Apoplejía, Convulsiones, Epilepsia, Heteroplasmia, MELAS, Migraña, Mutación, mtDNA Comportamiento de la mutación mtDNA A3243G en dos familias antioqueñas de pacientes diagnosticados con el síndrome MELAS

• Main Authors: Gabriel Bedoya Berrío, Andrés Ruiz Linares, Constanza Elena Duque Vélez, José William Cornejo Ochoa, María Victoria Parra Marín
• Format: Article
• Language: Spanish
• Published: Universidad de Antioquia 2010-02-01
• Series: Iatreia
• Subjects: Apoplejía, Convulsiones, Epilepsia, Heteroplasmia, MELAS, Migraña, Mutación, mtDNA
• Online Access: http://www.iatreia.udea.edu.co/index.php/iatreia/article/view/1321
• ISSN: 0121-0793; 2011-7965

<p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Mitochondrial DNA mutations cause mitochondrial cytopathies. Among them Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">(MELA) is the commonest. The transition 3243A>G in the Leucine tRNA is present in 80% of the patients.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Heteroplasmy is observed in mitochondrial cytopathies, characterized by the coexistence of mutant and wild type molecules in a cell. Depending on the level of heteroplasmy, function and clinical manifestations might result affected.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Objective</span></strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">: To test the degree of heteroplasmy of the mutation 3243G on its expression (syntoms) and nuclear-variants dependence.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Patients and methods</span></strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">: Mutations in the tRNALeu gene were sought in 34 patients by sequencing and PCR-RFLP.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Four SPA (specific population alleles) were typed in patients and their relatives carrying the mutation 3243A>G.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Results</span></strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">: The mutation 3243A>G in the Leucine tRNA gene was found in two patients. This mutation was screened in their relatives and the amount of mutant DNA (MDNA) was assessed. The index cases presented with the higher amounts of MDNA in both families. In family one, the mutation was detected in 14 members, three of which presented with short stature, one with hearing loss, one with type 2 diabetes, 8 with</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">migraine and one healthy individual. In family two the mutation was detected in one member with brain paralysis, two with migraine and one healthy individual.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">Conclusions</span></strong><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">: Severity of the symptoms in patients affected with MELAS is correlated with the amount of MDNA. Furthermore, it was found a correlation between MDNA and IAA, suggesting a possible effect of amerind nuclear ontext in The mitochondrial</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="line-height: 200%; font-family: ";Times New Roman";,";serif";; font-size: 12pt; mso-ansi-language: EN-US;" lang="EN-US">segregation and replication.</span></p> <p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ">Introducción: </span></strong><span style="line-height: 200%; font-family: ">mutaciones en mtDNA causan citopatias mitocondriales, la más común de ellas es el síndrome MELAS; la transición A3243G en tRNA de leucina (tRNALeu) se presenta en 80% de pacientes. La heteroplasmia, observada en citopatias mitocondriales, consiste en coexistencia de moléculas mutadas y normales en una célula, situación en la cual, dependiendo de su cantidad, afecta su función con expresión clínica variable.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ">Objetivo: </span></strong><span style="line-height: 200%; font-family: ">evaluar el comportamiento de la cantidad de heteroplasmia de la mutación 3243G en su expresión clínica y en la dependencia de variantes nucleares.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ">Pacientes y métodos: </span></strong><span style="line-height: 200%; font-family: ">se buscaron mutaciones en el gen que codifica para el tRNA de leucina por secuencia y por PCR-RFLP en 34 pacientes, y se tamizó en familiares de los portadores de la mutación. Se tipificaron cuatro Specific Population Allele (SPA) en pacientes y familiares con la mutación A3243G.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="line-height: 200%; font-family: ">Resultados: </span></strong><span style="line-height: 200%; font-family: ">se halló la mutación A3243G en el tRNALeu en dos pacientes, luego de tamizar la mutación A3243G en ambas familias se evaluó la cantidad de mtDNA mutado (MDNA), encontrando que los casos índices de ambas familias presentaron la mayor cantidad de MDNA; en la primera familia se detectó la mutación en 15 miembros que presentaron diversos síntomas.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><span style="line-height: 200%; font-family: ">En la segunda familia se detectó la mutación en un miembro con parálisis cerebral, en dos con migraña y en uno asintomático.</span></p><p class="MsoNormal" style="text-align: justify; line-height: 200%; margin: 0cm 0cm 0pt; mso-layout-grid-align: none;"><strong><span style="font-family: ">Conclusiones: </span></strong><span style="font-family: ">la severidad de los síntomas se correlaciona con la cantidad de MDNA, se encontró además correlación entre mtDNA mutado (MDNA) y el Índice de Ancestría Amerindio en cada individuo (IAA), indicando una posible influencia del contexto nuclear amerindio en la segregación y replicación mitocondrial.</span></p>