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Статті в журналах з теми "AADC Deficiency"
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Hwu, W. L., Y. H. Chien, N. C. Lee, and S. I. Muramatsu. "AADC Deficiency." Journal of the Neurological Sciences 381 (October 2017): 33–34. http://dx.doi.org/10.1016/j.jns.2017.08.142.
Повний текст джерела
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Marchese, Francesca, Elena Faedo, Maria Stella Vari, Patrizia Bergonzini, Michele Iacomino, Azzurra Guerra, Laura Franceschetti, et al. "Atypical Presentation of Aromatic L-Amino Acid Decarboxylase Deficiency with Developmental Epileptic Encephalopathy." Journal of Pediatric Epilepsy 10, no. 03 (February 9, 2021): 124–27. http://dx.doi.org/10.1055/s-0041-1723768.
Повний текст джерелаАнотація:
AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder resulting from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. The neurological features of AADC deficiency include early-onset hypotonia, oculogyric crises, ptosis, dystonia, hypokinesia, impaired development, and autonomic dysfunction. In this article, we reported a patient with genetically confirmed AADC deficiency presenting with developmental epileptic encephalopathy (DEE). Our patient was a boy with severe intractable epileptic spasms and DEE. The patient was evaluated for cognitive and neurologic impairment. Exome sequencing revealed a homozygous mutation (NM_000790.4:c.121C > A; p.Leu41Met) in the DDC gene. This case expands the clinical spectrum of AADC deficiency and strengthens the association between dopa decarboxylase deficiency and epilepsy. Additional studies are warranted to clarify the mechanisms linking dopa decarboxylase dysfunction to DEE.
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Montioli, Riccardo, and Carla Borri Voltattorni. "Aromatic Amino Acid Decarboxylase Deficiency: The Added Value of Biochemistry." International Journal of Molecular Sciences 22, no. 6 (March 19, 2021): 3146. http://dx.doi.org/10.3390/ijms22063146.
Повний текст джерелаАнотація:
Aromatic amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive neurometabolic disorder caused by mutations in the DDC gene, leading to a deficit of AADC, a pyridoxal 5′-phosphate requiring enzyme that catalyzes the decarboxylation of L-Dopa and L-5-hydroxytryptophan in dopamine and serotonin, respectively. Although clinical and genetic studies have given the major contribution to the diagnosis and therapy of AADC deficiency, biochemical investigations have also helped the comprehension of this disorder at a molecular level. Here, we reported the steps leading to the elucidation of the functional and structural features of the enzyme that were useful to identify the different molecular defects caused by the mutations, either in homozygosis or in heterozygosis, associated with AADC deficiency. By revisiting the biochemical data available on the characterization of the pathogenic variants in the purified recombinant form, and interpreting them on the basis of the structure-function relationship of AADC, it was possible: (i) to define the enzymatic phenotype of patients harboring pathogenic mutations and at the same time to propose specific therapeutic managements, and (ii) to identify residues and/or regions of the enzyme relevant for catalysis and/or folding of AADC.
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Kondakova, O. B., K. A. Kazakova, A. A. Lyalina, N. V. Lapshina, A. A. Pushkov, N. N. Mazanova, Yu I. Davydova, D. I. Grebenkin, I. V. Kanivets, and K. V. Savostyanov. "Family case of aromatic L-amino acid decarboxylase deficiency." Neuromuscular Diseases 12, no. 4 (December 13, 2022): 88–98. http://dx.doi.org/10.17650/2222-8721-2022-12-4-88-98.
Повний текст джерелаАнотація:
Aromatic L‑amino acid decarboxylase (AADC) deficiency is rare autosomal recessive neurometabolic disorder. It caused by generalized combined deficiency of serotonin, dopamine, norepinephrine and adrenaline. This disorder is characterized by muscular hypotonia, motor development delay, oculogyric crises and impairment of the autonomic nervous system.Laboratory diagnostic of AADC deficiency in Russian Federation includes determination of the concentration of 3‑O‑methyldophamine in dried blood spots by tandem mass spectrometry and molecular analysis of the DDC gene by Sanger sequencing or next generation sequencing.Therapy of AADC deficiency includes combination of drugs which increase the formation of dopamine, inhibit its reuptake and increase the residual activity of the enzyme. The first‑line drugs are selective dopamine agonists, monoamine oxidase inhibitors of type B and vitamin B6 supplements.We present the case of management and treatment of patients with AADC deficiency. The patient’s condition was improved by using of combination therapy with pyridoxal‑5‑phosphate, pramipexole and selegiline. Significant positive dynamics was achieved on pyridoxal‑5‑phosphate therapy for the first time.
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Micallef, J., S. Stockler-Ipsiroglu, C. D. van Karnebeek, R. Salvarinova-Zivkovic, and G. Horvath. "Recurrent Dystonic Crisis and Rhabdomyolysis Treated with Dantrolene in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency." Neuropediatrics 51, no. 03 (January 14, 2020): 229–32. http://dx.doi.org/10.1055/s-0039-3402010.
Повний текст джерелаАнотація:
AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal recessive inborn error of metabolism in which several neurotransmitters including serotonin, dopamine, norepinephrine and epinephrine are deficient. Symptoms typically appear in the first year of life and include oculogyric crises and dystonia, hypotonia, and global developmental delay. Dystonia is of particular concern as a dystonic storm can ensue leading to rhabdomyolysis. Rhabdomyolysis can become life-threating and therefore its recognition and prompt management is of significant importance. Here we present two cases of patients with AADC deficiency and a history of dystonic crisis causing rhabdomyolysis. We hypothesize that in addition to the hypodopaminergic, a hypercholinergic state is contributing to the pathophysiology of dystonia in AADC deficiency, as well as to the associated rhabdomyolysis. We were able to prevent rhabdomyolysis in both patients with using Dantrolene and we suggest using a trial of this medication in cases of sustained dystonic crisis in AADC deficiency patients.
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Rossignoli, Giada, Karolin Krämer, Eleonora Lugarà, Haya Alrashidi, Simon Pope, Carmen De La Fuente Barrigon, Katy Barwick, et al. "Aromatic l-amino acid decarboxylase deficiency: a patient-derived neuronal model for precision therapies." Brain 144, no. 8 (March 18, 2021): 2443–56. http://dx.doi.org/10.1093/brain/awab123.
Повний текст джерелаАнотація:
Abstract Aromatic l-amino acid decarboxylase (AADC) deficiency is a complex inherited neurological disorder of monoamine synthesis which results in dopamine and serotonin deficiency. The majority of affected individuals have variable, though often severe cognitive and motor delay, with a complex movement disorder and high risk of premature mortality. For most, standard pharmacological treatment provides only limited clinical benefit. Promising gene therapy approaches are emerging, though may not be either suitable or easily accessible for all patients. To characterize the underlying disease pathophysiology and guide precision therapies, we generated a patient-derived midbrain dopaminergic neuronal model of AADC deficiency from induced pluripotent stem cells. The neuronal model recapitulates key disease features, including absent AADC enzyme activity and dysregulated dopamine metabolism. We observed developmental defects affecting synaptic maturation and neuronal electrical properties, which were improved by lentiviral gene therapy. Bioinformatic and biochemical analyses on recombinant AADC predicted that the activity of one variant could be improved by l-3,4-dihydroxyphenylalanine (l-DOPA) administration; this hypothesis was corroborated in the patient-derived neuronal model, where l-DOPA treatment leads to amelioration of dopamine metabolites. Our study has shown that patient-derived disease modelling provides further insight into the neurodevelopmental sequelae of AADC deficiency, as well as a robust platform to investigate and develop personalized therapeutic approaches.
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Gantz, Emily, J. Daniel Sharer, and Tony M. McGrath. "Diagnosis of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency via Epilepsy Gene Panel Screening in a Patient with Atypical Presentation." Child Neurology Open 10 (January 2023): 2329048X2311610. http://dx.doi.org/10.1177/2329048x231161027.
Повний текст джерелаАнотація:
We describe an atypical presentation of a girl with aromatic L-amino acid decarboxylase (AADC) deficiency identified via a genetic testing program for children with epilepsy. At 21 months of age, she presented with poor head control, diffuse hypotonia, poor fixation, developmental delay, and dysphagia. She was lost to follow-up, then presented back at 3 years of age with staring spells and brief episodes of upward eye deviation. The diagnosis of unprovoked epilepsy allowed her to be included in a genetic testing program, which identified two heterozygous variants in the dopa decarboxylase (DCC) gene. Based on the genetic testing, plasma AADC enzyme activity and plasma 3-O-methyldopa results, a diagnosis of AADC deficiency was made when she was 4 years and 2 months of age. This case report shows that AADC deficiency can be the underlying diagnosis in patients with suspected epilepsy.
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Bisello, Giovanni, and Mariarita Bertoldi. "Compound Heterozygosis in AADC Deficiency and Its Complex Phenotype in Terms of AADC Protein Population." International Journal of Molecular Sciences 23, no. 19 (September 23, 2022): 11238. http://dx.doi.org/10.3390/ijms231911238.
Повний текст джерелаАнотація:
Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease due to mutations in the ddc gene producing AADC, a homodimeric pyridoxal 5′-phosphate-dependent enzyme. The disorder is often fatal in the first decade and is characterized by profound motor impairments and developmental delay. In the last two years, there has been a net rise in the number of patients and variants identified, maybe also pushed by the ongoing gene therapy trials. The majority of the identified genotypes are compound heterozygous (about 70%). Efforts are underway to reach early diagnosis, find possible new markers/new fast methods, and predict clinical outcome. However, no clear correlation of genotype-to-phenotype exists to date. Nevertheless, for homozygous patients, reliable results have been obtained using genetic methods combined with available computational tools on crystal structures corroborated by biochemical investigations on recombinant homodimeric AADC variants that have been obtained and characterized in solution. For these variants, the molecular basis for the defect has been suggested and validated, since it correlates quite well with mildness/severity of the homozygous phenotype. Instead, prediction for compound heterozygous patients is more difficult since complementation effects could happen. Here, by analyzing the existing literature on compound heterozygosity in AADC deficiency and other genetic disorders, we highlight that, in order to assess pathogenicity, the measurement of activity of the AADC heterodimeric variant should be integrated by bioinformatic, structural, and functional data on the whole protein constellation theoretically present in such patients. A wider discussion on symptomatic heterozygosity in AADC deficiency is also presented.
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Alfadhel, Majid, and Rana Kattan. "Aromatic Amino Acid Decarboxylase Deficiency Not Responding to Pyridoxine and Bromocriptine Therapy: Case Report and Review of Response to Treatment." Journal of Central Nervous System Disease 6 (January 2014): JCNSD.S12938. http://dx.doi.org/10.4137/jcnsd.s12938.
Повний текст джерелаАнотація:
Aromatic L-amino acid decarboxylase (AADC) deficiency (MIM #608643) is an autosomal recessive inborn error of monoamines. It is caused by a mutation in the DDC gene that leads to a deficiency in the AADC enzyme. The clinical features of this condition include a combination of dopamine, noradrenaline, and serotonin deficiencies, and a patient may present with hypotonia, oculogyric crises, sweating, hypersalivation, autonomic dysfunction, and progressive encephalopathy with severe developmental delay. We report the case of an 8-month-old boy who presented with the abovementioned symptoms and who was diagnosed with AADC deficiency based on clinical, biochemical, and molecular investigations. Treatment with bromocriptine and pyridoxine showed no improvement. These data support the findings observed among previously reported cohorts that showed poor response of this disease to current regimens. Alternative therapies are needed to ameliorate the clinical complications associated with this disorder.
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Wiznitzer, Max. "Gene therapy for children with AADC deficiency." Lancet Child & Adolescent Health 1, no. 4 (December 2017): 250–51. http://dx.doi.org/10.1016/s2352-4642(17)30124-4.
Повний текст джерелаДисертації з теми "AADC Deficiency"
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CAMPOS, Ana Clara Paixão. "Detecção de padrões espaciais na distribuição dos pacientes portadores de doença genética com deficiência física da Associação de Assistência à Criança Deficiente (AACD) de Pernambuco." Universidade Federal Rural de Pernambuco, 2013. http://www.tede2.ufrpe.br:8080/tede2/handle/tede2/4472.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Knowing the spatial pattern of patients with genetic disease with physical disabilities in the treatment of Pernambuco AACD is of great importance because it makes it possible to guide the basic care assistance to these individuals and provide solid basis for planning public health policies. However, there are few references in the literature using the tools of spatial analysis in the context of disability. This dissertation was structured in the form of two papers. In the first article the global Moran's I index was used to characterize the spatial pattern of the rate of patients with genetic disease with physical disabilities in the AACD treatment of Pernambuco and the results were compared with those obtained with the randomization test. In both approaches we found the existence of spatial pattern for the rate of patients with genetic disease with physical disabilities in the treatment of Pernambuco AACD when we took into account the rates of four municipalities closest to each location. In the second article we evaluated the performance of the global Moran's I index and the Mantel test with Spearman correlation, both using randomization to assess the statistical significance, regarding the ability to detect spatial pattern for the rate of patients with diseases genetic with physical disabilities in the AACD treatment of Pernambuco. The results showed that the global Moran's I index proved to be a more satisfactory method for detecting the spatial pattern, since it uses the information in its calculations of the neighborhood, and provide greater control of the rejection rates of the null hypothesis under study.
Conhecer o padrão espacial dos portadores de doença genética com deficiência física em tratamento na AACD de Pernambuco é de grande importância, pois torna possível orientar a assistência aos cuidados básicos desses indivíduos e fornecer base sólida para o planejamento de políticas públicas de saúde. Entretanto, existem poucas referências na literatura utilizando o instrumental da análise espacial no contexto da deficiência física. A presente dissertação foi estruturada na forma de dois artigos científicos. No primeiro artigo o Índice I global de Moran foi utilizado para caracterizar o padrão espacial da taxa de pacientes portadores de doença genética com deficiência física em tratamento na AACD de Pernambuco e os resultados encontrados foram comparados com os obtidos através do teste de aleatorização. Em ambas as metodologias constatou-se a existência de padrão espacial agregado para a taxa de pacientes portadores de doença genética com deficiência física em tratamento na AACD de Pernambuco quando se levou em consideração as taxas dos 4 municípios mais próximos de cada localidade. No segundo artigo foi avaliado o desempenho do índice I global de Moran e do teste de Mantel com correlação de Spearman, ambos utilizando aleatorização para avaliar a significância da estatística, no que tange a capacidade de detectar padrão espacial para a taxa de pacientes portadores de doenças genéticas com deficiência física em tratamento na AACD de Pernambuco. Os resultados indicaram que o índice I global de Moran mostrou-se uma metodologia mais satisfatória para detectar do padrão espacial, uma vez que utiliza em seus cálculos as informações da vizinhança, além de proporcionar maior controle das taxas de rejeição da hipótese nula em estudo.
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Schlunzen, Elisa Tomoe Moriya. "Mudanças nas práticas pedagógicas do professor: criando um ambiente construcionista contextualizado e significativo para crianças com necessidades especiais físicas." Pontifícia Universidade Católica de São Paulo, 2000. https://tede2.pucsp.br/handle/handle/9840.
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Previous issue date: 2000-03-30Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
This research presents the creation of a Significative and Contextualized Constructionist Environment based on the use of the new technologies to improve the teaching-learning process of physically handicapped children. This research includes the elaboration and consolidation of a methodological approach to be used with these children. This methodology was elaborated jointly with three teachers and with the computer science and pedagogic coordinators of the Associação de Assistência à Criança Deficiente - A.A.C.D.. In accordance with this methodology, the teacher uses the computer to value the student's productions in order to support knowledge construction, mediate the formalization of the curriculum concepts, create opportunities for student expression and to evaluate the students based upon their knowledge construction, their self perception and upon the statements of involved individuals. However, it was necessary to review the teacher's pedagogic practices and, consequently, his/her orientation. Consequently, the continuous in-service training sought to encourage the teacher's autonomy, to become self reflective, and to investigate his/her own actions. The new pedagogic practice was based upon the development of projects, allowing the students to solve important issues, generating their need and desire for learning. In this way, learning emerged from the student's interest and context by which the concepts were brought to life, formalized and learned in a global way, creating challenging learning situations, assisting the individual special needs. The results showed that the new learning environment supported a more pleasurable form of teaching, making learning more significant, contemplating the curriculum in a new way, supporting evaluation of the child's development, integrating and contextualizing concepts, valuing the potential and abilities of the special student. Finally, the children were able to discover themselves and to effect their environment, demonstrating cognitive, social, ethical, affective and emotional improvement, in an effort to define him/herself as a being in his totality
Esta pesquisa tem como objetivo a criação de um ambiente Construcionista Contextualizado e Significativo baseado no uso das novas tecnologias para melhorar o processo ensino-aprendizagem de crianças portadoras de necessidades especiais físicas. Como parte do trabalho, foi construída e consolidada uma abordagem metodológica para ser usada com estas crianças. Esta metodologia de trabalho foi elaborada conjuntamente com três professoras e com o auxílio da coordenadora de informática e pedagógica da Associação de Assistência à Criança Deficiente - A.A.C.D. De acordo com esta metodologia, o professor usa o computador para potencializar as produções do aluno, favorecendo a construção do conhecimento, mediando a formalização dos conceitos curriculares, oportunizando formas de expressão dos alunos, avaliando-os por meio da construção de seu conhecimento, de sua própria percepção e de depoimentos das pessoas envolvidas. No entanto, foi necessário rever as práticas pedagógicas do professor e, consequentemente, a sua postura. Dessa forma, foi realizada uma formação contínua e em serviço dos professores envolvidos, buscando a sua autonomia, incentivando-os a tornarem-se reflexivos e investigadores de sua própria prática. A estratégia usada para a nova prática pedagógica foi o desenvolvimento de projetos, permitindo aos alunos resolverem questões relevantes, gerando a necessidade e o desejo no aluno de aprender. Assim, a aprendizagem emergiu do interesse e do contexto do aluno, possibilitando que os conceitos fossem vividos, formalizados e aprendidos de maneira globalizada, criando situações desafiadoras, atendendo às diferentes necessidades especiais. Os resultados alcançados mostraram que o novo ambiente de aprendizagem permitiu uma maneira mais prazerosa de ensinar, de dar significado à aprendizagem, de contemplar o currículo, de avaliar o desenvolvimento da criança, de integrar e contextualizar os conceitos, valorizando o potencial e habilidades dos alunos especiais. Finalmente, eles puderam descobrir-se e atuar mais neste ambiente, havendo assim, uma melhora nos aspectos cognitivos, sociais, éticos, afetivos e emocionais, procurando encontrar-se como um ser em sua totalidade
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Chen, Yi-Jye, and 陳怡潔. "The cellular mechanism of gene therapy in AADC deficiency." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/23619330885553968692.
Повний текст джерелаАнотація:
碩士國立臺灣大學
分子醫學研究所
102
Aromatic L-amino acid decarboxylase (AADC) is responsible for the syntheses of dopamine and serotonin. AADC deficiency is an autosomal recessive disease. The metabolic abnormalities at birth, caused by mutations in the AADC gene, lead to severely reduced AADC activity. Hypotonia and oculogyric crises are the two most common symptoms of AADC deficiency. In addition, other common symptoms include developmental delay, hypokinesia, choreoathetosis, dystonia, limb hypertonia, insomnia, irritability, feeding and speech difficulties. AADC deficiency has an increased prevalence in the Taiwanese population due to the founder mutation IVS6+4A>T. Currently, treatment options are limited; only patients with relatively mild forms of the disease respond to drugs, and patients obtain relief from only a limited subset of symptoms. Drug therapy provides little or no benefit for many patients who often die during childhood. The gene therapy trial using the human AADC gene is currently undergo in Taiwan. The gene therapy is achieved by using an adeno-associated virus (AAV) type 2 vector to deliver the AADC gene into a brain area called the putamen in the patients with AADC deficiency. All patients showed improved motor function after treatment. However intracellular storage of dopamine requires expression of monoamine vesicular transporter, how could this gene therapy enhance the activity of the post-synaptic neuron in the putamen of striatum and persisted for long time is unclear. So we cultured neuroblastoma (N2a cells), primary medium spiny neurons and dopaminergic neurons in vitro, to investigate whether AADC produced by AADC-transfected cell could be secreted into medium (extracellular). 24hr post-transfection, culture medium and cell lysate was harvested for AADC activity analysis. HPLC analysis was used to detect ADDC activity by converting L-dopa to dopamine. The results reveal that AADC can be detected both extracellular and intracellular in AADC-transfected N2a cell, and the AADC activity were 0.264±0.05 nmol/min/ml and 3.12±0.53 nmol/min/mg (n=8) respectively. AADC activity released into medium was expressed by the ratio of AADC activity obtaining from culture medium divides by the combined AADC activity from cell lysate and culture medium. Our result showed that AADC can be secreted into medium (ratio=25 ±5%, n=8) while the cytotoxicity index (LDH release) is 12±2% (n=8). To investigate the underlining mechanism of AADC secretion, we treated N2a cell with Brefeldin A for inhibition of protein secretion and synthesis or transfected dominat negative Rab11 for blocking the traffick of proteins or vesicles between the trans-Golgi network (TGN) and recycling endosome. Neither treated BFA nor transfected dominat negative Rab11 can reduce AADC secretion. In conclusion, we transfected AADC gene into N2a cells and proved AADC can be secreted into extracellular space, although the cellular mechanism of secretion was still unclear. This study also established the primary culture experiment and provided valuable insight into cellular mechanism of gene therapy in AADC deficiency.
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bisello. "HUMAN AROMATIC L-AMINO ACID DECARBOXYLASE: WHEN STRUCTURE AND MOBILITY DRIVE EFFICIENT CATALYSIS. IMPLICATIONS FOR AADC DEFICIENCY." Doctoral thesis, 2021. http://hdl.handle.net/11562/1045846.
Повний текст джерелаАнотація:
L’enzima Decarbossilasi degli L-amino acidi aromatici (AADC) è responsabile della sintesi di due neurotrasmettitori essenziali: la dopamina e la serotonina. AADC deve la sua attività catalitica alla chimica del suo cofattore, il piridossale 5’-fosfato (PLP). La struttura cristallografica dell’enzima da mammifero (precisamente da maiale che ha il 90% di identità con l’enzima umano) nella sua forma olo venne risolta venti anni fa e tale risoluzione aprì la strada ad importanti studi strutturali. Dieci anni dopo venne pubblicata la struttura umana di AADC nella sua forma apo evidenziando quali cambiamenti conformazionali avvengono quando il PLP viene legato dall’enzima. Le strutture apo e olo AADC hanno avuto notevole importanza per la comprensione della patogenicità di varianti enzimatiche associate alla malattia chiamata ‘Deficit da AADC’ (AADCd, OMIM#608643). Questa malattia autosomica recessiva molto rara è dovuta prevalentemente a mutazioni missenso sul gene AADC. I pazienti affetti da AADCd mostrano un’amAromatic L-Amino Acid Decarboxylase (AADC) is the enzyme responsible for the synthesis of two essential neurotransmitter dopamine and serotonin from L-Dopa and L-hydroxytryptophan. AADC owes its specific catalytic activity to the chemistry of its cofactor, pyrydoxal-5’-phosphate (PLP). Almost 20 years ago, the crystal structure of a mammalian holoAADC (porcine, sharing 90% of sequence identity) was solved and the availability of its 3D structure paved the way to structural studies. Moreover, 10 years later, human apoAADC structure was published, shedding light on the conformational rearrangement occurring on the apo enzyme upon addition of PLP. Importantly, apo and holoAADC structures provided crucial insights for the comprehension of the pathogenicity of a number of AADC deficiency associated variants. AADC deficiency (OMIM#608643) is a rare autosomal recessive inborn disease due to missense mutations in the AADC gene. Patients bearing these mutations show mild to severe phenotypes, whose destiny is often fatal. Due to the rarity of the disease and to the heterogeneous response to the treatments, medications are not often satisfactory. In the past years, some efforts on human recombinant AADC pathogenic variants have tried to provide support to the research on AADC deficiency by means of biochemical and biophysical approaches determining the impact of the amino acid substitutions on the enzyme features. Here, a further contribution to the comprehension of the AADC deficiency is provided. The crystal structure of human holoAADC has been solved under different conditions, both in its native and ligand bound form. The combination of crystallographic studies, molecular dynamics simulations (MD) and site directed mutagenesis uncovered novel aspects of the AADC structure-function relationship. Moreover, the characterization of 21 novel identified pathogenic variants (spread on each AADC domain, N-terminal, Large and C-terminal Domains) led to the widening of the range of enzymatic phenotypes associated to AADC deficiency. The proposed combination of biochemical and kinetic studies permitted to determine correlations between structural and functional signals. Enzymatic phenotypes span from variants characterized by a mild phenotypes to variants (mainly located at the NTD-CTD interface) whose dramatic structural defects lead to a catalytic incompetence. In addition, MD simulations and in solutions data point out a critical role for the loop3 element that contains the essential catalytic residue Tyr332. A group of variants affecting loop3 has been identified as catalytically incompetent and their structural features have been dissected thanks also to the solving of the crystal structure of pathogenic variant L353P, which constitutes the first solved structure of an AADC variant. Altogether, this study on human AADC provides new elements for the comprehension of the structure-function relationship of AADC with a particular focus on protein dynamics and mobility. Lastly, structural details might represent the basis for both the designing of novel specific inhibitors and for a better comprehension of the molecular aspects of the variants associated with the AADC deficiency.
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Rossignoli, Giada. "Aromatic amino acids decarboxylase and histidine decarboxylase: deep functional investigations give insights into pathophysiological mechanisms with possible therapeutic implications." Doctoral thesis, 2019. http://hdl.handle.net/11562/995224.
Повний текст джерелаАнотація:
Aromatic amino acids decarboxylase and histidine decarboxylase (AADC and HDC) are two homologous enzymes responsible for the synthesis of dopamine/serotonin and histamine, respectively, and other minor signalling aromatic amines. All these molecules are main protagonists or regulators of several physiological pathways, which are fundamental both in central nervous system and in peripheral tissues. Alterations of their homeostasis, indeed, as well as of AADC and HDC functioning or expression, cause and/or participate in the development and progression of several often severe and disabling pathological conditions, such as AADC Deficiency and cholangiocarcinoma. Consequently, AADC and HDC characterization might be useful in the pathophysiological understanding of several diseases and in improving/developing new therapeutic strategies. However, the knowledge of the biochemical features of these two crucial enzymes is still rather limited. Thus, the aim of this thesis is to biochemically characterise human HDC, mostly unknown, and to individuate some possible regulative mechanisms for both HDC and AADC. In addition, a neuronal AADC Deficiency cell model, derived from patient induced pluripotent stem cells (iPSCs), was used to evaluate endogenous AADC features, as well as to research further alterations in dopaminergic pathway. Investigations on human recombinant HDC allowed to discover that, surprisingly, its conformation and catalytic efficiency are influenced by redox state: increasing oxidizing conditions, indeed, favour a more stable and active form of the dimeric enzyme, due to the presence of an intermolecular reversible disulphide bridge involving residue Cys180 of both subunits. Then, in solution analyses of a possible phosphorylation of AADC identified Ser193 as protein kinase A target site, and allowed the detection of an effect on enzyme kinetic parameters, in particular an increased affinity for its substrates. Finally, endogenous AADC levels analyses in dopaminergic neurons derived from AADC Deficiency patients suggested a possible positive feedback mechanism that could tend to increase AADC expression, and the same cell model showed alterations in other cell types besides neurons, in particular glia cells, suggesting that variations in neurons-glia cells Abstract 5 interplay could participate in the pathophysiology mechanisms of AADC Deficiency. Altogether, data and information obtained from the performed experiments have increased AADC and HDC knowledge, as well as paved the way for new hypothesis regarding possible efforts in the development of new disease treatments.
Книги з теми "AADC Deficiency"
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Pimentel, Leonardo Halley Carvalho, and Izabel Herika Gomes Matias Cronemberger, eds. Reabilitação: Teoria e Prática. Lestu Publishing Company, 2022. http://dx.doi.org/10.51205/lestu.978-65-996314-4-3.
Повний текст джерелаАнотація:
Reabilitação: Teoria e Prática reúne estudos sobre a medicina em reabilitação e o trabalho multiprofissional necessário para o atendimento a pessoas com deficiência física, intelectual e auditiva. Trata-se de uma obra robusta. Com 52 capítulos que discutem, não apenas os cuidados necessários às pessoas com deficiência e o devido envolvimento das famílias no processo, esse repositório fundamental, apresenta teorias, práticas e experiências das diferentes áreas profissionais que devem atuar conjuntamente. No trabalho de reabilitação, médicos de diversas especialidades, fisioterapeutas, psicológicos, fonoaudiólogos, assistentes sociais, nutricionistas, e demais áreas profissionais, atuam, combinando teorias e técnicas num processo contínuo e coordenado. Reabilitação: Teoria e Prática torna-se útil não apenas a estudantes e profissionais, mas também para gestores sobre uma referência importante para a atuação do Centro Integrado de Reabilitação (CEIR), criado em 2008 e gerenciado pela Associação Reabilitar, hoje, uma referência de excelência no atendimento de pessoas com deficiência no Brasil. A obra foi construída inicialmente para desvendar de forma científica o trabalho realizado pelos profissionais do CEIR, que acumulam experiências, desafios e oportunidades desenvolvidas no processo de reabilitação a partir de diferentes realidades, inovando dentro da perspectiva de reabilitação no Estado do Piauí, uma vez que esse foi o primeiro Centro com essa envergadura de trabalho realizada no Estado. A obra é dividida em 5 partes, cada uma com capítulos organizados de forma consistente para facilitar a localização das informações. Ricamente ilustrado, cada capítulo possui um corpo teórico, com diretrizes claras, exemplos e práticas que incluem temas como ortopedia e neurologia, garantindo uma compreensão abrangente da reabilitação apoiada pelas pesquisas clínicas mais recentes. A maioria dos protocolos da Instituição foi construída a partir da experiência e apoio inestimável da AACD (Associação de Assistência à Criança Deficiente) e ao longo do tempo foram sendo aperfeiçoados à luz da realidade e de necessidades específicas desse fazer profissional. Assim os profissionais foram motivados a produzir sob diversos olhares, através de relatos de experiências, estudos clínicos, situações consideradas inovadoras e outras, respeitando os preceitos éticos e o acúmulo de experiência profissional, na criação, manutenção e atualização constante de um Centro de Reabilitação. Toda a obra foi pautada em respeitabilidade à Lei Geral de Proteção de Dados (LGPD). O respeito à dignidade da pessoa com deficiência é o maior valor da obra, que envolve o princípio do “nada sobre nós sem nós”, mas, sobretudo, quando os autores se revestem do conhecimento científico para aperfeiçoar e disseminar novas práticas e intervenções profissionais.
Частини книг з теми "AADC Deficiency"
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Helman, Guy, Maria Belen Pappa, and Phillip L. Pearl. "Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis." In JIMD Reports, 23–27. Berlin, Heidelberg: Springer Berlin Heidelberg, 2014. http://dx.doi.org/10.1007/8904_2014_327.
Повний текст джерела
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Helman, Guy, Maria Belen Pappa, and Phillip L. Pearl. "Erratum to: Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis." In JIMD Reports, 97. Berlin, Heidelberg: Springer Berlin Heidelberg, 2014. http://dx.doi.org/10.1007/978-3-662-44578-5_344.
Повний текст джерела
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Spitz, M. A., M. A. Nguyen, S. Roche, B. Heron, M. Milh, P. de Lonlay, L. Lion-François, et al. "Chronic Diarrhea in l-Amino Acid Decarboxylase (AADC) Deficiency: A Prominent Clinical Finding Among a Series of Ten French Patients." In JIMD Reports, 85–93. Berlin, Heidelberg: Springer Berlin Heidelberg, 2016. http://dx.doi.org/10.1007/8904_2016_550.
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Hwu, Wuh-Liang, Ni-Chung Lee, Yin-Hsiu Chien, Shin-ichi Muramatsu, and Hiroshi Ichinose. "AADC Deficiency." In A New Era of Catecholamines in the Laboratory and Clinic, 273–84. Elsevier, 2013. http://dx.doi.org/10.1016/b978-0-12-411512-5.00013-0.
Повний текст джерела
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Hwu, Wuh-Liang, Ni-Chung Lee, Yih-Dar Shieh, Kai-Yuan Tzen, Pin-Wen Chen, Shin-ichi Muramatsu, Hiroshi Ichinose, and Yin-Hsiu Chien. "AADC Deficiency." In Catecholamine Research in the 21st Century, 3–4. Elsevier, 2014. http://dx.doi.org/10.1016/b978-0-12-800044-1.00002-7.
Повний текст джерелаТези доповідей конференцій з теми "AADC Deficiency"
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Liang Hwu, Paul Wuh, Yin Hsiu Chien, Ni Chung Lee, Sheng Hong Tseng, Chun Hwei Ta, Anne Marie Conway, Luciana Giugliani, Pedro Pachelli, Andressa Federhen, and Mark Pykett. "Safety and Improved Efficacy Outcomes in Children With AADC Deficiency Treated With Eladocagene Exuparvovec Gene Therapy: Results From Three Clinical Trials." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.049.
Повний текст джерелаАнотація:
Introduction: aromatic L-amino acid decarboxylase (AADC) deficiency, a rare genetic disorder of neurotransmitter synthesis, is characterized by motor developmental deficits and clinical features associated with the autonomic nervous system, including dyskinesia, and oculogyric crisis. Objective: To evaluate clinical outcomes in children with AADC deficiency treated with eladocagene exuparvovec, a recombinant adeno-associated virus vector containing the human cDNA encoding the AADC enzyme. Methods: In 3 open-label clinical studies, children with AADC deficiency who had no full head control and no ability to sit, stand, or walk received eladocagene exuparvovec as bilateral, intraputaminal, stereotactic infusions during a single operative session (total dose, 1.8 x 1011vg). Body weight, oculogyric crisis episodes, and adverse events (AE) were recorded. Results: In the 3 studies, patients aged 21 months to 8.5 years (N=26) received eladocagene exuparvovec, constituting the safety population. In the intent-to- treat population (N=21), mean body weight at baseline was 12.0 kg (median 10.5 kg) and increased to 15.2 kg (median 13.2 kg) at 12 months posttreatment. Frequency of oculogyric crises was improved at 12 months posttreatment. Dyskinesia was recorded as an AE in 23 patients in the safety population; most events were mild or moderate, occurred within 3 months after eladocagene exuparvovec treatment, generally responded to standard pharmacotherapy, and resolved in all patients by 10 months. Conclusions: In children with AADC deficiency who received eladocagene exuparvovec gene therapy, body weight increased and oculogyric crises and dyskinesia improved.
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Werner, Christian, Yin-Hsiu Chien, Ni-Chung Lee, Sheng-Hong Tseng, Chun-Hwei Tai, Wuh-Liang Hwu, Anne Marie Conway, and Mark Pykett. "AGIL-AADC Gene Therapy Results in Sustained Improvements in Motor and Developmental Milestones over 5 Years in Children with AADC Deficiency." In Abstracts of the 45th Annual Meeting of the Society for Neuropediatrics. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1698240.
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Kim, In-Ha, Yin-Hsiu Chien, Paul Wuh-Liang Hwu, Ni-Chung Lee, Sheng-Hong Tseng, and Chun-Hwei Tai. "Improved Motor Function in Children with AADC Deficiency Treated with Eladocagene Exuparvovec (PTC-AADC): Interim Findings from a Phase 2 Trial." In Abstracts of the 46th Annual Meeting of the Society for Neuropediatrics. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1739633.
Повний текст джерела
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Hwu, Paul Wuh-Liang, Yin-Hsiu Chien, Ni-Chung Lee, Sheng-Hong Tseng, Antonia Wang, Jim Wang, Traci Schilling, Sunay Ozdas, and Chun-Hwei Tai. "390 Efficacy of gene therapy with eladocagene exuparvovec in patients with AADC deficiency compared with natural history controls." In 10th Europaediatrics Congress, Zagreb, Croatia, 7–9 October 2021. BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health, 2021. http://dx.doi.org/10.1136/archdischild-2021-europaediatrics.390.
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