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Master's Dissertation
DOI
https://doi.org/10.11606/D.41.2021.tde-20052021-102922
Document
Author
Full name
Gabriela Koch Alvarenga
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2021
Supervisor
Committee
Passos Bueno, Maria Rita (President)
Giannetti, Juliana Gurgel
Perez, Ana Beatriz Alvarez
Title in Portuguese
Estudos de correlação genótipo-fenótipo em pacientes com a síndrome de Hipotonia Infantil com Retardo Psicomotor e Fácies Características 3 (IHPRF3)
Keywords in Portuguese
1. IHPFR3
2. TBCK
3. Correlação Genótipo-Fenótipo
Abstract in Portuguese
Mutações de perda de função em homozigose ou em heterozigose composta distribuídas em diferentes regiões do gene TBCK (TBC1 Domain Containing Kinase) resultam em uma desordem do neurodesenvolvimento de herança autossômica recessiva denominada como Hipotonia Infantil com Retardo Psicomotor e Fácies Características 3 (IHPRF3; OMIM 616900). Esta síndrome apresenta início dos sintomas ao nascimento ou no início da infância; a deficiência no desenvolvimento global, deficiência intelectual, hipotonia e algumas características dismórficas são os sintomas mais prevalentes. Apesar disso, os pacientes com IHPRF3 apresentam fenótipo bastante variável, não apresentando um Gestalt consistente e característico da desordem. Atualmente, se desconhece a correlação entre o genótipo e fenótipo na IHPRF3, cujo conhecimento pode contribuir para a elucidação dos mecanismos moleculares associados à doença bem como para melhor compreender o prognóstico da síndrome. Portanto, o presente estudo revisou a literatura referente a 37 casos de IHPRF3 reportados previamente, somados a 2 casos de pacientes brasileiras avaliados pelo Centro de Pesquisas sobre o Genoma Humano e Células Tronco (CEGH-CEL). O conjunto fenotípico de 42 características presentes na casuística foi correlacionado com as diferentes alterações genotípicas localizados em duas regiões distintas de TBCK (domínio Quinase e Não Quinase). Observou-se a existência de uma correlação entre pacientes com mutações localizadas no domínio Quinase do gene TBCK e as características hipotonia grave (p=0,012) e macroglossia (p=0,000). Além disto, observamos que algumas comorbidades estão sendo avaliadas na síndrome (ex: hipertrigliceridemia, osteoporose, hipotireoidismo, bexiga neurogênica, autismo, puberdade precoce e insuficiência adrenal) de maneira heterogênea, e dados relativos destas alterações clínicas ou laboratoriais só são referidos em alguns estudos. Assim sendo, é de grande valia o estabelecimento de um questionário padronizado para a avaliação da síndrome IHPRF3, de forma a proporcionar melhor caracterização clínica da doença e sua progressão. Estes conhecimentos são importantes para beneficiar os pacientes e suas famílias quanto ao melhor delineamento do prognóstico desta síndrome
Title in English
Genotype-phenotype studies in patients with Hypotonia Infantile with Psychomotor Retardacion and Characteristic Facies 3 (IHPRF3) syndrome
Keywords in English
1. IHPFR3
2. TBCK
3. Genotype-Phenotype Correlation
Abstract in English
Homozygous or compound heterozygous loss of function mutations, spread across different regions of the TBCK gene (TBC1 domain Containing Kinase) result in an inherited autosomal recessive neurodevelopmental disorder, known as Hypotonia Infantile with Psychomotor Retardation and Characteristic Facies 3 (IHPRF3; OMIM 616900). This syndrome has an onset of symptoms at birth or in early infancy; global developmental delay, intellectual disability, hypotonia and dysmorphic features are prevalent phenotypic features of the syndrome. Despite this, a clearly identifiable gestalt associated with this syndrome has not yet been identified, as multiple IHPRF3 patients showed a diverse phenotypic spectrum. To this day, the IHPRF3 genotype-phenotype correlation remains unknown, and its knowledge could contribute to elucidate molecular mechanisms associated with the syndrome, as well as to better comprehend the syndrome prognosis. Therefore, the present study reviewed the literature referred to 37 previously reported cases of IHPRF3, in addition to 2 cases of Brazilian patients assessed by Centro de Pesquisas sobre o Genoma Humano e Células Tronco (CEGH-CEL). The phenotypic set of 42 comorbidities present in the sample of this study was correlated with distinct mutations located across two main regions of the TBCK gene (Kinase and Non-Kinase domain). Throughout the statistical analysis of the genotype and phenotype data, severe hypotonia (p=0,012) and macroglossia (p=0,000) were more prevalent in IHPRF3 patients with mutations located within the Kinase domain. Furthermore, the phenotypical analysis led to the conclusion that some comorbidities are not being assessed a heterogeneous way in this syndrome (e.g.: hypertriglyceridemia, osteoporosis, hypothyroidism, neurogenic bladder, autism, precocious puberty and adrenal insufficiency) and the data of these clinical or laboratory alterations is only referred to in some studies. Hence, it would be of great value to establish a standard questionnaire for the evaluation of IHPRF3 syndrome, in order to provide a better clinical characterization of the disease and its progression. This information is key to help patients and their families have a more detailed prognosis of this syndrome
 
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Publishing Date
2021-05-23
 
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