Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes - PubMed (original) (raw)

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

Kazuko Hasegawa et al. Parkinsonism Relat Disord. 2009 May.

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.

PubMed Disclaimer

Figures

Fig. 1

Pedigree of Sagamihara family with PARK8-linked parkinsonism. Filled symbols indicate affected members. Slanted lines indicate deceased members. Cases 1 to 10 indicate fully examined members reported in this study. Cases 2 and 7 are from a small family pedigree that had branched off from the main family sometime between 1600 and 1700 AD (based on the haplotype analysis).

Fig. 2

Neuropathologic findings from 2 subjects (cases 3 and 7) with PARK8 parkinsonism in the current study. A, View of the substantia nigra in case 3. Neuronal cell loss and gliosis were mild compared with that seen in sporadic Parkinson disease. (Hematoxylin-eosin; original magnification, ×200.) B, Scanning view of the midbrain in case 3. Marked gliosis was seen in the area of the substantia nigra, especially the pars reticulata. (Holzer stain.) C, View of the locus ceruleus in case 3. Neuronal cells are well preserved. (Hematoxylin-eosin; original magnification, ×100.) D, View of the locus ceruleus in case 7. Neuronal cells are well preserved. (Hematoxylin-eosin; original magnification, ×100.)

Fig. 3

Neuropathologic findings from case 6 (A–C) and case 10 (D–F) in the current study. A, View of the putamen (case 6). Many oligodendroglia with positively stained cytoplasm are seen. (Anti-α-synuclein antibody; original magnification, ×200.) B, View of the cerebellum (case 6). Diffuse loss of Purkinje cells and granular neurons with gliosis in the white matter. (Hematoxylin-eosin; original magnification, ×100.) C, View of the putamen (case 6). Many glial cytoplasmic inclusions and protoplasmic astrocytes are seen. (Hematoxylin-eosin; original magnification, ×200.) D, View of the locus ceruleus (case 10) showing Lewy bodies. (Anti-α-synuclein antibody; original magnification, ×200.) E, View of the dorsal vagus nerve (case 10) showing Lewy bodies. (Anti-α-synuclein antibody; original magnification, ×200.) F, View of the locus ceruleus (case 10); some Lewy neurites also were observed. (Anti-α-synuclein antibody; original magnification, ×200.)

References

1. 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;51:296–301. - PubMed
1. Hasegawa K, Funayama M, Matsuura N, Furusawa H, Sakai F, Kowa H, et al. Analysis of alpha-synuclein, parkin, tau, and UCH-L1 in a Japanese family with autosomal dominant parkinsonism. Eur Neurol. 2001;46:20–4. - PubMed
1. Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44:595–600. - PubMed
1. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–7. - PubMed
1. Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, et al. International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 2008;7:583–90. - PMC - PubMed

Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes - PubMed (original) (raw)