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Déficit de alfa-1-antitripsina asociado a la variante Mmalton. Descripción de una familia
Alpha-1 antitrypsin deficiency associated with the Mmalton variant. Description of a family
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Description of a family" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">El 95% de los casos clínicos relacionados con el déficit de alfa-1-antitripsina (DAAT) están asociados al genotipo PI*ZZ, siendo el 5% restante correspondiente a los genotipos PI*SZ, PI*MZ o a combinaciones de PI*S o PI*Z con otros alelos deficientes o nulos extremadamente raros. Estos alelos raros representan el 1,6% de las variantes deletéreas anotadas en el Registro Español de Pacientes con Déficit de AAT siendo las más frecuentes la variante PI*Mmalton<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a>. Dicha variante muestra un comportamiento clínico similar al fenotipo PI*Z, siendo su diagnóstico habitualmente retrasado ante su similitud estructural con el alelo Pi M2. Presentamos el caso de 2 miembros de un mismo grupo familiar (<a class="elsevierStyleCrossRef" href="#tbl0005">tabla 1</a>) con diagnóstico de DAAT en relación con el alelo deficitario PI*Mmalton en su forma homocigótica.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">El caso índice era un varón de 47 años de edad, natural de la isla de la Gomera, con antecedentes personales de neumotórax espontáneo en 2005 y exfumador con índice paquetes-año de 30, que es remitido a la consulta de neumología por disnea a moderados esfuerzos (mMRC 2) de un año de evolución. Las pruebas funcionales respiratorias mostraron un FEV<span class="elsevierStyleInf">1</span>/FVC: 0,5; FEV<span class="elsevierStyleInf">1</span>: 1,73<span class="elsevierStyleHsp" style=""></span>l (51%); FVC: 3,38 l (77%); DLCO: 73% y KCO: 75%. La TAC de alta resolución describía la presencia de enfisema centrolobulillar y paraseptal de predominio en campos superiores. La ecografía abdominal no detectó signos de hepatopatía crónica, a pesar de mostrar una leve hipertransaminasemia. Hemograma y niveles de IgA, IgM, IgG e IgE se encontraban dentro de la normalidad. La determinación de los niveles de alfa-1-antitripsina (AAT) mediante nefelometría resultó disminuida de forma severa (16<span class="elsevierStyleHsp" style=""></span>mg/dl), por lo que se analizó la presencia de los alelos PI*S y PI*Z, que resultó negativa. Basándonos en la ausencia de dichas variantes deficitarias y dado los niveles AAT reflejado en el suero, se decide realizar el análisis molecular del gen SERPINA1 amplificándose tanto las regiones exónicas codificantes como las zonas intrónicas flanqueantes de los exones 4, 5 y 6. Dicho análisis reveló la presencia del alelo PI*Mmalton (F52del) en su forma homocigótica.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Su hermana, mujer de 42 años de edad y con antecedentes personales de exfumadora, con un índice paquetes-año de 35 negaba clínica respiratoria. Las pruebas funcionales respiratorias mostraron un FEV<span class="elsevierStyleInf">1</span>/FVC: 0,74; FEV<span class="elsevierStyleInf">1</span>: 2,68 l (96%); FVC: 3,62<span class="elsevierStyleHsp" style=""></span>l (110%); DLCO: 81% y KCO: 82%. La TAC de alta resolución, la ecografía abdominal y la analítica general se encontraban dentro de la normalidad. La determinación de AAT resultó disminuida de forma severa (19<span class="elsevierStyleHsp" style=""></span>mg/dl), siendo realizado el análisis molecular del gen SERPINA1, detectándose la presencia del alelo PI*Mmalton en su forma homocigótica.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Diversos registros de pacientes con DAAT describen al alelo PI*Mmalton como la tercera variante deficitaria más frecuente en España<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a>, no habiéndose descrito hasta la fecha su existencia en las Islas Canarias. Al igual que el gen Z, el alelo Mmalton produce una proteína mal plegada de la que un 80-90% se polimeriza en el hepatocito, siendo expresados niveles inferiores al 15% en sangre. A diferencia de nuestros casos, en los pacientes con PI*Mmalton en su forma homocigótica se ha descrito habitualmente la coexistencia de enfisema y cirrosis hepática<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">3,4</span></a>; sin embargo las formas heterocigóticas parecen mostrar un comportamiento mucho más heterogéneo. La mayoría de los pacientes PI*M/Mmalton no muestran alteración de la función pulmonar o hepática, a diferencia del genotipo PI*Z/Mmalton que parece relacionarse con un aumento del riesgo de desarrollar enfisema<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a>. En lo que respecta a la afectación hepática, Canva et al., describieron el caso de una paciente PI* Mmalton/M que desarrolló una enfermedad hepática terminal a pesar de no presentar antecedentes de hepatitis, abuso de alcohol o enfermedad hepática infantil<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">6</span></a>. Igualmente, Piras et al., describieron que al menos un 13% de los sujetos tanto homocigotos como heterocigotos para la variante PI*Mmalton mostraban datos de hepatopatía crónica<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">7</span></a>.</p><p id="par0025" class="elsevierStylePara elsevierViewall">En nuestro caso es destacable la heterogeneidad clínica manifestada por parte de nuestros pacientes, a pesar de la consanguinidad de estos y de una exposición al humo del tabaco de similar intensidad, lo que muestra diferentes patrones de comportamiento para un mismo genotipo PI*Mmalton/Mmalton.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Tabla 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Tabla " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">ATT: alfa-1-antitripsina.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Familia \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Antecedente de tabaquismo \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Niveles de ATT (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Genotipo \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Espirometría forzada \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Función hepática \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Caso 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sí \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mmalton/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Obstructiva \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Alterada \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hermana 1 del caso 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sí \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mmalton/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hermana 2 del caso 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">84,3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hija del caso 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">83,4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hijo del caso 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">85,8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Padre del caso 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">77,3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Obstructiva \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Madre del caso 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">No \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">90,3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M/Mmalton \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1260386.png" ] ] ] ] "descripcion" => array:1 [ "es" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Características de la familia a estudio</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliografía" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rare alpha-1-antitrypsin variants: Are they really so rare?" 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| Year/Month | Html | Total | |
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| 2023 July | 1 | 0 | 1 |
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| 2020 January | 68 | 25 | 93 |
| 2019 December | 54 | 24 | 78 |
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| 2019 October | 44 | 18 | 62 |
| 2019 September | 53 | 16 | 69 |
| 2019 August | 36 | 17 | 53 |
| 2019 July | 42 | 24 | 66 |
| 2019 June | 60 | 13 | 73 |
| 2019 May | 46 | 22 | 68 |
| 2019 April | 49 | 41 | 90 |
| 2019 March | 40 | 21 | 61 |
| 2019 February | 44 | 27 | 71 |
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| 2018 December | 51 | 17 | 68 |
| 2018 November | 73 | 35 | 108 |
| 2018 October | 110 | 27 | 137 |
| 2018 September | 57 | 13 | 70 |
| 2018 August | 3 | 0 | 3 |
| 2018 July | 2 | 0 | 2 |
| 2018 June | 1 | 0 | 1 |
| 2018 May | 30 | 0 | 30 |
| 2018 April | 56 | 7 | 63 |
| 2018 March | 41 | 11 | 52 |
| 2018 February | 49 | 8 | 57 |
| 2018 January | 29 | 8 | 37 |
| 2017 December | 41 | 15 | 56 |
| 2017 November | 23 | 9 | 32 |
| 2017 October | 31 | 9 | 40 |
| 2017 September | 42 | 7 | 49 |
| 2017 August | 27 | 14 | 41 |
| 2017 July | 39 | 12 | 51 |
| 2017 June | 40 | 20 | 60 |
| 2017 May | 63 | 19 | 82 |
| 2017 April | 40 | 18 | 58 |
| 2017 March | 38 | 35 | 73 |
| 2017 February | 1 | 3 | 4 |
| 2017 January | 3 | 5 | 8 |
| 2016 December | 15 | 10 | 25 |
| 2016 November | 5 | 5 | 10 |
| 2016 September | 0 | 1 | 1 |
| 2016 August | 1 | 1 | 2 |
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| 2016 June | 2 | 2 | 4 |
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