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Ataxia with ocular apraxia type 1 (AOA1) (APTX, W279* Mutation): neurological, neuropsychological, and molecular outlining of a heterogenous phenotype in four Colombian Siblings / Dora Lilia Hernández López  

Público ISBD Título : Ataxia with ocular apraxia type 1 (AOA1) (APTX, W279* Mutation): neurological, neuropsychological, and molecular outlining of a heterogenous phenotype in four Colombian Siblings Tipo de documento : documento electrónico Autores : Dora Lilia Hernández López, Fecha de publicación : 2022 Títulos uniformes : Molecular Neurobiology Idioma : Inglés (eng) Palabras clave : AOA1  APTX  Ataxia with ocular apraxia type 1  C2H2-type zinc fingers  Colombia  Latino population  W279* mutation Resumen : Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with ocular apraxia type 1 (AOA1) (OMIM: 606,350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with AlphaFold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding, the DNA-repair domain, and the whole 3D structure of APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 years old) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family's disease and general complex phenotype of hereditary ataxias. Mención de responsabilidad : David Aguillon, Daniel Vasquez, Lucia Madrigal, Sonia Moreno, Dora Hernández, Mario Isaza-Ruget, Juan Javier Lopez, Iván Landires, Virginia Nuñez-Samudio, Carlos M. Restrepo, Oscar M. Vidal, Jorge I. Vélez, Mauricio Arcos-Holzinger, Francisco Lopera & Mauricio Arcos-Burgos Referencia : Mol Neurobiol. 2022 Jun;59(6):3845-3858. DOI (Digital Object Identifier) : 10.1007/s12035-022-02821-7 PMID : 35420381 En línea : https://link.springer.com/article/10.1007/s12035-022-02821-7 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=6031 Ataxia with ocular apraxia type 1 (AOA1) (APTX, W279* Mutation): neurological, neuropsychological, and molecular outlining of a heterogenous phenotype in four Colombian Siblings [documento electrónico] / Dora Lilia Hernández López,  . - 2022. Obra : Molecular Neurobiology Idioma : Inglés (eng) Palabras clave : AOA1  APTX  Ataxia with ocular apraxia type 1  C2H2-type zinc fingers  Colombia  Latino population  W279* mutation Resumen : Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with ocular apraxia type 1 (AOA1) (OMIM: 606,350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with AlphaFold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding, the DNA-repair domain, and the whole 3D structure of APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 years old) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family's disease and general complex phenotype of hereditary ataxias. Mención de responsabilidad : David Aguillon, Daniel Vasquez, Lucia Madrigal, Sonia Moreno, Dora Hernández, Mario Isaza-Ruget, Juan Javier Lopez, Iván Landires, Virginia Nuñez-Samudio, Carlos M. Restrepo, Oscar M. Vidal, Jorge I. Vélez, Mauricio Arcos-Holzinger, Francisco Lopera & Mauricio Arcos-Burgos Referencia : Mol Neurobiol. 2022 Jun;59(6):3845-3858. DOI (Digital Object Identifier) : 10.1007/s12035-022-02821-7 PMID : 35420381 En línea : https://link.springer.com/article/10.1007/s12035-022-02821-7 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=6031

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