CHIEN HSIN FEN
Projetos de Pesquisa
Unidades Organizacionais
P IOT, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto de Ortopedia e Traumatologia, Hospital das Clínicas, Faculdade de Medicina - Médico
Instituto de Ortopedia e Traumatologia, Hospital das Clínicas, Faculdade de Medicina - Médico
7 resultados
Resultados de Busca
Agora exibindo 1 - 7 de 7
- DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease(2016) OLGIATI, Simone; QUADRI, Marialuisa; FANG, Mingyan; ROOD, Janneke P. M. A.; SAUTE, Jonas A.; CHIEN, Hsin Fen; BOUWKAMP, Christian G.; GRAAFLAND, Josja; MINNEBOO, Michelle; BREEDVELD, Guido J.; ZHANG, Jianguo; VERHEIJEN, Frans W.; BOON, Agnita J. W.; KIEVIT, Anneke J. A.; JARDIM, Laura Bannach; MANDEMAKERS, Wim; BARBOSA, Egberto Reis; RIEDER, Carlos R. M.; LEENDERS, Klaus L.; WANG, Jun; BONIFATI, VincenzoObjectiveDNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age<11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within approximate to 10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). MethodsThe DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. ResultsWe identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. InterpretationOur findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. Ann Neurol 2016;79:244-256
- Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency(2016) OLGIATI, Simone; SKORVANEK, Matej; QUADRI, Marialuisa; MINNEBOO, Michelle; GRAAFLAND, Josja; BREEDVELD, Guido J.; BONTE, Ramon; OZGUR, Zeliha; HOUT, Mirjam C. G. N. van den; SCHOONDERWOERD, Kees; VERHEIJEN, Frans W.; IJCKEN, Wilfred F. J. van; CHIEN, Hsin Fen; BARBOSA, Egberto Reis; CHANG, Hsiu-Chen; LAI, Szu-Chia; YEH, Tu-Hsueh; LU, Chin-Song; WU-CHOU, Yah-Huei; KIEVIT, Anneke J. A.; HAN, Vladimir; GDOVINOVA, Zuzana; JECH, Robert; HOFSTRA, Robert M. W.; RUIJTER, George J. G.; MANDEMAKERS, Wim; BONIFATI, VincenzoBackgroundECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations. MethodsClinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. ResultsThe first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations. ConclusionsThe phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. (c) 2016 International Parkinson and Movement Disorder Society
- Neuropathologic Findings in a Patient With Juvenile-Onset Levodopa-Responsive Parkinsonism Due to ATP13A2 Mutation(2021) CHIEN, Hsin Fen; RODRIGUEZ, Roberta Diehl; BONIFATI, Vincenzo; NITRINI, Ricardo; PASQUALUCCI, Carlos Augusto; GELPI, Ellen; BARBOSA, Egberto ReisObjective To describe the postmortem neuropathologic findings of a patient with Kufor Rakeb syndrome (KRS) due to ATP13A2 mutation. KRS is characterized by juvenile-onset levodopa-responsive parkinsonism associated with pyramidal signs, supranuclear gaze palsy, and cognitive impairment. Methods A detailed neuropathologic analysis of the brain was performed. The patient had a genetically confirmed ATP13A2 homozygous missense mutation and died at age 38 years, which was 26 years after the onset of his symptoms. Results The main brain neuropathologic findings were widespread neuronal and glial lipofuscin accumulation with no Lewy body-type inclusions and absence of alpha-synuclein-positive, tau-positive, beta-amyloid-positive, and TDP-43 protein-positive pathologies. Sparse iron deposits were observed in several brain areas, but no obvious axonal spheroids were identified. Discussion This is to our knowledge the first KRS postmortem neuropathologic description. Iron deposits were found but not associated with increased axonal spheroids, as frequently observed in neurodegeneration with brain iron accumulation. ATP13A2 mutations have been described in patients with neuronal ceroid lipofuscinosis (CLN). Moreover, animal models with these mutations develop neurodegenerative disorders with CLN pathology. Therefore, our findings support that ATP13A2 mutations may be considered a genetic etiology of neuronal lipofuscinosis.
- Mutations in TMEM230 are not a common cause of Parkinson's disease(2017) QUADRI, Marialuisa; BREEDVELD, Guido J.; CHANG, Hsiu-Chen; YEH, Tu-Hsueh; GUEDES, Leonor Correia; TONI, Vincenzo; FABRIZIO, Edito; MARI, Michele De; THOMAS, Astrid; TASSORELLI, Cristina; ROOD, Janneke P. M. A.; SADDI, Valeria; CHIEN, Hsin Fen; KIEVIT, Anneke J. A.; BOON, Agnita J. W.; STOCCHI, Fabrizio; LOPIANO, Leonardo; ABBRUZZESE, Giovanni; CORTELLI, Pietro; MECO, Giuseppe; COSSU, Giovanni; BARBOSA, Egberto Reis; FERREIRA, Joaquim J.; LU, Chin-Song; BONIFATI, Vincenzo
- ATP13A2-Related Neurodegeneration (PARK9) Without Evidence of Brain Iron Accumulation(2011) CHIEN, Hsin Fen; BONIFATI, Vincenzo; BARBOSA, Egberto Reis
- Mutation in the SYNJ1 Gene Associated with Autosomal Recessive, Early-Onset Parkinsonism(2013) QUADRI, Marialuisa; FANG, Mingyan; PICILLO, Marina; OLGIATI, Simone; BREEDVELD, Guido J.; GRAAFLAND, Josja; WU, Bin; XU, Fengping; ERRO, Roberto; AMBONI, Marianna; PAPPATA, Sabina; QUARANTELLI, Mario; ANNESI, Grazia; QUATTRONE, Aldo; CHIEN, Hsin F.; BARBOSA, Egberto R.; OOSTRA, Ben A.; BARONE, Paolo; WANG, Jun; BONIFATI, VincenzoAutosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis. (C) 2013 Wiley Periodicals, Inc.
- LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study(2018) QUADRI, Marialuisa; MANDEMAKERS, Wim; GROCHOWSKA, Martyna M.; MASIUS, Roy; GEUT, Hanneke; FABRIZIO, Edito; BREEDVELD, Guido J.; KUIPERS, Demy; MINNEBOO, Michelle; VERGOUW, Leonie J. M.; MASCARO, Ana Carreras; YONOVA-DOING, Ekaterina; SIMONS, Erik; ZHAO, Tianna; FONZO, Alessio B. Di; CHANG, Hsiu-Chen; PARCHI, Piero; MELIS, Marta; GUEDES, Leonor Correia; CRISCUOLO, Chiara; THOMAS, Astrid; BROUWER, Rutger W. W.; HEIJSMAN, Daphne; INGRASSIA, Angela M. T.; BUONAURA, Giovanna Calandra; ROOD, Janneke P.; CAPELLARI, Sabina; ROZEMULLER, Annemieke J.; SARCHIOTO, Marianna; CHIEN, Hsin Fen; VANACORE, Nicola; OLGIATI, Simone; WU-CHOU, Yah-Huei; YEH, Tu-Hsueh; BOON, Agnita J. W.; HOOGERS, Susanne E.; GHAZVINI, Mehrnaz; IJPMA, Arne S.; IJCKEN, Wilfred F. J. van; ONOFRJ, Marco; BARONE, Paolo; NICHOLL, David J.; PUSCHMANN, Andreas; MARI, Michele De; KIEVIT, Anneke J.; BARBOSA, Egberto; MICHELE, Giuseppe De; MAJOOR-KRAKAUER, Danielle; SWIETEN, John C. van; JONG, Frank J. de; FERREIRA, Joaquim J.; COSSU, Giovanni; LU, Chin-Song; MECO, Giuseppe; CORTELLI, Pietro; BERG, Wilma D. J. van de; BONIFATI, VincenzoBackground Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Methods Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. Findings Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59.8 years [SD 8.7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent-albeit limited-evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G -> A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immuno-cytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. Interpretation Our findings implicate LRP10 gene defects in the development of inherited forms of alpha-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets.