Louis C. Tan

Lewy bodies and parkinsonism in families with parkin mutations

Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early‐onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early‐onset Parkinsons disease (<41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2‐27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinsons disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early‐onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinsons disease.

Evaluation of somnolence in Parkinson’s disease: Comparison with age- and sex-matched controls

Abstract—The authors found a significantly higher prevalence of daytime somnolence in 201 patients with PD compared with 214 age- and sex-matched healthy control subjects (Epworth Sleepiness Scale score 5.6 vs 4.6). The prevalence of “sleep attacks” (SA) was about seven times higher in patients with PD than in control subjects (13.9% vs 1.9%;p < 0.0005). Multivariate analysis demonstrated that a higher dose of levodopa and longer duration of disease significantly predicted for SA in patients with PD. Epworth Sleepiness Scale scores of ≥10 had 71.4% sensitivity and 88.4% specificity for SA.

The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients

A common heterozygous leucine-rich repeat kinase 2 (LRRK2) mutation 6055G > A transition (G2019S) accounts for about 3-7% of familial Parkinsons disease (PD) and 1-1.6% sporadic PD in a number of European populations. To determine the prevalence of the G1019S mutation in our Asian population, we conducted genetic analysis of this mutation in 1000 PD and healthy controls. The G2019S mutation was not detected in any of our study subjects. The prevalence of G2019S mutation is rare (< 0.1%) in our population, suggesting that occurrence of this mutation may vary amongst different ethnic races. This has important clinical implication when implementing guidelines for genetic testing.

Novel ATP13A2 variant associated with Parkinson disease in Taiwan and Singapore.

Objectives: To assess the association of ATP13A2 gene mutation among patients with early onset Parkinson disease (EOPD, onset < 50 years) in ethnic Chinese population. Methods: Among 771 subjects, we studied 182 patients with EOPD and familial PD and 589 matched controls from two cohorts of Han Chinese in Taiwan and Singapore. The entire ATP13A2 coding region and intron-exon boundaries were sequenced in 71 probands and 70 controls in Taiwanese/ethnic Chinese. An additional 111 index patients with PD in Singapore and 589 controls were later screened to validate possible mutations that were found in the first set of study subjects. Results: We identified one novel missense variant, AL746Thr, in a single heterozygous state in three patients (two were from Taiwan and one was from Singapore) (1.7% in EOPD). The variant was not observed in 589 ethnicity matched controls. The frequency of this variant was significantly higher in PD cases than controls (p = 0.01, relative risk 4.3, 95% CI 1.9–4.3). The clinical phenotype and 18F-dopa PET image of ATP13A2 Ala78Thr carriers are similar to that seen in idiopathic PD. The variant is located between the highly conserved phosphorylation region and the fifth transmembrane domain of the ATP13A2 protein. Conclusions: A rare variant of the ATP13A2 was associated with an increased risk of Parkinson disease among ethnic Chinese in Asia. Further studies are needed to clarify the functional role of this genetic risk factor. GLOSSARY: cDNA = complementary DNA; EOPD = early onset Parkinson disease; ER = endoplasmic reticulum; RT-PCR = reverse-transcriptase PCR; SNP = single nucleotide polymorphism.

Analysis of LRRK2 functional domains in nondominant Parkinson disease.

A comprehensive sequence analysis of 29 exons that code for the functional domains of LRRK2 in 160 nondominant Parkinson disease (PD) patients was performed. Novel variant screening in a further 470 sporadic PD patients and 630 controls revealed two novel variants (R1067Q and IVS33 + 6 T>A), which are likely to be pathogenic in five patients. One patient presented initially with a typical essential tremor phenotype, expanding the phenotypic spectrum of LRRK2 mutations.

Levodopa induces dyskinesias in normal squirrel monkeys

This study assessed whether or not levodopa induces dyskinesias in normal (ie, unlesioned) squirrel monkeys. All six animals treated twice daily with levodopa (15 mg/kg with carbidopa by oral gavage) for two weeks developed choreoathetoid dyskinesias, whereas none of the vehicle‐treated animals displayed any abnormal movements. These dyskinesias did not merely reflect a generalized motor activation as locomotion was actually suppressed. The present data demonstrate that preexisting nigrostriatal damage is not necessary for the development of levodopa‐induced dyskinesias.

Analysis of GWAS-linked loci in Parkinson disease reaffirms PARK16 as a susceptibility locus

Objective: A genome-wide association study (GWAS) in the Japanese population identified 2 new Parkinson disease (PD) susceptibility loci on 1q32 (PARK16) (OMIM 613164) and BST1. We analyzed single nucleotide polymorphism (SNPs) located at the GWAS-linked loci (PARK16, PARK8, PARK1, and BST1) in a Chinese population and also conducted a meta-analysis in Asians by pooling 2 independent replication studies from Japan. Methods: We conducted an analysis of 13 SNPs associated with PD GWAS-linked loci in 2 case-control cohorts comprised of 1,349 ethnic Chinese subjects. Results: PARK16, PARK8, and PARK1 loci but not BST1 were found to be associated with PD. PARK16 SNPs were associated with a decreased risk while PARK1 and PARK8 SNPs were associated with an increased risk of PD. A pooled analysis of our Chinese cohorts and 2 Japanese replication cohorts involving 1,366 subjects with PD and 16,669 controls revealed robust association with these 3 loci and also BST1. There was a trend toward a stronger protective effect of SNPs at the PARK16 locus in sporadic PD compared to familial cases and in older compared to younger subjects. Conclusions: Our study reaffirms the role of GWAS-linked loci in PD in Asian subjects and the strength of association is similar between Chinese and Japanese subjects. Efforts to elucidate the associated gene within PARK16 locus are warranted.

LINGO1 VARIANT INCREASES RISK OF FAMILIAL ESSENTIAL TREMOR

Essential tremor (ET), a neurologic disorder characterized by postural and action tremor, is one of the most common adult-onset motor disorders.1,2 While linkage regions have been identified in Icelandic and North American families, the causative gene remains elusive.1–4 Recently, a sequence variant (rs9652490 G allele) of the LINGO1 gene was found to be associated with ET in the first genome-wide association study in European and American populations.5 Here we determined the linkage disequilibrium (LD) of single nucleotide polymorphisms (SNPs) 100 kb up/downstream of the implicated LINGO1 SNP and analyzed the SNP in a case control study in an Asian population.nnWe included consecutive patients with ET who presented to a tertiary referral center and examined by movement disorders neurologists following a methodology as previously described.6 We followed the diagnostic criteria of classic ET based on the recommendations of the Consensus Statement of the Movement Disorders Society in 1998.7 Patients with at least one affected first-degree relative were classified as familial ET. Controls of similar gender, race, and age as ET patients and physically examined by the authors at the Health Screening Unit of the same hospital were included. Informed consent from all the study subjects was taken and the work received approval from the institutional ethics committee.nnThe LINGO1 SNP (rs9652490) was screened …

LRRK2 R1628P increases risk of Parkinson’s disease: replication evidence

We showed that the frequency of a LRRK2 variant (c.4883Gxa0>xa0C, R1628P) was higher in Parkinson’s disease (PD) compared to controls (8.4 vs. 3.4%, Pxa0=xa00.046, OR 2.5, 95% CI 1.1–5.6). In the multivariate logistic regression (with adjustments made for the effect of age, age of onset, and gender), the heterozygous R1628P genotype was associated with an increased risk of PD compared to controls (OR 3.3, 95% CI 1.4– 7.9, Pxa0=xa00.007). We provided an independent confirmation that the R1628P variant increases the risk of PD among Chinese.

Marked variation in clinical presentation and age of onset in a family with a heterozygous parkin mutation

Parkin gene mutations have been detected in families with early‐onset autosomal recessive parkinsonism. We report a novel heterozygous 40 base pair deletion in exon 3 of the parkin gene that increases the susceptibility of carriers to develop parkinsonism/dystonia and manifests remarkable variability in regard to age of onset and phenotype in a single family. After identifying the new mutation in the proband of this kindred, family members were contacted and evaluated by a movement disorders specialist using standardized protocols and prospectively set diagnostic criteria. Importantly, examining physicians and family members were blinded to the genetic testing. Five affected members in two generations carried the parkin mutation. The proband and one of his brothers had disease onset at 24 years of age while another brother had disease at age 44. One exhibited multi‐focal dystonia and parkinsonism of 17 years duration, another suffered a unilateral slowly progressive parkinsonism over 13 years while the third suffered dystonia–parkinsonism of recent onset. A sibling pair in the preceding generation had mild previously undiagnosed parkinsonism. Clinicians should be aware that patients carrying a parkin gene mutation may present with dystonia–parkinsonism or very subtle parkinsonism with a markedly varied age of onset.