Biomarcadores de estrés oxidativo en la enfermedad de Huntington y otros desórdenes neurológicos: estudio comparativo

Fundamento: los biomarcadores de estrés oxidativo en la enfermedad de Huntington pudieran predecir el curso de la enfermedad y evaluar nuevos tratamientos, pero su naturaleza inespecífica parece impedir la identificación de algún marcador útil. Esclarecer similitudes y diferencias de este fenómeno y su comportamiento con características clínicas puede ser esencial. Objetivo comparar biomarcadores de estrés oxidativo entre pacientes con enfermedad de Huntington y con otros desórdenes neurológicos. Métodos se realizó un estudio analítico, retrospectivo y caso-control (enfermedad de Huntington esclerosis lateral amiotrófica, ataxia espinocerebelosa tipo 2 e ictus isquémico: en etapa aguda y crónica). Se recogieron variables demográficas, clínicas y marcadores de daño oxidativo (malonildialdehído, productos avanzados de oxidación a proteínas) y antioxidantes (superóxido dismutasa: catalasa: glutatión peroxidasa, capacidad antioxidante del plasma). Resultados hubo diferencias significativas del malonildialdehído en la enfermedad de Huntington respecto al control (p=0,02), pero no con el resto de los grupos. La enzima superóxido dismutasa en enfermedad de Huntington fue menor estadísticamente en comparación con esclerosis lateral amiotrófica, aunque para la catalasa fue superior en relación con el resto de los pacientes. El FRAP en enfermedad de Huntington resultó menor significativamente versus esclerosis lateral amiotrófica e ictus isquémico agudo. Los productos avanzados de la oxidación de proteína se correlacionaron directamente con las edades biológicas y de inicio de la enfermedad de Huntington. La actividad motora en la esclerosis lateral amiotrófica y el déficit neurológico en el ictus isquémico agudo se correlacionaron con el malonildialdehído y glutatión peroxidasa respectivamente. Conclusiones la enfermedad de Huntington parece mostrar características específicas en su sistema antioxidante. La oxidación de proteínas pudiera estar relacionada con la acumulación de huntingtina mutada en el tiempo.

Foundation: biomarkers of oxidative stress in Huntington's disease could predict the course of the disease and evaluate new treatments, but their nonspecific nature seems to prevent the identification of any useful marker. Clarifying similarities and differences of this phenomenon and its behavior with clinical characteristics may be essential. Objective: compare biomarkers of oxidative stress between patients with Huntington's disease and other neurological disorders. Methods: an analytical, retrospective and case-control study was carried out (Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar ataxia type 2 and ischemic stroke: acute and chronic stage). Demographic and clinical variables and markers of oxidative damage (malonildialdehyde, advanced protein oxidation products) and antioxidants (superoxide dismutase: catalase: glutathione peroxidase, plasma antioxidant capacity) were collected. Results: there were significant differences in malonyldialdehyde in Huntington's disease compared to the control (p=0.02), but not with the rest of the groups. The enzyme superoxide dismutase in Huntington's disease was statistically lower compared to amyotrophic lateral sclerosis, although for catalase it was higher in relation to the rest of the patients. FRAP in Huntington's disease was significantly lower versus amyotrophic lateral sclerosis and acute ischemic stroke. Advanced products of protein oxidation were directly correlated with the biological and onset ages of Huntington's disease. Motor activity in amyotrophic lateral sclerosis and neurological deficit in acute ischemic stroke were correlated with malonyldialdehyde and glutathione peroxidase, respectively. Conclusions: huntington's disease seems to show specific characteristics in its antioxidant system. Protein oxidation could be related to the accumulation of mutated huntingtin over time.

"I don't have Huntington's disease": the boundaries between acceptance and understanding / "Eu não tenho doença de Huntington": os limites entre aceitação e compreensão

Abstract Huntington's disease (HD) is an inherited disease that leads to an inexorable progression of motor, cognitive and psychiatric disturbances. In the initial stages, the symptoms are not clearly disabling, and the patient may present a lack of awareness about the symptoms themselves, which we call anosognosia. However, anosognosia might not justify all passivity of the HD patient in face of the diagnosis. Patients may also experience the denial of illness, as a stage of grief, expected to happen in the face of the diagnosis of any neurodegenerative disorder. In addition, people with HD tend to be more apathetic, and more silent, in regular consultations. In the present article, the authors express a point of view, discussing the behavior of the HD patient, in which there is a multifactorial passivity, in the face of the diagnosis and of the disease itself. Having the proper knowledge of this situation may prepare the neurologist to better understand the patient and the evolution of the disease.

Resumo A doença de Huntington (DH) é uma doença hereditária que leva a uma progressão inexorável de distúrbios motores, cognitivos e psiquiátricos. Nos estágios iniciais, os sintomas não são claramente incapacitantes e há uma falta de consciência sobre os próprios sintomas, o que chamamos de anosognosia. No entanto, anosognosia pode não justificar toda a passividade do paciente de HD diante do diagnóstico. Os pacientes também podem vivenciar a negação da doença, como um estágio de luto, o que é esperado acontecer diante do diagnóstico de qualquer doença neurodegenerativa. Além disso, as pessoas com DH tendem a ficar mais apáticas, mais silenciosas, nas consultas regulares. No presente artigo, os autores expressam um ponto de vista, discutindo acerca do comportamento do paciente com DH, em que há uma passividade multifatorial, frente ao diagnóstico e diante da doença em si. Ter conhecimento sobre essa situação pode preparar o neurologista para entender melhor o paciente e a evolução da doença.

Huntington, la enfermedad que transforma todo a su paso: Narrativas de cuidadoras familiares de la costa Caribe colombiana / Huntington, the disease that transforms everything in its path: Narratives of family caregivers from the Colombian Caribbean coast

Resumen Este estudio cualitativo pretende explorar las transformaciones experimentadas a nivel emocional, físico y social por cuidadoras familiares de pacientes con enfermedad de Huntington en la costa Caribe de Colombia. Las participantes se seleccionaron de la base de datos de la Fundación Factor H, lográndose un punto de saturación teórica con 10 historias de vida narradas desde la voz del cuidador y recolectadas entre agosto de 2020 y mayo de 2021. La guía de preguntas se refinó mediante panel de expertos y se empleó bajo el consentimiento de las participantes. La categoría central "Huntington, la enfermedad que transforma todo a su paso" se desagregó a partir de tres subcategorías: "Transforma mi mundo", "Transforma mi corazón y mi alma" y "Transforma mi cuerpo"; a partir de las cuales se obtuvo que el cuidado es ejercido en su totalidad por mujeres, quienes experimentaron pérdidas en diferentes esferas: educativo, social, laboral, afectivo con fuertes impactos en su salud física, emocional y, por ende, en su vida cotidiana. Se concluye que la enfermedad de Huntington está permeada por señales adversas para el paciente, su cuidador y la familia; de ahí la necesidad de centrar esfuerzos colectivos para su abordaje integral.

Abstract Qualitative study to explore the transformations experienced at an emotional, physical, and social level by family caregivers of patients with Huntington's disease on the Caribbean coast of Colombia. Participants were selected from the Factor H Foundation database, obtaining a theoretical saturation point with 10 life stories telling from the caregiver's voice, gathered between August 2020 and May 2021. The driving question was refined by a panel of experts and was used with the consent of the participants. The main category, "Huntington, the disease that transforms everything in its path," was divided into three subcategories: "Transforms my world," "Transforms my heart and soul," and "Transforms my body." These subcategories unveiled that caregivers are mostly women who experienced losses in different aspects of their lives: educational, social, work, affective with strong impacts on their physical and emotional health, and, therefore, in their daily life. It is concluded that Huntington's disease has adverse signals for the patient, their caregiver and the family; hence the need to focus collective efforts for its comprehensive approach.

De novo Huntington′s disease due to paternal intermediate alleles: a case report and literature review / 中华神经科杂志

Objective:To report the clinical manifestation and genetic characteristics of a case of de novo Huntington′s disease due to paternal intermediate alleles. Methods:Clinical data and imaging features of a middle-aged female, who complained of unstable walking without positive family history and was admitted to Xuanwu Hospital, Capital Medical University on September 20, 2022, were retrospectively analyzed. The serum samples of the patient and her parents were used to screen HTT gene dynamic mutation in accordance with the principle of informed consent and voluntary. And the relevant literatures were reviewed. Results:This is a 38-year-old female with progressive course, who presented as ataxia, involuntary movement at the end of extremities, dystonia, and cognitive impairment. Imaging results showed atrophy of bilateral caudate nuclei, as well as decreased glucose metabolism of bilateral caudate nuclei, putamen and partial cortex. Genetic testing showed the abnormal expansion of polymorphic trinucleotide (CAG) repeats in HTT gene and confirmed the diagnosis of Huntington′s disease. The CAG repeat length of the patient was 17/47 (pathopoiesis), of the father was 17/35 (intermediate alleles), and of the mother was 17/17 (normal). Conclusions:Paternal intermediate alleles may cause the first case of Huntington′s disease in a family. Importantly, HTT gene screening should be performed for the patient and parents when the diagnosis of Huntington′s disease is clinically possible despite negative family history, to prevent the misdiagnosis.

Juvenile Huntington's disease in northern Brazil: a case series report / Doença de Huntington juvenil no norte do Brasil: relato de uma série de casos

Introduction: Huntington's disease (HD) is a neurodegenerative disorder caused by CAG expansion repeats in the HTT gene. Usually, the symptoms start to manifest in mid-adulthood. In about 5% of cases, however, the signs begin before the age of 20 years. These cases are known as juvenile HD (JHD). Objective: here we report a case series of JHD from Amazonas, a state where data are scarce due to the restricted access to specialized medical assistance for diagnosis and care. Case series: the patients were attended by neurologists specialized in movement disorders at Manaus. Two cases manifested the disease in childhood (6 and 7 years old) and two cases, in adolescence (12 and 16 years old). All cases showed dystonia and parkinsonism as predominant motor disorders. Moreover, signs of cognitive decline, depression, and psychosis were observed in all patients. Conversely, cerebellar signs, gait disturbances, seizures, and some psychiatric symptoms were variable among the cases. Expansion size varied from 66 to 84 to CAG repeats and the difference in age at onset between parent and child varied from 23 to 43 years. Conclusion: to our knowledge, these are the first clinical reports of JHD in northern Brazil. These cases illustrate the variability in clinical phenotypes and genetic features of JHD cases. Furthermore, they can contribute to the awareness of HD here, both by professionals and the public in general.

Introdução: a doença de Huntington (DH) é um distúrbio neurodegenerativo causado pela expansão de repetições CAG no gene HTT. Geralmente, os sintomas começam a se manifestar na vida adulta tardia. Em cerca de 5% dos casos, no entanto, os sinais começam antes da idade de 20 anos. Esses casos são conhecidos como DH juvenil (DHJ). Objetivo: neste estudo, nós reportamos uma série de casos de DHJ do Amazonas, um estado onde os dados ainda são escassos devido ao acesso restrito à assistência médica especializada para o diagnóstico e cuidado. Série de casos: os pacientes foram atendidos por neurologistas especializados em transtornos do movimento em Manaus. Dois casos manifestaram a doença na infância (6 e 7 anos) e dois casos, na adolescência (12 e 16 anos). Todos os casos apresentaram distonia e parkinsonismo como sintomas motores predominantes. Sinais de declínio cognitivo, depressão e psicose também foram observados em todos os pacientes. Por outro lado, sinais cerebelares, distúrbios da marcha, convulsões e alguns sintomas psiquiátricos foram variáveis entre os casos. O tamanho da expansão CAG variou de 66 a 84 repetições e a diferença na idade de início dos sintomas entre pais e filhos variou de 23 a 43 anos. Conclusão: ao nosso conhecimento, estes são os primeiros relatos clínicos da DHJ na região Norte. Esses casos ilustram a variabilidade nos fenótipos clínicos e nas características genéticas dos casos de DHJ. Além disso, eles podem contribuir para a conscientização da DH na região, tanto pelos profissionais quanto pelo público geral.

Modelagem celular in vitro da Doença de Huntington com ácido 3-nitropropiônico e ácido quinolínico & Avaliação das funções neuroprotetoras da adenosina / In vitro cell modeling of Huntington's Disease with 3-nitropropionic acid and quinolinic acid and evaluation of the neuroprotective functions of adenosine

A Doença de Huntington (Huntington's disease - HD) trata-se de uma patologia neurodegenerativa hereditária caracteriza por meio da expressão das proteínas huntingtinas mutantes (mHtt), das mortes dos neurônios espinhais médios (medium spiny neurons MSNs) GABAérgicos D2-positivos do striatum e da hipercinesia. Uma hipótese se refere à função das mHtts de potencializarem os efeitos excitotóxicos das estimulações dos receptores de NMDA (NMDAR) por meio da inibição da succinato desidrogenase, resultando em desequilibrio das [Ca2+]i, estresse oxidativo e apoptose. A adenosina agonista dos receptores purinérgicos P1 tem sido descrita por conta das suas funções neuroprotetoras e neuromodulatórias. Assim, estabelecemos dois modelos in vitro da HD fundamentados nas neurodiferenciações das linhagens murinas de célula-tronco embrionárias E14-TG2a e progenitoras neurais do hipocampo HT-22; seguidas pelos tratamentos com ácido quinolínico (QA) agonista seletivo dos NMDARs , na ausência e na presença do ácido 3-nitropropiônico (3-NP) inibidor irreversível da succinato desidrogenase. Estes modelos foram utilizados nas avaliações das funções neuroprotetoras da adenosina. Os neurônios pós-mitóticos das culturas de E14-TG2a diferenciadas foram caracterizados conforme os MSNs GABAérgicos do striatum; enquanto os neurônios HT-22 diferenciados foram caracterizados de modo inespecífico. Metodologia: imunofluorescência (microscopia e citometria); PCR em tempo real; análise das variações dos potenciais das membranas plasmáticas e das variações transientes das [Ca2+]i por microfluorimetria; e quantificações das reduções do AlamarBlue® (% de sobrevida celular) e das atividades extracelulares de LDH (U/L) (necrose) por espectrometria. Avaliamos a capacidade do 3-NP de potencializar os efeitos excitotóxicos do QA comparando dois grupos de neurônios HT-22 diferenciados: QA 8mM (EC50) (controle); e 3-NP 5mM/QA 8mM. Avaliarmos o potencial neuroprotetor da adenosina comparando quatro grupos de neurônios HT-22 diferenciados: QA 8mM; adenosina 250µM/QA 8mM; 3-NP 5mM/QA 8mM; 3-NP 5mM/adenosina 250µM/QA 8mM. Os neurônios pós-mitóticos derivados das E14TG2a foram classificados como MSNsGABAérgicos do striatum integrantes de uma cultura neuronal heterogênea semelhante às conexões nigroestriatais, corticoestriatais, striatonigral e striatopallidal. Os neurônios HT-22 diferenciados perfaziam uma cultura neuronal heterogênea, não totalmente madura, composta por neurônios glutamatérgicos, dopaminérgicos, colinérgicos e GABAérgicos. Os neurônios HT-22 diferenciados 3-NP 5mM apresentaram menores % de sobrevida celular após os tratamentos com QA 8mM por 24h (p<0.05); e maiores amplitudes das variações das [Ca2+]i dependentes do QA 8mM (p<0.05) (cinética 6 minutos). Por outro lado, os neurônios HT-22 diferenciados pré- tratados com 3-NP 5mM apresentaram menores atividades extracelulares de LDH após o tratamento com QA 8mM por 24h menor proporção de necrose. Os pré-tratamentos com adenosina 250µM indicaram uma tendência dos efeitos neuroprotetores (p>0.05) maiores % de sobrevida celular; menores atividades extracelulares de LDH; e menores amplitudes das variações transientes das [Ca2+]i. Em conjunto, nossos resultados indicam que a inibição da succinato desidrogenase potencializa os efeitos excitotóxicos dos NMDARs por meio da alteração das [Ca2+]i e, provavelmente, dos mecanismos de morte celular; enquanto a adenosina apenas tendeu à neuroproteção

Huntington's disease (HD) is a hereditary neurodegenerative pathology characterized by mutant huntingtin proteins (mHtt) expression, striatum D2-positive GABAergic medium spiny neurons (MSNs) cell death and hyperkinetic motor symptoms development. One hypothesis refers to the principle that mHtt potentiates the excitotoxic effects of NMDA receptor (NMDAR) stimulation by the inhibition of mitochondrial succinate dehydrogenase, resulting in [Ca2+]i imbalance, oxidative stress and apoptosis. Adenosine P1 purinergic receptor agonist is related to neuroprotective and neuromodulatory functions. Thus, we established two in vitro HD models based on the neurodifferentiation of murine embryonic stem cell lines E14-TG2a and hippocampal neuroprogenitor cell line HT-22 followed by treatment with quinolinic acid (QA) selective agonist of NMDARs , in the absence and in the presence of 3-nitropropionic acid (3-NP) irreversible inhibitor of succinate dehydrogenase. These models were used to assess the neuroprotective functions of adenosine. Post-mitotic neurons from differentiated E14-TG2a cultures were characterized according to striatum's GABAergic MSNs; while the differentiated HT-22 neurons were characterized in a non-specific way. Methodology included immunofluorescence (microscopy and cytometry); real-time PCR; analysis of variations in the plasma membrane potentials and of transient variations in the [Ca2+]i by microfluorimetry; and quantification of AlamarBlue® reductions (% cell survival) and of extracellular LDH activity (U/L) (necrosis) by spectrometry. We evaluated the ability of 3-NP to potentiate the excitotoxic effects of QA by comparing two groups of differentiated HT-22 neurons: 8mM QA (control); and 5mM 3-NP/8mM QA. We evaluated the neuroprotective potential of adenosine comparing four groups of differentiated HT-22 neurons: QA 8mM; 250µM adenosine/8mM QA; 5mM 3-NP/8mM QA; 5mM 3-NP/250µM adenosine/8mM QA. Postmitotic neurons derived from E14TG2a were classified as striatums GABAergic MSNs that are part of a heterogeneous neuronal culture similar to nigrostriatal, corticostriatal, striatonigral, and striatopallidal connections. Differentiated HT-22 neurons consisted of a heterogeneous neuronal culture and not fully mature glutamatergic,dopaminergic, cholinergic and GABAergic neurons. Differentiated HT-22 neurons following 5mM 3-NP treatment showed lower % cell survival after treatments with 8mM QA for 24h (p<0.05); and higher amplitudes of the variations of [Ca2+]i induced by 8mM QA (p<0.05) (kinetics 6 minutes). On the other hand, differentiated HT-22 neurons 5mM 3-NP showed lower extracellular LDH activities after treatment with 8mM QA for 24h indicating a lower proportion of necrotic cells. Pretreatments with 250µM adenosine indicated a trend towards neuroprotective effects, such as higher percentages of cell survival; lower extracellular LDH activities; and lower amplitudes of transient variations of [Ca2+]i. Taken together, our results indicate that succinate dehydrogenase inhibition potentiated the excitotoxic effects of NMDARs by altering [Ca2+]i and, probably, cell death mechanisms, while adenosine only to neuroprotection

La enfermedad de Huntington: una difícil relación entre los enfermos y el derecho a la salud en Colombia / Huntington's Disease: A Difficult Relationship between Patients and the Right to Health in Colombia / A doença de Huntington: uma difícil relação entre os doentes e o direito à saúde na Colômbia

Resumen Introducción: el derecho a la salud está consagrado en la Constitución Política y en la Ley Estatutaria de Salud 1751 de 2015. Las personas con enfermedad de Huntington requieren atención especializada e interdisciplinaria, por ser un complejo trastorno genético neurodegenerativo, que comienza en mitad de la vida adulta y no es curable. Materiales y métodos: estudio cualitativo, en diferentes regiones, mediante entrevistas en visita familiar, observación participante y revisión documental. Los resultados son fruto del análisis, realizado según postulados de la teoría fundamentada con origen en la sociología. Resultados: se encontró una difícil relación de las personas con el sistema de salud: los que buscan atención, encuentran múltiples barreras que tratan de superar a través de la tutela, viven en ciudades principales o intermedias con alguna atención que los favorezca. Otros, en regiones distantes como Chocó y Juan de Acosta (Atlántico) emprenden pocas acciones en una suerte de "desesperanza aprendida", como propone Seligman: "no hacer nada porque nada va a funcionar". Conclusión: ellos presentan la enfermedad en estado genuino, no reciben atención y sus condiciones son precarias hasta estados de desnutrición y abandono. La mayoría no tuvo acceso al trabajo formal; por lo tanto, no tendrán posibilidad de la pensión de invalidez o vejez, otros se debaten en el proceso de lograrla, y se encuentran en condiciones de pobreza y precariedad.

Abstract Introduction: The right to health is enshrined in the Political Constitution of Colombia as well as in the Statutory Health Legislation 1751 of 2015. Patients with Huntington's disease require specialized and interdisciplinary care because of the complex genetic neurodegenerative nature of the disorder, which usually affects the middle-aged individuals and is incurable. Materials and methods: This qualitative study was conducted in different regions, followed by data collection through interviews during family visits, participant observation, and documentary review. The results are a part of the analysis, which was conducted according to the grounded theory postulates with an origin in sociology. Results: A difficult relationship was noticed between the individuals and health system, indicating that those seeking care encounter multiple barriers and then attempt to overcome them through tutelage and live in principal or intermediate cities with favorable care availabilities. Others living in remote regions, such as Chocó and Juan de Acosta on the Atlantic, undertake only a few actions as a sort of "learned helplessness," better summarized by Seligman as "doing nothing because nothing will work." Conclusion: The results of the present study indicate that Huntington's disease in the genuine state receives no care and that the conditions of these patients are precarious to the states of malnutrition and abandonment. The majority of these patients have no access to formal employment; thus, they see no possibility for disability pension or retirement, while others debate about the process of achieving it and suffering from poverty and precariousness.

Resumo Introdução: o direito à saúde está consagrado na Constituição Política e na Lei Sanitária Estatutária 1751 de 2015. Pessoas com doença de Huntington requerem atendimento especializado e interdisciplinar por se tratar de uma doença genética neurodegenerativa complexa, que se inicia na metade da vida adulta e não é curável. Materiais e métodos: estudo qualitativo, realizado em diferentes regiões. A coleta foi realizada por meio de entrevistas em visitas familiares, observação participante e revisão documental. Os resultados são fruto de análises, realizadas de acordo com os postulados da teoria fundamentada com origem na sociologia. Resultados: constatou-se a difícil relação entre as pessoas e o sistema de saúde: quem busca atendimento encontra múltiplas barreiras que tentam superar por meio de processo judicial, moram em cidades principais ou intermediárias com algum atendimento que os favorece. Outros, vivem em regiões distantes como Chocó e Juan de Acosta no Atlântico, empreendem poucas tentativas de processo judicial como uma espécie de "desesperança aprendida" como propõe Seligman: "não faça nada porque nada vai funcionar". Conclusão: os pacientes apresentam a doença de forma genuína, não recebem atenção médica e vivem em condições precárias com certo grau de desnutrição e em estado de abandono. A maioria não teve acesso ao trabalho formal, portanto, não terá a possibilidade de receber aposentadoria por invalidez ou idade, outros estão lutando para obtê-lo, e se encontram em condições de pobreza e precariedade.

Efeito do treinamento muscular respiratório em pacientes com doença de Huntington: relato de casos / Effect of muscular respiratory training in Huntington disease's patients: study cases

Introdução: A doença de Huntington (DH) é uma doença neurodegenerativa progressiva, caracterizada pela tríade: alterações motoras, distúrbios psiquiátricos e disfunção cognitiva. Os pacientes com DH apresentarão restrição da mobilidade, que, futuramente, irá ocasionar fraqueza muscular generalizada. Objetivo: Avaliar os efeitos do treinamento da musculatura respiratória com o uso do Threshold em pacientes diagnosticados com DH atendidos na clínica escola de Fisioterapia do Centro Universitário Unieuro. Métodos: Os participantes foram submetidos ao programa de treinamento da musculatura respiratória com o uso do Threshold® IMT. O programa consiste em 3 séries com 5 repetições ao dia, por 3 semanas. Ao final do treinamento os pacientes foram reavaliados, e os resultados obtidos foram comparados com os resultados obtidos na avaliação inicial. Resultados: Após 3 semanas de treinamento, o paciente 1 apresentou como melhor resultado da pressão inspiratória máxima e da pressão expiratória máxima igual a 50 cmH2O e no teste de caminhada de 6 minutos percorreu 261 metros. Já o paciente 2 apresentou como melhor resultado da pressão inspiratória máxima 70 cmH2O e da pressão expiratória máxima 60 cmH2O, e no teste de caminhada de 6 minutos percorreu 146 metros. Conclusão: Conclui-se que o treinamento muscular respiratório pode ser benéfico para os pacientes com doença de Huntington, porém são necessários mais estudos para determinar o melhor protocolo para os mesmos. (AU)

Introduction: Huntington's disease (DH) is a progressive neurodegenerative disease, characterized by the triad: motor alterations, psychiatric disorders and cognitive dysfunction. Patients with HD will exhibit mobility restriction, which in the future will lead to generalized muscle weakness. Objective: To evaluate the effects of respiratory muscle training with the use of Threshold in patients diagnosed with DH treated at the Clinical School of Physical therapy of Unieuro University Center. Methods: Participants underwent respiratory muscle training with Threshold® IMT. The program consists of 3 sets with 5 replicates per day, for 3 weeks. At the end of the training the patients were reassessed, and the results obtained were compared with the results obtained in the initial evaluation. Results: After 3 weeks of training, patient 1 presented the best result of maximal inspiratory pressure and maximal expiratory pressure equal to 50 cmH20 and walked in the 6-minute walk test 261 meters. Already, patient 2 presented the best inspiratory pressure result 70 cmH2O and the maximum expiratory pressure 60 cmH2O, and in the 6-minute walk test it ran 146 meters. Conclusion: We concluded that respiratory muscle training may be beneficial for patients with Huntington's disease, but further studies are needed to determine the best protocol for them. (AU)

The roles of epigenetic modifications in neurodegenerative diseases / 浙江大学学报·医学版

In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.

Psychosis in Huntington´s Disease. a rare and Under-Investigated Psychiatric Manifestation / Psychosis in Huntington's Disease: uma manifestação psiquiátrica rara e pouco investigada

Introduction: Psychotic symptoms are among the least prevalent and under-investigated psychiatric manifestations (PM) of Huntington's disease (HD). Case report: We herein report a case of a 31-year-old male patient who presented PM with a predominance of negative symptoms, without any significant abnormal movement. HD was diagnosed based on positive DNA analysis and family history. HD imposes longitudinal follow-up through a multidisciplinary approach in order to improve the quality of life and prognosis. Conclusion: This case report highlights the importance of comprehending the PM in the initial presentation of HD so that the diagnosis is not delayed until the onset of motor symptoms.

Introdução: Os sintomas psicóticos estão entre as manifestações psiquiátricas (MP) menos prevalentes e pouco investigadas da doença de Huntington (DH). Relado de caso: Relatamos o caso de um paciente do sexo masculino, 31 anos, que apresentou MP com predomínio de sintomas negativos, sem qualquer movimento anormal significativo. A DH foi diagnosticada com base em uma análise de DNA positiva e na história familiar. A DH impõe um acompanhamento longitudinal por meio de uma abordagem multidisciplinar, a fim de melhorar a qualidade de vida e o prognóstico. Conclusão: Este relato de caso destaca a importância da compreensão das MPs na apresentação inicial da DH, para que o diagnóstico não seja atrasado até ao aparecimento dos sintomas motores

Hardy-Weinberg Equilibrium in different mitochondrial haplogroups of four genes associated with neuroprotection and neurodegeneration / Equilíbrio de Hardy-Weinberg em diferentes haplogrupos mitocondriais de quatro genes associados à neuroproteção e neurodegeneração

ABSTRACT Background: Malfunctioning or damaged mitochondria result in altered energy metabolism, redox equilibrium, and cellular dynamics and is a central point in the pathogenesis of neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis. Therefore, it is of utmost importance to identify mitochondrial genetic susceptibility markers for neurodegenerative diseases. Potential markers include the respiratory chain enzymes Riboflavin kinase (RFK), Flavin adenine dinucleotide synthetase (FAD), Succinate dehydrogenase B subunit (SDHB), and Cytochrome C1 (CYC1). These enzymes are associated with neuroprotection and neurodegeneration. Objective: To test if variants in genes RFK, FAD, SDHB and CYC1 deviate from Hardy-Weinberg Equilibrium (HWE) in different human mitochondrial haplogroups. Methods: Sequence variants in genes RFK, FAD, SDHB and CYC1 of 2,504 non-affected individuals of the 1,000 genomes project were used for mitochondrial haplogroup assessment and HWE calculations in different mitochondrial haplogroups. Results: We show that RFK variants deviate from HWE in haplogroups G, H, L, V and W, variants of FAD in haplogroups B, J, L, U, and C, variants of SDHB in relation to the C, W, and A and CYC1 variants in B, L, U, D, and T. HWE deviation indicates action of selective pressures and genetic drift. Conclusions: HWE deviation of particular variants in relation to global populational HWE, could be, at least in part, associated with the differential susceptibility of specific populations and ethnicities to neurodegenerative diseases. Our data might contribute to the epidemiology and diagnostic/prognostic methods for neurodegenerative diseases.

RESUMO Introdução: Mitocôndrias defeituosas ou danificadas resultam em alterações do metabolismo energético, equilíbrio redox e dinâmica celular e são, portanto, identificadas como o ponto central da patogênese em muitos distúrbios neurológicos, como a doença de Alzheimer, a doença de Parkinson, a doença de Huntington e a Esclerose Lateral Amiotrófica. Portanto, é de fundamental importância identificar marcadores de susceptibilidade genética mitocondrial para doenças neurodegenerativas. Entre os potenciais marcadores relevantes estão as enzimas da cadeia respiratória riboflavina quinase (RFK), flavina adenina dinucleotídeo sintetase (FAD), succinato desidrogenase subunidade B (SDHB) e citocromo C1 (CYC1). Estas enzimas estão associadas à neuroproteção e à neurodegeneração. Objetivo: Testar se variantes nas sequências dos genes RFK, FAD, SDHB e CYC1 desviam do Equilíbrio de Hardy-Weinberg (HWE) em diferentes haplogrupos mitocondriais humanos. Métodos: Neste trabalho utilizamos os variantes nos genes RFK, FAD, SDHB e CYC1 de sequências de 2.504 indivíduos não afetados do projeto de 1.000 genomas para o cálculo dos valores de HWE em diferentes haplogrupos mitocondriais. Resultados: As variantes de RFK desviam de HWE nos haplogrupos G, H, L, V e W, variantes de FAD nos haplogrupos B, J, L, U e C, variantes de SDHB em relação às variantes C, W e A e CYC1 em B, L, U, D e T. O desvio de HWE indica a ação de pressões seletivas e desvio genético. Conclusões: O desvio do HWE de variantes particulares em relação ao HWE populacional global poderia estar, pelo menos em parte, associado à suscetibilidade diferencial de populações e etnias específicas a doenças neurodegenerativas. Nossos dados podem contribuir para a epidemiologia e métodos diagnósticos/prognósticos para doenças neurodegenerativas.

Free carnitine and branched chain amino acids are not good biomarkers in Huntington's disease / Carnitina livre e aminoácidos de cadeia ramificada não são bons biomarcadores na doença de Huntington

ABSTRACT Background: Huntington's disease (HD), caused by an expanded CAG repeat at HTT, has no treatment, and biomarkers are needed for future clinical trials. Objective: The objective of this study was to verify if free carnitine and branched chain amino acids levels behave as potential biomarkers in HD. Methods: Symptomatic and asymptomatic HD carriers and controls were recruited. Age, sex, body mass index (BMI), age of onset, disease duration, UHDRS scores, and expanded CAG tract were obtained; valine, leucine, isoleucine, and free carnitine were measured. Baseline and longitudinal analysis were performed. Results: Seventy-four symptomatic carriers, 20 asymptomatic carriers, and 22 non-carriers were included. At baseline, valine levels were reduced in symptomatic and asymptomatic HD carriers when compared to non-carriers. No difference in free carnitine or isoleucine+leucine levels were observed between groups. BMI of symptomatic individuals was lower than those of non-carriers. Valine levels correlated with BMI. Follow-up evaluation was performed in 43 symptomatic individuals. UHDRS total motor score increased 4.8 points/year on average. No significant reductions in BMI or valine were observed, whereas free carnitine and isoleucine+leucine levels increased. Conclusions: Although valine levels were lower in HD carriers and were related to BMI losses observed in pre-symptomatic individuals, none of these metabolites seem to be biomarkers for HD.

RESUMO Introdução: A doença de Huntington (DH), causada por uma repetição CAG expandida no HTT, não possui tratamento e biomarcadores são necessários para futuros ensaios clínicos. Objetivo: Nosso objetivo foi verificar se os níveis de carnitina livre e aminoácidos de cadeia ramificada se comportam como potenciais biomarcadores na DH. Métodos: Portadores sintomáticos e assintomáticos e controles foram recrutados. Idade, sexo, índice de massa corporal (IMC), idade de início, duração da doença, escores UHDRS e trato CAG expandido foram obtidos; valina, leucina, isoleucina e carnitina livre foram medidas. Foram realizadas análises basal e longitudinal. Resultados: Setenta e quatro portadores sintomáticos, 20 portadores assintomáticos e 22 não portadores foram incluídos. No início do estudo, os níveis de valina estavam reduzidos em portadores de DH sintomáticos e assintomáticos quando comparados aos não portadores. Não foram observadas diferenças nos níveis de carnitina livre ou isoleucina + leucina entre os grupos. O IMC dos indivíduos sintomáticos foi menor que o dos não portadores. Níveis de valina correlacionaram-se com o IMC. Avaliação de acompanhamento foi realizada em 43 indivíduos sintomáticos. A pontuação do escore motor total da UHDRS aumentou 4,8 pontos/ano em média. Não foram observadas reduções significativas no IMC ou na valina, enquanto os níveis de carnitina livre e isoleucina+leucina aumentaram. Conclusões: Embora os níveis de valina tenham sido menores nos portadores de DH e estivessem relacionados às perdas de IMC observadas em indivíduos pré-sintomáticos, nenhum desses metabólitos parece ser biomarcador para a DH.

Research progress on microRNAs in Huntington's disease / 中国临床药理学与治疗学

Huntington's disease (HD) is a monogenic genetic disease of neurodegenerative disorders caused by repeated amplification of CAG trinucleotides in the first exon of the Huntingtin gene (HTT), and there are no treatments which could forestall or slow Huntington's disease. The protein product encoded by HTT is called huntingtin (Htt). The mutated huntingtin protein (mHtt) is easy to form aggregation which is toxic, leading to a series of cytological abnormalities and neuronal dysfunction. MicroRNA (miRNA) plays an important role in the post-transcriptional regulation of genes whose expression is related to the pathological process of Huntington's disease. miRNA is becoming the promising biomarker for the treatment of HD. Recent studies on the regulation of specific miRNAs in HD and the prediction of their target genes may provide a potential role for the treatment of HD. This review highlights the research progress on miRNAs in the occurrence of HD.

La vida cotidiana de las personas con Enfermedad de Huntington: el proceso de perderse de sí mismo / The Everyday Life of People with Huntington Disease: The Process of Losing Yourself

En esta investigación se preguntó por la vida cotidiana de las personas con Enfermedad de Huntington (EH), una enfermedad genética, neurodegenerativa que se desarrolla en la vida adulta joven y que se caracteriza por la triada de alteraciones de la conducta, motoras y cognitivas, lleva a la muerte en un proceso crónico de 10 a 20 años y aún no existe para ella tratamiento curativo, es considerada enfermedad huérfana debido a que se presenta en menos de 1 en 5000 personas en Colombia. El objetivo fue comprender cómo viven la vida cotidiana las personas con dicha enfermedad. Se utilizó como referente metodológico el paradigma comprensivo, siguiente los postulados de la teoría fundamentada de Strauss y Corbin. Los datos se construyeron a partir de entrevistas semiestructuradas y en conversación informal, en visita familiar a personas afectadas o a riesgo, es decir, hijos de las afectadas. Fueron 33 participantes de diferentes regiones del país, como Bogotá, Medellín, Santa Marta y Chocó y principalmente Juan de Acostas en el Atlántico paradigmático por ser la segunda región del mundo con mayor número de afectados después de Venezuela; se complementó la información con entrevistas a familiares, cuidadores, líderes de asociaciones y personas expertas en el tema; se realizó revisión documental, observación participante y se elaboró diario de campo. El análisis y la recolección fueron concurrentes, se hicieron preguntas y comparaciones a los datos, de donde surgió la categoría central perderse de sí mismo hasta la muerte, para explicar la vida cotidiana de las personas con EH a partir de un esquema explicativo que se compone de cuatro categorías, el contexto que involucra las subcategorías el micro-contexto de las regiones, el sistema de salud, la situación económica y las intervenciones del estado y las asociaciones y fundaciones; la otra categoría tiene que ver con perderse de sí mismo, se compone de las subcategorías: lo que sabíamos de la enfermedad, reconocerse a riesgo, no darse cuenta, tener consciencia de la enfermedad, los cambios y las pérdidas; la dependencia y la pérdida del yo hasta la muerte y las consecuencias para los que cuidan. La otra categoría fue nombrada las relaciones de amores y amarguras apoyos y desafíos que se compone de los arreglos familiares, las relaciones difíciles distantes y dolorosas y las relaciones con los amigos y vecinos y la cuarta categoría, la vida cotidiana que se compone de organizar el tiempo, las mismas rutinas, el cuidado y la muerte. Las personas desarrollan la vida en un contexto de pobreza y precariedad, la cual se incrementa con la enfermedad que los empobrece más, al perder el empleo los pocos que lo tenían de manera formal, no logran la pensión de invalidez y la enfermedad incrementa los gastos con nuevas necesidades. La relación con el sistema de salud es difícil y no se compadece con la legislación que existe en nuestro Estado social de derecho; frente a estas condiciones en algunas regiones existen recursos del Estado para atender a aquellos que llegan a la vulnerabilidad psicosocial y desafiliación como la condición de calle. Las asociaciones y fundaciones emprenden acciones que no logran ser suficientes en medio de tanta precariedad. En esta complejidad de pobreza y enfermedad, las relaciones familiares aunque en muchos casos se des-configuran hasta el abandono, en otras se reconfiguran en arreglos familiares y apoyos solidarios en los que se comparte la pobreza. Las alteraciones de la salud mental de los afectados son un desafío para la convivencia. Cuando inician los síntomas muchos de los afectados no se dan cuenta de ello, lo que dificulta la atención y los pone en riesgo, al igual que a otros por su quehacer en la vida cotidiana. La enfermedad pasa por un proceso de cambios, pérdidas y deterioro tanto del cuerpo como de la mente, que además de llevar a la pérdida del yo, estigmatiza, sobre todo por los movimientos y las alteraciones de la conducta. Las personas van perdiendo lo que eran hasta llegar a requerir de un cuidador del cual llegan a ser dependientes al perder entre tantas otras cosas, el lenguaje, la deglución y la movilidad. En esta condición de cautiverio en su propio ser sin salida, se estructuró de los datos la teoría sustantiva sobre la vida cotidiana de las personas con enfermedad de Huntington: La inversión del mito de la caverna, de la alegoría de Platón que expresa que los habitantes de la caverna nacieron prisioneros y solo podían ver las sombras reflejadas por la hoguera en la pared; las personas afectadas por la EH, nacieron libres, al iniciar la enfermedad ingresan a la caverna, la cual los limita, los encoge, los reduce, los deja prisioneros en su propio cuerpo y del exterior solo tienen las sombras, los recuerdos. No hay salida de la caverna, la salida es la muerte. Conclusión: La vida de las personas con EH es de gran adversidad y precariedad, presentan necesidades especiales con relación a la población general por lo que su intervención, por la complejidad, requiere atención interdisciplinaria e intersectorial en la cual el cuidado de enfermería tiene importancia para ofrecer educación y liderar programas en todos los niveles de prevención. Las acciones de cuidado requieren enfermeros competentes con estructura en los patrones de conocimiento de Carper: empírico, personal, ético, estético y los de Chinn y Kramer sociopolítico y emancipatorio. (AU)

This research examined about people with Huntington's Disease daily life (HD), is a genetic, neurodegenerative disease that develops in young adult life and is characterized by triad alteration from behavioral, motor and cognitive disorders, It leads to death in a chronic process from 10 to 20 years and there is not curative treatment for it yet, it is considered an orphan disease because it occurs in less than 1 in 5000 people in Colombia. Its objective was to understand daily life from those people with this disease. A comprehensive paradigm was used as a methodological reference, following Strauss and Corbin's e postulates from grounded theory Data were constructed from semi-structured interviews and in informal conversation, in family visits to affected or at-risk people, that is, children of those affected. There were 33 participants from different regions of our country, such as Bogotá, Medellin, Santa Marta and Chocó and mainly Juan de Acosta in the Atlantic, paradigmatic for the reason that it is the second region in the world with the highest number of affected people after Venezuela; the information was complemented with interviews with family members, caregivers, association leaders and experts in this subject; Documentary review, participant observation and field diary was prepared. The analysis and collection were concurrent, questions and comparisons were made to the data, from which the central category arose from losing itself to death, to explain the daily life of people with HD from an explanatory scheme that is composed of four categories, the context involves the subcategories micro-context from regions, health system, the economic situation and the state's interventions and the associations and foundations; the other category has to do with losing oneself, it is made up by subcategories: what we knew about the disease, recognizing oneself at risk, not realizing it, being aware of the disease, changes and losses; dependence and loss of self until death and them consequences for those who care. The other category about family relationship was named the relationships of love and bitterness, supports and challenges that is made up, difficult distant and painful relationships and relationships with friends and neighbors and the fourth category, the daily life that is made up of organizing the time, the same routines, care and death. Due to poverty and precariousness's context in which people develop their life, it increases with this disease that impoverishes them, moreover, when they lost their employment: the few who had it formally lose their jobs, they do not obtain a disability benefits and the disease increases expenses with new essentials. Their relationship with the health system is difficult and does not concordance with our legislation that exists in our law at social state level; In the face of these conditions in some regions there are some resources from our state to meet those who reach psychosocial vulnerability and disaffiliation as the street condition. The associations and foundations undertake actions that cannot be enough in the midst of such precariousness. In this complexity of poverty and disease, family relationships, although in many cases they are family breakdown until abandonment, in others they are reconfigured into family arrangements and solidarity support in which poverty is shared. Mental health alterations from those suffered are challenge for a peaceable living. When those symptoms begin many of those affected do not realize it, which makes attention difficult and puts them at risk, as well as others for their daily life's work the disease goes through a process of changes, losses and deterioration of both the body and the mind, which in addition to leading to the loss of the self, stigmatizes, especially the movements and alterations of behavior. People lose what they were until they came to require a caregiver that they become dependent upon losing, among many other things, language, swallowing and mobility. In this captivity condition in his/her own dead-end being, the substantive theory about the daily life of people with Huntington's disease was structured from data: Cave myth, inversion is a Plato's allegory that expresses that the inhabitants Prisoners were born from the cave and could only see the shadows reflected by the fire on the wall; people affected by HD, were born free, at the beginning of the disease they enter into a cave, which limits them, shrinks them, reduces them, leaves them prisoners in their own bodies and from the outside they only have shadows, memories. There is no exit from this cave, his/her exit is death. Conclusion: Daily life from people with HD is of great adversity and precariousness, they have special essentials in relation to general population, so their intervention, due to the complexity, requires interdisciplinary and intersectoral assistance in which nursing care is important for offer education and lead programs at all levels of prevention and include palliative care at the end of life. Care actions require competent nurses with structure in Carper's knowledge patterns: empirical, personal, ethical, aesthetic and those of socio-political and emancipatory Chinn and Kramer. (AU)

Theory of mind impairment in Huntington's disease patients and their relatives / Déficits en teoría de la mente en pacientes con enfermedad de Huntington y sus familiares

ABSTRACT Huntington disease (HD) is an autosomal dominant genetic disorder characterized by movement disorders, cognitive impairment, and psychiatric symptoms. Relatives of HD patients experience a great burden as the latter suffer from altered social conduct and deterioration of interpersonal relationships. Theory of mind (ToM) is the ability to attribute mental states (to oneself and others). Deficits in ToM are thought to have a role in the changes in empathy and interpersonal difficulties that HD patients face. Methods: We conducted a cross sectional study to compare ToM task scores of patients with mild to moderate HD, their relatives (spouse or at-risk first-degree relative with a negative gene test) and controls.Individuals with dementia or depression were excluded. The ToM test battery included Spanish versions of the Reading Mind in the Eyes Test (RMET), Happé's Strange Stories (Social and Physical Stories subtests) and the Hinting Task. Results: The series comprised 12 HD patients, 12 relatives and 12 controls. The HD patients showed lower affective ToM scores than controls (RMET 19 [3.5] vs 23.9 [2.7], p = 0.016). Cognitive ToM tasks scores were lower in HD patients than controls as well (Happé's Social Stories 9 [2.6] vs 13 [1.9], p = 0.001; the Hinting Task 13.6 [3.4] vs 17.5 [4.0], p = 0.009). In the Hinting Task, HD relatives had lower scores in than controls (13 [3.2] vs 17.5 [4.0], p = 0.009) and similar scores to controls in the rest of the battery. Conclusion: The HD patients with mild to moderate disease severity and their relatives show ToM deficits.

RESUMEN La enfermedad de Huntington (EH) es una enfermedad genética autosómica dominante caracterizada por trastornos del movimiento, deterioro cognitivo y síntomas psiquiátricos. Los familiares de las personas con EH experimentan gran carga dado que los pacientes sufren de conducta social alterada y deterioro de relaciones interpersonales. La Teoría de la mente (ToM) consiste en la habilidad para atribuir estados mentales (a uno mismo o a otros). Se piensa que déficits en ToM tienen un rol en los cambios en empatia y en las dificultades interpersonales que los pacientes con EH enfrentan. Métodos: Condujimos un estudio transversal para comparar el desempeño en puntajes de tareas de ToM en pacientes con EH leve a moderada, sus familiares (pareja o familiar en riesgo con prueba genética negativa) y controles sanos. Se excluyó a sujetos con demencia o depresión. La batería de pruebas de ToM incluyó versiones en español de la prueba de lectura de la mente en los ojos (RMET), Historias Extrañas de Happé (subpruebas Social y Física) y Hinting Task. Resultados: La serie consistió de 12 pacientes con EH, 12 familiares y 12 controles. Los pacientes con EH mostraron puntajes menores de tareas de ToM afectiva que los controles (RMET 19 [3.5] vs 23.9 [2.7], p = 0.016). Los puntajes de tareas de ToM cognitiva fueron inferiores a los controles en los pacientes con EH (Historias Sociales de Happé 9 [2.6] vs 13 [1.9], p = 0.001; Hinting task 13.6 [3.4] vs 175 [4.0], p = 0.009). En la Hinting task los familiares de pacientes con EH mostraron puntajes inferiores que los de los controles (13 [3.2] vs 175 [4.0], p = 0.009) y puntajes similares a aquellos de los controles en el resto de la batería. Conclusión: Los pacientes con EH con enfermedad leve a moderada y sus familiares muestran déficits en tareas de ToM.

Juvenile-onset Huntington’s Disease: A Rare Case Report

Juvenile-onset Huntington’s disease (JHD) is a rare autosomal dominant neurodegenerative disorder of the central nervoussystem characterized by the presence of abnormal involuntary movements, rigidity, and ataxic gait. We are presenting a rarecase of a 9-year-old male who was referred to the Radiology Department of Gandhi Medical College and Hamidia Hospital formagnetic resonance imaging (MRI) brain with complaints of progressive impairment of gait, bradykinesia, and marked posturalinstability for the past 2 years. The patient also had a history of episodes of seizures for 4 years. MRI findings revealed: Atrophyof bilateral caudate nuclei and putamina of basal ganglia.

Frecuencia De Casos Juveniles Con Enfermedad De Huntington En Población Mexicana / Frequency Of Juvenile Huntington´S Disease In A Mexican Population

Resumen Objetivo: El propósito de este estudio es determinar la prevalencia de casos juveniles en una muestra de sujetos mexicanos con enfermedad de Huntington (EH) confirmada molecularmente. Métodos: Se incluyeron pacientes con inicio clínico antes de los 21 años de edad que acudieron a la clínica de trastornos del movimiento del Instituto Nacional de Neurología y Neurocirugía. La información demográfica y clínica se obtuvo de la revisión de expedientes. Resultados: Se revisaron un total de 198 casos de pacientes con diagnóstico de EH, de los cuales el 6.5% (n=13) correspondió a formas juveniles. La media de edad para el inicio de síntomas fue de 17.8 ± 3.9 años. La puntuación media del UHDRS-motor fue de 46.2 ± 17.4 puntos. El síntoma motor predominante fue corea en el 53.8% de los casos. El 84.6% de los afectados presentó al menos una alteración neuropsiquiátrica. Conclusión: Se detectó que el fenotipo motor de estos pacientes fue dominantemente corea, contrario a lo reportado mundialmente hasta ahora, es decir, nuestro grupo presentó clínica motora atípica de EHJ.

Abstract Objective: The purpose of this study is to know the prevalence of juvenile cases in a sample of mexican subjects with confirmed Huntington Disease (HD). Methods: Patients with clinical debut before 21 years of age were included who attended at movement disorders clinic of the National Institute of Neurology and Neurosurgery. The demographic and clinical information was obtained from the review of files. Results: A total of 198 cases of patients diagnosed with HD were reviewed, of which 6.5% (n = .13) corresponded to juvenile forms. The mean age for the onset of symptoms was 17.8 ± 3.9 years. The mean score of the UHDRS-motor was 46.2 ± 17.4 points. The predominant motor symptom was chorea in (53.8%) of the cases. 84.6% of those affected presented at least one neuropsychiatric disorder. Conclusion: It was detected that the dominant motor phenotype of these patients was chorea compared to the world reports until now, accordingly to that, our group of juvenile HD shows atypical motor clinical.

Effect of Apolipoprotein E Genotypes on Huntington's Disease Phenotypes in a Han Chinese Population / 神经科学通报·英文版

Huntington's disease (HD) is an autosomal dominant degenerative disease that mainly encompasses movement, cognition, and behavioral symptoms. The apolipoprotein E (APOE) gene is thought to be associated with many neurodegenerative diseases. Here, we enrolled a cohort of 223 unrelated Han Chinese patients with HD and 1241 unrelated healthy controls in Southeastern China and analyzed the correlation between APOE genotypes and HD phenotypes. The results showed that the frequency of the E4 allele (7.1%) in HD patients was statistically less than that in controls (12.0%) (P =0.004). In addition, we divided patients into motor-onset and non-motor-onset groups, and analyzed the relationship with APOE genotypes. The results, however, were negative. Furthermore, the age at onset (AAO), defined as the age at the onset of motor symptoms, was compared in each APOE genotype subgroup and multivariate regression analysis was used to exclude the interference of CAG repeat length on AAO, but no association was found between APOE genotypes and AAO. Finally, we analyzed adult-onset HD to exclude the interference caused by juvenile HD (n = 13), and the results were negative. Therefore, our study suggests that APOE may not be a genetic modifier for HD, especially for adult-onset HD among Chinese of Han ethnicity. To the best of our knowledge, this is the first study of the correlation between APOE genotypes and HD phenotypes in a Han Chinese population.

Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts from Patients with Huntington's Disease / 神经科学通报·英文版

Huntington's disease (HD) is a deadly neurodegenerative disease with abnormal expansion of CAG repeats in the huntingtin gene. Mutant Huntingtin protein (mHTT) forms abnormal aggregates and intranuclear inclusions in specific neurons, resulting in cell death. Here, we tested the ability of a natural heat-shock protein 90 inhibitor, Gedunin, to degrade transfected mHTT in Neuro-2a cells and endogenous mHTT aggregates and intranuclear inclusions in both fibroblasts from HD patients and neurons derived from induced pluripotent stem cells from patients. Our data showed that Gedunin treatment degraded transfected mHTT in Neuro-2a cells, endogenous mHTT aggregates and intranuclear inclusions in fibroblasts from HD patients, and in neurons derived from induced pluripotent stem cells from patients in a dose- and time-dependent manner, and its activity depended on the proteasomal pathway rather than the autophagy route. These findings also showed that although Gedunin degraded abnormal mHTT aggregates and intranuclear inclusions in cells from HD patient, it did not affect normal cells, thus providing a new perspective for using Gedunin to treat HD.

The molecular mechanism of autophagy and its research progress in neurodegenerative diseases / 解放军医学杂志

Autophagy is a life process mediated by the intracellular lysosomes that can degrade intracellular misfolded proteins and aging damaged organelles, and is widely found in eukaryotic cells. Autophagy plays a crucial role in maintaining cell homeostasis and the recycling of material and energy. Some specific functions of autophagy have been identified in many tissues and organs resent years. Notably, the role of autophagy in neurodegenerative diseases has been paid more and more attention. Neurodegenerative diseases are a pathological process characterized by neuronal autophagy dysfunction and abnormal protein aggregation and folding. Studies have showed that autophagy can reduce amyloid accumulation in Alzheimer disease (AD), promote the clearance of Lewy bodies in Parkinson's disease (PD) and reduce the level of huntington protein in Huntington's disease (HD). In addition, natural drugs including resveratrol, trehalose and curcumin have been shown to play an active role in neurodegenerative diseases by regulation of autophagy. Therefore, understanding the molecular mechanisms of autophagy is critical for the treatment of neurodegenerative disease. This review focused on the molecular mechanism of autophagy and its research progress in neurodegenerative diseases, aiming to provide reference for the clinical treatment of neurodegenerative disease.