Scientific Letter
Acute intermittent porphyria in a paediatric population in the region of Murcia: Phenotype and prevalence
Porfiria aguda intermitente en población pediátrica de la región de Murcia: fenotipo y prevalencia
M.J. Sánchez-Solera,
, M. Barreda-Sánchezb, M.J. Ballesta-Martíneza,c, G. Glóverc,d, E. Guillén-Navarroa,c,e
Corresponding author
a Sección Genética Médica, Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
b UCAM-Universidad Católica de Murcia, Murcia, Spain
c CIBERER, Instituto de Salud Carlos III, Madrid, Spain
d Centro de Bioquímica y Genética Clínica, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain
e Cátedra de Genética Médica, UCAM-Universidad Católica de Murcia, Murcia, Spain
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It is caused by a partial deficiency of the hydroxymethylbilane synthase (HMBS) enzyme resulting from mutations in the <span class="elsevierStyleItalic">HMBS</span> gene. Recently, a prevalence of 6.3 cases per million inhabitants has been reported for Spain,<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">1</span></a> but a higher prevalence is estimated for the Region of Murcia due to the founder effect of the c.669_698del mutation.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It typically manifests as intermittent attacks of abdominal pain accompanied by other gastrointestinal, cardiovascular, neurological and/or psychiatric symptoms, and many precipitating factors are known, such as prolonged fasting or the consumption of alcohol or certain drugs (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The prevalence of AIP in the paediatric population is unknown, symptomatic cases are exceptional, and the reported clinical manifestations are variable. Only one prospective study has been conducted, in Sweden, by Hultdin et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">3</span></a>; it included 61 patients aged less than 18 years, of whom 10% experienced attacks (all experienced mild abdominal pain).</p><p id="par0020" class="elsevierStylePara elsevierViewall">Although diagnosing AIP in children poses great challenges, this disease should be suspected in patients with nonspecific gastrointestinal, neurological and/or psychiatric manifestations, and should be included in the differential diagnosis of abdominal pain of unknown origin. When suspected, the preferred screening method is the Hoesch test (qualitative detection of PBG in urine), increasingly used in Spain as a result of the launching of the PAGORA project (Acute Porphyria Screening Protocol for patients with unexplained acute abdominal pain in the emergency department), to be followed by specific enzymatic or genetic testing. The management is based on removal of precipitating factors, symptomatic treatment and increased intake of carbohydrates in mild to moderate cases; there is evidence supporting the efficacy of the administration of hemin as haem arginate in severe cases,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">4</span></a> and recently Andreeva et al. have published a note about a research project on the use of genetic therapy in these patients (2014).<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">We performed a retrospective review of the medical records of patients aged less than 18 years with a molecular diagnosis of AIP after the positive identification of a family history of AIP (affected parent) during the followup by the medical genetics department. We analysed the prevalence, phenotype and genotype of these cases.</p><p id="par0030" class="elsevierStylePara elsevierViewall">We present the cases of nine patients, with a mean age at diagnosis of 7 years (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The prevalence is 28 cases per million inhabitants (total population under 18 years in Murcia, 320,698). The mean duration of followup after diagnosis was 23 months (range, 3–40 months), and according to the documentation, none of the patients experienced attacks during the followup. At age 2, case 9 experienced an episode of mild abdominal pain after the molecular diagnosis of AIP, so he was admitted to the hospital and diagnosed with pain of unknown origin (urine PBG was not measured to assess for a possible attack).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Four cases (45%) presented with associated abnormalities. Cases 7 and 8 presented with language delay. Case 7 also suffered from sideroblastic anaemia caused by a homozygous c.683G<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>T mutation in the <span class="elsevierStyleItalic">SLC25A38</span> gene. Case 5 had multiple congenital anomalies compatible with VACTERL association (imperforate anus with rectovesical fistula, lumbar hemivertebrae, superior vena cava draining into the coronary sinus, polycystic left kidney and left grade 5 vesicoureteral reflux).</p><p id="par0040" class="elsevierStylePara elsevierViewall">Case 4 (history of intrauterine growth restriction [IUGR]; birth weight, 1630<span class="elsevierStyleHsp" style=""></span>g below first percentile) had significant growth retardation at age 3 years (weight and height below first percentile).</p><p id="par0045" class="elsevierStylePara elsevierViewall">The mother of case 4 was diagnosed during pregnancy. She had an acute attack during gestation and required intravenous administration of haem. The child was delivered by emergency C-section due to IUGR and maternal preeclampsia at 36 weeks gestation.</p><p id="par0050" class="elsevierStylePara elsevierViewall">To conclude, the results of our study support the hypothesis that there is a high prevalence of AIP in children in our region due to the founder effect of the c.669_698del mutation: 28 cases per million inhabitants. All patients were asymptomatic at diagnosis and remained so during followup (with a possible unconfirmed attack in case 9), which may be due to the young age of the population under study (7 years). We found a high rate of associated abnormalities (language delay, multiple congenital anomalies, etc.) that had not been reported previously, so additional follow-up studies need to be conducted on larger samples. Attacks during pregnancy could be a risk factor for IUGR in the newborn and hypertension in the mother, but this aspect is still being debated.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">6</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Early diagnosis is essential in order to implement measures to avoid attack-precipitating factors, to address the chronic problems caused by the disease, and to provide adequate counselling to the family.</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: Sánchez-Soler MJ, Barreda-Sánchez M, Ballesta-Martínez MJ, Glóver G, Guillén-Navarro E. Porfiria aguda intermitente en población pediátrica de la región de Murcia: fenotipo y prevalencia. 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title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Clemastine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Clonidine \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">Co-trimoxazole \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Danazol \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">Dapsone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Dihydralazine \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">Dimenhydrinate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metamizole \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">Ergot derivatives \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Erythromycin \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">Etamsylate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ethosuximide \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">Etomidate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Griseofulvin \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">Ketoconazole \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Meprobamate \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">Methyldopa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sulphonamides \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">Methysergide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nalidixic acid \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">Orphenadrine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oxcarbazepine \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">Tolbutamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phenylbutazone \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">Phenytoin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pyrimidone \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">Pyrazolone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pyrazinamide \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab982524.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Precipitating drugs.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "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">Case \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">Age at diagnosis (years) \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">Sex \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">Associated anomalies \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">Affected parent \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"><span class="elsevierStyleItalic">HMBS</span> gene mutations \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Father, asymptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Father, asymptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IUGR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mother, symptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VACTERL association \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Father, asymptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Father, asymptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Father, symptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sideroblastic anaemia and language delay \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Father, asymptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Language delay \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mother, symptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.669_698del \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">9 \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">M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mother, asymptomatic AIP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">c.76C<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>T \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab982523.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Summary of epidemiologic characteristics, phenotype and genotype of the cases.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0035" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The incidence of inherited porphyrias in Europe" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "G. Elder" 1 => "P. Harper" 2 => "M. Badminton" 3 => "S. Sandberg" 4 => "J.C. Deybach" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10545-012-9544-4" "Revista" => array:6 [ "tituloSerie" => "J Inherit Metab Dis" "fecha" => "2013" "volumen" => "36" "paginaInicial" => "849" "paginaFinal" => "857" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23114748" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0040" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel HMBS founder muttion and significant intronic olymorphism in Spanish patients with acute intermittent porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "E. Guillén-Navarro" 1 => "P. Carbonell" 2 => "G. Glover" 3 => "M. Sánchez-Solís" 4 => "A. Fernández-Barreiro" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1046/j.1529-8817.2003.00114.x" "Revista" => array:6 [ "tituloSerie" => "Ann Hum Genet" "fecha" => "2004" "volumen" => "68" "paginaInicial" => "509" "paginaFinal" => "514" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15469427" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0045" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Acute intermittent porphyria in childhood: a population-based study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J. Hultdin" 1 => "A. Schmauch" 2 => "A. Wikberg" 3 => "G. Dahlquist" 4 => "C. Andersson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Acta Paediatr" "fecha" => "2003" "volumen" => "92" "paginaInicial" => "562" "paginaFinal" => "568" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12839285" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0050" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Best practice guidelines on clinical management of acute attacks of porphyria and their complications" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "British and Irish Porphyria Network" "etal" => false "autores" => array:5 [ 0 => "P. Stein" 1 => "M. Badminton" 2 => "J. Barth" 3 => "D. Rees" 4 => "M.F. Stewart" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/0004563212474555" "Revista" => array:6 [ "tituloSerie" => "Ann Clin Biochem" "fecha" => "2013" "volumen" => "50" "paginaInicial" => "217" "paginaFinal" => "223" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23605132" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0055" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Augmenting PBGD expression in the liver as a Novel Gene Therapy for Acute Intermittent Porphyria (AIPgene). European commission project summaries" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "L. Andreeva" 1 => "J. Holder" 2 => "A. Mathur" 3 => "M. Simons" 4 => "A. Sinusas" 5 => "T. Fahmy" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/humc.2014.2506" "Revista" => array:6 [ "tituloSerie" => "Hum Gene Ther Clin Dev" "fecha" => "2014" "volumen" => "25" "paginaInicial" => "61" "paginaFinal" => "63" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24933563" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0060" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A retrospective analysis of outcome of pregnancy in patients with acute porphyria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.T. Marsden" 1 => "D.C. Rees" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10545-010-9142-2" "Revista" => array:6 [ "tituloSerie" => "J Inherit Metab Dis" "fecha" => "2010" "volumen" => "33" "paginaInicial" => "591" "paginaFinal" => "596" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20567908" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:3 [ "titulo" => "Acknowledgments" "texto" => "<p id="par0060" class="elsevierStylePara elsevierViewall">We want to thank the patients and their families for their collaboration. This study was partially funded by the <span class="elsevierStyleGrantSponsor" id="gs1">UCAM-Universidad Católica de Murcia</span> (<span class="elsevierStyleGrantNumber" refid="gs1">PMAFI/09/14</span>). M. Barreda-Sánchez is a graduate student on a predoctoral fellowship awarded by the same university.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/23412879/0000008400000002/v1_201601300058/S2341287915002914/v1_201601300058/en/main.assets" "Apartado" => array:4 [ "identificador" => "38181" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Scientific letters" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23412879/0000008400000002/v1_201601300058/S2341287915002914/v1_201601300058/en/main.pdf?idApp=UINPBA00005H&text.app=https://analesdepediatria.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2341287915002914?idApp=UINPBA00005H" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 12 | 9 | 21 |
| 2024 October | 56 | 34 | 90 |
| 2024 September | 74 | 30 | 104 |
| 2024 August | 99 | 49 | 148 |
| 2024 July | 76 | 30 | 106 |
| 2024 June | 96 | 30 | 126 |
| 2024 May | 79 | 58 | 137 |
| 2024 April | 58 | 22 | 80 |
| 2024 March | 74 | 33 | 107 |
| 2024 February | 63 | 29 | 92 |
| 2024 January | 81 | 21 | 102 |
| 2023 December | 157 | 16 | 173 |
| 2023 November | 88 | 36 | 124 |
| 2023 October | 78 | 23 | 101 |
| 2023 September | 58 | 16 | 74 |
| 2023 August | 65 | 19 | 84 |
| 2023 July | 54 | 23 | 77 |
| 2023 June | 59 | 30 | 89 |
| 2023 May | 82 | 27 | 109 |
| 2023 April | 37 | 16 | 53 |
| 2023 March | 82 | 24 | 106 |
| 2023 February | 43 | 15 | 58 |
| 2023 January | 39 | 27 | 66 |
| 2022 December | 57 | 49 | 106 |
| 2022 November | 58 | 38 | 96 |
| 2022 October | 69 | 43 | 112 |
| 2022 September | 63 | 44 | 107 |
| 2022 August | 61 | 53 | 114 |
| 2022 July | 43 | 33 | 76 |
| 2022 June | 38 | 36 | 74 |
| 2022 May | 49 | 30 | 79 |
| 2022 April | 84 | 36 | 120 |
| 2022 March | 112 | 45 | 157 |
| 2022 February | 95 | 29 | 124 |
| 2022 January | 69 | 32 | 101 |
| 2021 December | 56 | 44 | 100 |
| 2021 November | 59 | 39 | 98 |
| 2021 October | 80 | 71 | 151 |
| 2021 September | 60 | 39 | 99 |
| 2021 August | 81 | 43 | 124 |
| 2021 July | 64 | 22 | 86 |
| 2021 June | 84 | 35 | 119 |
| 2021 May | 69 | 38 | 107 |
| 2021 April | 142 | 74 | 216 |
| 2021 March | 107 | 46 | 153 |
| 2021 February | 69 | 23 | 92 |
| 2021 January | 84 | 26 | 110 |
| 2020 December | 73 | 30 | 103 |
| 2020 November | 48 | 22 | 70 |
| 2020 October | 58 | 23 | 81 |
| 2020 September | 72 | 23 | 95 |
| 2020 August | 63 | 16 | 79 |
| 2020 July | 49 | 17 | 66 |
| 2020 June | 52 | 17 | 69 |
| 2020 May | 57 | 31 | 88 |
| 2020 April | 61 | 21 | 82 |
| 2020 March | 50 | 22 | 72 |
| 2020 February | 68 | 23 | 91 |
| 2020 January | 52 | 14 | 66 |
| 2019 December | 42 | 25 | 67 |
| 2019 November | 46 | 15 | 61 |
| 2019 October | 29 | 12 | 41 |
| 2019 September | 50 | 11 | 61 |
| 2019 August | 31 | 25 | 56 |
| 2019 July | 35 | 23 | 58 |
| 2019 June | 59 | 30 | 89 |
| 2019 May | 69 | 11 | 80 |
| 2019 April | 56 | 21 | 77 |
| 2019 March | 55 | 19 | 74 |
| 2019 February | 49 | 20 | 69 |
| 2019 January | 53 | 20 | 73 |
| 2018 December | 44 | 30 | 74 |
| 2018 November | 65 | 38 | 103 |
| 2018 October | 78 | 39 | 117 |
| 2018 September | 49 | 16 | 65 |
| 2018 August | 2 | 0 | 2 |
| 2018 July | 3 | 0 | 3 |
| 2018 June | 3 | 0 | 3 |
| 2018 May | 4 | 0 | 4 |
| 2018 April | 18 | 0 | 18 |
| 2018 March | 16 | 0 | 16 |
| 2018 February | 9 | 0 | 9 |
| 2018 January | 15 | 0 | 15 |
| 2017 December | 14 | 0 | 14 |
| 2017 November | 18 | 0 | 18 |
| 2017 October | 8 | 0 | 8 |
| 2017 September | 14 | 0 | 14 |
| 2017 August | 14 | 0 | 14 |
| 2017 July | 14 | 0 | 14 |
| 2017 June | 19 | 11 | 30 |
| 2017 May | 20 | 11 | 31 |
| 2017 April | 7 | 8 | 15 |
| 2017 March | 9 | 4 | 13 |
| 2017 February | 6 | 3 | 9 |
| 2017 January | 7 | 0 | 7 |
| 2016 December | 20 | 7 | 27 |
| 2016 November | 30 | 9 | 39 |
| 2016 October | 30 | 11 | 41 |
| 2016 September | 32 | 6 | 38 |
| 2016 August | 23 | 4 | 27 |
| 2016 July | 28 | 15 | 43 |
Show all
