Hiroyo Yoshino

Clinical heterogeneity of α-synuclein gene duplication in Parkinson's disease

Recently, genomic multiplications of α‐synuclein gene (SNCA) have been reported to cause hereditary early‐onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinsons disease (ADPD).

Novel PINK1 mutations in early-onset parkinsonism

PINK1 was recently found to be associated with PARK6 as the causative gene. We performed mutation analysis in eight inbred families whose haplotypes link to the PARK6 region. We identified six pathogenic mutations (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated families. All sites of mutations were novel, suggesting that PINK1 may be the second most common causative gene next to parkin in parkinsonism with the recessive mode of inheritance. Ann Neurol 2004;56:424–427

Mitochondrial complex I and II activities of lymphocytes and platelets in Parkinson's disease.

SummaryMitochondrial Complex I deficiencies have been described not only in the brain but also in the skeletal muscle and platelets in Parkinsons disease (PD). We report activities of Complex I, II, III, and IV in lymphocytes and platelets in 20 patients with PD and age-matched controls. A small but a significant decrease in the platelet Complex I activity was found in PD (9.14±1.86 units/mg protein) compared with that in the control (12.37±2.66 units/mg protein) (P=0.0002). The lymphocyte Complex I activity was about the same between PD and the control. The activity of Complex II was slightly diminished in both platelets and lymphocytes in PD. Rather small decrease in the platelet Complex I activity in PD may be clinically non-significant. But it may indicate the presence of a qualitatively similar abnormality in platelets as in the nigro-striatal neurons. The cause for decrease in the Complex II activity is unknown at this moment. Further studies seem necessary.

Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism

The authors performed PINK1 mutation analysis of 51 families with autosomal recessive Parkinson disease (ARPD). They found two novel PINK1 mutations: one was a homozygous deletion (13516-18118del) and the other a homozygous missense mutation (C388R). Clinically, the patients with the deletion had dementia. Thus, early-onset PD with dementia may be considered PINK1-linked parkinsonism. Furthermore, patients with PINK1 mutations form 8.9% of parkin- and DJ-1-negative ARPD families.

CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study

BACKGROUND Identification of causative genes in mendelian forms of Parkinsons disease is valuable for understanding the cause of the disease. We did genetic studies in a Japanese family with autosomal dominant Parkinsons disease to identify novel causative genes. METHODS We did a genome-wide linkage analysis on eight affected and five unaffected individuals from a family with autosomal dominant Parkinsons disease (family A). Subsequently, we did exome sequencing on three patients and whole-genome sequencing on one patient in family A. Variants were validated by Sanger sequencing in samples from patients with autosomal dominant Parkinsons disease, patients with sporadic Parkinsons disease, and controls. Participants were identified from the DNA bank of the Comprehensive Genetic Study on Parkinsons Disease and Related Disorders (Juntendo University School of Medicine, Tokyo, Japan) and were classified according to clinical information obtained by neurologists. Splicing abnormalities of CHCHD2 mutants were analysed in SH-SY5Y cells. We used the Fishers exact test to calculate the significance of allele frequencies between patients with sporadic Parkinsons disease and unaffected controls, and we calculated odds ratios and 95% CIs of minor alleles. FINDINGS We identified a missense mutation (CHCHD2, 182C>T, Thr61Ile) in family A by next-generation sequencing. We obtained samples from a further 340 index patients with autosomal dominant Parkinsons disease, 517 patients with sporadic Parkinsons disease, and 559 controls. Three CHCHD2 mutations in four of 341 index cases from independent families with autosomal dominant Parkinsons disease were detected by CHCHD2 mutation screening: 182C>T (Thr61Ile), 434G>A (Arg145Gln), and 300+5G>A. Two single nucleotide variants (-9T>G and 5C>T) in CHCHD2 were confirmed to have different frequencies between sporadic Parkinsons disease and controls, with odds ratios of 2·51 (95% CI 1·48-4·24; p=0·0004) and 4·69 (1·59-13·83, p=0·0025), respectively. One single nucleotide polymorphism (rs816411) was found in CHCHD2 from a previously reported genome-wide association study; however, there was no significant difference in its frequency between patients with Parkinsons disease and controls in a previously reported genome-wide association study (odds ratio 1·17, 95% CI 0·96-1·19; p=0·22). In SH-SY5Y cells, the 300+5G>A mutation but not the other two mutations caused exon 2 skipping. INTERPRETATION CHCHD2 mutations are associated with, and might be a cause of, autosomal dominant Parkinsons disease. Further genetic studies in other populations are needed to confirm the pathogenicity of CHCHD2 mutations in autosomal dominant Parkinsons disease and susceptibility for sporadic Parkinsons disease, and further functional studies are needed to understand how mutant CHCHD2 might play a part in the pathophysiology of Parkinsons disease. FUNDING Japan Society for the Promotion of Science; Japanese Ministry of Education, Culture, Sports, Science and Technology; Japanese Ministry of Health, Labour and Welfare; Takeda Scientific Foundation; Cell Science Research Foundation; and Nakajima Foundation.

Phenotypic spectrum of patients with PLA2G6 mutation and PARK14-linked parkinsonism

Background: PLA2G6 is the causative gene for infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome. Based on previous reports, patients with PLA2G6 mutations could show axonal dystrophy, dystonia, dementia, and cerebellar signs. Recently, PLA2G6 was also reported as the causative gene for early-onset PARK14-linked dystonia-parkinsonism. Methods: To clarify the role of PLA2G6 mutation in parkinsonism, we conducted mutation analysis in 29 selected patients with very early-onset (≤30, mean 21.2 ± 8.4 years, ±SD) parkinsonism. These patients had other clinical features (e.g., mental retardation/dementia [14/29], psychosis [15/29], dystonia [11/29], and hyperreflexia [11/29]). Results: Two novel compound heterozygous PLA2G6 mutations were detected (patient A: p.F72L/p.R635Q; patients B1 and B2: p.Q452X/p.R635Q). All 3 patients had early-onset l-dopa–responsive parkinsonism with dementia and frontotemporal lobar atrophy. Disease progression was relatively rapid. SPECT in patient B1 showed frontotemporal lobar hypoperfusion. MRI in patient A showed iron accumulation in the substantia nigra and striatum. Conclusions: Although the clinical presentation of PLA2G6-associated neurodegeneration was reported to be homogeneous, our findings suggest patients with PLA2G6 mutation could show heterogeneous phenotype such as dystonia-parkinsonism, dementia, frontotemporal atrophy/hypoperfusion, with or without brain iron accumulation. Based on the clinical heterogeneity, the functional roles of PLA2G6 and the roles of PLA2G6 variants including single heterozygous mutations should be further elucidated in patients with atypical parkinsonism, dementia, or Parkinson disease. PLA2G6 mutations should be considered in patients with early-onset l-dopa–responsive parkinsonism and dementia with frontotemporal lobar atrophy.

Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries

We screened LRRK2 mutations in exon 41 in 904 parkin‐negative Parkinsons disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single‐founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single‐founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac 123I‐metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations.

Polymorphism in the parkin gene in sporadic Parkinson's disease.

We report polymorphism of the parkin gene in 160 sporadic Parkinsons disease (PD) patients and controls. Three polymorphisms were found: a G‐to‐A transition in exon 4 (S/N167), a C‐to‐T transition in exon 10 (R/W366), and a G‐to‐C transition in exon 10 (V/L380). Genotype distributions and allele frequencies of S/N167 and V/L380 did not differ significantly between the two groups. The R/W366 allele frequency was significantly lower in PD patients (1.2 vs 4.4%). The level of protection from PD provided by this allele was 3.60 (95% CI; range, 0.45–6.50), suggesting that it may be a protective factor against PD. Ann Neurol 1999;45:655–658

PARK9-linked parkinsonism in eastern Asia: mutation detection in ATP13A2 and clinical phenotype.

PARK9, a form of autosomal recessive parkinsonism, or Kufor-Rakeb syndrome (KRS), is characterized by subacute or slowly progressive, juvenile-onset, levodopa-responsive parkinsonism, pyramidal signs, dementia, and supranuclear gaze palsy.1–5 Recently, ATP13A2 was identified as the causative gene for PARK9 in Chilean and Jordanian families.4 This gene contains 29 exons encoding a lysosomal type 5 P-type ATPase. Six mutations have been reported in only five probands so far.4,5 Here, we describe a Japanese patient with KRS with a novel mutation who developed early onset parkinsonism, dementia, and other features. We also describe PET findings of PARK9 -linked parkinsonism. ### Methods. Haplotype analysis was conducted in 117 (mainly Japanese) patients with early onset (≤50, 26.8 ± 11.7 years, mean ± SD) parkinsonism. Among them, 14 patients had dementia. Patients who exhibited homozygosity on PARK9 locus by haplotype analysis underwent direct sequencing for all 29 exons (e-Methods on the Neurology ® Web site at www.neurology.org); the remaining patients underwent direct sequencing for exons 13, 16, and 26, in which mutations …

Is Parkinson's disease a mitochondrial disorder?

Parkinsons disease (PD) is a common degenerative disease, but its etiology is still unknown. However, since the discovery of MPTP, many investigators have been interested in the mitochondrial function in PD. We investigated mitochondrial functions in PD patients using the methods which have successfully been applied to mitochondrial myopathies (MM), i.e. assay of lactate and pyruvate, measurement of muscle mitochondrial respiratory enzyme activities and Southern blot analysis of muscle mitochondrial DNA. Parkinsons disease patients did not differ from controls in the mean blood and CSF (cerebrospinal fluid) lactate and pyruvate levels at the basal resting state or during an aerobic exercise. But mitochondrial complex I activity of the skeletal muscle was significantly decreased in PD. In the Southern blot analysis, we could not find major deletions or insertions of mitochondrial DNA in PD. Our studies disclosed a differential mitochondrial impairment between PD and MM. We discuss the implication of our observation.