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Spinocerebellar ataxia type 17 (SCA17) is caused by CAG repeat expansion in the TATA-box binding protein gene. Studies of several polyglutamine (polyQ) expansion diseases have suggested that the expanded polyQ proteins misfold and induce oxidative stress to contribute to cell death. Substantial deficits in peripheral tissues including lymphocytes have been shown and these peripheral abnormalities could also be found in neurons possessing polyQ disease proteins. In this study, we used a lymphoblastoid cell model to investigate the functional implication of SCA17 expanded alleles and assess the potential therapeutic strategies that may ameliorate the effects of expanded polyQ. Proteomics studies of patient/control pairs including two-dimensional (2-D) gel electrophoresis, mass spectrometry and immunoblotting were conducted. A total of 8 proteins with reduced expression changes greater than 1.3-fold were identified, including previously reported HSPA5 and HSPA8. Among 6 proteins further semi-quantified by immunoblotting and real-time PCR, the reduced expression of HYOU1, PDIA3, P4HB, NQO1 and HMOX1 was confirmed. Treatment with resveratrol and genipin up-regulated NQO1 and HMOX1 expression and reduced oxidative stress in patients' lymphoblastoid cells. The results illustrate downregulation of proteins involved in the endoplasmic reticulum stress response (HYOU1, HSPA5, PDIA3, and P4HB) and Nrf2-ARE signaling (NQO1 and HMOX1) in SCA17 lymphoblastoid cells. Compounds increasing anti-oxidative activity such as resveratrol and genipin may serve as a potential therapeutic strategy for SCA17.

Mutations in HTRA2 have been reported to associate with Parkinson’s disease (PD). This study investigates if the genetic variants in HTRA2 contribute to Taiwanese PD. HTRA2 cDNA fragments from 80 patients with early-onset PD (onset ≤50 years) were sequenced. The identified variants were further examined for a cohort of PD and ethnically matched controls. A novel heterozygous R36W was identified in one early-onset and two late-onset PD patients, which was absent in 606 normal controls. The clinical features and 99mTc-TRODAT-1 SPECT image of the early-onset patient carrying R36W were similar to that of idiopathic PD. The R36W mutation of the patient was inherited from his mother whose SPECT revealed asymmetric reduction of 99mTc-TRODAT-1 uptake in the left striatum, suggesting that the defect of the nigrostriatal pathway may be attributable to the R36W in this family. Protein subcellular fractionation further revealed that R36W affected the processing of the proprotein after transport into mitochondria. Although the functional assays are promising, a larger cohort of both cases and controls should be screened to clarify the role of R36W in Taiwanese PD pathogenicity.

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.

Background Tolosa-Hunt syndrome (THS) manifests as a benign or an inflammatory type disease. The nosography differences between these types remain to be elucidated. We aimed to analyze and compare the clinical presentations of benign and inflammatory THS. Methods The ward patients who presented with THS from January 1990 to May 2011 were retrospectively reviewed. THS was diagnosed according to the recommendations of the International Headache Society. Results Of the 53 THS cases (49 patients), 30 (56.6%) were classified as benign and 23 (43.4%) as inflammatory THS. There were strong similarities between the groups in terms of clinical manifestations, laboratory findings, responses to glucocorticoid treatment, and outcomes. However, patients with inflammatory THS tended to be younger (mean age, 43.4 years; p 0.5 mg/kg/day) and low-dose (≤0.5 mg/kg/day) prednisolone were equally effective in relieving symptoms in both groups ( p > 0.05). Conclusion Benign and inflammatory THS were highly similar in terms of nosography. The responses to glucocorticoid treatment were generally good except in patients with orbital pseudotumors.

Spinocerebellar ataxia type 8 (SCA8) involves the expansion of CTG/CAG repeats from the overlapping ataxin 8 opposite strand (ATXN8OS) and ataxin 8 (ATXN8) genes located on chromosome 13q21. Although being transcribed, spliced and polyadenylated in the CTG orientation, ATXN8OS does not itself appear to be protein coding, as only small open reading frames (ORFs) were noted. In the present study we investigated the translation of a novel 102 amino acids containing-ORF in the ATXN8OS RNA. Expression of chimeric construct with an in-frame ORF-EGFP gene demonstrated that ATXN8OS RNA is translatable. Using antiserum raised against ORF, ATXN8OS ORF expression was detected in various human cells including lymphoblastoid, embryonic kidney 293, neuroblastoma IMR-32, SK-N-SH, SH-SY5Y cells and human muscle tissue. The biological role of the ATXN8OS ORF and its connection to SCA8 remains to be determined.

Spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17 as well as Huntington’s disease are a group of neurodegenerative disorders caused by expanded CAG repeats encoding a long polyglutamine (polyQ) tract in the respective proteins. Evidence has shown that the accumulation of intranuclear and cytoplasmic misfolded polyQ proteins leads to apoptosis and cell death. Thus suppression of aggregate formation is expected to inhibit a wide range of downstream pathogenic events in polyQ diseases. In this study, we established a high-throughput aggregation screening system using 293 ATXN3/Q75-GFP cells and applied this system to test the aqueous extract ofPaeonia lactiflora(P. lactiflora) and its constituents. We found that the aggregation can be significantly prohibited byP. lactifloraand its active compound paeoniflorin. Meanwhile,P. lactifloraand paeoniflorin upregulated HSF1 and HSP70 chaperones in the same cell models. Both of them further reduced the aggregation in neuronal differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate howP. lactifloraand paeoniflorin are likely to work on polyQ-aggregation reduction and provide insight into the possible working mechanism ofP. lactiflorain SCA3. We anticipate our paper to be a starting point for screening more potential herbs for the treatment of SCA3 and other polyQ diseases.

Essential tremor (ET), which is one of the most common movement disorders, may lead to severe interference in quality of life. The first genome-wide association study (GWAS) has identified an association of the LINGO1 variant (rs9652490) with ET in Americans and Europeans. Recently, a second GWAS that was performed in a European population has discovered a new variant (rs3794087) of the main glial glutamate transporter (SLC1A2) that increases the risk of ET with an odds ratio of about 1.4. SLC1A2 encodes for the major glial high-affinity glutamate reuptake transporter in the brain and is a potential ET susceptibility gene. Because replication in a different ethnic population is important for validating a finding, we conducted a case-control study to investigate the SLC1A2 variant in an Asian cohort with ET in Taiwan. A total of 542 subjects (273 ET patients and 269 controls) were included. The results showed that rs3794087 was associated with ET among the Taiwanese. The odds ratio was 1.37. Our results were similar to those of the second GWAS of ET in Europeans, and this confirms that SLC1A2 may be a good functional candidate gene for ET. A replication study in another independent population is of importance to validate this association.

We report on a 28-year-old man who presented with right hand tremor, bradykinesia, and rigidity of his right side extremities. Our case report emphasizes that markedly asymmetrical parkinsonism can be an initial presentation of adult-onset Huntington's disease (HD), and different clinical presentations can be observed in members of an individual HD family with the same CAG repeat length.

Kuo-Hsuan Chang,1,* I-Cheng Chen,1,* Hsuan-Yuan Lin,2 Hsuan-Chiang Chen,2 Chih-Hsin Lin,1 Te-Hsien Lin,2 Yu-Ting Weng,1 Chih-Ying Chao,1 Yih-Ru Wu,1 Jung-Yaw Lin,2 Guey-Jen Lee-Chen,2 Chiung-Mei Chen1 1Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 2Department of Life Science, National Taiwan Normal University, Taipei, Taiwan, Republic of China *These authors contributed equally to this work Background: Alzheimer’s disease (AD) and several neurodegenerative disorders known as tauopathies are characterized by misfolding and aggregation of tau protein. Although several studies have suggested the potential of traditional Chinese medicine (TCM) as treatment for neurodegenerative diseases, the role of TCM in treating AD and tauopathies have not been well explored.Materials and methods: Tau protein was coupled to the DsRed fluorophore by fusing a pro-aggregation mutant of repeat domain of tau (ΔK280 tauRD) with DsRed. The ΔK280 tauRD-DsRed fusion gene was then used to generate Tet-On 293 and SH-SY5Y cell clones as platforms to test the efficacy of 39 aqueous extracts of TCM in reducing tau misfolding and in neuroprotection.Results: Seven TCM extracts demonstrated a significant reduction in tau misfolding and reactive oxidative species with low cytotoxicity in the ΔK280 tauRD-DsRed 293 cell model. Glycyrrhiza inflata and Panax ginseng also demonstrated the potential to improve neurite outgrowth in the ΔK280 tauRD-DsRed SH-SY5Y neuronal cell model. G. inflata further rescued the upregulation of ERN2 (pro-apoptotic) and downregulation of unfolded-protein-response-mediated chaperones ERP44, DNAJC3, and SERP1 in ΔK280 tauRD-DsRed 293 cells.Conclusion: This in vitro study provides evidence that G. inflata may be a novel therapeutic for AD and tauopathies. Future applications of G. inflata on animal models of AD and tauopathies are warranted to corroborate its effect of reducing misfolding and potential disease modification. Keywords: Alzheimer’s disease, tauopathy, tau misfolding, TCM extracts, G. inflata, UPR-mediated chaperones

Matrix metalloproteinases (MMPs) function in the degradation of extracellular matrix and are considered to play a role in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). MMPs activities are modulated by tissue inhibitors of metalloproteinases (TIMPs). This study examined whether the genetic polymorphisms of MMP-3, gelatinase (MMP-2 and MMP-9), TIMP-2, and TIMP-1 were associated with PD in Taiwan. A total of 359 PD patients and 332 controls were enrolled. The candidate genetic variants included MMP-2 rs2285053 (−735 C > T), MMP-3 rs3025058 (−1171 5A > 6A), MMP-9 rs3918241 (−1831 T > A), rs17576 (G > A, R279Q), and rs3787268 (G > A, intron), TIMP-1 rs4898 (T > C, F124F), and TIMP-2 rs7503607 (−269 G > T). Associations were tested by logistic regression, adjusted with gender and age at onset. Minor allele frequency of TIMP-1 rs4898 (36.0%) was significantly lower in the male PD patients than in the male controls (51.2%) (χ2 test, P = 0.004). When adjusted with gender and age at onset, MMP-9 rs17576 AA genotype was associated with PD susceptibility in a recessive fashion (odds ratios [OR] = 2.28, 95% confidence intervals [95% CI] = 1.12–4.62, P = 0.02). In males, TIMP-1 rs4898 C allele was associated with a protective effect on PD (OR = 0.75, 95% CI = 0.60–0.94, P = 0.014). We did not find association between the examined genetic variants of MMP-2, MMP-3, and TIMP-2 and PD susceptibility. This is the first study that demonstrated a protective effect of TIMP-1 rs4898 C allele on male PD and a modest association of MMP-9 rs17576 AA genotype with PD susceptibility in the Taiwan population. Further replication is needed for confirmation.

Neuromyelitis optica (NMO), which was previously considered a variant of multiple sclerosis (MS), is characterized by recurrent optic neuritis and longitudinally extensive spinal cord lesions. It has been shown that the level of haptoglobin in cerebrospinal fluid (CSF) is elevated in NMO. However, it is uncertain whether this change is specific to NMO, or is also seen in MS and other neurological diseases.We used an enzyme-linked immunosorbent assay (ELISA) to measure the haptoglobin levels in the CSF and serum in 25 NMO, 16 MS, and 15 Alzheimer's disease (AD) patients and 22 controls.The CSF haptoglobin concentration of the NMO patients (0.309±0.074mg/dl, P0.001) was significantly higher than that of MS patients (0.081±0.016mg/dl) and AD patients (0.058±0.011mg/dl), and the controls (0.060±0.009mg/dl), whereas the serum haptoglobin and albumin concentrations in the serum and CSF did not differ significantly across groups. NMO patients (0.59±0.15, P=0.001) demonstrated a higher haptoglobin index than MS patients (0.13±0.01), AD patients (0.12±0.03), and the controls (0.17±0.04). Furthermore, the haptoglobin concentration and haptoglobin index in the CSF correlated significantly with the expanded disability scale score (EDSS) in NMO patients.The high CSF haptoglobin concentration in NMO may be explained by increased intrathecal haptoglobin synthesis. The correlation between CSF haptoglobin concentration/haptoglobin index and EDSS highlights the potential of haptoglobin as a biomarker of NMO.

Oxidative stress has been reported as one of the pathogeneses of Parkinson's disease (PD). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of the target genes involved in antioxidant pathway. The promoter polymorphisms of the Nrf2-encoding gene, NFE2L2, have been shown to affect the promoter activity. Inconsistent findings of the associations between NFE2L2 promoter polymorphisms and PD have been reported in a multiple candidate gene study, a whole-genome association study, and a case–control study in multiple ethnicity groups. This study enrolled a total of 1006 individuals composed of 480 PD patients and 526 controls to evaluate if there was an association of the NFE2L2 promoter polymorphisms with PD susceptibility in the Taiwan population. Three promoter single nucleotide polymorphisms (SNPs) rs35652124, rs6706649, and rs6721961 were examined using polymerase chain reaction and restriction analysis. The associations of each of the SNPs and the haplotypes constructed by the variations with PD susceptibility were examined. In spite of adequate statistic power, we observe no association of the three SNPs and their haplotypes with PD in a Taiwanese population. One of the reasons for the association disparity may include the genomic differences in ethnicities and environmental factors in different geographical regions.

It has been suggested that a common LRRK2 polymorphic variant (A419V (rs34594498 C >T)) may be a risk factor among Asians (especially in Taiwan). In this study, we examined this variant in a larger and independent Taiwan cohort. We found the frequency of the variant (A419V) to be very rare in our Taiwan PD and controls (?0.6%). Further studies were conducted in two other Chinese populations (Singapore and China), comprising of a total of 3004 subjects including 1517 PD patients and 1487 control subjects. However, our multi-center Chinese study revealed that the frequency of the variant was rare (?0.4%) and was not associated with risk of PD, suggesting that the variant is not a major risk factor for PD among Chinese, at least in our study population.

Background and purpose: Recent studies have suggested increased prevalence of impulsive/compulsive behaviors (ICB) in patients with Parkinson’s disease (PD) as compared to general population in different ethnic groups. The spectrum of these behaviors includes dopamine dysregulation syndrome (DDS), punding, pathological gambling (PG), hypersexuality (HS), binge eating (BE), and compulsive shopping (CS). Methods: Two hundred and seventy-eight consecutive patients with idiopathic PD regularly followed-up at an outpatient clinic were interviewed and screened for the ICB between September 2008 and December 2008 using designated diagnostic criteria. All patients who screened positive for ICB or obsessive-compulsive disorder (OCD) were further confirmed by an experienced psychiatrist. Results: Of all the studied patients, 15 patients confirmed to have ICB (lifetime prevalence: 5.60%), 3 (1.12%) were diagnosed to have DDS, 1 (0.37%) punding, 4 (1.49%) PG, 8 (2.99%) HS, 1 (0.37%) BE, 0 (0%) CS. OCD was found in one patient (0.37%). Conclusions: The prevalence of ICB is lower in Taiwan as compared with the Caucasians, with similar risk factors. The possible reasons include differences in ethnicity, environmental, cultural, and social factors as well as the dosage and selection of dopaminergic medications.

The purpose of this study was to compare the pattern of hand muscle involvement in Hirayama disease (HD) and amyotrophic lateral sclerosis (ALS).We reviewed findings of upper limb nerve conduction studies of 46 HD patients and 60 ALS patients. The findings from 54 healthy subjects were used for comparison.In HD, the ulnar compound muscle action potential (CMAP) amplitude was more severely reduced than the median one, and the reverse pattern was observed in ALS. The mean ulnar/median (U/M) CMAP amplitude ratio was significantly lower in HD (0.64 ± 0.79) and abnormally higher in ALS (2.15 ± 1.77) compared with normal subjects (0.89 ± 0.23). An abnormally low U/M CMAP amplitude ratio (0.6) was encountered in 34 patients with HD and in 1 with ALS. A U/M CMAP amplitude ratio ≥4.5 or absent median motor response was found only in ALS.Our findings demonstrate different patterns of hand muscle involvement between these two diseases.

Background/Purpose Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a rare neurodegenerative disorder presenting with insidious onset of weakness in bulbar and limb muscles. Information regarding long-term clinical and functional progression has been limited, especially for the Taiwanese population. The purpose of the study aimed to investigate early diagnosis and long-term prognosis of SBMA. Methods We retrospectively analyzed 21 genetically confirmed SBMA patients who visited our hospital between 1993 and 2010, focusing on clinical symptoms, nerve conduction studies, and functional disability. We also analyzed the relationship between length of cytosine-adenine-guanine (CAG) repeats and age of disease onset. Results Weakness developed at a mean age of 39 ± 7 years (mean ± standard deviation). The length of CAG repeats and age at onset of weakness showed inverse (but nonsignificant) correlation. The most common symptoms at initial presentation were hand tremor (86%), limb weakness (86%), and perioral fasciculation (76%). Creatine kinase (CK) was elevated in 17 out of 18 patients. Initial nerve conduction studies showed statistical difference from normal controls, especially decreased amplitudes of compound motor action potential (CMAP) and sensory nerve action potential (SNAP). Functional disability showed very slow progression, with only three patients becoming wheelchair-dependent during follow-up at a median age of 72 years. Conclusion Patients with SBMA may present with a myriad of symptoms, including limbs weakness, tremor, muscle atrophy, and perioral fasciculations. Elevated serum CK and decreased CMAP and SNAP amplitudes were supportive laboratory findings of SBMA. Disease progression was gradual, and most patients remained functionally independent many years after the onset of weakness.

Huntington's disease (HD) is a progressive neurodegenerative disease caused by an unstable CAG trinucleotide repeat expansion. The need for biomarkers of onset and progression in HD is imperative, since currently reliable outcome measures are lacking. We used two-dimensional electrophoresis and mass spectrometry to analyze the proteome profiles in cerebrospinal fluid (CSF) of 6 pairs of HD patients and controls. Prothrombin, apolipoprotein A-IV (Apo A-IV) and haptoglobin were elevated in CSF of the HD patients in comparison with the controls. We used western blot as a semi-quantified measurement for prothrombin and Apo A-IV, as well as enzyme linked immunosorbent assay (ELISA) for measurement of haptoglobin, in 9 HD patients and 9 controls. The albumin quotient (Qalb), a marker of blood-brain barrier (BBB) function, was not different between the HD patients and the controls. The ratios of CSF prothrombin/albumin (prothrombin/Alb) and Apo A-IV/albumin (Apo A-IV/Alb), and haptoglobin level were significantly elevated in HD. The ratio of CSF prothrombin/Alb significantly correlated with the disease severity assessed by Unified Huntington's Disease Rating Scale (UHDRS). The results implicate that increased CSF prothrombin, Apo A-IV, and haptoglobin may be involved in pathogenesis of HD and may serve as potential biomarkers for HD.

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. Here, we report that the transcript of the peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor that is critical for energy homeostasis, was markedly downregulated in multiple tissues of a mouse model (R6/2) of HD and in lymphocytes of HD patients. Therefore, downregulation of PPARγ seems to be a pathomechanism of HD. Chronic treatment of R6/2 mice with an agonist of PPARγ (thiazolidinedione, TZD) rescued progressive weight loss, motor deterioration, formation of mutant Htt aggregates, jeopardized global ubiquitination profiles, reduced expression of two neuroprotective proteins (brain-derived neurotrophic factor and Bcl-2) and shortened life span exhibited by these mice. By reducing HTT aggregates and, thus, ameliorating the recruitment of PPARγ into HTT aggregates, chronic TZD treatment also elevated the availability of the PPARγ protein and subsequently normalized the expression of two of its downstream genes (the glucose transporter type 4 and PPARγ coactivator-1 alpha genes). The protective effects described above appear to have been exerted, at least partially, via direct activation of PPARγ in the brain, as TZD was detected in the brains of mice treated with TZD and because a PPARγ agonist (rosiglitazone) protected striatal cells from mHTT-evoked energy deficiency and toxicity. We demonstrated that the systematic downregulation of PPARγ seems to play a critical role in the dysregulation of energy homeostasis observed in HD, and that PPARγ is a potential therapeutic target for this disease.

Family history is a risk factor for stroke. The objective of this study was to investigate whether stroke subtypes and gender might have a familial contribution to stroke.Detailed family history analysis was used to investigate the parents or siblings of the probands and controls who were classified into 3 groups: probands, outpatient controls, and spouse controls. The lifetime risk (LTR) of stroke was estimated using a Cox proportional hazard model.The 684 probands and controls yielded 1066 parents and 3247 siblings. Compared to the parents and siblings of the controls, those of the stroke patients had a significantly higher LTR. The findings were consistent between probands with cerebral infarction (CI) or cerebral hemorrhage (CH), independent of diabetes, hypertension, and smoking. With regard to gender, family history of stroke was significant for both parents and siblings of the CH or CI patients, but not for the fathers of CI patients and sisters of CH patients. The family history of stroke was associated with an increased risk of stroke of all subtypes, except cardioembolism.This study supported the familial contribution to stroke in the case of both CI and CH but not cardioembolism, independent of the established risk factors for stroke. Gender differences in familial clustering of stroke subtypes were also revealed. These results warrant further molecular genetic studies.

Background and object There was no Chinese questionnaire to evaluate the health-related quality of life (HRQoL) in patients with hemifacial spasm (HFS). In this study, we aimed to validate a new disease-specific HRQoL scale for HFS (HFS-36) in Chinese version, and compared it to SF-36, a generic HRQoL scale. Patients and Methods The HFS-36 Chinese version was modified from English version of HFS-30, including subscales of mobility, activities of daily living (ADL), emotional well-being, stigma, social support, cognition, bodily discomfort, and communication. All the items were scored on the 5-point scales, ranging from 0(never) to 4(always). Patients with HFS were asked to answer HFS-36 and SF-36 questionnaires on the same day before and 6-8 weeks after Botulinum toxin (BTX) injections, respectively. The reliability and validity of HFS-36 scale were evaluated statistically. Results Totally, 103 patients (68 females; 35 males) were recruited in this study, with a mean age of 57.6 ± 11.5 years and a mean duration of HFS for 7.6 ± 5.8 years. The intra-class correlation (ICC) and Cronbach's α were over 0.7 in the majority of items. HFS-36 showed a good correlation to HFS severity before BTX treatment and a significant improvement of subscale scoring after BTX treatment. HFS-36 also had a significant correlation to the mental health of SF-36. Conclusions The Chinese version of HFS-36 demonstrated a good reliability and validity in subscales of motility, ADL, emotion well-being, stigma and bodily discomfort. The HRQoL was significantly improved after BTX treatment assessed by HFS-36 or SF-36. Compared to SF-36, HFS-36 scale was more sensitive and specific to evaluate the HRQoL in HFS.

Early onset Parkinson's disease (PD) has been associated with mutations in Parkin. We screened Parkin mutations in a cohort of Taiwanese early onset PD using direct cDNA sequencing. Two deletions (Ex2-3del and Ex5del), one point mutation (R334C), one 86-bp IVS9 insertion (c.1084intron+), and two polymorphisms (S167N and V380L) were identified. The mutations identified are heterozygous and none of the mutation carriers possess two Parkin mutations. The c.1084intron+ was due to a novel IVS9 g > a change. To assess the association of IVS9 g > a, S167N and V380L with the risk of PD, we conducted a case–control study in a cohort of PD and ethnically matched controls. Although the difference is not significant, the V380L C allele frequency was notably lower in PD patients than the controls and a trend toward decrease in risk of developing PD was evident (odds ratio: 0.71, 95% confidence interval: 0.53–0.97, P = 0.029). Contrarily the IVS9 g > a a allele frequency was notably higher in PD patients than the controls and a trend toward increase in risk of developing PD was also evident (odds ratio: 1.65, 95% confidence interval: 1.06–2.59, P = 0.028). Quantitative real-time PCR showed that the relative Parkin c.1084intron+ mRNA expression was increased in PD patients with IVS9 ga genotype as compared to gg genotype. Pairwise genotype analysis revealed that IVS9 gg genotype strengthens the negative association of the V380L GC genotype with PD (odds ratio: 0.67, 95% confidence interval: 0.48–0.94, P = 0.021). The results of Parkin mutation/polymorphism screening may contribute to our understanding of PD. © 2009 Wiley-Liss, Inc.

Guillain-Barré syndrome (GBS) is an autoimmune inflammatory polyradiculoneuropathy that causes acute areflexic paralysis with a high risk of respiratory failure. Previously, using two-dimensional gel electrophoresis and mass spectrometry, we found that the transthyretin level was altered in the cerebrospinal fluid (CSF) of GBS patients when compared to that in CSF of control patients.We used enzyme-linked immunosorbent assay (ELISA) to measure the transthyretin levels in the CSF and serum from 22 GBS, 4 Miller-Fisher syndrome (MFS), 9 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 22 multiple sclerosis (MS), 10 Alzheimer's disease (AD), and 6 viral meningitis (VM) patients, and 18 controls.The results show that CSF transthyretin concentration of the GBS patients is significantly higher than that of the control, MS, AD and VM patients (p0.05), although not significantly different from that of MFS and CIDP patients.The increased CSF transthyretin level may be explained by barrier dysfunction or decreased CSF flow in the GBS patients along with increased intrathecal synthesis of transthyretin that might be a protective response to nerve damage.

Background Spinocerebellar ataxia type 8 (SCA8) involves the expression of an expanded CTG/CAG combined repeats (CR) from opposite strands producing CUG expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and a polyglutamine expansion protein (ataxin 8, ATXN8). The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad. Results Using stably induced cell models expressing 0, 23, 88 and 157 CR, we study the role of ATXN8OS transcripts in SCA8 pathogenesis. In the absence of doxycycline, the stable ATXN8OS CR cell lines exhibit low levels of ATXN8OS expression and a repeat length-related increase in staurosporine sensitivity and in the number of annexin positive cells. A repeat length-dependent repression of ATXN8OS expression was also notable. Addition of doxycycline leads to 25~50 times more ATXN8OS RNA expression with a repeat length-dependent increase in fold of ATXN8OS RNA induction. ChIP-PCR assay using anti-dimethyl-histone H3-K9 and anti-acetyl-histone H3-K14 antibodies revealed increased H3-K9 dimethylation and reduced H3-K14 acetylation around the ATXN8OS cDNA gene in 157 CR line. The repeat length-dependent increase in induction fold is probably due to the increased RNA stability as demonstrated by monitoring ATXN8OS RNA decay in cells treated with the transcriptional inhibitor, actinomycin D. In cells stably expressing ATXN8OS, RNA FISH experiments further revealed ribonuclear foci formation in cells carrying expanded 88 and 157 CR. Conclusion The present study demonstrates that the expanded CUG-repeat tracts are toxic to human cells and may affect ATXN8OS RNA expression and stability through epigenetic and post-transcriptional mechanisms.

Increased oxidative stress contributes to neuronal dysfunction in Parkinson's disease (PD). We investigated whether the pathological changes in PD brains may also be present in peripheral tissues. Leukocyte 8-hydroxydeoxyguanosine (8-OHdG), plasma malondialdehyde (MDA), erythrocyte glutathione peroxidase (GPx) and plasma vitamin E (Vit E) were measured for 211 PD patients and 135 healthy controls. Leukocyte 8-OHdG and plasma MDA were elevated, whereas erythrocyte GPx and plasma Vit E were reduced in PD patients when compared to the controls. After adjusting for environmental factors, logistic regression analysis showed that PD severity was independently correlated with 8-OHdG and MDA level, and inversely correlated with GPx activity and Vit E level. Leucocyte 8-OHdG level was continuously increased with advanced PD Hoehn–Yahr stages, while plasma MDA level peaked at early disease stages, among PD patients. These results suggest increased oxidative damage and decreased anti-oxidant capacity in peripheral blood, and a significant correlation between leucocyte 8-OHdG level and disease severity in PD.

The inverse association of the functional ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y variant with Parkinson’s disease (PD) among Caucasian populations has been debated. We conducted a large-scale analysis to investigate the age-of-onset effect of the UCHL1 variant in PD among ethnic Chinese. Individual data sets from 5 centers comprising a total of 4088 study subjects were analyzed. In the univariate analysis, only data from 1 center showed a trend towards a protective effect among young subjects. However, in the combined analysis, no significant association between the UCHL1 variant and PD was detected (A allele frequency 0.531 vs. 0.528, p = 0.87, OR 1.01, 95% CI 0.92–1.1). Among subjects less than 60 years old, the OR is 0.99 (95% CI 0.84–1.16, p = 0.88). A multivariate logistic regression analysis showed that family history, UCHL1 variant and the interaction of UCHL1 variant and age at onset (p = 0.816) were not significantly associated with PD.

PPP2R2B, a protein widely expressed in neurons throughout the brain, regulates the protein phosphatase 2A (PP2A) activity for the microtubule-associated protein tau and other substrates. Altered PP2A activity has been implicated in spinocerebellar ataxia 12, Alzheimer's disease (AD), and other tauopathies. Through a case-control study and a reporter assay, we investigated the association of PPP2R2B CAG repeat polymorphism with Taiwanese AD, essential tremor (ET), Parkinson's disease (PD), and schizophrenia and clarified the functional implication of this polymorphism. The distribution of the alleles was not significantly different between patients and controls, with 68.6-76.1% alleles at lengths of 10, 13, and 16 triplets. No expanded alleles were detected in either group. However, the frequency of the individuals carrying the short 5-, 6-, and 7-triplet alleles was notably higher in patients with AD (5/180 [2.8%], Fisher's exact test, P = 0.003; including 2 homozygotes) and ET (4/132 [3.0%], Fisher's exact test, P < 0.001) than in the controls (1/625 [0.2%]). The PPP2R2B transcriptional activity was significantly lower in the luciferase reporter constructs containing the (CAG)(5-7) allele than in those containing the common 10-, 13-, and 16-triplet alleles in both neuroblastoma and embryonic kidney cells. Therefore, our preliminary results suggest that the PPP2R2B gene CAG repeat polymorphism may be functional and may, in part, play a role in conferring susceptibility to AD and ET in Taiwan.

Common genetic variants that increase the risk for Parkinson's disease may differentiate patient subgroups and influence future individualized therapeutic strategies. Herein we show evidence for leucine-rich repeat kinase 2 (LRRK2) c.4883G>C (R1628P) as a risk factor in ethnic Chinese populations. A study of 1,986 individuals from 3 independent centers in Taiwan and Singapore demonstrates that Lrrk2 R1628P increases risk for Parkinson's disease (odds ratio, 1.84; 95% confidence interval, 1.20-2.83; p = 0.006). Haplotype analysis suggests an ancestral founder for carriers approximately 2,500 years ago. These findings support the importance of LRRK2 variants in sporadic Parkinson's disease. Ann Neurol 2008.

Endoplasmic reticulum (ER) chaperone heat shock 70 kDa protein 5 (HSPA5/GRP78) is known to be involved in the metabolism of amyloid precursor protein and neuronal death in Alzheimer’s disease (AD) could arise from dysfunction of the ER. Through a case–control study and an expression assay, we investigated the association of HSPA5 −415 G/A (rs391957), −370 C/T (rs17840761) and −180 del/G (rs3216733) polymorphisms with Taiwanese AD. The overall genotype and allele frequency distribution at the completely linked −415 G/A and −180 del/G sites showed significant difference between AD cases and controls (P = 0.020 and 0.009, respectively). A decrease in risk of developing AD was demonstrated for −415 AA/−180 GG genotype [OR = 0.38, 95% confidence interval (CI) = 0.18–0.75, P = 0.007] and −415 A/−180 G allele (OR = 0.69, 95% CI = 0.51–0.91, P = 0.009). The HSPA5 transcriptional activity of the −415 A/−180 G allele was significantly lower than that of the −415 G/−180 del alleles, whereas induction of HSPA5 expression after ER stress was markedly increased in the cells with the −415 A/−180 G allele. Therefore, our preliminary results may suggest a protective role of the HSPA5 −415 A/−180 G allele in Taiwanese AD susceptibility.

The reaction of aryl substituted α,β‐unsaturated nitroalkenes 1a–g with triallylaluminum 2 in ether solution at 0°C generated low to high yields of 4,5‐unsaturated nitroalkenes 3a–g after adding the nitronate to an ice‐cold solution of dilute hydrobromic acid. The yields of products 3h–j were increased substantially when the alkyl substituted α,β‐unsaturated nitroalkene 1h and the highly hindered α,β‐unsaturated nitroalkenes 1i and 1j reacted with 2 in the presence of aluminum chloride. The most important thing is triallylaluminum was prepared from allyl bromide and pure elemental Al, not from Grignard reagent.

Increased oxidative stress and mitochondrial abnormalities contribute to neuronal dysfunction in Huntington’s disease (HD). We investigated whether these pathological changes in HD brains may also be present in peripheral tissues. Leukocyte 8-hydroxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) were elevated, and activities of erythrocyte Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and glutathione peroxidase (GPx) reduced in 16 HD patients when compared to 36 age- and gender-matched controls. Deleted and total mitochondrial DNA (mtDNA) copy numbers were increased, whereas the mRNA expression levels of mtDNA-encoded mitochondrial enzymes are not elevated in HD leukocytes compared to the normal controls. Plasma MDA levels also significantly correlated with HD disease severity. These results indicate means to suppress oxidative damage or to restore mitochondrial functions may be beneficial to HD patients. Plasma MDA may be used as a potential biomarker to test treatment efficacy in the future, if confirmed in a larger, longitudinal study.

Antiphospholipid syndrome (APS) is identified as the presence of antiphospholipid antibodies (aPLs) in patients with vascular thrombosis and/or pregnancy morbidity (including fetal death, premature birth and habitual abortion). Neurological manifestations in patients with APS are common, whereas movement disorders are rarely seen. We report an extremely rare case of APS presented with parkinsonism and review the literature to address the clinical profile and possible pathophysiologic mechanism of this disorder.

Inflammatory events may contribute to the pathogenesis of Parkinson's disease (PD) and interleukin 1 (IL-1) may exert both neurotoxic and neuroprotective effects. We conducted a case-control study in a cohort of 493 PD cases and 388 ethnically matched controls to investigate the association of IL-1alpha C-889T and IL-1beta C-511T polymorphisms with the risk of PD. No significant difference in the genotype distribution of the analyzed polymorphisms was found between PD and controls. However, after stratification by age, individuals over 70 years of age carrying IL-1alpha-889 C/T genotype demonstrated a significant decrease in risk of developing PD (OR = 0.44; 95% CI = 0.22-0.88, p = 0.021) and the decrease is strengthened by IL-1beta-511 T-carrying genotype (OR = 0.28; 95% CI = 0.11-0.71, p = 0.008). Our data suggest that IL-1alpha, acting synergistically with IL-1beta, plays role in PD susceptibility among Taiwanese people older than 70 years of age.

Neuroinflammation is emerging as an important pathway involved in Parkinson's disease (PD) pathogenesis. Herein, we investigated the effect of 4 top PD-associated genetic variants in Caucasians listed on the top risk loci identified by meta-analysis of genome wide-association studies in PDGene database (http://www.pdgene.org/top_results), including serine threonine kinase 39 (STK39) rs1955337, bone marrow stromal cell antigen 1 (BST1) rs11724635, major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) rs9275326, and signal peptide peptidase-like 2B (SPPL2B) rs62120679, by genotyping 596 Han-Chinese patients with PD and 597 age-matched control subjects. Compared with subjects with STK39 rs1955337 GG genotype, those with TT genotype had a 1.64-fold increased risk of PD (95% confidence interval: 1.13–2.39, P = 0.010). The recessive model also demonstrated an increased PD risk in TT genotype (odds ratio: 1.59, 95% confidence interval: 1.12–2.27) compared with the other genotypes (GT + GG). PD patients demonstrate a similar genotypic and allelic frequency in BST1 rs11724635, HLA-DQB1 rs9275326, and SPPL2B rs62120679 compared with controls. These findings suggested that the STK39 rs1955337 TT genotype is a risk factor for Han-Chinese patients with PD in Taiwan. The ethnic discrepancies of the other 3 genetic variants may indicate a distinct genetic background of neuroinflammation between PD patients in Han-Chinese and Caucasians.

Background: Prior studies suggested that protein kinase Cη ( PRKCH ) 1425G/A polymorphism was associated with lacunar infarction. This study examined whether the association was independent of traditional risk factors in each of the stroke subtypes. Methods: This study included 206 ischemic stroke patients and 337 controls. Multivariable logistic regression was used for analyses. Co-variables of age, sex, hypertension, diabetes mellitus (DM), and smoking were included to delineate independency of associations. Result: PRKCH 1425G/A was associated with ischemic stroke [odds ratio (OR) =1.5, 95% confidence interval (CI): 1.1-2.2, p = 0.024] when adjusted for age and sex. However, the significance of association became borderline when adjusted for co-variables (OR = 1.5, 95% CI: 1.004-2.3, p = 0.048). Of the infarction subtypes, PRKCH 1425G/A was associated with lacunar infarction (OR = 1.8, 95% CI: 1.1-2.9, p = 0.025), which remained significant when adjusted for co-variables (OR = 2.0, 95% CI: 1.1-3.5, p = 0.015). No association was found between the polymorphism and the other infarction subtypes. When stratified by age group, the magnitude of significance became stronger in patients >65 years old. Specifically, PRKCH 1425G/A was significantly associated with ischemic stroke in patients older than 65 years, when adjusted for all co-variables (OR = 2.0, 95% CI: 1.05-3.8, p = 0.036). Still, in patients older than 65 years, the association was only observed in lacunar infarction when adjusted for all co-variables (OR = 4.2, 95% CI: 1.7-10, p = 0.001). No association of PRKCH 1425G/A with stroke and any of the subtypes was identified in patients >65 years old. Conclusion: The association between PRKCH 1425G/A and lacunar infarction was independent of traditional stroke risk factors. PRKCH 1425G/A in stroke susceptibility differed between infarction subtypes and age groups.

A critical role of mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). The association of mitochondrial DNA (mtDNA) polymorphisms 9055G/A, 10398G/A and 13708G/A with PD has been controversial. In this study we analyzed whether these three genetic polymorphisms are associated with PD in a cohort of 416 PD cases and 372 ethnically matched controls. The allele frequency distribution of any of these three analyzed polymorphisms was not significantly different between the cases and the controls. None of the six haplotypes derived influences risk of PD. Notably, after stratification by age, individuals over 70 years of age carrying the haplotype 9055G-10398A-13708G demonstrated a significant decrease in risk of developing PD (OR = 0.44, 95% CI = 0.24-0.80, p = 0.008). These results suggest that the mtDNA haplotype 9055G-10398A-13708G plays a role in PD susceptibility among Taiwanese people older than 70 years of age.

Background Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. The prevalence of PD is approximately 2% of the population over 65 years of age and 1.7 million PD patients (age ≥ 55 years) live in China. Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan. Methods 305 patients and 176 genetically unrelated healthy controls were examined by neurologists and the diagnosis of PD was based on the published criteria. The region of interest was amplified with standard polymerase chain reaction (PCR). PCR fragments then were directly sequenced in both forward and reverse directions. Differences in genotype frequencies between groups were assessed by the X 2 test, while X 2 analysis was used to test for the Hardy-Weinberg equilibrium. Results Of the 305 patients screened we identified 27 (9%) with heterozygous G2385R variant. This mutation was only found in 1 (0.5%) in our healthy control samples (odds ratio = 16.99, 95% CI: 2.29 to 126.21, p = 0.0002). Sequencing of the entire open reading frame of LRRK2 in G2385R carriers revealed no other variants. Conclusion These data suggest that the G2385R variant contributes significantly to the etiology of PD in ethnic Han Chinese individuals. With consideration of the enormous and expanding aging Chinese population in mainland China and in Taiwan, this variant is probably the most common known genetic factor for PD worldwide.

To the Editor: The strongest variant (rs7702187) associated with Parkinson disease (PD [MIM 168600]) reported in the whole-genome association study by Maraganore et al.1 was evaluated in two independent case-control series of patients from Finland and Taiwan, as were four other variants located within SEMA5A (MIM 609297). The Finnish series comprised 146 patients with sporadic PD (mean age 67.2 years, range 38–88 years; 41% women) and 135 neurologically normal, healthy control subjects (mean age 65.8 years, range 37–80 years; 64% women). All individuals were recruited from the neurological outpatient clinics of the Helsinki University Central Hospital and Seinajoki Central Hospital. The Taiwanese series consisted of 303 patients with sporadic PD (mean age 61.9 years, range 24–91 years; 46.2% women) and 171 control individuals (mean age 60.1 years, range 31–86 years; 43.9% women). Patients were selected from the neurological clinic of Chang-Gung Memorial Hospital. Individuals with evidence of secondary parkinsonism or with atypical features such as early dementia, ophthalmoplegia, early autonomic failure, and pyramidal signs were not included in this study. All patients included in the study fulfilled PD diagnosis criteria.2 All participants signed an informed consent form. Taqman Assays-by-Design SNP Genotyping Assays (Applied Biosystems) were employed for allelic discrimination of all SNPs. Differences in allele and genotype distributions were analyzed using the χ2 test, and two-tailed P values are presented. Haplotype frequency comparisons between cases and controls were performed with PHASE version 2.1 software.3 One thousand permutations were performed for each comparison. The COCAPHASE module of the UNPHASED statistical package was used for linkage-disequilibrium (LD) analyses.4 Power calculations were performed with PS version 2.1.30.5 Allele and genotype frequency information for each of the markers is shown in table 1. None of the markers showed any significant association with disease in the Finnish series. However, we were able to replicate the reported association with marker rs7702187 in the Taiwanese cohort (odds ratio [OR] = 1.53, 95% CI 1.12–2.10, P=.007). Genotype analysis showed that individuals homozygous for the A allele had a significantly decreased risk of PD compared with those heterozygous or homozygous for the T allele (OR = 0.60, 95% CI 0.41–0.88, P=.009). A significant association was also found for the rs3798097 marker, which is located in the 5′ UTR region of SEMA5A (OR for the C allele was 1.71, 95% CI 1.06–2.73, P=.025). Table 1 Genotype and Allele Frequency Distribution of the Polymorphisms Analyzed across SEMA5A on Chromosome 5 Both populations showed a complete lack of LD for any pairs of neighboring polymorphisms (all D′ values were

This study reviewed the clinical characteristics of nine patients, the female-to-male ratio being 2 (6/3), with corticobasal syndrome (CBS) from 2001 to 2006. The mean age of onset was 60.33±5.20 years. The most popular symptom was rigidity (100%), followed by bradykinesia (88.89%), apraxia (88.89%) and dystonia (66.67%). The common presentations in neuropsychological assessment included frontal dysfunction (88.89%), disorientation (66.67%), memory impairments (66.67%) and visuospecial defects (66.67%). Single proton emission-computed tomography (CT) showed hypoperfusion at contralateral basal ganglia, thalamic, parietal or temporal region in eight of nine patients. This investigation suggests that functional neuroimages and neuropsychological tests are useful tools for the diagnosis of CBS.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant and sporadic Parkinson's disease (PD). We report here the frequency of a common heterozygous mutation, 2877510G>A, which produces a glycine-to-serine amino acid substitution at codon 2019 in idiopathic Taiwanese PD. The extreme rarity of the G2019S mutation in our population suggests the occurrence of this mutation resulted from a common European founder.

Mutations in the PINK1 gene have been shown to cause autosomal recessive Parkinson's disease (PD) and/or early onset sporadic PD in Italy, Spain, North America, Ireland, and Asia. However, there are limited data on PINK1 mutations in sporadic early onset Asian PD patients. To determine the prevalence of PINK1 mutation in Taiwanese population, we conducted genetic analysis of PINK1 mutation in 73 early onset sporadic PD and 94 normal control subjects. We only identified a novel single heterozygous mutation R 407Q mutation in exon 6 of this gene in one patient at the age onset of 54. Overall, these data indicate that PINK1 mutations are rare in our population. Based on our results, unless common mutational hotspots are identified, routine testing for this mutation at least in our population may not be cost-effective.

This study was to determine whether polymorphisms of heat shock protein 70-1 (HSP70-1) and tumor necrosis factor α (TNF-α) are associated with the risk of Alzheimer’s disease (AD) and vascular dementia (VaD). Using the criteria of the NINCDS-ADRDA and NINDS-AIREN, 125 AD patients, 57 VaD patients and 109 ethnically matched nondemented controls were enrolled. The HSP70-1 –110 A/C and TNF-α –1031 T/C, –863 C/A and –857 C/T polymorphisms were analyzed by means of genotype or haplotype association methods. None of the four genotypes examined showed a statistically significant difference in genotype distribution between the AD cases and controls. However, the HSP70-1 –110 CC genotype occurred more frequently among AD cases (p = 0.0821; odds ratio: 2.08; 95% confidence interval, CI: 0.92–4.98). The overall genotype distribution among the VaD cases tended to be different at the HSP70-1 –110 and TNF-α –1031 sites (p = 0.0604 and 0.0316, respectively). The HSP70-1 –110 CC genotype was more frequent (p = 0.0459), and the association of the –110 CC genotype with VaD was evident (p = 0.0207; odds ratio: 3.22; 95% CI: 1.20–8.87). The more frequent TNF-α –1031 TC genotype (p = 0.0614) was also evidently associated with VaD (p = 0.0209; odds ratio: 2.32; 95% CI: 1.14–4.78). Multivariate analysis demonstrated the synergistic effect of the HSP70-1 –110 CC and TNF-α –1031 TC/CC genotypes on VaD (p = 0.0091; odds ratio: 10.09; 95% CI: 2.01–75.97). Haplotype analysis among TNF-α –1031, –863, –857 sites revealed that –1031C–857C may act as a risk haplotype among VaD cases (p = 0.0132, odds ratio: 2.26; 95% CI: 1.19–4.33). Our results suggest a potential protective role for HSP70 in both VaD and AD, whereas TNF-α may act as a risk factor only for VaD, and not for AD.

Background Miyoshi distal myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) were found to map to the same mutant gene encoding for dysferlin on chromosome 2p13. Most reported cases were large inbred kindreds whose members demonstrated both MM and LGMD2B phenotypes. Objective To investigate the clinical, neurophysiological, histopathological, and genetic features in 4 patients with MM from 2 unrelated Chinese families demonstrating linkage to the dysferlin locus. Results All patients were characterized by early adult onset, preferential atrophy, and weakness of calf muscles, marked elevation of serum creatine kinase levels, and absence of dysferlin staining. Magnetic resonance imaging showed fatty and fibrotic tissue signals in the affected muscles. Genetic analysis revealed novel compound heterozygous mutations, 1310+1G to A and GGG to GTC transition at nucleotide 1650 ( G426V ) in one family and another novel compound heterozygous mutation, a deletion of C at nucleotide 477 and a CCG to CTG transition at nucleotide 6576 (P2068L), in the other family. Conclusion Miyoshi distal myopathy in these 2 Chinese families demonstrated a homogenous phenotype and compound heterozygous mutations. Among the 4 mutations, 3 were novel mutations that, to our knowledge, have not been reported previously.

Peripheral neuropathy is usually subtle or subclinical in patients with multiple system atrophy (MSA). A 54-year-old man who initially presented with sensory polyneuropathy developed extrapyramidal and cerebellar signs and autonomic failure typical of MSA 7 years later. Sural nerve biopsy disclosed a prominent loss of large myelinated fibers, whereas the unmyelinated fibers were totally spared. These findings imply that sensory neuropathy can be part of the multiple-site degeneration in MSA, and that predominant involvement of large myelinated fibers of the sensory nerves can be a presenting feature.

Relapsing polychondritis (RP) is a rare disease characterized by recurrent inflammation of cartilaginous structures. Its involvement of central nervous system is uncommon. We report the case of a 71-year-old woman whose initial manifestations were RP and meningitis and whose subsequent attack of RP was associated with a left cerebral infarction. The patient responded to steroid therapy in both attacks of RP.

We report on a 28-year-old man who presented with right hand tremor, bradykinesia, and rigidity of his right side extremities. Our case report emphasizes that markedly asymmetrical parkinsonism can be an initial presentation of adult-onset Huntington's disease (HD), and different clinical presentations can be observed in members of an individual HD family with the same CAG repeat length.