and pathologic variability suggests Lrrk2 acts upstream from other proteins implicated in neurodegeneration. Specific mutations may be associated with alternative progressive supranuclear gaze palsy-like or ‘pure’ nigral degeneration phenotypes. A different effect on Lrrk2 kinase activity may play a role in such heterogeneity.

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Familial parkinsonism: Study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes

Cited by 103 publications

References 21 publications

Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease

Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease

Parkinson’s Disease

Leucine-Rich Repeat Kinase 2 Gene-Associated Disease: Redefining Genotype-Phenotype Correlation

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