Kumar M. Prakash

Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study.

We and others found two polymorphic LRRK2 (leucine‐rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5–1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese. Hum Mutat 31:561–568, 2010.

The role of clinical neurophysiology in bioterrorism

Chemical and biological agents have been used as weapons of mass destruction for a long time and presents as a serious threat to mankind. They have been used in many great wars and terrorist attacks with devastating results. The knowledge about these weapons of mass destruction is crucial to health care providers. Early recognition of the clinical characteristics of poisoning as a result of these chemical and biological agents is important to initiate appropriate therapy and minimizing casualties. Neurophysiological investigations when integrated with clinical features are helpful in early identification of some of these agents, especially when serological confirmation is not rapidly available. In this review, we have focused on chemical and biological weapons, which affect the nervous system and the role of clinical neurophysiology in such conditions.

The impact of non‐motor symptoms on the quality of life of Parkinson's disease patients: a longitudinal study

Non‐motor symptoms (NMSs) are common amongst patients with Parkinsons disease (PD); however, little is known about their influence on the health‐related quality of life (QoL) over a defined follow‐up period. The study was aimed to establish the impact of NMSs on the QoL of patients with PD over a 2‐year follow‐up period.

DRD3 variant and risk of essential tremor

Linkage analysis studies in Icelandic and North American families have identified three genetic loci where the causative essential tremor (ET) gene could be located: chromosome 3q13 (ETM1), 2p22-p25 (ETM2), and 6p23.1–3 The A265G variant in the HS1-BP3 gene has been shown to associate with familial ET.4 ETM2 has previously been linked to ET in our population.5 Though the HS1-BP3 variant was not found in our patients with ET,4 the possible association with other variants of HS1-BP3 or other genes has not been excluded. The dopamine D3 receptor ( DRD3 ) gene is located near the ETM1 locus. Recently, a functional DRD3 variant (Ser9Gly) was found to be associated with risk and age at onset of ET in American and French populations.6 The Gly-9 (G) allele cosegregated with ET in 23 families and Gly-9 homozygotes appeared to have more severe ET symptoms.6 Furthermore, in vitro studies showed that dopamine-mediated cAMP response was increased and mitogen-associated protein kinase (MAPK) was prolonged with the G allele.6 The biologic plausibility of the DRD3 Ser9Gly variant, the concordance of the clinical …

Clinical features of childhood onset essential tremor

Childhood onset essential tremor (ET) is uncommon. It is not clear as to whether ethnicity‐specific differences may influence the phenotypic features. To determine the frequency and clinical characteristics of childhood ET in a tertiary referral center. In a prospective evaluation of 120 consecutive ET patients in a movement disorders clinic, we found a 15.5% (19) frequency of childhood onset ET patients. The mean age of onset and mean age was 10.8 ± 4.1 (6–16) years and 25.7 ± 15.0 (16–73) years consisting of 73.6% (14/19) men and 26.4% (5/19) women. A positive family history of ET was present in 11 of 19 (52.6%). Presence of a head tremor was observed in 2/19 (10.5%). We highlighted a relatively high frequency (15,5%) of childhood ET in our Asian cohort. In addition, we drew attention to the male preponderance and the low frequency of head tremor in childhood ET corroborating study findings in white ET patients. These observations appear to transcend ethnic and cultural differences and lend further support that gender difference may play a role in the pathogenesis and expression of ET.

Identification of a novel risk variant in the FUS gene in essential tremor

Objective: A nonsense mutation in the amyotrophic lateral sclerosis gene FUS has been found to segregate in a large family with essential tremor (ET). Coding variants in this gene have not been comprehensively evaluated in ET. We conducted a genetic analysis of FUS for pathogenic and novel coding variants in 2 case-control cohorts among ethnic Chinese. Methods: In a study that involved 7,548 subjects, we first sequenced all the exon and exon-intronic boundaries of FUS in 84 ET samples. Potential causative variants that were identified were then genotyped in 2 separate case-control cohorts involving 263 additional ET samples and 5,919 controls (set 1) and 250 ET cases and 250 controls (set 2), and 782 diseased controls of Chinese ethnicity from 2 different Asian countries. Results: We identified a novel variant, Met392Ile, in exon 12 of the FUS gene. This variant was associated with ET in set 1 (odds ratio = 4.72 [95% confidence interval = 1.90–11.71], p = 0.0037). The association was subsequently validated in set 2 (joint analysis odds ratio = 3.92 [95% confidence interval = 1.57–9.82], p = 8.6 × 10−4). No association was observed in another neurologic cohort of patients with Parkinson disease, and no other potential pathogenic mutations were identified. Conclusion: We identified a novel risk variant, Met392Ile, in the FUS gene that increases susceptibility of ET among ethnic Chinese. Further studies in other ethnic populations are needed to determine whether this is an ethnic-specific risk factor.

Absence of A673T amyloid-β precursor protein variant in alzheimer's disease and other neurological diseases

The rare variant A673T in the amyloid-β precursor protein (APP) gene has been shown to reduce the risk of cognitive impairment. We genotyped the variant in 8721 Asian individuals comprising 552 with Alzheimers disease and vascular dementia, 790 with Parkinsons disease, and 7379 controls. The A673T variant was absent in all of the subjects. Our finding suggests that the A673T protective variant is not relevant in our Asian population. Studies in other ethnic populations would clarify whether this variant is specific to specific races/ethnicities.

Sensitivities of sensory nerve conduction study parameters in carpal tunnel syndrome.

Summary: It is generally accepted that median sensory nerve conduction studies are more sensitive than motor nerve conduction studies in the electrodiagnostic evidence of carpal tunnel syndrome (CTS). This study was conducted to compare the sensitivities of various parameters of sensory nerve conduction studies in the diagnosis of CTS.This prospective study included 88 consecutive patients (151 hands) with CTS and 106 control subjects. CTS was diagnosed clinically by two neurologists. Median sensory nerve responses with wrist stimulation were determined. The onset and peak latencies, peak-to-peak amplitudes, negative peak duration, and area were measured. The differences between the peak and onset latencies were also calculated as a measure of waveform temporal dispersion. Among each measured parameter, values between the 2.5th and the 97.5th percentile range of the control subjects served as the normal limits.Among the 151 hands with suspected CTS, five (3.3%) had normal electrodiagnostic studies and 146 (96.7%) had at least one abnormal electrodiagnostic study. Among the 146 hands with an abnormality, 138 had abnormal onset latency, 143 had abnormal peak latency, and 88 had abnormal difference between peak and onset latency. In addition, 87 had abnormal amplitude, 70 had abnormal duration, and 59 had abnormal area. The sensitivity was 91.4% for onset latency, 94.7% for peak latency, 58.3% for difference between peak and onset latency, 57.6% for amplitude, 46.4% for duration, and 39.1% for area.Our study shows that in patients with CTS, the most sensitive sensory nerve conduction parameter is the peak latency. Studying various additional sensory nerve conduction parameters did not significantly increase the diagnostic yield.

Mycophenolate mofetil – as an adjunctive immunosuppressive therapy in refractory myasthenia gravis: The Singapore experience

We report our experience, using mycophenolate mofetil (MyM) as an adjunctive immunosuppressive therapy in patients with severe, refractory and high dose steroid-dependent myasthenia gravis (MG). Five patients were commenced on MyM in addition to other immunosuppressive therapies. All had significant clinical improvement and no subsequent myasthenic crisis requiring intensive care unit admission. MyM was well tolerated and no serious adverse effects were observed. MyM is an effective adjunctive therapy for the treatment of severe, refractory and steroid-dependent MG in our experience.

Lrrk2 R1628P variant is a risk factor for essential tremor

Essential tremor (ET) and Parkinsons disease (PD) are two of the most common adult onset movement disorders with overlapping clinical features. PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present initially with an ET phenotype. To address the possibility of a common genetic link between ET and PD, we examined the association between a common LRRK2 R1628P gene variant and ET. The LRRK2 R1628P was genotyped in ET cases and matched healthy controls. A total of 1277 subjects comprising of 450 ET cases and 827 controls were included. There were 40 heterozygote (GG to CG) variant out of 450 ET cases (genotypic frequency 8.9%) and 36 heterozygote variant (GG to CG, genotypic frequency 4.3%) and one homozygote variant (GG to CC) out of 827 controls. Subjects carrying the R1628P variant had a twofold increased risk of ET (p = 0.0035, OR = 2.20 and 95% confidence interval is 1.30–3.73). Using a case control methodology, we demonstrated an association between a known PD risk variant, LRRK2 R1628P, with ET. Subjects carrying the R1628P variant had twice the risk of developing ET. The sharing of a similar gene risk variant suggests a possible pathophysiologic link between PD and ET.