Jonathan Carr

Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: A case-control study

BACKGROUND Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinsons disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility. METHODS LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinsons Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants. FINDINGS 121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012). INTERPRETATION The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity. FUNDING Michael J Fox Foundation and National Institutes of Health.

Neurological abnormalities in first-episode schizophrenia : Temporal stability and clinical and outcome correlates

OBJECTIVE Neurological abnormalities in subjects with schizophrenia have been regarded as diagnostically non-specific and non-localising. This study assessed the temporal stability of neurological abnormalities in subjects with first-episode schizophrenia over the course of 12 months. We also examined their relationships with psychiatric symptoms, medication effects and treatment outcome. METHOD The sample comprised 66 largely medication-naive subjects who were treated according to a fixed protocol. We performed a factor analysis of the Neurological Evaluation Scale (NES) items, and relationships between the NES factors and various clinical and outcome measures were explored. RESULTS Five NES factors were identified, explaining 68.4% of the variance. While the NES total scores did not change significantly over time, poor performance on motor sequencing tests was related to longer duration of untreated psychosis, and showed a tendency to improve as psychiatric symptoms resolved. The most interesting finding was that high scores on the motor sequencing factor predicted the emergence of persistent dyskinesia at 24 months (ANCOVAR F(1, 20) = 19.287, p = 0.0002). CONCLUSIONS Two NES factors (motor sequencing and attention) are reasonably replicable across samples, and have potential relevance for the further exploration of the pathogenesis of schizophrenia, as well as possible clinical applications.

Attention and visual dysfunction in Parkinson's disease☆

Visual processing extends from the retinal level to the ventral temporal lobe, and is modified by top-down and bottom-up processing. Complex visual hallucinations (VH) are commonly a feature of disorders which affect temporal lobe structures, frequently in association with impairment of ascending monoaminergic pathways. When Parkinsons disease (PD) is associated with VH, pathological changes characteristically affect the temporal lobes, a finding which is recapitulated by imaging findings. However, a major association of VH is with cognitive decline, and this is typically linked to deficits in attention and working memory, both of which are modulated by dopamine. Similarly, dopamine plays a crucial role in the function of prefrontal cortex, in addition to controlling access to consciousness via gating mechanisms that are dependent on the basal ganglia.

Molecular analysis of the parkin gene in South African patients diagnosed with Parkinson's disease

Parkinsons disease (PD) is a common movement disorder which may arise from mutations in the parkin gene. To date, more than 100 different parkin mutations have been reported. The aim of the present study was to determine the frequency of point mutations and homozygous exon deletions in the parkin gene in a group of 91 South African patients diagnosed with PD. Mutation screening of the 12 exons of parkin was performed using single strand conformation polymorphism analysis and the high-resolution melt technique. Six different mutations were identified: four putative disease-causing missense heterozygous changes (H200Q, D280N, E310D and R402C) and two homozygous exon deletions (exons 3 and 4, and exon 4). The D280N and R402C variants have both previously been described but their pathogenic status has been equivocal. In the present study, the D280N variant was observed in three early onset PD-affected siblings and was not present in a 63-year-old unaffected sibling. This data provide further support for the pathogenicity of this variant which is situated within the first RING finger of the RING-box. None of the four missense variants were detected in over 100 ethnic-matched control chromosomes. We conclude that point mutations and homozygous exon deletions in the parkin gene are not a major cause of PD in the South African population. Further studies on this group of patients are needed to determine the contribution of heterozygous exon deletions and insertions in parkin. The present study is the first report on the molecular etiology of PD in South African patients.

Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans

Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinsons disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.

A South African mixed ancestry family with Huntington disease-like 2: Clinical and genetic features

Huntington disease‐like 2 (HDL2) is a neurodegenerative disorder caused by an expansion of a CTG repeat in the junctophilin‐3 gene (JPH3). A limited number of HDL2 families have been reported, all of apparently Black African ancestry. We report on a South African family that presented with progressive dementia and a movement disorder affecting numerous family members. Genotyping of the JPH3 CTG repeat revealed pathogenic expansions in three affected individuals. Whereas HDL2 is thought to be clinically indistinguishable from Huntington disease (HD), 2 of the patients in this study presented with clinical symptoms that differed substantially from HD; one had myoclonus and the other had Parkinsonism. Moreover, brain magnetic resonance imaging scans of these patients showed imaging features atypical for HD. Mitochondrial DNA and Y‐chromosome DNA analysis on a family member showed that his maternal and paternal ancestries are typical of that found among the South African mixed ancestry or colored population. A difference in the distribution of CTG repeats between Caucasian and Black individuals was detected. We conclude that the phenotype of HDL2 is broad and can differ from that of typical HD. The diagnosis therefore should be considered in a wide spectrum of neuropsychiatric and abnormal movement presentations.

Autosomal dominant dystonia-plus with cerebral calcifications

Objective: To report genealogic, clinical, imaging, neuropathologic, and genetic data from a Canadian kindred with dystonia and brain calcinosis originally described in 1985. Methods: The authors performed clinical examinations and CT and PET studies of the head and analyzed blood samples. One autopsy was performed. Results: The family tree was expanded to 166 individuals. No individuals were newly affected with dystonia, but postural tremor developed in two. The mean age at symptom onset was 19 years. Eight individuals had dystonia: three focal, one segmental, one multifocal, and three generalized. Seven displayed additional signs: chorea, intellectual decline, postural tremor, and dysarthria. CT studies were performed on five affected and 10 at-risk family members. All affected individuals and eight at-risk individuals had brain calcinosis. PET scans in two individuals showed reduced D1- and D2-receptor binding and reduced uptake of 6-[18F]fluoro-l-dopa. Autopsy of one affected individual showed extensive depositions of calcium in the basal ganglia, thalamus, cerebral white matter, and cerebellum. No specific immunohistochemistry abnormalities were seen. Genome search data showed no evidence of linkage to the previously described loci IBGC1, DYT1, and DYT12. Conclusions: The phenotype of this family consists of dystonia-plus syndrome. Brain calcium deposits vary in severity and distribution, suggesting that calcifications alone are not entirely responsible for the observed clinical signs. Further studies are needed to elucidate the etiology of this heterogeneous group of disorders.

LRRK2 G2019S mutation: frequency and haplotype data in South African Parkinson’s disease patients

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most significant genetic cause of Parkinson’s disease (PD). The exact function of LRRK2 is currently unknown but the presence of multiple protein interaction domains including WD40 and ankyrin indicates that it may act a scaffold for assembly of a multi-protein signaling complex. The G2019S mutation in LRRK2 represents the most clinically relevant PD-causing mutation and has been found in both familial and sporadic forms of the disorder. This mutation is situated in the highly conserved kinase MAPKKK domain, and has been found in up to 40% of PD patients from North African Arabic, 30% of Ashkenazi Jewish and ~10% of Portuguese and Spanish populations. Although extensively investigated in numerous European and North American populations, studies on the frequency of G2019S in African countries have been rare. The present study is the first on the South African population. High-resolution melt analysis was used to identify the G2019S mutation and it was found in 2% (4/205) of the patients studied. G2019S was not found in any of the Black PD patients screened. In all four G2019S-positive probands the mutation was shown to be present on the common haplotype referred to as haplotype 1. This reveals that the four South African G2019S-positive probands (three Caucasian and one of mixed ancestry) share a common ancestor with the other haplotype 1-associated families reported worldwide.

The prevalence and genetics of Parkinson's disease in sub-Saharan Africans

Parkinsons disease (PD) is under-studied in Black Sub-Saharan African (SSA) populations. To date, there have been only six prevalence and no incidence studies. The crude prevalence of PD in SSA varies from 7 to 20 per 100,000, which is appreciably lower than in Caucasian populations. There are a limited number of published studies (nine) on the genetic factors associated with PD in SSA populations. Mutations have been reported in the parkin gene, and are restricted to only three patients (two Black South Africans and one Zambian). No mutations have been identified in the LRRK2, SNCA, PINK, or DJ-1 genes. Given the unique ancestry of SSA populations, their inclusion in genetic studies may provide a substantial contribution to the identification of novel genetic factors and genetic-environmental interactions underlying this disorder. More initiatives are needed to drive further research on PD in these populations and to facilitate collaborative projects across Africa.

Analysis of viral and genetic factors in South African patients with multiple sclerosis

A significant association was previously demonstrated between multiple sclerosis (MS) and the functional 5′-(GT)n polymorphism in the promoter region of the SLC11A1 gene, which has been implicated in both autoimmune and infectious disease susceptibility. In the present study the role of viral infection was investigated in South African MS patients in relation to specific SLC11A1 genotypes. Serum and peripheral blood mononuclear cells (PBMC) of 49 MS patients, 33 close relatives and 39 unrelated controls previously genotyped for SLC11A1 were screened for the presence of MS-associated retrovirus (MSRV) and two herpes virus (HHV-6 and EBV) sequences. Expression of the pol gene of MSRV was detected in the serum RNA of 34/49 (69%) MS patients whilst absent in the serum of 39 unrelated healthy control individuals (p < 0.001) but was also present in 23/33 (70%) of the unaffected close relatives of the patients. HHV-6 and EBV sequences were detected in both MS patients and control individuals. The viral sequences were not confined to a specific SLC11A1 genotype. Infection with these viruses is excluded as the primary cause for MS in the South African population since no significant differences were detected between MS patients and their unaffected close family members.