Objective: To determine whether mutations in the genes for α-synuclein or β-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). Methods: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for α-synuclein and β-synuclein, as α-synuclein alterations cause PD and β-synuclein may modulate α-synuclein aggregation and neurotoxicity. Results: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the β-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the β-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients’ population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H β-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and α-synuclein aggregation without evidence of β-synuclein aggregation. Conclusion: Mutations in the β-synuclein gene may predispose to DLB.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of α-synuclein in characteristic inclusions known as ‘Lewy bodies’. As mutations altering α-synuclein structure or increasing α-synuclein expression level can cause familial forms of PD or related Lewy body disorders, α-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in ‘synucleinopathies’. β-synuclein is closely related to α-synuclein and has been shown to inhibit α-synuclein aggregation and ameliorate α-synuclein neurotoxicity. We generated β-synuclein transgenic mice and observed a marked reduction in α-synuclein protein expression in the cortex of mice over-expressing β-synuclein. This reduction in α-synuclein protein expression was not accompanied by decreases in α-synuclein mRNA expression. Using the prion protein promoter α-synuclein A53T mouse model of PD, we demonstrated that over-expression of β-synuclein could retard the progression of impaired motor performance, reduce α-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of α-synuclein neurotoxicity in such bigenic mice to the ability of β-synuclein to reduce α-synuclein protein expression based upon I ¹²⁵ autoradiography quantification. Our findings indicate that increased expression of β-synuclein protein results in a reduction of α-synuclein protein expression. As increased expression of α-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.

Background Dementia with Lewy bodies (DLB) is characterized by early dementia and associated visual hallucinations, parkinsonism, and fluctuations in cognition. Few families with DLB have been described with detailed clinical, pathological, and genetic assessments. Objective To investigate the clinical, neuropathological, and genetic characteristics of families with 2 or more autopsy-proven cases of DLB. Design Consecutive cases with the neuropathological diagnosis of DLB were reviewed as part of a case series. Families included in this study have 2 or more autopsy-proven cases of DLB available and a positive family history of dementia. We obtained clinical and neuropathological data on all first-degree relatives. Neuropathological evaluations included α-synuclein immunostaining for Lewy body detection. We conducted apolipoprotein E genotyping and sequenced the α-, β-, γ-synuclein, and parkin genes. Setting Subjects were selected from the neuropathology core of the University of Washington's Alzheimer's Disease Research Center. Patients The study investigated 2 families. Clinical information was obtained from 10 individuals in family 1 and 7 individuals in family 2. Neuropathological examinations were conducted in 3 individuals in family 1 and 2 individuals in family 2. Main Outcome Measures Each subject was examined for the presence of clinical symptoms and neuropathological findings consistent with DLB. Results While all affected individuals presented with dementia in both families, only individuals in family 1 developed visual hallucinations and delusions. Parkinsonism, if present, occurred later in the course of illness. Neuropathological examination revealed Lewy bodies in all patients, while 1 patient from each family also met the neuropathological criteria for Alzheimer disease. All affected individuals carried at least 1APOE(apolipoprotein E) ϵ4 allele, while there were no nucleotide alterations in the synuclein or parkin genes. Conclusions Familial DLB exists, although there is substantial clinical and neuropathological heterogeneity within and between families. Additional clinicopathologic and genetic studies are necessary to further our understanding of DLB.

HLA-B*15:02 screening before carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ-SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder associated with an unstable and expanded CAG repeat. We analyzed this locus from various sources including MJD families, Acadian, African American, Caucasian, Greenland Inuit and Thai populations. The range of the CAG repeat size was 14–40 in the normal alleles while the MJD alleles contained 73–78 repeats in our studies. We found 25 different alleles on normal chromosomes with a heterozygosity of 0.86 in combined populations. The most common alleles were 23 (22.9%) and 14 (25.5%) repeats. We also examined 16 chimpanzees and various Old World monkeys: a pigtail macaque, a mangabey and 12 rhesus macaques. The DNA sequences surrounding the CAG repeat did not vary among species. The range of the number of the CAG repeats is 13–14 in macaques, 16 in mangabey and 14–20 in chimpanzees. Variant CAA or AAG triplets in the CAG repeat tracts were found in all 268 human, 28 monkey and 32 chimpanzee chromosomes. As reported in a previous study [ Kawaguchi et al. (1994)Nature Genet . 8, 221–228] the common variant positions were the third (CAA), fourth (AAG) and sixth (CAA) positions. However, we found three human chromosomes containing CAG at the sixth position and the mangabey had AAG at the ninth position. In addition, we found CAG at the fourth position and AAG at the sixth position in all macaque chromosomes. The nu-cleotide following the CAG repeat tract was usually G in all species studied. However, we sometimes found C at this position in human and chimpanzee chromosomes. Interestingly, this variant C was found in all expanded chromosomes and in 54.5% of chromosomes with 27–40 CAG repeats but it was not found in any chromosomes with less than 20 CAG repeats. We hypothesize that the variant C may be associated with CAG repeat instability.