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1.
Mov Disord ; 35(12): 2343-2347, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32949189

RESUMO

BACKGROUND: In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction. OBJECTIVE: To demonstrate linkage and to identify the underlying genetic cause of disease. METHODS: Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed. RESULTS: Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS. CONCLUSIONS: Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.


Assuntos
Coreia , Síndrome da Unha-Patela , Humanos , Proteínas com Homeodomínio LIM/genética , Síndrome da Unha-Patela/genética , Crânio , Fatores de Transcrição/genética
2.
Mol Cell Neurosci ; 88: 118-129, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29289683

RESUMO

The three factors, p53, the microRNA-34 family and Sirtuin 1 (SIRT1), interact in a positive feedback loop involved in cell cycle progression, cellular senescence and apoptosis. Each factor in this triad has roles in metabolic regulation, maintenance of mitochondrial function, and regulation of brain-derived neurotrophic factor (BDNF). Thus, this regulatory network holds potential importance for the pathophysiology of Huntington's disease (HD), an inherited neurodegenerative disorder in which both mitochondrial dysfunction and impaired neurotrophic signalling are observed. We investigated expression of the three members of this regulatory triad in the R6/2 HD mouse model. Compared to wild-type littermates, we found decreased levels of miR-34a-5p, increased SIRT1 mRNA and protein levels, and increased levels of p53 protein in brain tissue from R6/2 mice. The upregulation of SIRT1 did not appear to lead to an increased activity of the enzyme, as based on measures of p53 acetylation. In other words, the observed changes did not reflect the known interactions between these factors, indicating a general perturbation of the p53, miR-34a and SIRT1 pathway in HD. This is the first study investigating the entire triad during disease progression in an HD model. Given the importance of these three factors alone and within the triad, our results indicate that outside factors are regulating - or dysregulating - this pathway in HD.


Assuntos
Doença de Huntington/genética , MicroRNAs/genética , Sirtuína 1/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/fisiologia , Linhagem Celular , Modelos Animais de Doenças , Doença de Huntington/metabolismo , Camundongos Transgênicos , Transdução de Sinais , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
3.
Brain ; 139(Pt 5): 1605-14, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26994750

RESUMO

Cross-sectional neuroimaging studies in non-depressed individuals have demonstrated an inverse relationship between daylight minutes and cerebral serotonin transporter; this relationship is modified by serotonin-transporter-linked polymorphic region short allele carrier status. We here present data from the first longitudinal investigation of seasonal serotonin transporter fluctuations in both patients with seasonal affective disorder and in healthy individuals. Eighty (11)C-DASB positron emission tomography scans were conducted to quantify cerebral serotonin transporter binding; 23 healthy controls with low seasonality scores and 17 patients diagnosed with seasonal affective disorder were scanned in both summer and winter to investigate differences in cerebral serotonin transporter binding across groups and across seasons. The two groups had similar cerebral serotonin transporter binding in the summer but in their symptomatic phase during winter, patients with seasonal affective disorder had higher serotonin transporter than the healthy control subjects (P = 0.01). Compared to the healthy controls, patients with seasonal affective disorder changed their serotonin transporter significantly less between summer and winter (P < 0.001). Further, the change in serotonin transporter was sex- (P = 0.02) and genotype- (P = 0.04) dependent. In the patients with seasonal affective disorder, the seasonal change in serotonin transporter binding was positively associated with change in depressive symptom severity, as indexed by Hamilton Rating Scale for Depression - Seasonal Affective Disorder version scores (P = 0.01). Our findings suggest that the development of depressive symptoms in winter is associated with a failure to downregulate serotonin transporter levels appropriately during exposure to the environmental stress of winter, especially in individuals with high predisposition to affective disorders.media-1vid110.1093/brain/aww043_video_abstractaww043_video_abstract.


Assuntos
Transtorno Afetivo Sazonal/diagnóstico , Transtorno Afetivo Sazonal/metabolismo , Estações do Ano , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Benzilaminas/metabolismo , Radioisótopos de Carbono/metabolismo , Estudos de Casos e Controles , Estradiol/sangue , Feminino , Humanos , Estudos Longitudinais , Masculino , Neuroimagem , Tomografia por Emissão de Pósitrons , Progesterona , Escalas de Graduação Psiquiátrica , Ensaio Radioligante , Transtorno Afetivo Sazonal/diagnóstico por imagem , Triptofano/sangue , Adulto Jovem
4.
Scand J Clin Lab Invest ; 77(8): 617-621, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29037082

RESUMO

Fabry disease is an X- linked inherited lysosomal storage disease caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A). The possible pathological significance of the D313Y variant in the GLA gene has not been verified and it may be a Fabry variant. Our aim was to elucidate whether the presence of the D313Y variant influenced the α-Gal A activity or resulted in Fabry symptoms or Fabry organ involvement. In two Danish families the presence of the D313Y variant did not result in reduced α-Gal A activity or clinical Fabry manifestations in males, and the presence in Fabry females did not significantly enhance the phenotype of a known causative mutation in the GLA gene (G271S). Our findings indicate that the D313Y variant is not causative to nor enhancing Fabry disease phenotype. The D313Y variant in the GLA gene was not disease causative in 2 Danish families. Investigating male family members were crucial in excluding the Fabry phenotype, and thus very important for proper genetic counceling of all family members, as well as overdiagnosing a devastating genetic disease.


Assuntos
Doença de Fabry/genética , Mutação de Sentido Incorreto , alfa-Galactosidase/genética , Adulto , Idoso , Células Cultivadas , Criança , Análise Mutacional de DNA , Doença de Fabry/enzimologia , Feminino , Fibroblastos/enzimologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Leucócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Linhagem , Inativação do Cromossomo X , alfa-Galactosidase/metabolismo
5.
Hum Mol Genet ; 23(3): 717-29, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24070868

RESUMO

Activation of caspase-6 in the striatum of both presymptomatic and affected persons with Huntington's disease (HD) is an early event in the disease pathogenesis. However, little is known about the role of caspase-6 outside the central nervous system (CNS) and whether caspase activation might play a role in the peripheral phenotypes, such as muscle wasting observed in HD. We assessed skeletal muscle tissue from HD patients and well-characterized mouse models of HD. Cleavage of the caspase-6 specific substrate lamin A is significantly increased in skeletal muscle obtained from HD patients as well as in muscle tissues from two different HD mouse models. p53, a transcriptional activator of caspase-6, is upregulated in neuronal cells and tissues expressing mutant huntingtin. Activation of p53 leads to a dramatic increase in levels of caspase-6 mRNA, caspase-6 activity and cleavage of lamin A. Using mouse embryonic fibroblasts (MEFs) from YAC128 mice, we show that this increase in caspase-6 activity can be mitigated by pifithrin-α (pifα), an inhibitor of p53 transcriptional activity, but not through the inhibition of p53's mitochondrial pro-apoptotic function. Remarkably, the p53-mediated increase in caspase-6 expression and activation is exacerbated in cells and tissues of both neuronal and peripheral origin expressing mutant huntingtin (Htt). These findings suggest that the presence of the mutant Htt protein enhances p53 activity and lowers the apoptotic threshold, which activates caspase-6. Furthermore, these results suggest that this pathway is activated both within and outside the CNS in HD and may contribute to both loss of CNS neurons and muscle atrophy.


Assuntos
Caspase 6/metabolismo , Músculo Esquelético/metabolismo , Proteínas do Tecido Nervoso/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Benzotiazóis/farmacologia , Caspase 6/genética , Células Cultivadas , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Lamina Tipo A/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Músculo Esquelético/patologia , Mutação , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Tolueno/análogos & derivados , Tolueno/farmacologia , Proteína Supressora de Tumor p53/genética
6.
Histopathology ; 62(7): 994-1001, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23570304

RESUMO

AIMS: To investigate in prion diseases the in-situ localization of prion protein oligomers sharing a common epitope with amyloid oligomers involved in a range of neurodegenerative diseases. METHODS AND RESULTS: We performed immunohistochemistry on sporadic Creutzfeldt-Jakob disease (sCJD) (n = 9) and hereditary Gerstmann-Sträussler-Scheinker disease (GSS) (n = 1) specimens with the anti-oligomer antibody A11 to determine the localization of reactive species. We found that A11 reactivity in the sCJD specimens was localized to the cerebral and cerebellar cortices both in spongiform and adjacent, non-spongiform areas, reminiscent of multicentric or diffuse plaques. In the GSS specimens, we found that staining was closely associated with kuru-like plaques, and that A11-reactive species colocalized with protease-resistant prion protein (Prp(Sc)). We also observed sporadic neuronal cytosolic staining in both types of specimen. CONCLUSIONS: We confirm that intracellular and extracellular A11-reactive species are present in situ in sCJD cases and GSS, and that immunoreactivity for A11 and Prp(Sc) overlaps. We argue that the A11-reactive species are indeed composed of oligomeric Prp(Sc), and suggest that the toxic effects of Prp(Sc) oligomers could be related to the generic oligomeric conformation recognized by A11.


Assuntos
Síndrome de Creutzfeldt-Jakob/patologia , Doença de Gerstmann-Straussler-Scheinker/patologia , Proteínas PrPC/metabolismo , Doenças Priônicas/patologia , Idoso , Idoso de 80 Anos ou mais , Síndrome de Creutzfeldt-Jakob/metabolismo , Feminino , Doença de Gerstmann-Straussler-Scheinker/congênito , Doença de Gerstmann-Straussler-Scheinker/metabolismo , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos , Doenças Priônicas/metabolismo , Conformação Proteica , Isoformas de Proteínas/metabolismo
7.
J Huntingtons Dis ; 12(4): 371-376, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37927269

RESUMO

Incidence of cancer is markedly reduced in patients with the hereditary neurodegenerative polyglutamine (polyQ) diseases. We have very poor knowledge of the underlying molecular mechanisms, but the expanded polyQ sequence is assumed to play a central role, because it is common to the respective disease related proteins. The inhibition seems to take place in all kinds of cells, because the lower cancer frequency applies to nearly all types of tumors and is not related with the characteristic pathological changes in specific brain tissues. Further, the cancer repressing mechanisms appear to be active early in life including in pre-symptomatic and early phase polyQ patients. Autophagy plays a central role in clearing proteins with expanded polyQ tracts, and autophagy modulation has been demonstrated and particularly investigated in Huntington's disease (HD). Macroautophagy may be dysfunctional due to defects in several steps of the process, whereas increased chaperone-mediated autophagy (CMA) has been shown in HD patients, cell and animal models. Recently, CMA is assumed to play a key role in prevention of cellular transformation of normal cells into cancer cells. Investigations of normal cells from HD and other polyQ carriers could therefore add further insight into the protective mechanisms of CMA in tumorigenesis, and be important for development of autophagy based strategies to prevent malignant processes leading to cancer and neurodegeneration.


Assuntos
Autofagia Mediada por Chaperonas , Doença de Huntington , Neoplasias , Animais , Humanos , Doença de Huntington/metabolismo , Incidência , Autofagia/genética , Proteína Huntingtina
9.
J Gene Med ; 14(8): 521-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22786763

RESUMO

BACKGROUND: Frontotemporal dementia is the second most common form of young-onset dementia after Alzheimer's disease, and several genetic forms of frontotemporal dementia are known. A rare genetic variant is caused by a point mutation in the CHMP2B gene. CHMP2B is a component of the ESCRT-III complex, which is involved in endosomal trafficking of proteins targeted for degradation in lysosomes. Mutations in CHMP2B result in abnormal endosomal structures in patient fibroblasts and patient brains, probably through a gain-of-function mechanism, suggesting that the endosomal pathway plays a central role in the pathogenesis of the disease. METHODS: In the present study, we used lentiviral vectors to efficiently knockdown CHMP2B by delivering microRNA embedded small hairpin RNAs. RESULTS: We show that CHMP2B can be efficiently knocked down in patient fibroblasts using an RNA interference approach and that the knockdown causes reversal of the abnormal endosomal phenotype observed in patient fibroblasts. CONCLUSIONS: This is the first description of a treatment that reverses the cellular pathology caused by mutant CHMP2B and suggests that RNA interference might be a feasible therapeutic strategy. Furthermore, it provides the first proof of a direct link between the disease-causing mutation and the cellular phenotype in cells originating from CHMP2B mutation patients.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Demência Frontotemporal/terapia , Interferência de RNA , Análise de Variância , Células Cultivadas , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Endossomos/metabolismo , Endossomos/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Técnicas de Silenciamento de Genes , Terapia Genética , Vetores Genéticos , Humanos , Lentivirus/genética , Fenótipo , RNA Interferente Pequeno/genética , Tetraspanina 30/metabolismo , Transcrição Gênica
10.
PLoS One ; 17(11): e0277767, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36383556

RESUMO

The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme α-galactosidase A. In the present study we present the molecular and biochemical data of the Danish Fabry cohort and report 20 years' (2001-2020) experience in cascade genetic screening at the Danish National Fabry Disease Center. The Danish Fabry cohort consisted of 26 families, 18 index patients (9 males and 9 females, no available data for 8 index-patients) and 97 family members with a pathogenic GLA variant identified by cascade genetic testing (30 males and 67 females). Fourteen patients (5 males and 9 females; mean age of death 47.0 and 64.8 years respectively) died during follow-up. The completeness of the Fabry patient identification in the country has resulted in a cohort of balanced genotypes according to gender (twice number of females compared to males), indicating that the cohort was not biased by referral, and further resulted in earlier diagnosis of the disease by a lower age at diagnosis in family members compared to index-patients (mean age at diagnosis: index-patients 42.2 vs. family members 26.0 years). Six previously unreported disease-causing variants in the GLA gene were discovered. The nationwide screening and registration of Fabry disease families provide a unique possibility to establish a complete cohort of Fabry patients and to advance current knowledge of this inherited rare lysosomal storage disorder.


Assuntos
Doença de Fabry , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Fabry/diagnóstico , Doença de Fabry/epidemiologia , Doença de Fabry/genética , alfa-Galactosidase/genética , Testes Genéticos , Genótipo , Dinamarca/epidemiologia , Mutação
11.
Mol Genet Metab ; 104(3): 314-8, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21641253

RESUMO

Fabry disease, an X-linked lysosomal storage disorder, results from the deficient activity of α-galactosidase A (α-Gal A). In affected males, the clinical diagnosis is confirmed by the markedly decreased α-Gal A activity. However, in female heterozygotes, the α-Gal A activity can range from low to normal due to random X-chromosomal inactivation, and diagnostic confirmation requires identification of the family's α-Gal A gene mutation. In a young female who had occasional acroparesthesias, corneal opacities, and 15 to 50% of the lower limit of normal leukocyte α-Gal A activity, α-Gal A sequencing in two expert laboratories did not identify a confirmatory mutation, presenting a diagnostic dilemma. A renal biopsy proved diagnostic and renewed efforts to detect an α-Gal A mutation. Subsequent gene dosage analyses identified a large α-Gal A deletion confirming her heterozygosity, and she was started on enzyme replacement therapy. Thus, gene dosage analyses can detect large deletions (>50bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas.


Assuntos
Doença de Fabry/diagnóstico , Dosagem de Genes/genética , Triagem de Portadores Genéticos/métodos , Deleção de Sequência/genética , alfa-Galactosidase/genética , Adolescente , Biópsia , Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , Doença de Fabry/patologia , Feminino , Componentes do Gene , Humanos , Rim/patologia , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , alfa-Galactosidase/metabolismo
12.
EMBO Mol Med ; 13(11): e14095, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34632710

RESUMO

Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p-eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.


Assuntos
Degenerações Espinocerebelares , Expansão das Repetições de Trinucleotídeos , Ataxia , Humanos , Proteínas do Tecido Nervoso/genética , Penetrância , Proteínas , RNA Longo não Codificante/genética , Degenerações Espinocerebelares/genética
13.
Neurobiol Dis ; 40(3): 656-62, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20727971

RESUMO

We studied systemic and brain glucose and lactate metabolism in Huntington's disease (HD) patients in response to ergometer cycling. Following termination of exercise, blood glucose increased abruptly in control subjects, but no peak was seen in any of the HD patients (2.0 ± 0.5 vs. 0.0 ± 0.2mM, P < 2 × 10(-6)). No difference was seen in brain metabolism parameters. Reduced hepatic glucose output in the HD mouse model R6/2 following a lactate challenge, combined with reduced phosphoenolpyruvate carboxykinase and increased pyruvate kinase activity in the mouse liver suggest a reduced capacity for gluconeogenesis in HD, possibly contributing to the clinical symptoms of HD. We propose that blood glucose concentration in the recovery from exercise can be applied as a liver function test in HD patients.


Assuntos
Glicemia/análise , Encéfalo/metabolismo , Exercício Físico/fisiologia , Gluconeogênese/fisiologia , Doença de Huntington/metabolismo , Ácido Láctico/metabolismo , Animais , Western Blotting , Teste de Esforço/métodos , Feminino , Humanos , Doença de Huntington/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Testes de Função Hepática/métodos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
J Gene Med ; 11(7): 559-69, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19434604

RESUMO

BACKGROUND: Viral vectors have been used in several different settings for the delivery of small hairpin (sh) RNAs. However, most vectors have utilized ubiquitously-expressing polymerase (pol) III promoters to drive expression of the hairpin as a result of the strict requirement for precise transcriptional initiation and termination. Recently, pol II promoters have been used to construct vectors for RNA interference (RNAi). By embedding the shRNA into a micro RNA-context (miRNA) the endogenous miRNA processing machinery is exploited to achieve the mature synthetic miRNA (smiRNA), thereby expanding the possible promoter choices and eventually allowing cell type specific down-regulation of target genes. METHODS: In the present study, we constructed lentiviral vectors expressing smiRNAs under the control of pol II promoters to knockdown gene expression in cell culture and in the brain. RESULTS: We demonstrate robust knockdown of green fluorescent protein using lentiviral vectors driving RNAi from the ubiquitously-expressing promoter of the cytomegalovirus (CMV) and, in addition, we show for the first time neuron-specific knockdown in the brain using a neuron-specific promoter. Furthermore, we show that the expression pattern of the presumed ubiquitously-expressing CMV promoter changes over time from being expressed initially in neurons and glial cells to being expressed almost exclusively in neurons in later stages. CONCLUSIONS: In the present study, we developed vectors for cell-specific RNAi for use in the brain. This offers the possibility of specifically targeting RNAi to a subset of cells in a complex tissue and may prove to be of great importance in the design of future gene therapeutic paradigms.


Assuntos
Vetores Genéticos , Lentivirus , Neurônios/fisiologia , Interferência de RNA , Animais , Linhagem Celular , Feminino , Técnicas de Silenciamento de Genes , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Lentivirus/genética , Lentivirus/metabolismo , Neurônios/citologia , Fosfopiruvato Hidratase/genética , Fosfopiruvato Hidratase/metabolismo , Ratos , Ratos Sprague-Dawley
15.
J Peripher Nerv Syst ; 14(3): 159-64, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19909479

RESUMO

Fabry disease is a genetic lysosomal disorder with dysfunction of the lysosomal enzyme alpha-galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system and with neuropathy as a prominent manifestation. Neurological symptoms include pain and autonomic dysfunction. This study examined peripheral autonomic nerve function in 19 female patients with Fabry disease and 19 sex and age-matched controls by measuring (1) sweat production following acetylcholine challenge; (2) the sympathetically mediated vasoconstrictor responses to inspiratory gasp, stress, and the cold pressor test; and (3) cutaneous blood flow following capsaicin. The vasoconstrictor response to inspiratory gasp was increased in Fabry patients compared to controls (p = 0.03), while the response to cold and mental stress did not change. Female patients with Fabry disease had a reduced sweat response to iontophoresis of acetylcholine (p = 0.04) and a smaller capsaicin-induced flare compared to controls. These findings suggest that female patients both have an impaired C-fiber function and local abnormalities in blood vessels and sweat glands.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Doença de Fabry/fisiopatologia , Fibras Nervosas Amielínicas/fisiologia , Pele/fisiopatologia , Glândulas Sudoríparas/fisiopatologia , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Pele/irrigação sanguínea , Pele/inervação , Sudorese/fisiologia , Adulto Jovem
16.
J Neuroendocrinol ; 31(7): e12699, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30776164

RESUMO

Huntington's disease (HD) is a heritable neurodegenerative disorder, characterised by metabolic disturbances, along with cognitive and psychiatric impairments. Targeting metabolic HD dysfunction via the maintenance of body weight and fat mass and restoration of peripheral energy metabolism can improve the progression of neurological symptoms. In this respect, we focused on the therapeutic potential of the orexigenic peptide hormone ghrelin, which plays an important role in promoting a positive energy balance. In the present study, we found a significant disruption of circadian metabolic regulation in a R6/2 mouse HD model in the late stage of disease. Daily circadian rhythms of activity, energy expenditure, respiratory exchange ratio and feeding were strongly attenuated in R6/2 mice. During the rest phase, R6/2 mice had a higher total activity, elevated energy expenditure and excessive water consumption compared to control mice. We also found that, in the late stage of disease, R6/2 mice had ghrelin axis deficiency as a result of low circulating ghrelin levels, in addition to down-regulation of the ghrelin receptor and several key signalling molecules in the hypothalamus, as well as a reduced responsiveness to exogenous peripheral ghrelin. We demonstrated that, in pre-symptomatic mice, responsiveness to ghrelin is preserved. Chronic ghrelin treatment efficiently increased lean body mass and decreased the energy expenditure and fat utilisation of R6/2 mice in the early stage of disease. In addition, ghrelin treatment was also effective in the normalisation of drinking behaviour and the rest activity of these mice. Ghrelin treatment could provide a novel therapeutic possibility for delaying disease progression; however, deficiency in ghrelin receptor expression could limit its therapeutic potential in the late stage of disease.


Assuntos
Grelina/metabolismo , Doença de Huntington/metabolismo , Animais , Composição Corporal , Ritmo Circadiano , Modelos Animais de Doenças , Ingestão de Alimentos , Metabolismo Energético , Feminino , Camundongos Transgênicos , Atividade Motora , Fenótipo
17.
DNA Cell Biol ; 27(5): 251-6, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18241033

RESUMO

Hedgehog (HH) signaling plays a critical role during embryogenesis and regulates early development of multiple tissues and organs, including the central nervous system. Although much has been revealed of the diverse functions of the HH signaling pathway, it is still unclear how the effects of altered HH signaling are interpreted by specific cell types. We have investigated the role of the HH transcription factor glioma-associated oncogene homolog 1 (GLI1) in the human Ntera2/D1 (NT2) embryonal carcinoma stem cell line. The study revealed that expression of GLI1 and its direct transcriptional target Patched (PTCH) is downregulated in the early stages of retinoic acid-induced neuronal differentiation of NT2 cells. To identify transcriptional targets of the HH transcription factor GLI1 in NT2 cells, we performed global expression profiling following GLI1 RNA interference (RNAi). Of the 8500 transcripts represented on the microarrays, expression of 88 genes was downregulated and expression of 26 genes was upregulated. Nineteen of these genes are involved in cell cycle and proliferation. Further, GLI1 RNAi leads to a significant decrease in NT2 proliferation and changes expression of G1 phase cyclins. In conclusion, our results suggest that GLI1 is involved in cell cycle and proliferation control in the embryonal carcinoma stem cell line NT2.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Células-Tronco de Carcinoma Embrionário/metabolismo , Fase G1/fisiologia , Fatores de Transcrição/fisiologia , Biomarcadores Tumorais/genética , Diferenciação Celular , Células-Tronco de Carcinoma Embrionário/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno/farmacologia , Transdução de Sinais , Transcrição Gênica , Tretinoína/farmacologia , Proteína GLI1 em Dedos de Zinco
18.
Genet Med ; 9(12): 812-8, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18091430

RESUMO

PURPOSE: We investigated the bone mineral status in patients with untreated Fabry disease (FD). METHODS: Descriptive, cross-sectional study in 53 patients with FD investigating bone mineral density (BMD)/content (dual energy x-ray absorptiometry scan), bone metabolism (parathyroid hormone, osteocalcin, and insulin-like growth factor I), and renal function (ethylene diamine tetraacetic acid clearance). RESULTS: Mean BMD z score at the lumbar spine and femoral neck were -0.05 +/- 1.46 SD and -0.37 +/- 1.02 SD, respectively. Approximately 50% had osteopenia in the hip or lumbar spine and additionally four had osteoporosis. Multivariate analysis including body weight, impaired renal function, and genotype overall explained 48% of the variance in lumbar spine BMD (P < 0.001), whereas body weight, impaired renal function, and menopausal status in the female population accounted for more than 50% of the variation in BMD of both the lumbar spine and femoral neck (both P < 0.001). Twenty percent of patients had hyperparathyroidism. Although the level of parathyroid hormone was significantly associated with impaired renal function, osteocalcin levels were significantly higher in patients with lumbar spine osteopenia or osteoporosis than in those with normal BMD. CONCLUSIONS: Osteopenia was present in approximately 50% of patients with untreated FD. Whether BMD and bone metabolism will improve after enzyme replacement therapy remains to be established.


Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico , Doença de Fabry/complicações , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Índice de Massa Corporal , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/etiologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia
19.
J Neurol Sci ; 241(1-2): 95-8, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16310805

RESUMO

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus. The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19. The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare. We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia. Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son. The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband. This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6.


Assuntos
Canais de Cálcio/genética , Transmissão Vertical de Doenças Infecciosas , Linhagem , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos , Idoso , Antecipação Genética , Análise Mutacional de DNA , Feminino , Humanos , Ataxias Espinocerebelares/etnologia
20.
J Neurol Sci ; 362: 326-32, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26944172

RESUMO

Huntington's disease (HD) is a dominantly inherited, progressive neurological disorder caused by a CAG repeat elongation in the huntingtin gene. In addition to motor-, psychiatric- and cognitive dysfunction, peripheral disease manifestations in the form of metabolic changes and cellular dysfunction are seen. Blood levels of a wide range of hormones, metabolites and proteins have been analyzed in HD patients, identifying several changes associated with the disease. However, a comprehensive panel of liver function tests (LFT) has not been performed. We investigated a cohort of manifest and premanifest HD gene-expansion carriers and controls, using a clinically applied panel of LFTs. Here, we demonstrate that the level of alkaline phosphatase is increased in manifest HD gene-expansion carriers compared to premanifest HD gene-expansion carriers and correlate with increased disease severity indicated by the Unified Huntington's disease rating scale-Total Functional Capacity Score (UHDRS-TFC). For gamma-glutamyl transferase, elevated levels were more frequent in the manifest groups than in both the HD gene-expansion negative controls and premanifest HD gene-expansion carriers. Finally, the manifest HD gene-expansion carriers displayed moderate increases in total cholesterol and blood glucose relative to the premanifest HD gene-expansion carriers, as well as increased C-reactive protein relative to HD gene-expansion negative controls. Our results show that LFT values are elevated more frequently in manifest compared to premanifest HD gene-expansion carriers and controls. The majority of the manifest HD gene-expansion carriers receive medication, and it is possible that this can influence the liver function tests performed in this study.


Assuntos
Doença de Huntington/sangue , Doença de Huntington/complicações , Hepatopatias/etiologia , Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Proteína C-Reativa , Transtornos Cognitivos/etiologia , Estudos de Coortes , Feminino , Humanos , Doença de Huntington/genética , Hepatopatias/genética , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Adulto Jovem , gama-Glutamiltransferase/sangue
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