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The mitochondrial DNA m.3243A>G mutation can affect mitochondrial function and lead to a wide phenotypic spectrum, including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, diabetes mellitus, hearing impairment, cardiac involvement, epilepsy, migraine, myopathy, and cerebellar ataxia. However, m.3243A>G has been rarely reported in patients with cerebellar ataxia as their predominant manifestation. The aim of this study is to investigate the prevalence and clinical features of m.3243A>G in a Taiwanese cohort of cerebellar ataxia with unknown genetic diagnosis. This retrospective cohort study conducted the mutation analysis of m.3243A>G by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 232 unrelated Han Chinese patients with genetically-undetermined cerebellar ataxia. The clinical presentation and neuroimaging features of patients with m.3243A>G mutation-related cerebellar ataxia were characterized. We identified two patients harboring m.3243A>G mutation. These patients have suffered from apparently sporadic and slowly progressive cerebellar ataxia since age 52 and 35 years, respectively. Both patients had diabetes mellitus and/or hearing impairment. The neuroimaging studies revealed generalized brain atrophy with predominantly cerebellar involvement in both individuals and bilateral basal ganglia calcifications in one of the patients. Mitochondrial m.3243A>G mutation accounted for 0.9% (2/232) of genetically-undetermined cerebellar ataxia in the Han Chinese cohort in Taiwan. These findings highlight the importance of investigating m.3243A>G in patients with genetically-undetermined cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES in genetic diagnosis of clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing variants in unrelated probands with defined familial stroke by candidate gene/hotspot screening and/or WES, depending on stroke subtypes and neuroimaging features at a referral center. The clinical significance of each variant was determined according to the American College of Medical Genetics guidelines. Among 161 probands (mean age at onset 53.2 ± 13.7 years; male 63.4%), 33 participants (20.5%) had been identified with 19 pathogenic/likely pathogenic variants (PVs; WES applied 152/161 = 94.4%). Across subtypes, the highest hit rate (HR) was intracerebral hemorrhage (ICH, 7/18 = 38.9%), particularly with the etiological subtype of structural vasculopathy (4/4 = 100%, PVs in ENG, KRIT1, PKD1, RNF213); followed by ischemic small vessel disease (SVD, 15/48 = 31.3%; PVs in NOTCH3, HTRA1, HBB). In contrast, large artery atherosclerosis (LAA, 4/44 = 9.1%) and cardioembolism (0/11 = 0%) had the lowest HR. NOTCH3 was the most common causative gene (16/161 = 9.9%), presenting with multiple subtypes of SVD (n = 13), ICH (n = 2), or LAA (n = 1). Importantly, we disclosed two previously unreported PVs, KRIT1 p.E379* in a familial cerebral cavernous malformation, and F2 p.F382L in a familial cerebral venous sinus thrombosis. The contribution of monogenic etiologies was particularly high in familial ICH and SVD subtypes in our Taiwanese cohort. Utilizing subtype-guided hotspot screening and/or subsequent WES, we unraveled monogenic causes in 20.5% familial stroke probands, including 1.2% novel PVs. Genetic diagnosis may enable early diagnosis, management and lifestyle modification. Among 161 familial stroke probands, 33 (20.5%) had been identified pathogenic or likely pathogenic monogenic variants related to stroke. The positive hit rate among all subtypes was high in intracerebral hemorrhage (ICH) and ischemic small vessel disease (SVD). Notably, two previously unreported variants, KRIT1 p.E379* in a familial cerebral cavernous malformation and F2 p.F382L in familial cerebral venous sinus thrombosis, were disclosed. CVT cerebral venous thrombosis; HTN Hypertensive subtype; LAA large artery atherosclerosis; SV structural vasculopathy; U Undetermined. [ABSTRACT FROM AUTHOR]

Mutations in the neurofilament light polypeptide gene (NEFL) are an uncommon cause of Charcot-Marie-Tooth disease (CMT). The aim of this study is to elucidate the clinical characteristics and genetic spectrum of NEFL -related neuropathy in a Taiwanese CMT cohort. Mutational analysis of the coding regions of NEFL was performed by Sanger sequencing or targeted resequencing. Twenty-one patients from nine CMT pedigrees, identified from a cohort of 508 unrelated CMT patients, were found to have a NEFL mutation. Genetic, clinical and electrophysiological features were analyzed. Six NEFL mutations were identified, including two novel ones (p.P8S, p.N98Y). NEFL p.E396K was the most common mutation, accounting for 33.3% of the patients in our cohort. All patients manifested sensorimotor polyneuropathy with a mean age of disease onset of 13.5 ± 9.6 (1–40) years. Their motor nerve conduction velocities (MNCVs) of the ulnar nerve ranged from 22.1 to 48.7 m/s. Seventy percent of the patients could be classified as intermediate CMT with ulnar MNCVs between 25 and 45 m/s. Six of the 21 patients (28.6%) had additional features of central nervous system (CNS) involvement, including motor developmental delay, spasticity, cerebellar signs, neuropathic pain and scoliosis. NEFL mutations account for 1.8% (9/508) of the CMT patients in Taiwan. The present study delineates the clinical and genetic characteristics of NEFL -related neuropathy in Taiwan, and highlights that ulnar MNCV above 25 m/s and CNS involvement may serve as diagnostic clues for NEFL -related neuropathy. [ABSTRACT FROM AUTHOR]

Background/purpose: The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD).Methods: Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies.Results: A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1-420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan-Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10-7).Conclusion: Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks. [ABSTRACT FROM AUTHOR]

Despite mass mortality, hard clams remain among the main cultured shellfish in Taiwan. Using cross-sectional data, this study applies threshold regression modeling with stocking density and feed costs as the threshold variables to explore the nonlinear relationship between input and output factors. The findings show that the production output levels may be increased by different combinations of factor inputs and variations in input factors. More specifically, the higher output levels may be achieved by increasing labor input while reducing capital input factors in farming households with a higher stocking density (HSD > 1,087,870 inds/ha) or higher feed cost (HFC > 13,889 NTD/ha). Farming households with a lower stocking density (LSD ≤ 1,087,870 inds/ha) may enhance production output levels by increasing feed input while reducing capital inputs. Moreover, the maximum output level of HSD and HFC farming households was estimated to reach 9255 kg/ha and 9807 kg/ha, respectively. Results of the production output simulation suggest that the feeding cost per hectare in LSD households should not exceed 25,119 NTD to avoid overfeeding, which may cause culture deterioration and lower survival rates. As such, farmers are advised to adjust their feed costs according to the stocking density to maximize production output. [ABSTRACT FROM AUTHOR]

Milkfish, Chanos chanos, is often cultured with white shrimp, Penaeus indicus, to maintain ecological stability and increase profits. This study uses the outputs and cost data of 169 milkfish farmers in Taiwan for the years 2018 and 2019 and applies translog cost function modeling to analyze the production scale economy and input–input demand combinations of two stocking densities (<10,000, ≥10,000 fry/ha) and two fry stocking sizes (2–3 in. and ≥4 in.). The study found that high‐density stocking (≥10,000 fry/ha) of small or large milkfish fry has economies of scale overall. Thus, the average culture cost may be reduced by expanding the scale of milkfish production. High‐density stocking of small fry exhibits a comparatively higher own‐price elasticity of fry. As such, farmers are sensitive to fry price variations. The study also found that labor and capital exhibit the highest substitutability. Capital inputs may thus be increased to mitigate the effects of wage increments. In terms of production, the four observed clusters do not exhibit cost complementarity. Moreover, the survival rate of white shrimp in high‐density stocking milkfish polycultures is relatively low. It is thus recommended to strictly control the stocking density of white shrimp and to minimize the risk of excessively high stocking densities by stocking white shrimp in batches. [ABSTRACT FROM AUTHOR]

Objective: Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods: Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results: Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation: CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants. [ABSTRACT FROM AUTHOR]

Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16), also named as Gordon Holmes syndrome, which is characterized by cerebellar ataxia, cognitive decline, and hypogonadism. Additionally, several heterozygous mutations in STUB1 have recently been described as a cause of autosomal dominant spinocerebellar ataxia type 48. STUB1 encodes C-terminus of HSC70-interacting protein (CHIP), which functions as an E3 ubiquitin ligase and co-chaperone and has been implicated in several neurodegenerative diseases. In this study, we identified two SCAR16 pedigrees from 512 Taiwanese families with cerebellar ataxia. Two compound heterozygous mutations in STUB1, c.[433A>C];[721C>T] (p.[K145Q];[R241W]) and c.[433A>C];[694T>G] (p.[K145Q];[C232G]), were found in each SCAR16 family by Sanger sequencing, respectively. Among them, STUB1 p.R241W and p.C232G were novel mutations. SCAR16 seems to be an uncommon ataxic syndrome, accounting for 0.4% (2/512) of our cohort with cerebellar ataxia. Clinically, the three patients from the two SCAR16 families presented with cerebellar ataxia alone or in combination with cognitive impairment. The brain MRIs showed a marked cerebellar atrophy of the patients. In conclusion, SCAR16 is an important but often neglected diagnosis of cerebellar ataxia of unknown cause, and the isolated cerebellar ataxia without involvement of other systems cannot be a basis to exclude the possibility of STUB1-related disease. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan. Methods: Mutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was ascertained by the presence of biallelic CYP7B1 mutations. The SPG5 patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using the Spastic Paraplegia Rating Scale (SPRS) and the disability score. Two microsatellite markers as well as 18 single‐nucleotide polymorphism (SNP) markers flanking CYP7B1 were genotyped to assess the founder effect of the CYP7B1 p.R112* mutation. Results: Nineteen SPG5 patients from 17 families were identified. They typically presented an insidious onset progressive spastic paraparesis with proprioception involvement beginning at age 8 to 40 years. Their MRIs often showed white matter abnormalities in bilateral occipito‐parietal regions, spinal cord atrophy, and mild cerebellar atrophy. Six different mutations in CYP7B1 were recognized, including three novel ones (p.N131Ifs*4, p.A295V, and p.L439R). CYP7B1 p.R112* was the most common mutation and present in 88.2% of the 17 SPG5 pedigrees. The patients with homozygous CYP7B1 p.R112* mutations had a milder clinical severity. Detailed haplotype analyses demonstrated a shared haplotype in the 25 individuals carrying at least one single allele of CYP7B1 p.R112*, suggesting a founder effect. Interpretation: This study delineates the distinct clinical and genetic features of SPG5 in Taiwan and provides useful information for the diagnosis and management of SPG5, especially in patients of Chinese descent. [ABSTRACT FROM AUTHOR]

Objective: Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited neuropathies. Mutations in more than 90 genes have been implicated in CMT; however, the mutational spectrum of CMT in Chinese population remains obscure. This study aims to provide a comprehensive overview of the frequency of mutations in Taiwanese patients with CMT and look for genotype‐phenotype correlations. Methods: Mutational analyses were performed on 427 unrelated Taiwanese patients with CMT by polymorphic microsatellite markers analysis or real‐time fluorescent PCR for PMP22 duplication, Sanger sequencing for GJB1 mutations, and targeted sequencing covering 124 genes causing or relevant to inherited neuropathies. We also correlated the genotypes with the phenotypic features, such as age at disease onset and ulnar motor nerve conduction velocity. Results: Pathogenic mutations were identified in 312 patients (73.1%; 312/427), including 208 patients with a PMP22 duplication, 40 patients with a GJB1 mutation, and 64 patients with a mutation in one of other 18 CMT genes. A confirmed molecular diagnosis was achieved in 84.4% (266/315) of the patients with demyelinating CMT and 41.1% (46/112) of the patients with axonal CMT. Mutations in MPZ, MFN2, or NEFL are the most frequent disease causes in patients with infantile‐onset CMT (≤2 years), while PMP22 duplications and mutations in GJB1, MFN2, or MPZ are the frequent causes among patients with childhood‐ or adolescence‐onset CMT (3–9 years). Interpretation: This study provides a genotype‐phenotype landscape of CMT in Taiwan and highlights the unique spectrum of CMT genes frequencies among patients of Chinese origin. [ABSTRACT FROM AUTHOR]

Objective: The clinical and genetic profiles of hereditary transthyretin amyloidosis (ATTR) in Chinese populations remain elusive. We aim to characterize the features of ATTR in a Taiwanese cohort of Han Chinese descent. Methods: Seventy‐nine patients with molecularly confirmed ATTR from 57 Taiwanese families were identified by sequencing the transthyretin gene (TTR). The clinical and electrophysiological data were scrutinized. Cardiac involvement of ATTR was evaluated by echocardiography and cardiac scintigraphy. Four microsatellite and seven single‐nucleotide polymorphism markers flanking TTR were genotyped to investigate the founder effect of the TTR Ala97Ser mutation. Results: Most of the patients had a peripheral neuropathy with variable autonomic symptoms. The average age at disease onset (AO) was 58.2 ± 7.2 years, and the male patients had an earlier AO than female patients (56.6 ± 5.7 years vs. 61.8 ± 8.9 years, P = 0.013). Electrophysiological studies revealed a generalized axonal sensorimotor polyneuropathy and isolated median neuropathy in 84.5% and 15.5% of the patients, respectively. Up to 80% of the patients with ATTR had symptomatic or subclinical cardiac involvement. Six TTR mutations were identified in the participants including one novel mutation Glu89Asp. Among them, Ala97Ser was the most common mutation, accounting for 91.2% of the ATTR pedigrees. Detailed haplotype analyses demonstrated a shared haplotype in the 47 patients with the Ala97Ser mutation, suggesting a founder effect. Interpretation: The present study delineates the distinct features of ATTR in Taiwan and provides useful information for the diagnosis and management of ATTR, especially in patients of Chinese descent. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3–6 and leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders with common features of adult-onset cerebellar ataxia. Many patients with clinically suspected SCA are subsequently diagnosed with common SCA gene mutations. Previous reports suggest some common mitochondrial DNA (mtDNA) point mutations and mitochondrial DNA polymerase gene (POLG1) mutations might be additional underlying genetic causes of cerebellar ataxia. We tested whether mtDNA point mutations A3243G, A8344G, T8993G, and T8993C, or POLG1 mutations W748S and A467T are found in patients with adult-onset ataxia who did not have common SCA mutations. Methods: Four hundred seventy-six unrelated patients with suspected SCA underwent genetic testing for SCA 1, 2, 3, 6, 7, 8, 10, 12, 17, and DRPLA gene mutations. After excluding these SCA mutations and patients with paternal transmission history, 265 patients were tested for mtDNA mutations A3243G, A8344G, T8993G, T8993C, and POLG1 W748S and A467T mutations. Results: No mtDNA A3243G, A8344G, T8993G, T8993C, or POLG1 W748S and A467T mutation was detected in any of the 265 ataxia patients, suggesting that the upper limit of the 95% confidence interval for the prevalence of these mitochondrial mutations in Chinese patients with adult-onset non-SCA ataxia is no higher than 1.1%. Conclusions: The mtDNA mutations A3243G, A8344G, T8993G, T8993C, or POLG1 W748S and A467T are very rare causes of adult-onset ataxia in Taiwan. Routine screening for these mutations in ataxia patients with Chinese origin is of limited clinical value. [Copyright &y& Elsevier]

Background: Charcot–Marie–Tooth disease type 1 (CMT1) is the most common inherited peripheral neuropathy and represents a genetically heterogeneous condition. In addition to the peripheral myelin protein 22 gene (PMP22) duplication (CMT1A), myelin protein zero gene (MPZ) mutations may account for a certain portion of CMT1 patients (CMT1B). Objectives: The authors analyzed the MPZ mutations in Taiwanese patients who do not have PMP22 duplication. Specifically, their clinical and molecular features were characterized. Materials and methods: Twenty-four of 57 unrelated Taiwanese patients with CMT1 were selected after excluding the CMT1A duplication. Subsequent analysis of the coding regions of the MPZ gene was performed with single-strand-conformation polymorphism (SSCP), which was then followed by nucleotide sequencing. Results: Four missense mutations and one 4-base pair (bp) deletion, respectively, were identified in five patients, of which one mutation, c.173 T>A, has never been previously reported. Three missense mutations were located in exon 2, the other one in exon 3, and the deletion in exon 6. Conclusions: This study expands the number of CMT1 associated MPZ mutation and suggests that analysis of the coding sequence of MPZ should be performed in all CMT patients without CMT1A duplication to clarify their disease nature. [Copyright &y& Elsevier]

Abstract: Spinocerebellar ataxia (SCA) is a clinically, pathologically, and genetically heterogeneous group of dominantly inherited neurodegenerative disorders. SCA31 has recently been reported to be associated with a complex penta-nucleotide (TGGAA)n repeat insertion in the introns of TK2 and BEAN. In this study we excluded SCA31 mutation from 119 unrelated patients with molecularly unassigned hereditary cerebellar ataxia, out of 512 pedigrees, after mutations in SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and dentatorubral-pallidoluysian atrophy (DRPLA) had been excluded. Our data indicate that SCA31 is absent or rare in the Chinese population on Taiwan. [Copyright &y& Elsevier]

Background Charcot Marie Tooth disease type 1A (CMT1A) is the most commonly inherited demyelinating polyneuropathy with variable phenotypes, affected by several comorbidities, especially diabetes mellitus (DM). Previous studies showed that DM exacerbates the clinical manifestations of CMT1A. Patients and methods We retrospectively evaluated patients with CMT1A in our hospital, and identified three groups among 12 cases, which comprised four patients with CMT1A, four with CMT1A + DM, and four with DM. We reviewed the CMT neuropathy score (CMTNS), electrophysiological data, and histomorphological parameters of the sural nerve, including fiber density, myelin thickness, axon diameter, g-ratio, regenerative clusters, and regeneration ratio. Results The CMTNS was significantly higher in patients with CMT1A + DM (21.5 ± 2.52) than in those with CMT1A only (10.8 ± 4.4; p = 0.03). Pathological findings in patients with CMT1A + DM included a significant decrease of myelinated fiber density ( p = 0.02) and reduction in the regenerative ratio ( p = 0.01), indicating severe degeneration with impaired regeneration. In non-parametric analyses, DM was found to play a more important role than CMT1A in influencing nerve degeneration and regeneration. Conclusions In patients with CMT1A, DM exacerbated clinical and pathological manifestations including increased loss of myelinated fibers, abnormal axon–myelin interaction, and impaired nerve regeneration. [ABSTRACT FROM AUTHOR]

Background: Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder caused by mutations in the ABCD1 gene. The clinical manifestations of ALD vary widely with some patients presenting with adrenomyeloneuropathy (AMN) that resembles the phenotype of hereditary spastic paraplegia (HSP). The aim of this study is to investigate the frequency, spectrum, and clinical features of ABCD1 mutations in Taiwanese patients with HSP phenotype.Methods: Mutational analysis of the ABCD1 gene was performed in 230 unrelated Taiwanese patients with clinically suspected HSP by targeted resequencing. Clinical, electrophysiological, and neuroimaging features of the patients carrying an ABCD1 pathogenic mutation were characterized.Results: Ten different ABCD1 mutations were identified in eleven patients, including two novel mutations (p.Q177Pfs*17 and p.Y357*) and eight ever reported in ALD cases of other ethnicities. All patients were male and exhibited slowly progressive spastic paraparesis with onset ages ranging from 21 to 50 years. Most of them had additional non-motor symptoms, including autonomic dysfunction in nine patients, sensory deficits in seven, premature baldness in seven, skin hyperpigmentation in five, psychiatric symptoms in one and cerebellar ataxia in one. Seven of the ten patients who ever received nerve conduction studies showed axonal polyneuropathy. Magnetic resonance imaging (MRI) revealed diffuse spinal cord atrophy in seven patients, cerebral white matter hyperintensity in one patient, and cerebellar involvement in one patient.Conclusions: ABCD1 mutations account for 4.8% (11/230) of the cases with HSP phenotype in Taiwan. This study highlights the importance to consider ABCD1 mutations in patients with clinically suspected HSP of unknown genetic causes. [ABSTRACT FROM AUTHOR]

Aim: To investigate the clinical and genetic features of hereditary spastic paraplegia (HSP) type 3A (SPG3A) in Taiwan.Methods: Mutational analysis of the ATL1 gene was performed for 274 unrelated Taiwanese HSP patients. The diagnosis of SPG3A was ascertained by the presence of a heterozygous pathogenic mutation in ATL1. The SPG3A patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using Spastic Paraplegia Rating Scale (SPRS) and disability score. Nineteen single nucleotide polymorphism (SNP) markers flanking ATL1 were genotyped for haplotype analysis of ATL1 p.R416C mutation.Results: Eighteen SPG3A patients from 11 families were identified. They typically presented a pure form HSP phenotype with disease onset ranging from age 1-68 years. Five heterozygous ATL1 mutations were identified, including p.R239C, p.V253I, p.Y336H, p.P342R and p.R416C. ATL1 p.R416C was the most common mutation and presented in five SPG3A pedigrees. Haplotype analyses demonstrated a shared haplotype in the 12 individuals carrying a p.R416C allele.Conclusion: SPG3A accounts for 4% (11 out of 274) of HSP in the Taiwanese cohort. Patents with the ATL1 p.R416C mutation in Taiwan may descend from a common ancestor. This study defines the clinical and genetic features of SPG3A in Taiwan and provides useful information for the diagnosis and management, especially in patients of Han Chinese descent. [ABSTRACT FROM AUTHOR]

Abstract Mutations in the annexin A11 gene (ANXA11) have been recently identified in British patients and Italian patients with amyotrophic lateral sclerosis (ALS), and their role in other ALS populations remains unclear. The aim of this study was to investigate the ANXA11 mutations in a Taiwanese ALS cohort. Mutational analysis of ANXA11 was performed in 286 unrelated Taiwanese patients with ALS by Sanger sequencing. Eight ANXA11 missense variants were identified initially, and only one of them was absent from population databases. This missense variant, p.Q362L, was identified in 1 single patient with apparently sporadic ALS, and no further strong evidence was available to support its pathogenicity. Therefore, it is classified as a variant of uncertain significance. Our data indicate that pathogenic ANXA11 mutations are absent or rare in ALS patients in Taiwan. [ABSTRACT FROM AUTHOR]

Mutations in the MATR3 gene were just recently identified to cause familial amyotrophic lateral sclerosis, and their role in amyotrophic lateral sclerosis (ALS) in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in MATR3 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of MATR3 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 169 patients remained elusive after mutations in SOD1 , C9ORF72 , TARDBP , FUS , ATXN2 , OPTN , VCP , UBQLN2 , SQSTM1 , PFN1 , HNRNPA1 , and HNRNPA2B1 had been excluded. We identified 1 heterozygous missense mutation, p.Ala72Thr (c.214G>A), in 1 patient with bulbar-onset and apparently sporadic ALS. The frequency of MATR3 mutations in ALS patients in Taiwan is, therefore, approximately 0.5% (1 of 207). This study reports a novel MATR3 mutation and stresses on the importance to consider MATR3 mutation as a possible etiology of ALS. [ABSTRACT FROM AUTHOR]

Abstract: A GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene was recently identified as an important cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations. The role of the C9ORF72 repeat expansion in ALS in Chinese populations has received little attention. We therefore performed mutation analyses in a Taiwanese cohort of 22 unrelated familial ALS (FALS) patients and 102 sporadic ALS patients of Han Chinese descent. The C9ORF72 mutation was found in 4 FALS (18.2%; 4/22) and 2 sporadic ALS patients (2.0%; 2/102). The C9ORF72 repeat numbers in the 300 healthy controls and the 118 ALS patients without the C9ORF72 mutation ranged from 3 to 15. Needle biopsy in the left frontal cortex of 1 patient with FALS-frontotemporal dementia revealed numerous cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions and minimal neuritis, consistent with type B frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) pathology. This study clearly demonstrates the existence and importance of the C9ORF72 hexanucleotide repeat expansion in a Taiwanese ALS cohort of Chinese origin, and supports the global presence of the C9ORF72 repeat expansion in ALS. [Copyright &y& Elsevier]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system, characterized by pathogenic anti-Aquaporin-4 antibodies (AQP4-Ab). Given that infections can trigger autoimmune responses, we investigated the association between Hepatitis B virus (HBV) infection and NMOSD., Methods: HBV and hepatitis C virus serologies were analyzed in 105 NMOSD patients, 85 multiple sclerosis (MS) patients, and 1,661 healthy Taiwanese controls. Participants were classified into four HBV infection statuses (acute, chronic, resolved, and never infected), and further grouped by vaccination status. Logistic regression was used to estimate odds ratios (OR) for NMOSD development in individuals with chronic or resolved HBV infection., Results: Among those born before the Taiwan's universal vaccination program, 63.4 % of NMOSD patients had resolved HBV infection, compared to 30.6 % of MS patients and 16.4 % of controls. Resolved HBV infection was associated with a 2.3-fold increased risk for NMOSD development (95 % CI, 1.4-3.8), but not with MS risk. In the post-vaccination cohort, resolved HBV infection remained more frequent in NMOSD patients (8.7 %) than in MS (0 %) and controls (1.8 %). NMOSD patients with resolved HBV infection had later disease onset by 14.6 years and higher Expanded Disability Status Scale (EDSS) scores compared to those without HBV infection, even after adjusting for age and sex (3.5 ± 1.9 vs. 2.2 ± 1.8, p < 0.001)., Conclusion: Preceding HBV infection is prevalent among Taiwanese NMOSD patients and is associated with increased disease risk, older age at onset, and greater disability. Screening for HBV is essential for NMOSD patients, particularly in endemic regions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: There have been limited data on idiopathic intracranial hypertension (IIH) in Asians and there remain uncertainties whether a cerebrospinal fluid (CSF) pressure of 250 mm CSF is an optimum diagnostic cutoff. The aims of the present study included (1) characterization of IIH patients in Taiwan, (2) comparisons among different diagnostic criteria for IIH, and (3) comparisons between patients with CSF pressures of > 250 and 200-250 mm CSF., Methods: This retrospective study involved IIH patients based on the modified Dandy criteria from two tertiary medical centers in Taiwan. Clinical manifestations were retrieved from electronic medical records, and findings on ophthalmologic examination and magnetic resonance images (MRIs) were reviewed., Results: A total of 102 patients (71 F/31 M, mean age 33.4 ± 12.2 years, mean CSF pressure 282.5 ± 74.5 mm CSF) were identified, including 46 (45.1%) with obesity (body-mass index ≥ 27.5), and 57 (62.6%) with papilledema. Overall, 80 (78.4%), 55 (53.9%), 51 (50.0%), and 58 (56.9%) patients met the Second and Third Edition of International Classification of Headache Disorders, Friedman, and Korsbæk criteria, respectively. Patients in the 200-250 mm CSF group (n = 40) were less likely to have papilledema (48.5% vs. 70.7%, p = 0.035), transient visual obscuration (12.5% vs. 33.9%, p = 0.005), and horizontal diplopia (10.0% vs. 30.6%, p = 0.006), and had fewer signs on MRIs (2.2 ± 1.3 vs. 2.8 ± 1.0, p = 0.021) when compared with those with CSF pressures > 250 mm CSF (n = 62). However, the percentages of patients with headache (95.0% vs. 87.1%, p = 0.109) at baseline, chronic migraine at six months (31.6% vs. 25.0%, p = 0.578), and visual field defect (86.7% vs. 90.3%, p = 0.709) were similar., Conclusions: It was found that obesity and papilledema were less common in Asian IIH patients when compared with Caucasian patients. Although patients with CSF pressures of 200-250 mm CSF had a less severe phenotype, the risks of having headache or visual loss were comparable to those in the > 250 mm CSF group. It is possible that a diagnostic cutoff of > 200 mm CSF could be more suitable for Asians, although further studies are still needed., (© 2024. The Author(s).)

Background: To examine the efficacy and safety of patisiran, an RNA interference therapeutic, in patients from Taiwan with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy., Methods: The APOLLO phase 3 trial included patients from Taiwan who received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks (q3w) for 18 months (18 M), followed by patisiran 0.3 mg/kg q3w in an ongoing global open-label extension (OLE) study. The primary endpoint was change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 18 M., Results: Eighteen Taiwanese patients were enrolled in APOLLO (patisiran, n = 8; placebo, n = 10; all A97S gene variant) and 14 continued in the global OLE. In this Taiwanese sub-population, beneficial treatment effects at 18 M were observed in mNIS+7 (least squares mean difference in change from baseline [patisiran-placebo], -26.5 points; 95% confidence interval: -45.5, -7.5). Patients who switched from placebo to patisiran demonstrated slowing of polyneuropathy progression at month 12 in the global OLE, while those who received patisiran in APOLLO maintained the beneficial treatment effects. Patisiran had an acceptable safety profile in the Taiwanese sub-population., Conclusion: This analysis suggests that patisiran is well tolerated and may provide a substantial clinical benefit for Taiwanese patients with hATTR amyloidosis with polyneuropathy., Trial Registration Information: The studies were registered on the ClinicalTrials.gov. The APOLLO study ClinicalTrials.gov identifier is NCT01960348 (https://clinicaltrials.gov/ct2/show/NCT01960348), with the registration date of October 10, 2013, and the first patient was enrolled on December 13, 2013. For the global OLE, the ClinicalTrials.gov identifier is NCT02510261 (https://clinicaltrials.gov/ct2/show/NCT02510261) with the registration date of July 29, 2015, and the first patient was enrolled on July 13, 2015., Classification of Evidence: This study provides Class II evidence that treatment with patisiran is safe and efficacious in Taiwanese patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background/purpose: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 15 (SPG15) is an autosomal recessive subtype caused by ZFYVE26 mutations. The aim of this study was to investigate the frequency and clinical and genetic features of ZFYVE26 mutations in a Taiwanese HSP cohort., Methods: Mutational analysis of the coding regions of ZFYVE26 was performed by targeted resequencing in the 195 unrelated Taiwanese patients with HSP. All of the patients were of Han Chinese ethnicity. Clinical, neuropsychological, electrophysiological evaluations and imaging studies were collected., Results: Among the 195 patients, only one SPG15 patient was identified. The patient had a novel recessive ZFYVE26 frameshift truncating mutation, p.R1806Gfs∗36 (c.5415delC), and presented with insidious onset spastic weakness of lower-extremities and cognitive impairment. Neuropsychological assessment revealed deficits in executive function, visual naming, category verbal fluency, and manual dexterity. Brain MRI showed thin corpus callosum and the "ears of lynx" sign., Conclusion: SPG15 accounts for approximately 0.5% (1/195) of the Taiwanese HSP cohort. This study identified the first Taiwanese SPG15 case and delineated the clinical, genetic, neuropsychological, and neuroimaging features. These findings expand the mutational spectrum of ZFYVE26 and also broaden the knowledge of clinical and neuropsychological characteristics of SPG15., Competing Interests: Declarations of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The GGC repeat expansion in the 5'-untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID). To determine if the NIID repeat expansion contributes to amyotrophic lateral sclerosis (ALS), we screened 304 unrelated ALS patients and 637 healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. None of the ALS patients carried the GGC repeat expansion. The sizes of the GGC repeats ranged from 7 to 36 in the ALS patients and 4 to 46 in the controls. The distribution of the GGC repeat sizes did not differ between the two groups. Our findings indicate that the NOTCH2NLC GGC repeat expansion is absent or extremely rare in Taiwanese patients with ALS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The NEK1 gene has been recently implicated in amyotrophic lateral sclerosis (ALS). This study aims to assess the influence of NEK1 variants on the occurrence of ALS and investigate the spectrum and clinical features of NEK1 loss-of-function (LOF) variants in a Taiwanese ALS cohort., Methods: We screened 325 unrelated ALS patients for coding variants in NEK1 by targeted resequencing and queried the Taiwan Biobank database for NEK1 coding variants in 1000 Taiwanese healthy individuals. The clinical features of the patients with a NEK1 LOF variant were analyzed., Results: Six patients and two healthy individuals carried NEK1 LOF variants. The rare missense variants with minor allele frequencies <0.1% in Taiwanese population were present in 2.8% of the ALS patients and 1.6% of the healthy subjects. NEK1 LOF variants, but not rare missense variants, are significantly enriched in the ALS patients (P = 0.0037 and 0.24, Fisher's exact test). The odds ratio of an individual carrying a NEK1 LOF variant to develop ALS is 9.39 (95% confidence interval: 1.88-46.7). All the six patients carrying a NEK1 LOF variant had a hand-onset ALS with an onset age from 52 to 64 years. Comparing with ALS patients without a NEK1 LOF variant, patients with a NEK1 LOF variant tend to have a hand-onset disease (P = 0.0008, Fisher's exact test)., Interpretation: Our study supports the pathogenic role of NEK1 LOF variants and demonstrates their spectrum and clinical features in a Taiwanese cohort with ALS., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To test the hypothesis that the prevalence and clinical effect of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been underestimated in Asian populations., Methods: The Taiwan Biobank, containing 1,517 Taiwanese genome sequences, was queried for pathogenic NOTCH3 cysteine-altering mutations. NOTCH3 mutations identified in the reference population were genotyped in 7,038 stroke- and dementia-free individuals and 800 patients with ischemic stroke. NOTCH3 genotyping, clinical manifestations, and the severity of white matter lesions on MRI were compared between the 2 groups., Results: Three cysteine-altering NOTCH3 variants (p.R544C, p.C853Y, and p.C884Y) were identified from the Taiwan Biobank. We confirmed that the NOTCH3 p.R544C mutation was present in a significant number of individuals in Taiwan, including 60 of the 7,038 healthy controls (0.9%), 17 of the 800 patients with ischemic stroke (2.1%), and 16 of the 245 patients with small vessel occlusion (SVO) stroke (6.5%). The other 2 cysteine-altering mutations were rarely detected. After adjusting for vascular risk factors, harboring the p.R544C variant resulted in a 3.40-fold increased risk for overall stroke and an 11.05-fold increased risk for SVO stroke ( p = 0.0001 and 3.9 × 10 -10 , respectively). Three symptom-free individuals carrying the p.R544C mutation had extensive leukoencephalopathy typical of CADASIL at age 59, 66, and 67, suggesting that p.R544C-related CADASIL could remain subclinical at advanced age., Conclusion: The NOTCH3 p.R544C variant is an important risk factor for SVO stroke in Taiwan. Phenotypic variation among individuals carrying a NOTCH3 mutation indicates the existence of disease-modifying factors in CADASIL., (© 2019 American Academy of Neurology.)

Introduction: Mutations in the PUM1 gene were recently identified to cause spinocerebellar ataxia type 47 (SCA47). However, their role in cerebellar ataxia in various populations remains elusive. The aim of this study was to elucidate the frequency and spectrum of PUM1 mutations in a cohort of Taiwanese patients with molecularly undetermined cerebellar ataxia., Methods: Mutational analyses of PUM1 were performed by Sanger sequencing in a cohort of 248 unrelated patients with cerebellar ataxia of unknown cause, including 108 with autosomal-dominantly inherited cerebellar ataxia, 45 with autosomal-recessively inherited cerebellar ataxia, and 95 with apparently sporadic cerebellar ataxia. Among them, the genetic causes of ataxia remained unknown after excluding mutations responsible for SCA1, 2, 3, 6, 7, 8, 10, 12, 17, 19/22, 23, 26, 27, 28, 31, 35, 36, dentatorubral-pallidoluysian atrophy and Friedreich's ataxia., Results: Two heterozygous missense PUM1 variants were identified in two patients with apparently sporadic cerebellar ataxia, including a known disease-causing mutation (p.R1139W) and a variant of uncertain significance (p.K151R). The patient carrying the p.R1139W mutation had a slowly progressive, relatively pure cerebellar ataxia, presenting with gait unsteadiness, limb dysmetria, ataxic dysarthria and saccadic pursuit., Conclusion: Our findings support the pathogenic role of PUM1 mutations in cerebellar ataxia and emphasize the importance of considering PUM1 mutations as a possible etiology of cerebellar ataxia., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Purpose: Homozygous and compound heterozygous mutations in the high temperature requirement serine peptidase A1 gene ( HTRA1 ) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. However, heterozygous HTRA1 mutations were recently identified to be associated with autosomal dominant cerebral small vessel disease (SVD). The present study aims at investigating the clinical features, frequency, and spectrum of HTRA1 mutations in a Taiwanese cohort with SVD., Methods: Mutational analyses of HTRA1 were performed by Sanger sequencing in 222 subjects, selected from a cohort of 337 unrelated patients with SVD after excluding those harboring a NOTCH3 mutation. The influence of these mutations on HTRA1 protease activities was characterized., Results: Seven novel heterozygous mutations in HTRA1 were identified, including p.Gly120Asp, p.Ile179Asn, p.Ala182Profs*33, p.Ile256Thr, p.Gly276Ala, p.Gln289Ter, and p.Asn324Thr, and each was identified in 1 single index patient. All mutations significantly compromise the HTRA1 protease activities. For the 7 index cases and another 2 affected siblings carrying a heterozygous HTRA1 mutation, the common clinical presentations include lacunar infarction, intracerebral hemorrhage, cognitive decline, and spondylosis at the fifth to sixth decade of life. Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior, 3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia., Conclusions: Heterozygous HTRA1 mutations account for 2.08% (7 of 337) of SVD in Taiwan. The clinical and neuroradiological features of HTRA1 -related SVD and sporadic SVD are similar. These findings broaden the mutational spectrum of HTRA1 and highlight the pathogenic role of heterozygous HTRA1 mutations in SVD., (© 2018 American Heart Association, Inc.)

Mutations in the cyclin F gene (CCNF) have been recently identified in a small number of patients with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia, and their role in patients with ALS in Taiwan remains elusive. The aim of this study was to elucidate the frequency and spectrum of CCNF mutations in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of the CCNF gene were performed using Sanger sequencing in a cohort of 255 unrelated patients with ALS. Among these patients, the genetic diagnoses of 204 patients remained unclear after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, TUBA4A, and TKB1 had been investigated. Two novel heterozygous missense mutations in CCNF, p.S222P (c.664T>C) and p.S532R (c.1596C>T), were identified; 1 in each patient with apparently sporadic ALS. In vitro functional study demonstrated that both mutations result in a general and cyclin F-mediated ubiquitin-proteasome pathway dysfunction. The frequency of CCNF mutations in ALS patients in Taiwan is, therefore, approximately 0.8% (2/255). These findings expand the mutational spectrum of CCNF and also emphasize the pathogenic role of CCNF mutations in ALS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Point mutations in the peripheral myelin protein 22 (PMP22) gene have been identified to cause demyelinating Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsy (HNPP). To investigate the mutation spectrum of PMP22 in Han-Chinese population residing in Taiwan, 53 patients with molecularly unassigned demyelinating CMT and 52 patients with HNPP-like neuropathy of unknown genetic causes were screened for PMP22 mutations by Sanger sequencing. Three point mutations were identified in four patients with demyelinating CMT, including c.256 C > T (p.Q86X) in two, and c.310delA (p.I104FfsX7) and c.319 + 1G > A in one each. One PMP22 missense mutation, c.124 T > C (p.C42R), was identified in a patient with HNPP-like neuropathy. The clinical presentations of these mutations vary from mild HNPP-like syndrome to severe infantile-onset demyelinating CMT. In vitro analyses revealed that both PMP22 p.Q86X and p.I104FfsX7 mutations result in truncated PMP22 proteins that are almost totally retained within cytosol, whereas the p.C42R mutation partially impairs cell membrane localization of PMP22 protein. In conclusion, PMP22 point mutations account for 7.5% and 1.9% of demyelinating CMT and HNPP patients with unknown genetic causes, respectively. This study delineates the clinical and molecular features of PMP22 point mutations in Taiwan, and emphasizes their roles in demyelinating CMT or HNPP-like neuropathy.

Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene cause a wide spectrum of neurological diseases, ranging from paroxysmal kinesigenic dyskinesia (PKD) to mental retardation and epilepsy. Previously, seven PKD-related PRRT2 heterozygous mutations were identified in the Taiwanese population: P91QfsX, E199X, S202HfsX, R217PfsX, R217EfsX, R240X and R308C. This study aimed to investigate the disease-causing mechanisms of these PRRT2 mutations. We first documented that Prrt2 was localized at the pre- and post-synaptic membranes with a close spatial association with SNAP25 by synaptic membrane fractionation and immunostaining of the rat neurons. Our results then revealed that the six truncating Prrt2 mutants were accumulated in the cytoplasm and thus failed to target to the cell membrane; the R308C missense mutant had significantly reduced protein expression, suggesting loss-of function effects generated by these mutations. Using in utero electroporation of shRNA into cortical neurons, we further found that knocking down Prrt2 expression in vivo resulted in a delay in neuronal migration during embryonic development and a marked decrease in synaptic density after birth. These pathologic effects and novel disease-causing mechanisms may contribute to the severe clinical symptoms in PRRT2-related diseases., Competing Interests: All authors declare no conflicts of interest.

Mutations in the TBK1 gene were just recently identified to cause amyotrophic lateral sclerosis (ALS), and their role in ALS in various populations remains unclear. The aim of this study was to determine the frequency and spectrum of mutations in TBK1 in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of TBK1 were carried out by direct nucleotide sequencing in a cohort of 207 unrelated patients with ALS. Among them, the genetic diagnoses of 168 patients remained elusive after mutations in SOD1, C9ORF72, TARDBP, FUS, ATXN2, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, HNRNPA2B1, MATR3, CHCHD10, and TUBA4A had been excluded. We identified one nonsense mutation, p.R444X (c.1330C>T), in one patient with apparently sporadic ALS-frontotemporal dementia. In vitro functional study demonstrated the p.R444X mutation resulting in a truncated TANK-binding kinase 1 (TBK1) protein product, low protein expression, and loss of kinase function and interaction with optineurin. The frequency of TBK1 mutations in ALS patients in Taiwan is, therefore, approximately 0.5% (1/207). This study reports a novel TBK1 mutation and stresses on the importance to consider TBK1 mutation as a possible etiology of ALS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: A small group of patients with inherited neuropathy that has been shown to be caused by mutations in the BSCL2 gene. However, little information is available about the role of BSCL2 mutations in inherited neuropathies in Taiwan., Methodology and Principal Findings: Utilizing targeted sequencing, 76 patients with molecularly unassigned Charcot-Marie-Tooth disease type 2 (CMT2) and 8 with distal hereditary motor neuropathy (dHMN), who were selected from 348 unrelated patients with inherited neuropathies, were screened for mutations in the coding regions of BSCL2. Two heterozygous BSCL2 mutations, p.S90L and p.R96H, were identified, of which the p.R96H mutation is novel. The p.S90L was identified in a pedigree with CMT2 while the p.R96H was identified in a patient with apparently sporadic dHMN. In vitro studies demonstrated that the p.R96H mutation results in a remarkably low seipin expression and reduced cell viability., Conclusion: BSCL2 mutations account for a small number of patients with inherited neuropathies in Taiwan. The p.R96H mutation is associated with dHMN. This study expands the molecular spectrum of BSCL2 mutations and also emphasizes the pathogenic role of BSCL2 mutations in molecularly unassigned hereditary neuropathies.

Background: Mutations in the GARS gene have been identified in a small number of patients with Charcot-Marie-Tooth disease (CMT) type 2D or distal spinal muscular atrophy type V, for whom disease onset typically occurs during adolescence or young adulthood, initially manifesting as weakness and atrophy of the hand muscles. The role of GARS mutations in patients with inherited neuropathies in Taiwan remains elusive., Methodology and Principal Findings: Mutational analyses of the coding regions of GARS were performed using targeted sequencing of 54 patients with molecularly unassigned axonal CMT, who were selected from 340 unrelated CMT patients. Two heterozygous mutations in GARS, p.Asp146Tyr and p.Met238Arg, were identified; one in each patient. Both are novel de novo mutations. The p.Asp146Tyr mutation is associated with a severe infantile-onset neuropathy and the p.Met238Arg mutation results in childhood-onset disability., Conclusion: GARS mutations are an uncommon cause of CMT in Taiwan. The p.Asp146Tyr and p.Met238Arg mutations are associated with early-onset axonal CMT. These findings broaden the mutational spectrum of GARS and also highlight the importance of considering GARS mutations as a disease cause in patients with early-onset neuropathies.

Objective: To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort., Methods: Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs., Results: Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6., Conclusions: SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions., (© 2014 American Academy of Neurology.)

Identification of genetic mutations has been of burgeoning importance in amyotrophic lateral sclerosis (ALS) in recent years. The aim of this study was to determine the frequency and spectrum of mutations in major ALS-causing genes in a Taiwanese ALS cohort of Han Chinese origin. Mutational analyses of the SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, PFN1, HNRNPA1, and HNRNPA2B1 genes were carried out by direct sequencing in 161 unrelated patients with ALS, including 30 with familial ALS (FALS) and 131 with sporadic ALS (SALS). The CAG repeat size in ATXN2 and the GGGGCC repeat expansion in C9ORF72 of the patients were also investigated. Mutations were identified in 33 patients (20.5%, 33/161), including 22 with FALS and 11 with SALS. Mutations were identified most frequently in SOD1 (7.5%). Three mutations are novel, including SOD1 p.G10A, SOD1 p.D83N, and OPTN p.L494W. These findings broaden the spectrum of ALS-causing mutations and are indispensable for designing optimal strategies of mutational analysis and genetic counseling of ALS for patients of Chinese origin., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To describe a novel mutation in TRK-fused gene (TFG) as a new cause of dominant axonal Charcot-Marie-Tooth disease (CMT) identified by exome sequencing and further characterized by in vitro functional studies., Methods: Exome sequencing and linkage analysis were utilized to investigate a large Taiwanese family with a dominantly inherited adult-onset motor and sensory axonal neuropathy in which mutations in common CMT2-implicated genes had been previously excluded. Functional effects of the mutant gene products were investigated in vitro., Results: Exome sequencing of 2 affected individuals in this family revealed a novel heterozygous mutation, c.806G>T (p.Gly269Val), in TFG that perfectly cosegregates with the CMT2 phenotype in all 27 family members. This mutation occurs at an evolutionarily conserved residue and is absent in the 1,140 ethnically matched control chromosomes. Genome-wide linkage study also supported its disease-causative role. Cell transfection studies showed that the TFG p.Gly269Val mutation increased the propensity of TFG proteins to form aggregates, resulting in sequestration of both mutant and wild-type TFG proteins and might thus deplete functional TFG molecules. The secreted Gaussia luciferase reporter assay demonstrated that inhibition of endogenous TFG compromised the protein secretion pathways, which could only be rescued by expressing wild-type TFG but not the p.Gly269Val altered proteins. TFG mutation was not found in 55 additional unrelated patients with CMT2, suggesting its rarity., Conclusion: This study identifies a new cause of dominant CMT2 and highlights the importance of TFG in the protein secretory pathways that are essential for proper functioning of the human peripheral nervous system., (© 2014 American Academy of Neurology.)

Mutations in the 5' non-coding region of GJB1 are rarely reported in patients with Charcot-Marie-Tooth disease (CMT). We therefore aimed to assess the frequency and identities of the GJB1 5' non-coding region mutations in a cohort of CMT. We analyzed the 5' non-coding region of GJB1 (including the promoter P2 and exon 1b) in 91 unrelated CMT patients without an identified genetic cause. Two mutations, c.-529T>C, and c.-459C>T, were identified in one patient each. One polymorphism, c.-713G>A, was also identified in 53 patients and 73 of the 100 control subjects. The luciferase reporter assays showed that c.-459C>T significantly reduced the luciferase expression with or without SOX10 activation, whereas c.-529T>C impaired the expression only with SOX10 co-expression. c.-713G>A had no apparent functional effect. Mutations in the 5' non-coding region of GJB1 account for 0.8% (2 of 251) of CMT and 2.2% (2 of 91) of genetically unassigned CMT in a Taiwanese cohort. As previously demonstrated, c.-459C>T and c.-529T>C may cause CMT through compromising GJB1 expression whereas c.-713G>A is a benign variant. This study highlights the pathogenic role of the GJB1 5' non-coding region mutations in CMT, and suggests that their identification should be considered for CMT patients without commonly observed mutations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Mutations in the PRRT2 gene have recently been identified in patients with familial paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) and patients with sporadic PKD/IC from several ethnic groups. To extend these recent genetic reports, we investigated the frequency and identities of PRRT2 mutations in a cohort of Taiwanese patients with PKD/IC., Methodology and Principal Findings: We screened all 3 coding exons of PRRT2 for mutations in 28 Taiwanese patients with PKD/IC. Among them, 13 had familial PKD/IC and 15 were apparently sporadic cases. In total, 7 disparate mutations were identified in 13 patients, including 8 familial cases and 5 apparently sporadic cases. The mutations were not present in 500 healthy controls. Four mutations were novel. One patient had a missense mutation and all other patients carried PRRT2 mutations putatively resulting in a protein truncation. Haplotype analysis revealed that 5 of the 7 patients with the PRRT2 p.R217Pfs*8 mutation shared the same haplotype linked to the mutation., Conclusions and Significance: PRRT2 mutations account for 61.5% (8 out of 13) of familial PKD/IC and 33.3% (5 out of 15) of apparently sporadic PKD/IC in the Taiwanese cohort. Most patients with the PRRT2 p.R217Pfs*8 mutation in Taiwan likely descend from a single common ancestor. This study expands the spectrum of PKD/IC-associated PRRT2 mutations, highlights the pathogenic role of PRRT2 mutations in PKD/IC, and suggests genetic heterogeneity within idiopathic PKD.

Background: Charcot-Marie-Tooth disease type 2 (CMT2) is a clinically and genetically heterogeneous group of inherited axonal neuropathies. The aim of this study was to extensively investigate the mutational spectrum of CMT2 in a cohort of patients of Han Chinese., Methodology and Principal Findings: Genomic DNA from 36 unrelated Taiwanese CMT2 patients of Han Chinese descent was screened for mutations in the coding regions of the MFN2, RAB7, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8, DNM2, AARS and YARS genes. Ten disparate mutations were identified in 14 patients (38.9% of the cohort), including p.N71Y in AARS (2.8%), p.T164A in HSPB1 (2.8%), and p.[H256R]+[R282H] in GDAP1 (2.8%) in one patient each, three NEFL mutations in six patients (16.7%) and four MFN2 mutations in five patients (13.9%). The following six mutations were novel: the individual AARS, HSPB1 and GDAP1 mutations and c.475-1G>T, p.L233V and p.E744M mutations in MFN2. An in vitro splicing assay revealed that the MFN2 c.475-1G>T mutation causes a 4 amino acid deletion (p.T159&#95;Q162del). Despite an extensive survey, the genetic causes of CMT2 remained elusive in the remaining 22 CMT2 patients (61.1%)., Conclusions and Significance: This study illustrates the spectrum of CMT2 mutations in a Taiwanese CMT2 cohort and expands the number of CMT2-associated mutations. The relevance of the AARS and HSPB1 mutations in the pathogenesis of CMT2 is further highlighted. Moreover, the frequency of the NEFL mutations in this study cohort was unexpectedly high. Genetic testing for NEFL and MFN2 mutations should, therefore, be the first step in the molecular diagnosis of CMT2 in ethnic Chinese.

Purpose: Gluten sensitivity (GS) is related to the pathogenesis of sporadic or hereditary ataxia., Methods: Total of 194 healthy controls and patients with either hereditary ataxia (n=207) or sporadic ataxia (n=361) were tested for the circulating gluten-related autoantibodies which serve as biomarkers to interpret the existence of GS., Results: The incidences of GS in each population were 1% in normal subjects, 2% in hereditary ataxia patients and 9% in sporadic ataxia patients. High serum level of anti-gliadin IgG/IgA and t-transglutaminase IgA were disclosed at the sporadic ataxia patients compared with normal subjects. However, the anti-gliadin IgG is more specific to the disease of sporadic ataxia., Conclusion: Relatively higher incidence of GS was found in the population of sporadic ataxia patients but not in either normal subjects or hereditary ataxia patients in Taiwan. Anti-gliadin IgG still is a very powerful indicator to implicate the immune-related sporadic ataxia and we conclude that GS-related sporadic ataxia exists in Taiwan with linkage to autoimmune events.

Background and Purpose: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disorder caused by NOTCH3 mutations and characterized by recurrent subcortical infarctions, dementia and leukoencephalopathy. So far, most clinical, molecular and neuroimaging information has come from Caucasians. Therefore, we investigated the spectrum of NOTCH3 mutations and MRI features in CADASIL patients of Chinese origin on Taiwan., Methods: Mutational analysis of NOTCH3 exons 2 to 23 by direct nucleotide sequencing was performed in patients with clinically suspected CADASIL. MRI findings were retrospectively evaluated and scored using a modified Schelten's scale., Results: Nine different point mutations of NOTCH3 were identified in 21 unrelated patients. Intriguingly, 47.6 % were in exon 11, and 19 % in each of exon 4 and 18. R544C was very common and present in all patients with a mutation in exon 11. Many patients with NOTCH3 R544C share the same haplotype linked to the mutation using markers D19S929 and D19S411, which flank the NOTCH3. The sensitivity of T2-weighted MRI detecting anterior temporal abnormality was only 42.9 %. Furthermore, the neuroimaging evidence of intracerebral hemorrhage (ICH) was present in 23.8 % of the 21 patients., Conclusions: A population-specific mutational spectrum of CADASIL was found in the Chinese patients on Taiwan. The Chinese patients carrying NOTCH3 R544C may descend from a common ancestor. Anterior temporal hyperintensity on T2-weighted MRI may not be a sensitive marker for CADASIL. ICH is a relatively common manifestation of CADASIL in East Asians, especially in the presence of hypertension.

Background: Transthyretin (TTR) variants of familial amyloid neuropathies (FAP) form a heterogenous group of autosomal dominantly inherited diseases. TTR gene analysis in several nationalities (Japanese, Portuguese, French, and British) has shown many distinguishing characteristics in the genotype-phenotype correlation. In Chinese, there are only a few reports of private TTR gene mutations belonging to single kindred., Materials and Methods: We collected five patients with autosomal dominant inheritant sensorimotor polyneuropathy and tissue-proved amyloid deposition. The diagnosis of FAP was established on the mutation of the TTR gene detected by direct sequencing. Haplotype analysis was conducted in four of these patients., Results and Conclusions: These five FAP patients shared an identical missense mutation, Ala97Ser, in the TTR gene. This mutation presented with a constellation of late-onset polyneuropathy, preceding carpal tunnel syndrome, and outstanding autonomic dysfunction. Heart was the most frequently involved vital organ. Haplotype analysis hinted independent origins although the numbers were limited. Our study is the first case series gathering from the Chinese-Taiwanese population. We proposed a possible hot-spot mutation of the TTR gene, Ala97Ser, in this ethnic.

The purpose of this study of dementia screening was to obtain different cutoff scores of the Cognitive Abilities Screening Instrument, Chinese versions (CASI C-2.0) for subjects with different educational backgrounds. The diagnosis of dementia was based on the Diagnostic and Statistical Manual of Mental Disorders, ed 3 revised or ed 4 criteria. To diagnose Alzheimer's disease, the guidelines of the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association was followed. The severity of dementia was determined on the Clinical Dementia Rating scale. Altogether 2,096 subjects, aged 65 years and more, were included. Of them, 1,178 were normal and 918 were demented. Their performance on CASI C-2.0 was influenced by their education and age. Gender difference on CASI C-2.0 scores was only significant in the illiterate, but not in the literate group. We recommend that the population be divided into three levels, namely those who (1) had no formal education (Edu = 0); (2) received 1-5 years of schooling (Edu = 1-5), and (3) received 6 or more years of education (Edu >/=6). The cutoff scores of CASI C-2.0 in the diagnosis of dementia in these three educational groups were as follows: Edu = 0: 49/50 (sensitivity = 0.83; specificity = 0.85); Edu = 1-5: 67/68 (sensitivity = 0.83; specificity = 0.91), and Edu >/=6: 79/80 (sensitivity = 0.89; specificity = 0.90)., (Copyright 2002 S. Karger AG, Basel)