Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type ... more 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.
To the Editor: Cerebral cavernous malformations (CCMs) are vascular malformations containing a cl... more To the Editor: Cerebral cavernous malformations (CCMs) are vascular malformations containing a cluster of aberrantly dilated, thin-walled capillaries in the brain and/or spinal cord. Patients with CCMs are susceptible to intracerebral hemorrhage, seizure and headache. CCM disease can be sporadic or inherited, and patients with hereditary CCMs often present with multiple CCMs. To date, three genes have been implicated in hereditary CCMs, namely CCM1 (OMIM 604214; KRIT1), MGC4607 (CCM2, OMIM 607929) and PDCD10 (CCM3, OMIM 609118). Although the genetic and phenotypic features of CCMs have been reported in several Caucasian cohorts, information in Asian populations remains sparse. To fill this gap of knowledge, we performed genetic analysis in Taiwanese patients with CCMs. The protocol for this study was approved by the institutional review board of Taipei Veterans General Hospital. Mutational analysis of CCM1, CCM2 and CCM3 in 19 unrelated Taiwanese patients of Han
Journal of the Formosan Medical Association, Sep 1, 2022
BACKGROUND/PURPOSE The long-term disease course and efficacy of maintenance therapies have rarely... more 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.
Background and Objectives The GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC was... more Background and Objectives The GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy. Methods This cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed. Results One hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21–55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID. Discussion The NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort. Classification of Evidence This study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.
Journal of The Chinese Medical Association, Nov 28, 2022
Background: Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cau... more Background: Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cause of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) spectrum diseases. The aim of this study was to investigate the role of HTT repeat expansions in a Taiwanese cohort with ALS. Methods: We analyzed the numbers of CAG repeats in exon 1 of HTT in a cohort of 410 Taiwanese patients with ALS and 1514 control individuals by utilizing polymerase chain reaction and amplicon fragment length analysis. Results: Only one of the 410 ALS patients carried a reduced-penetrance HD-causing allele with 39 CAG repeats, and none had an expanded HTT CAG repeats ≥40. The patient presented with rapidly progressive bulbar-onset ALS with disease onset at the age of 64 years. He had neither chorea nor cognitive impairment. He had a family history of chorea, but no other family member manifested with ALS. None of the 1514 control individuals carried an HTT expanded allele with CAG repeats larger than 37 repeats. Conclusion: The HTT allele with 39 CAG repeats could be a genetic factor linked to ALS susceptibility.
OBJECTIVE: The present study aims at ascertaining whether GGCCTG expansion in NOP56 is present in... more OBJECTIVE: The present study aims at ascertaining whether GGCCTG expansion in NOP56 is present in the Chinese SCA patients in Taiwan. BACKGROUND: Expansion of GGCCTG hexanucleotide repeat in the intron 1 of NOP56 was identified as the cause spinocerebellar ataxia type 36 (SCA36), a rare SCA subtype accompanied by motor neuron involvement. Only 19 SCA36 families have been reported in the literature to date. Most of them resided in two enclosed regions, Costa da Morte in Spain and the Chugoku region in Japan. DESIGN/METHODS: The present study included 109 unrelated probands with molecularly unassigned SCA from 512 pedigrees in Taiwan. Repeat-primer PCR analysis was employed to detect abnormal expansion of the GGCCTG hexanucleotide repeat in NOP56. To quantify the repeat number of GGCCTG expansion, lymphoblastoid cell lines (LCLs) from four SCA cases and three controls were obtained for Southern blot. RESULTS: Three large pedigrees with autosomal dominant ataxic syndrome were found to have abnormal GGCCTG expansions in NOP56. Genotype data were available from seven affected patients, one pre-manifest carrier and five healthy siblings. A perfect segregation of the expanded hexanucleotide repeat was confirmed in all pedigrees. A founder haplotype with four markers spanning 4.5 Kb on chromosome 20p13 were identified in the three families, suggesting that GGCCTG was derived from a common ancestor. The common features of SCA36 include a slowly progressive clinical course, trunk/limb ataxia, hyperreflexia and thigh muscle atrophy. The age at onset ranged from the fourth to fifth decade. Hearing impairment and tongue atrophy were frequently reported in the literature, but was rarely found in our patients. CONCLUSIONS: SCA36 is an uncommon subtype of SCA, accounting for 0.6[percnt] (3/512) of SCA in people of Han-Chinese descent in Taiwan. GGCCTG expansion could also account for SCA36 in ethnic Chinese besides Spaniard and Japanese. Disclosure: Dr. Liao has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Tsai has nothing to disclose. Dr. Soong has nothing to disclose.
We investigated 98 Taiwanese patients with molecularly unassigned hereditary spastic paraplegia (... more We investigated 98 Taiwanese patients with molecularly unassigned hereditary spastic paraplegia (HSP) and found none of them had the NOTCH2NLC GGC repeat expansion, which is the cause of neuronal intranuclear inclusion disease (NIID). Our findings suggest that the NOTCH2NLC GGC repeat expansion may not contribute to HSP.
BackgroundPolyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an exp... more BackgroundPolyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ‐encoding CAG repeats in the disease‐causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3).ObjectiveWe set out to identify common genetic variant(s) that may affect the AO of polyQ diseases.MethodsThree hundred thirty‐seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of PIAS1 because PIAS1 is an E3 SUMO (small ubiquitin‐like modifier) ligase for huntingtin (HTT), the protein linked to HD.ResultsBiochemical analyses revealed that the ability of PIAS1S510G to interact with mutant huntingtin (mHTT) was less than th...
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Abstract Intermediate-length CAG repeats in ATXN2 have been well recognized as a genetic risk fac... more Abstract Intermediate-length CAG repeats in ATXN2 have been well recognized as a genetic risk factor for amyotrophic lateral sclerosis (ALS). However, the role of similar trinucleotide repeat expansions in the TATA-box binding protein gene (TBP), another disease-associated gene for inherited ataxia, in ALS remains elusive. To assess the association between TBP trinucleotide repeat expansions and ALS, we investigated the repeat lengths in 325 unrelated ALS patients and 1500 controls in the Taiwanese population. The most common size of repeats in the patients and controls were both 36. The repeat lengths ranged from 29 to 46 repeats in the ALS patients and 27 to 43 repeats in the controls. Two ALS patients carried a TBP allele with a repeat number equal or greater than 44 (44 and 46). The patient with the 46 trinucleotide repeats also had a C9ORF72 GGGGCC hexanucleotide repeat expansion. The odds ratio of an individual carrying the CAG/CAA repeats ≥ 44 to have ALS is 23.2 (95% confidence interval: 1.11–484.24; p = 0.04). Our findings suggest that intermediate-length CAG/CAA repeat expansions in TBP may associate with ALS risk.
OBJECTIVE: To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type ... more 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. BACKGROUND: There have been limited studies addressing the clinical and genetic features of SCA35. One study conducted in a Caucasian population revealed that none of 118 patients with sporadic cerebellar ataxia carried any TGM6 mutation. To further delineate this rare SCA subtype, we searched for TGM6 mutation in the molecularly unassigned Taiwanese SCA families. 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 transfe...
Objective: The aim of this study is to investigate clinical severity and disease progression of f... more Objective: The aim of this study is to investigate clinical severity and disease progression of five spinocerebellar ataxias (SCAs) in Taiwan. Background: SCAs are a group of inherited neurodegenerative diseases mainly affecting cerebellum. There have been very few longitudinal cohort studies of SCAs in Asian populations. Design/Methods: Patients with SCA1, SCA2, SCA3, SCA6 or SCA17 were recruited from the Neurology Clinic of Taipei Veterans General Hospital from 2007 to 2016. Participants were interviewed annually and evaluated using the scale for the assessment and rating of ataxia (SARA) for five years. The annual progression rates in SARA total score and subscores were compared among patients with different SCA subtypes by linear mixed model. Predictors for the progression rates of SARA total score in each SCA subtype were analyzed. Results: A total of 199 patients with SCA, including 10 with SCA1, 37 with SCA2, 118 with SCA3, 25 with SCA6 and 9 with SCA17, were enrolled. The me...
Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type ... more 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.
To the Editor: Cerebral cavernous malformations (CCMs) are vascular malformations containing a cl... more To the Editor: Cerebral cavernous malformations (CCMs) are vascular malformations containing a cluster of aberrantly dilated, thin-walled capillaries in the brain and/or spinal cord. Patients with CCMs are susceptible to intracerebral hemorrhage, seizure and headache. CCM disease can be sporadic or inherited, and patients with hereditary CCMs often present with multiple CCMs. To date, three genes have been implicated in hereditary CCMs, namely CCM1 (OMIM 604214; KRIT1), MGC4607 (CCM2, OMIM 607929) and PDCD10 (CCM3, OMIM 609118). Although the genetic and phenotypic features of CCMs have been reported in several Caucasian cohorts, information in Asian populations remains sparse. To fill this gap of knowledge, we performed genetic analysis in Taiwanese patients with CCMs. The protocol for this study was approved by the institutional review board of Taipei Veterans General Hospital. Mutational analysis of CCM1, CCM2 and CCM3 in 19 unrelated Taiwanese patients of Han
Journal of the Formosan Medical Association, Sep 1, 2022
BACKGROUND/PURPOSE The long-term disease course and efficacy of maintenance therapies have rarely... more 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.
Background and Objectives The GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC was... more Background and Objectives The GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy. Methods This cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed. Results One hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21–55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID. Discussion The NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort. Classification of Evidence This study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.
Journal of The Chinese Medical Association, Nov 28, 2022
Background: Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cau... more Background: Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cause of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) spectrum diseases. The aim of this study was to investigate the role of HTT repeat expansions in a Taiwanese cohort with ALS. Methods: We analyzed the numbers of CAG repeats in exon 1 of HTT in a cohort of 410 Taiwanese patients with ALS and 1514 control individuals by utilizing polymerase chain reaction and amplicon fragment length analysis. Results: Only one of the 410 ALS patients carried a reduced-penetrance HD-causing allele with 39 CAG repeats, and none had an expanded HTT CAG repeats ≥40. The patient presented with rapidly progressive bulbar-onset ALS with disease onset at the age of 64 years. He had neither chorea nor cognitive impairment. He had a family history of chorea, but no other family member manifested with ALS. None of the 1514 control individuals carried an HTT expanded allele with CAG repeats larger than 37 repeats. Conclusion: The HTT allele with 39 CAG repeats could be a genetic factor linked to ALS susceptibility.
OBJECTIVE: The present study aims at ascertaining whether GGCCTG expansion in NOP56 is present in... more OBJECTIVE: The present study aims at ascertaining whether GGCCTG expansion in NOP56 is present in the Chinese SCA patients in Taiwan. BACKGROUND: Expansion of GGCCTG hexanucleotide repeat in the intron 1 of NOP56 was identified as the cause spinocerebellar ataxia type 36 (SCA36), a rare SCA subtype accompanied by motor neuron involvement. Only 19 SCA36 families have been reported in the literature to date. Most of them resided in two enclosed regions, Costa da Morte in Spain and the Chugoku region in Japan. DESIGN/METHODS: The present study included 109 unrelated probands with molecularly unassigned SCA from 512 pedigrees in Taiwan. Repeat-primer PCR analysis was employed to detect abnormal expansion of the GGCCTG hexanucleotide repeat in NOP56. To quantify the repeat number of GGCCTG expansion, lymphoblastoid cell lines (LCLs) from four SCA cases and three controls were obtained for Southern blot. RESULTS: Three large pedigrees with autosomal dominant ataxic syndrome were found to have abnormal GGCCTG expansions in NOP56. Genotype data were available from seven affected patients, one pre-manifest carrier and five healthy siblings. A perfect segregation of the expanded hexanucleotide repeat was confirmed in all pedigrees. A founder haplotype with four markers spanning 4.5 Kb on chromosome 20p13 were identified in the three families, suggesting that GGCCTG was derived from a common ancestor. The common features of SCA36 include a slowly progressive clinical course, trunk/limb ataxia, hyperreflexia and thigh muscle atrophy. The age at onset ranged from the fourth to fifth decade. Hearing impairment and tongue atrophy were frequently reported in the literature, but was rarely found in our patients. CONCLUSIONS: SCA36 is an uncommon subtype of SCA, accounting for 0.6[percnt] (3/512) of SCA in people of Han-Chinese descent in Taiwan. GGCCTG expansion could also account for SCA36 in ethnic Chinese besides Spaniard and Japanese. Disclosure: Dr. Liao has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Tsai has nothing to disclose. Dr. Soong has nothing to disclose.
We investigated 98 Taiwanese patients with molecularly unassigned hereditary spastic paraplegia (... more We investigated 98 Taiwanese patients with molecularly unassigned hereditary spastic paraplegia (HSP) and found none of them had the NOTCH2NLC GGC repeat expansion, which is the cause of neuronal intranuclear inclusion disease (NIID). Our findings suggest that the NOTCH2NLC GGC repeat expansion may not contribute to HSP.
BackgroundPolyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an exp... more BackgroundPolyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ‐encoding CAG repeats in the disease‐causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3).ObjectiveWe set out to identify common genetic variant(s) that may affect the AO of polyQ diseases.MethodsThree hundred thirty‐seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of PIAS1 because PIAS1 is an E3 SUMO (small ubiquitin‐like modifier) ligase for huntingtin (HTT), the protein linked to HD.ResultsBiochemical analyses revealed that the ability of PIAS1S510G to interact with mutant huntingtin (mHTT) was less than th...
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2020
Abstract Intermediate-length CAG repeats in ATXN2 have been well recognized as a genetic risk fac... more Abstract Intermediate-length CAG repeats in ATXN2 have been well recognized as a genetic risk factor for amyotrophic lateral sclerosis (ALS). However, the role of similar trinucleotide repeat expansions in the TATA-box binding protein gene (TBP), another disease-associated gene for inherited ataxia, in ALS remains elusive. To assess the association between TBP trinucleotide repeat expansions and ALS, we investigated the repeat lengths in 325 unrelated ALS patients and 1500 controls in the Taiwanese population. The most common size of repeats in the patients and controls were both 36. The repeat lengths ranged from 29 to 46 repeats in the ALS patients and 27 to 43 repeats in the controls. Two ALS patients carried a TBP allele with a repeat number equal or greater than 44 (44 and 46). The patient with the 46 trinucleotide repeats also had a C9ORF72 GGGGCC hexanucleotide repeat expansion. The odds ratio of an individual carrying the CAG/CAA repeats ≥ 44 to have ALS is 23.2 (95% confidence interval: 1.11–484.24; p = 0.04). Our findings suggest that intermediate-length CAG/CAA repeat expansions in TBP may associate with ALS risk.
OBJECTIVE: To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type ... more 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. BACKGROUND: There have been limited studies addressing the clinical and genetic features of SCA35. One study conducted in a Caucasian population revealed that none of 118 patients with sporadic cerebellar ataxia carried any TGM6 mutation. To further delineate this rare SCA subtype, we searched for TGM6 mutation in the molecularly unassigned Taiwanese SCA families. 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 transfe...
Objective: The aim of this study is to investigate clinical severity and disease progression of f... more Objective: The aim of this study is to investigate clinical severity and disease progression of five spinocerebellar ataxias (SCAs) in Taiwan. Background: SCAs are a group of inherited neurodegenerative diseases mainly affecting cerebellum. There have been very few longitudinal cohort studies of SCAs in Asian populations. Design/Methods: Patients with SCA1, SCA2, SCA3, SCA6 or SCA17 were recruited from the Neurology Clinic of Taipei Veterans General Hospital from 2007 to 2016. Participants were interviewed annually and evaluated using the scale for the assessment and rating of ataxia (SARA) for five years. The annual progression rates in SARA total score and subscores were compared among patients with different SCA subtypes by linear mixed model. Predictors for the progression rates of SARA total score in each SCA subtype were analyzed. Results: A total of 199 patients with SCA, including 10 with SCA1, 37 with SCA2, 118 with SCA3, 25 with SCA6 and 9 with SCA17, were enrolled. The me...
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