Background
The LRRK2 gene is associated with Parkinson's disease (PD) as a number of mutations within the gene have been shown to be susceptibility factors. Studies on various global populations have ...determined that mutations such as G2019S, G2385R, and R1628P in LRRK2 increase the risk of developing PD while the N551K‐R1398H haplotype is associated with conferring protection against developing PD. Here we report a study looking at the N551K and R1398H variants for the first time in the Malaysian population.
Methods
Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age‐ and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay.
Results
A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta‐analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H.
Conclusion
This study reports that the N551K‐R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.
Variants in the LRRK2 gene, N551K and R1398H have a significant protective association Malays and Chinese in a case–control study on Parkinson's Disease in Malaysia.
Purposeless groaning has been reported in advanced progressive supranuclear palsy. We present a case of purposeless groaning occurring as a primary complaint in a patient with advanced Parkinson's ...disease. Purposeless groaning is thought to be a manifestation of disinhibition and perseveration due to frontal-subcortical dysfunction. Proper recognition of this phenomenon will help clinicians to avoid unnecessary investigations and treatment (e.g., prescription of opioid medications).
To determine whether probiotics are effective for constipation, a common and often difficult-to-treat problem, in Parkinson disease (PD).
In this double-blind, randomized, placebo-controlled, ...single-center trial, 280 patients with PD were screened, and 72 eligible patients were block-randomized (1:1) to receive either multistrain probiotics capsules (n = 34) or identical-appearing placebo (n = 38), for 4 weeks. The primary endpoint was the change in the average number of spontaneous bowel movements (SBM) per week during the last 2 weeks of intervention compared with the 2-week preintervention phase, recorded by daily stool diary. Secondary outcome measures included changes in stool consistency, constipation severity score, and quality of life related to constipation. Satisfaction with intervention received was assessed. Change in levels of fecal calprotectin, a marker of intestinal inflammation, was an exploratory outcome.
SBM increased by 1.0 ± 1.2 per week after treatment with probiotics and decreased by 0.3 ± 1.0 per week in the placebo group (mean difference 1.3, 95% confidence interval 0.8-1.8,
< 0.001). Significant improvements were also seen for secondary outcomes after correction for multiple comparisons, including stool consistency (
= 0.009) and quality of life related to constipation (
= 0.001). In the treatment group, 65.6% reported satisfaction with the intervention vs only 21.6% in the placebo group (
< 0.001). One patient (2.9%) in the treatment group withdrew due to a nonserious adverse event. Fecal calprotectin did not change significantly during the study.
Multistrain probiotics treatment was effective for constipation in PD. Further studies are needed to investigate the long-term efficacy and safety of probiotics in PD, as well as their mechanisms of action.
NCT03377322.
This study provides Class I evidence that, for people with PD, multistrain probiotics significantly increased the average number of SBM per week.
We present a case of beta-propeller protein-associated neurodegeneration, a form of neurodegeneration with brain iron accumulation. The patient harbored a novel mutation in the WDR45 gene. A detailed ...video and description of her clinical condition are provided. Her movement disorder phenomenology was characterized primarily by limb stereotypies and gait dyspraxia. The patient's disability was advanced by the time iron-chelating therapy with deferiprone was initiated, and no clinical response in terms of cognitive function, behavior, speech, or movements were observed after one year of treatment.
Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmentaldisorder with an incidence of one per million,characterized by paroxysmal alternating hemiplegia, eye movementabnormalities, ...dystonia, and epilepsy.1 In 2012, mutationsin the ATP1A3 gene encoding the Na+-K+-ATPase α3 subunit(originally discovered in rapid-onset dystonia-parkinsonism)were identified as the cause for AHC.1,2 However, the diagnosisof AHC is still often delayed or missed. We report a case of AHCdiagnosed in adulthood; to our knowledge, this is the first reportin a person of Malay ethnicity. KCI Citation Count: 1
IMPORTANCE: Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the ...largest population worldwide (ie, Asian). OBJECTIVES: To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. DESIGN SETTING, AND PARTICIPANTS: Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson’s Disease Society Brain Bank Criteria. MAIN OUTCOMES AND MEASURES: Genotypes of common variants, association with disease status, and polygenic risk scores. RESULTS: Of 31 575 samples identified, 6724 PD cases (mean SD age, 64.3 10 years; age at onset, 58.8 10.6 years; 3472 53.2% men) and 24 851 controls (age, 59.4 11.4 years; 11 030 45.0% men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10−10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10−3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10−12). CONCLUSIONS AND RELEVANCE: This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta–genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.
Screening for orthostatic hypotension (OH) is integral in Parkinson's disease (PD) management, yet evidence-based guidelines on best practice methods for diagnosing OH in PD are lacking.
We ...investigated the frequency and correlates of OH, symptomatic OH, and neurogenic OH, in a large consecutively recruited PD cohort (n = 318), and compared the diagnostic performance of the sit-to-stand vs. the supine-to-stand blood pressure (BP) test. We evaluated the utility of continuous BP monitoring and tilt table testing in patients with postural symptoms or falls who were undetected to have OH with clinic-based BP measurements. Disease severity, fluid intake, orthostatic and overactive bladder symptoms, falls, comorbidities and medication history were evaluated.
Patients’ mean age was 66.1 ± 9.5years, with mean disease duration 7.8 ± 5.5years. OH frequency was 35.8 % based on the supine-to-stand test. OH in PD was significantly associated with older age, lower body mass index, longer disease duration, worse motor, cognitive and overactive bladder symptoms and functional disabilities, falls, and lower fluid intake. A similar profile was seen with asymptomatic OH. Three quarters of OH were neurogenic, with the majority also having supine hypertension. The sit-to-stand test had a sensitivity of only 0.39. One quarter of patients were additionally diagnosed with OH during continuous BP monitoring.
The sit-to-stand test substantially underdiagnoses OH in PD, with the important practice implication that supine-to-stand measurements may be preferred. Screening for OH is warranted even in asymptomatic patients. Adequate fluid intake, treatment of urinary dysfunction and falls prevention are important strategies in managing PD patients with OH.
•Orthostatic hypotension (OH) is prevalent in PD (35.8 %) and frequently asymptomatic.•PD patients with OH have reduced fluid intake and worse overactive bladder symptoms.•OH in PD is usually neurogenic, with the majority also having supine hypertension.•The sit-to-stand BP test substantially underdiagnoses OH in PD.•Continuous BP monitoring can be useful in cases undetected during bedside testing.
GBA
variants are associated with increased risk and earlier onset of Parkinson’s disease (PD), and more rapid disease progression especially with “severe” variants typified by p.L483P.
GBA
mutation ...screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of
GBA
variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (
n
= 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All
GBA
coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous
GBA
alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50 years) vs. late-onset patients across all three ethnicities (9.1–13.2% vs. 1.0–3.2%). The most common variant was p.L483P (including Rec
Nci
I,
n
= 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of
GBA
-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in
GBA
-variant carriers. This represents the largest study on
GBA
variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting
GBA
pathways.
Progressive supranuclear palsy (PSP) is a rare, disabling, neurodegenerative disease, with few studies done in Asian populations.
We prospectively characterized the clinical features and disease ...burden in a consecutively-recruited multi-ethnic Asian PSP cohort. Patients were extensively phenotyped using the Movement Disorder Society (MDS-PSP) clinical diagnostic criteria and the PSP-Clinical Deficits Scale (PSP-CDS). Caregiver burden was measured using the modified Zarit Burden Interview (ZBI). Investigations (neuroimaging and genetic tests) were reviewed.
There were 104 patients (64.4% male; 67.3% Chinese, 21.2% Indians, 9.6% Malays), consisting of 48.1% Richardson syndrome (PSP-RS), 37.5% parkinsonian phenotype (PSP–P), and 10.6% progressive gait freezing phenotype (PSP-PGF). Mean age at motor onset was 66.3 ± 7.7 years, with no significant differences between the PSP phenotypes. Interestingly, REM-sleep behaviour disorder (RBD) symptoms and visual hallucinations (considered rare in PSP) were reported in 23.5% and 22.8% of patients, respectively, and a family history of possible neurodegenerative or movement disorder in 20.4%. PSP-CDS scores were highest (worst) in PSP-RS; and correlated moderately with disease duration (rs = 0.45, P < 0.001) and weakly with caregiver burden (rs = 0.22, P = 0.029) in the overall cohort. Three of 48 (6.3%) patients who had whole-exome sequencing harboured pathogenic/likely pathogenic GBA variants.
Significant heterogeneity in clinical features and disease burden, and high rates of RBD symptoms, visual hallucinations, and familial involvement were observed in this relatively large cohort. Our findings highlight important considerations when assessing Asian patients, and provide further support for the notion of overlapping neurobiology between PSP and Lewy body disorders.
•Asian PSP patients were prospectively classified using MDS-PSP diagnostic criteria.•A novel rating scale (PSP-CDS) was applied to evaluate disease severity.•PD-linked gene variants were found in well-defined Richardson syndrome cases.•Patients/caregivers frequently reported RBD symptoms and/or visual hallucinations.•There may be racial differences in disease occurrence and underlying genetics in PSP.
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