Familial Parkinsonism: Study of Original Sagamihara PARK8 (I2020T) Kindred with Variable Clinicopathologic Outcomes

Overview

Journal Parkinsonism Relat Disord

Specialty Neurology

Date 2008 Sep 23

PMID 18804399

Citations 53

Authors

Kazuko Hasegawa

A Jon Stoessl

Teruo Yokoyama

Hisayuki Kowa

Zbigniew K Wszolek

Saburo Yagishita

Affiliations

Soon will be listed here.

Abstract

Background: Since the causative gene linked to PARK8 parkinsonism was identified as LRRK2, LRRK2 gene mutations have been found to occur in about 4% of patients with hereditary Parkinson disease (PD); this percentage is even higher in certain populations. Moreover, no clear clinical differences between PARK8-linked parkinsonism and sporadic PD have been identified. Neuropathologic findings have been diverse in PARK8 parkinsonism, but few of the clinicopathologic examinations have been performed in the same family tree. We aimed to describe PET and neuropathologic findings in members of the same family tree with PARK8 parkinsonism.

Methods: We conducted PET of 2 subjects and neuropathologically examined 8 subjects in the same family from the Sagamihara district, the original source of PARK8-linked parkinsonism (I2020T mutation).

Results: The results of the PET scans were virtually identical to those seen in sporadic PD. The neuropathologic study results showed pure nigral degeneration with no Lewy bodies in 6 cases. One case, however, showed the presence of Lewy bodies and was similar neuropathologically to conventional PD with Lewy bodies. Another case had multiple system atrophy pathology.

Conclusions: Our study of PARK8-linked parkinsonism affecting several members of the same pedigree shows that the same gene mutation can induce diverse neuropathologies, even if the clinical picture and PET findings are virtually identical.

Citing Articles

Updated MDSGene review on the clinical and genetic spectrum of LRRK2 variants in Parkinson´s disease.

Kruger C, Lim S, Buhrmann A, Fahrig F, Gabbert C, Bahr N NPJ Parkinsons Dis. 2025; 11(1):30.

PMID: 39962078 PMC: 11832785. DOI: 10.1038/s41531-025-00881-9.

Widespread Distribution of α-Synuclein Oligomers in -related Parkinson's Disease.

Sekiya H, Franke L, Hashimoto Y, Takata M, Nishida K, Futamura N bioRxiv. 2025; .

PMID: 39764048 PMC: 11702646. DOI: 10.1101/2024.12.18.629265.

Multiple system atrophy: an update and emerging directions of biomarkers and clinical trials.

Liu M, Wang Z, Shang H J Neurol. 2024; 271(5):2324-2344.

PMID: 38483626 PMC: 11055738. DOI: 10.1007/s00415-024-12269-5.

Formation of templated inclusions in a forebrain α-synuclein mouse model is independent of LRRK2.

Dues D, Ma Y, Nguyen A, Offerman A, Beddows I, Moore D Neurobiol Dis. 2024; 188.

PMID: 38435455 PMC: 10906965. DOI: 10.1016/j.nbd.2023.106338.

Perspective on the current state of the LRRK2 field.

Taymans J, Fell M, Greenamyre T, Hirst W, Mamais A, Padmanabhan S NPJ Parkinsons Dis. 2023; 9(1):104.

PMID: 37393318 PMC: 10314919. DOI: 10.1038/s41531-023-00544-7.

References

Dachsel J, Ross O, Mata I, Kachergus J, Toft M, Cannon A . Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathol. 2006; 113(5):601-6. DOI: 10.1007/s00401-006-0178-1. View

Orimo S, Ozawa E, Nakade S, Sugimoto T, Mizusawa H . (123)I-metaiodobenzylguanidine myocardial scintigraphy in Parkinson's disease. J Neurol Neurosurg Psychiatry. 1999; 67(2):189-94. PMC: 1736461. DOI: 10.1136/jnnp.67.2.189. View

NUKADA H, Kowa H, Saitoh T, Tazaki Y, Miura S . [A big family of paralysis agitans (author's transl)]. Rinsho Shinkeigaku. 1978; 18(10):627-34. View

Ross O, Toft M, Whittle A, Johnson J, Papapetropoulos S, Mash D . Lrrk2 and Lewy body disease. Ann Neurol. 2006; 59(2):388-93. DOI: 10.1002/ana.20731. View

Goldstein D, Imrich R, Peckham E, Holmes C, Lopez G, Crews C . Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation. Neurology. 2007; 69(16):1580-4. DOI: 10.1212/01.wnl.0000268696.57912.64. View

Gaig C, Marti M, Ezquerra M, Rey M, Cardozo A, Tolosa E . G2019S LRRK2 mutation causing Parkinson's disease without Lewy bodies. J Neurol Neurosurg Psychiatry. 2007; 78(6):626-8. PMC: 2077973. DOI: 10.1136/jnnp.2006.107904. View

Giasson B, Covy J, Bonini N, Hurtig H, Farrer M, Trojanowski J . Biochemical and pathological characterization of Lrrk2. Ann Neurol. 2006; 59(2):315-22. DOI: 10.1002/ana.20791. View

Inoue M, Yagishita S, Ryo M, Hasegawa K, Amano N, Matsushita M . The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems. Acta Neuropathol. 1997; 93(6):585-91. DOI: 10.1007/s004010050655. View

Adams J, van Netten H, Schulzer M, Mak E, McKenzie J, Strongosky A . PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. Brain. 2005; 128(Pt 12):2777-85. DOI: 10.1093/brain/awh607. View

10.

Wszolek Z, Pfeiffer B, Fulgham J, Parisi J, Thompson B, Uitti R . Western Nebraska family (family D) with autosomal dominant parkinsonism. Neurology. 1995; 45(3 Pt 1):502-5. DOI: 10.1212/wnl.45.3.502. View

11.

Ishizawa T, Mattila P, Davies P, Wang D, Dickson D . Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol. 2003; 62(4):389-97. DOI: 10.1093/jnen/62.4.389. View

12.

Giordana M, DAgostino C, Albani G, Mauro A, Di Fonzo A, Antonini A . Neuropathology of Parkinson's disease associated with the LRRK2 Ile1371Val mutation. Mov Disord. 2006; 22(2):275-8. DOI: 10.1002/mds.21281. View

13.

Hasegawa K, Funayama M, Matsuura N, Furusawa H, Sakai F, Kowa H . Analysis of alpha-synuclein, parkin, tau, and UCH-L1 in a Japanese family with autosomal dominant parkinsonism. Eur Neurol. 2001; 46(1):20-4. DOI: 10.1159/000050751. View

14.

Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F . A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol. 2002; 51(3):296-301. DOI: 10.1002/ana.10113. View

15.

Rajput A, Dickson D, Robinson C, Ross O, Dachsel J, Lincoln S . Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology. 2006; 67(8):1506-8. DOI: 10.1212/01.wnl.0000240220.33950.0c. View

16.

Wszolek Z, Vieregge P, Uitti R, Gasser T, Yasuhara O, McGeer P . German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia - Longitudinal observations. Parkinsonism Relat Disord. 2008; 3(3):125-39. DOI: 10.1016/s1353-8020(97)00013-8. View

17.

Wszolek Z, Pfeiffer R, Tsuboi Y, Uitti R, McComb R, Stoessl A . Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology. 2004; 62(9):1619-22. DOI: 10.1212/01.wnl.0000125015.06989.db. View

18.

Healy D, Falchi M, OSullivan S, Bonifati V, Durr A, Bressman S . Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 2008; 7(7):583-90. PMC: 2832754. DOI: 10.1016/S1474-4422(08)70117-0. View

19.

Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S . Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004; 44(4):601-7. DOI: 10.1016/j.neuron.2004.11.005. View

20.

Funayama M, Hasegawa K, Ohta E, Kawashima N, Komiyama M, Kowa H . An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol. 2005; 57(6):918-21. DOI: 10.1002/ana.20484. View