Scientific Letter
Alpha-1 Antitrypsin Deficiency Associated With the Mmalton Variant. Description of a Family
Déficit de alfa-1-antitripsina asociado a la variante Mmalton. Descripción de una familia
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Description of a Family" "tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "617" "paginaFinal" => "618" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Juan Marco Figueira Gonçalves, Francisco Martínez Bugallo, David Díaz Pérez, María Dolores Martín Martínez, Ignacio García-Talavera" "autores" => array:5 [ 0 => array:4 [ "nombre" => "Juan Marco" "apellidos" => "Figueira Gonçalves" "email" => array:1 [ 0 => "juanmarcofigueira@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Francisco" "apellidos" => "Martínez Bugallo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "David" "apellidos" => "Díaz Pérez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "María Dolores" "apellidos" => "Martín Martínez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Ignacio" "apellidos" => "García-Talavera" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Neumología y Cirugía Torácica, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Tenerife, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Unidad de Genética, Servicio de Análisis Clínicos, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Tenerife, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Déficit de alfa-1-antitripsina asociado a la variante Mmalton. Descripción de una familia" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Up to 95% of cases related with alpha-1 antitrypsin deficiency (AATD) are associated with the PI*ZZ genotype, while the other 5% are associated with PI*SZ and PI*MZ genotypes or other extremely rare combinations of PI*S or PI*Z with other deficiency or null alleles. These rare alleles account for 1.6% of the deleterious variants recorded in the Spanish Register of Patients with AAT Deficiency, and the most common of these is the PI*Mmalton variant.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">1</span></a> The clinical manifestations of this variant are similar to those of the PI*Z phenotype, and diagnosis is typically delayed by its structural similarity to the Pi M2 allele. We report the case of 2 members of the same family group (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) with a diagnosis of AATD associated with homozygous deficiency PI*Mmalton allele.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">The index case was a 47-year-old man, native of the island of Gomera (Canary Islands, Spain), with a clinical history of spontaneous pneumothorax in 2005, and former smoker of 30 pack-years, referred to the respiratory medicine clinic due to a 1-year history of dyspnea on moderate exertion (mMRC 2). Lung functional tests showed FEV<span class="elsevierStyleInf">1</span>/FVC: 0.5; FEV<span class="elsevierStyleInf">1</span>: 1.73 l (51%); FVC: 3.38 l (77%); DLCO: 73%; and KCO: 75%. High-resolution computed tomography (HRCT) revealed centrilobular and paraseptal emphysema, predominantly in the upper fields. Abdominal ultrasonography found no signs of chronic liver disease, despite mildly elevated transaminases. Complete blood count and IgA, IgM, IgG and IgE levels were within normal limits. Alpha-1 antitrypsin (AAT) was determined by nephelometry, revealing severely reduced levels (16<span class="elsevierStyleHsp" style=""></span>mg/dl), so DNA testing was performed to determine the presence of PI*S and PI*Z alleles, but the result was negative. Given the absence of these deficiency variants and the low AAT levels in serum, we performed a molecular analysis of the SERPINA1 gene, amplifying both coding exonic regions and flanking intronic sequences of exons 4, 5, and 6. This analysis revealed the presence of the homozygous PI*Mmalton (F52del) allele.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The patient's sister, 42 years old, former smoker of 35 pack-years denied any respiratory symptoms. Lung functional tests showed FEV<span class="elsevierStyleInf">1</span>/FVC: 0.74; FEV<span class="elsevierStyleInf">1</span>: 2.68 l (96%); FVC: 3.62 l (110%); DLCO: 81%; and KCO: 82%. HRCT, abdominal ultrasonography, and general laboratory tests were all normal. AAT determination revealed severely reduced levels (19<span class="elsevierStyleHsp" style=""></span>mg/dl), and molecular analysis of the SERPINA1 gene detected the homozygous PI*Mmalton allele.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Various AADT patient registries describe the PI*Mmalton allele as the third most common deficiency variant in Spain,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">2</span></a> although this is the first report of its existence in the Canary Islands. Like the Z gene, the Mmalton allele produces improperly folded protein, of which 80%–90% is polymerized in the hepatocyte, expressing levels of less than 15% in blood. The co-existence of emphysema and hepatic cirrhosis is often described in patients with homozygous PI*Mmalton,<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">3,4</span></a> although this was absent from our cases; however, the behavior of the heterozygous forms appears to be far more variable. Most PI*M/Mmalton patients have no changes in lung or liver function, in contrast to the PI*Z/Mmalton genotype that appears to be associated with an increased risk of emphysema.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">5</span></a> With regard to liver involvement, Canva et al. described the case of a PI* Mmalton/M patient who developed end-stage liver disease despite no history of hepatitis, alcohol abuse or liver disease in childhood.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">6</span></a> Similarly, Piras et al., found that less than 13% of subjects with either the homozygous or heterozygous PI*Mmalton variant showed evidence of chronic liver disease.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Our case is remarkable because of the clinical differences observed in our patients, despite their consanguinity and similar exposure to tobacco smoke at a similar intensity, demonstrating different patterns of clinical manifestations of the same PI*Mmalton/Mmalton genotype.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Figueira Gonçalves JM, Martínez Bugallo F, Díaz Pérez D, Martín Martínez MD, García-Talavera I. Déficit de alfa-1-antitripsina asociado a la variante Mmalton. Descripción de una familia. Arch Bronconeumol. 2016;52:617–618.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">AAT: Alpha-1 antitrypsin.</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">Family \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">Smoking History \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">AAT Levels (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">Genotype \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">Forced Spirometry \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">Liver Function \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">Case 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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">Obstructive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Altered \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">Sister 1 of case 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" 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">Sister 2 of case 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="char" 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">Daughter of case 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="char" 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">Son of case 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="char" 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">Father of case 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="char" 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">Obstructive \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">Mother of case 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="char" 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 => "xTab1260339.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Characteristics of Study Family.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0040" "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 | |
|---|---|---|---|
| 2024 November | 7 | 4 | 11 |
| 2024 October | 60 | 29 | 89 |
| 2024 September | 53 | 24 | 77 |
| 2024 August | 65 | 43 | 108 |
| 2024 July | 43 | 23 | 66 |
| 2024 June | 61 | 19 | 80 |
| 2024 May | 63 | 27 | 90 |
| 2024 April | 43 | 26 | 69 |
| 2024 March | 47 | 16 | 63 |
| 2024 February | 28 | 20 | 48 |
| 2023 December | 1 | 2 | 3 |
| 2023 March | 4 | 3 | 7 |
| 2023 February | 36 | 22 | 58 |
| 2023 January | 42 | 38 | 80 |
| 2022 December | 58 | 40 | 98 |
| 2022 November | 45 | 18 | 63 |
| 2022 October | 50 | 44 | 94 |
| 2022 September | 28 | 36 | 64 |
| 2022 August | 39 | 36 | 75 |
| 2022 July | 32 | 38 | 70 |
| 2022 June | 30 | 52 | 82 |
| 2022 May | 33 | 23 | 56 |
| 2022 April | 47 | 27 | 74 |
| 2022 March | 47 | 36 | 83 |
| 2022 February | 30 | 34 | 64 |
| 2022 January | 45 | 46 | 91 |
| 2021 December | 46 | 33 | 79 |
| 2021 November | 50 | 44 | 94 |
| 2021 October | 67 | 47 | 114 |
| 2021 September | 50 | 53 | 103 |
| 2021 August | 29 | 39 | 68 |
| 2021 July | 41 | 30 | 71 |
| 2021 June | 56 | 28 | 84 |
| 2021 May | 46 | 50 | 96 |
| 2021 April | 121 | 111 | 232 |
| 2021 March | 113 | 17 | 130 |
| 2021 February | 52 | 35 | 87 |
| 2021 January | 41 | 19 | 60 |
| 2020 December | 49 | 17 | 66 |
| 2020 November | 62 | 21 | 83 |
| 2020 October | 43 | 28 | 71 |
| 2020 September | 45 | 14 | 59 |
| 2020 August | 58 | 18 | 76 |
| 2020 July | 47 | 30 | 77 |
| 2020 June | 46 | 7 | 53 |
| 2020 May | 55 | 12 | 67 |
| 2020 April | 57 | 15 | 72 |
| 2020 March | 47 | 15 | 62 |
| 2020 February | 42 | 23 | 65 |
| 2020 January | 38 | 14 | 52 |
| 2019 December | 54 | 32 | 86 |
| 2019 November | 51 | 25 | 76 |
| 2019 October | 53 | 14 | 67 |
| 2019 September | 68 | 17 | 85 |
| 2019 August | 44 | 19 | 63 |
| 2019 July | 38 | 17 | 55 |
| 2019 June | 44 | 19 | 63 |
| 2019 May | 80 | 22 | 102 |
| 2019 April | 83 | 36 | 119 |
| 2019 March | 72 | 28 | 100 |
| 2019 February | 35 | 20 | 55 |
| 2019 January | 33 | 11 | 44 |
| 2018 December | 38 | 15 | 53 |
| 2018 November | 63 | 20 | 83 |
| 2018 October | 76 | 34 | 110 |
| 2018 September | 30 | 17 | 47 |
| 2018 May | 17 | 2 | 19 |
| 2018 April | 54 | 4 | 58 |
| 2018 March | 27 | 5 | 32 |
| 2018 February | 44 | 5 | 49 |
| 2018 January | 88 | 10 | 98 |
| 2017 December | 42 | 8 | 50 |
| 2017 November | 21 | 9 | 30 |
| 2017 October | 15 | 7 | 22 |
| 2017 September | 25 | 13 | 38 |
| 2017 August | 26 | 17 | 43 |
| 2017 July | 32 | 10 | 42 |
| 2017 June | 28 | 21 | 49 |
| 2017 May | 35 | 12 | 47 |
| 2017 April | 28 | 15 | 43 |
| 2017 March | 21 | 10 | 31 |
| 2016 December | 0 | 1 | 1 |
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