Investigação clínica e genética em pacientes com ataxia congênita
Data
2023-09-29
Autores
Raslan, Ivana Rocha 
Orientadores
Pedroso, José Luiz
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: Ataxia congênita é um grupo heterogêneo de desordens que pertence ao
grupo das ataxias hereditárias. O fenótipo clássico das ataxias congênitas caracteriza se por hipotonia e atraso no desenvolvimento motor nos primeiros meses de vida,
seguido de ataxia cerebelar de início na infância precoce. O curso da doença é não
progressivo na maioria dos pacientes, e muitos destes são erroneamente
diagnosticados com paralisia cerebral atáxica. Apesar do amplo desenvolvimento das
técnicas de sequenciamento de nova geração, muitos pacientes com ataxia congênita
permanecem sem um diagnóstico genético específico. Estabelecer uma origem
genética é importante diante da possibilidade de identificar e acompanhar possíveis
comorbidades, bem como de permitir melhores orientações quanto ao prognóstico e
risco de recorrência familiar. Atualmente, o diagnóstico genético tornase relevante
diante do desenvolvimento de técnicas de terapia genética para condições
neurológicas específicas. Objetivo: Analisar um grupo de pacientes brasileiros com
diagnóstico de ataxia congênita e caracterizar o fenótipo, o padrão radiológico e o
genótipo presentes. Metodologia: Foram selecionados 30 pacientes com diagnóstico
de ataxia congênita acompanhados no ambulatório de Ataxia da Universidade Federal
de São Paulo (Unifesp). Todos os pacientes foram avaliados quanto aos fatores
clínicos e padrão de neuroimagem cerebral. Para investigação genética foi realizado
o exame Exoma completo em todos os participantes. Resultados: O fenótipo de
ataxia cerebelar pura foi encontrado em 56,7% dos pacientes. Hipoplasia cerebelar à
neuroimagem estava presente em 55,2% da amostra e alterações encefálicas
supratentoriais foram infrequentes. Um padrão genético heterogêneo foi encontrado,
permitindo a identificação de variantes patogênicas/provavelmente patogênicas em
46,7% dos pacientes, envolvendo 11 diferentes genes (ALDH5A1, CACNA1A,
EXOSC3, MME, ITPR1, KIF1A, STXBP1, SNX14, SPTBN2, TMEM240, TUBB4A),
com um adicional de 33,3% variantes classificadas como de significado incerto,
envolvendo oito diferentes genes (BRF1, CACNA1G, CC2D2A, CWF19L1, PEX10,
SCN2A, STXBP1 e TGH1L). Como padrão genético predominante, foram encontradas
mutações em heterozigose, herança autossômica dominante, associada a casos
esporádicos de ataxia congênita. Mutações novas foram descritas nos genes MME,
TUBB4A e TMEM240. As mutações nos genes MME, TUBB4A e ITPR1 foram
associadas a fenótipos distintos dos descritos na literatura até o momento (expansão
fenotípica). Conclusão: Nosso estudo reafirma a heterogeneidade clínica e genética
dos quadros de ataxia congênita, confirmandose a dificuldade em estabelecer uma
relação fenótipo e genótipo. O Exoma completo é apontado como ferramenta
diagnóstica eficaz na investigação etiológica de pacientes com ataxia congênita,
permitindo identificação de variantes genéticas em 80% dos pacientes e o
estabelecimento de um diagnóstico genético específico em 46,7% dos pacientes. O
estudo aponta a importância das mutações monoalélicas na etiologia genética das
ataxias congênitas.
Background: Congenital ataxia is a rare and heterogeneous group of disorders that belongs to the extensive group of hereditary ataxias. The classical phenotype is characterized by hypotonia and developmental motor delay in the first months of life, followed by cerebellar ataxia in early childhood. The course of the disease is mainly nonprogressive and a lot of patients have been mistakenly diagnosed with ataxia cerebral palsy. Despite the wide development of next generation sequence in the last two decades, a lot of patients with congenital ataxia remain without a specific genetic diagnosis. Establishing an exact genetic origin is important, as it is the best way to identify and monitor possible comorbidities, makes prognostic guidance possible, and allows to advise about the risk of recurrence in the family. Currently, genetic diagnosis became more important in view of the development of gene therapy techniques for specific neurological diseases. Objectives: Analyze a cohort of Brazilian patients with congenital ataxia and characterize the phenotype, radiological features and genetically involved pattern. Methods: We recruited 30 patients diagnosed with congenital ataxia that were being treated in the Ataxia Unit in Federal University of São Paulo (Unifesp). All patients were evaluated for clinical factors and brain neuroimaging pattern. Wholeexome sequencing (WES) analysis was done in all patients. Results: The phenotype of pure cerebellar ataxia was found in 56,7% of the patients. Cerebellar hypoplasia in neuroimaging was present in 55,7% of the sample and supratentorial encephalic alterations were infrequent. A heterogeneous genetic pattern was found, making it possible to identify pathogenic/probably pathogenic variants in 46,7% of the patients, involving eleven different genes (ALDH5A1, CACNA1A, EXOSC3, MME, ITPR1, KIF1A, STXBP1, SNX14, SPTBN2, TMEM240, TUBB4A), with an additional 33,3% variants classified as having an uncertain meaning, involving eight different genes (BRF1, CACNA1G, CC2D2A, CWF19L1, PEX10, SCN2A, STXBP1, and TGH1L). As predominant genetic pattern, mutations were found in heterozygosity, dominant autosomal heritage, associated to sporadic cases of congenital ataxia. Novel pathogenic mutations were described in genes MME, TUBB4A and TMEM240. The mutations in genes MME, TUBB4A and TMEM240 were associated to distinct phenotypes than those described in literature so far (phenotypical expantion). Conclusion: Our study reinforces the clinical and genetical heterogenous features involved in congenital ataxias, confirming the difficulty in establishing a relation between phenotype and genotype. The WES is pointed as a diagnosis tool effective in the investigation of genetic variants in 80% of the patients and the establishment of a genetic diagnosis in 46,7% of the patients. The study points out the importance of monoallelic mutations in the congenital ataxia genetic etiology.
Background: Congenital ataxia is a rare and heterogeneous group of disorders that belongs to the extensive group of hereditary ataxias. The classical phenotype is characterized by hypotonia and developmental motor delay in the first months of life, followed by cerebellar ataxia in early childhood. The course of the disease is mainly nonprogressive and a lot of patients have been mistakenly diagnosed with ataxia cerebral palsy. Despite the wide development of next generation sequence in the last two decades, a lot of patients with congenital ataxia remain without a specific genetic diagnosis. Establishing an exact genetic origin is important, as it is the best way to identify and monitor possible comorbidities, makes prognostic guidance possible, and allows to advise about the risk of recurrence in the family. Currently, genetic diagnosis became more important in view of the development of gene therapy techniques for specific neurological diseases. Objectives: Analyze a cohort of Brazilian patients with congenital ataxia and characterize the phenotype, radiological features and genetically involved pattern. Methods: We recruited 30 patients diagnosed with congenital ataxia that were being treated in the Ataxia Unit in Federal University of São Paulo (Unifesp). All patients were evaluated for clinical factors and brain neuroimaging pattern. Wholeexome sequencing (WES) analysis was done in all patients. Results: The phenotype of pure cerebellar ataxia was found in 56,7% of the patients. Cerebellar hypoplasia in neuroimaging was present in 55,7% of the sample and supratentorial encephalic alterations were infrequent. A heterogeneous genetic pattern was found, making it possible to identify pathogenic/probably pathogenic variants in 46,7% of the patients, involving eleven different genes (ALDH5A1, CACNA1A, EXOSC3, MME, ITPR1, KIF1A, STXBP1, SNX14, SPTBN2, TMEM240, TUBB4A), with an additional 33,3% variants classified as having an uncertain meaning, involving eight different genes (BRF1, CACNA1G, CC2D2A, CWF19L1, PEX10, SCN2A, STXBP1, and TGH1L). As predominant genetic pattern, mutations were found in heterozygosity, dominant autosomal heritage, associated to sporadic cases of congenital ataxia. Novel pathogenic mutations were described in genes MME, TUBB4A and TMEM240. The mutations in genes MME, TUBB4A and TMEM240 were associated to distinct phenotypes than those described in literature so far (phenotypical expantion). Conclusion: Our study reinforces the clinical and genetical heterogenous features involved in congenital ataxias, confirming the difficulty in establishing a relation between phenotype and genotype. The WES is pointed as a diagnosis tool effective in the investigation of genetic variants in 80% of the patients and the establishment of a genetic diagnosis in 46,7% of the patients. The study points out the importance of monoallelic mutations in the congenital ataxia genetic etiology.