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BACKGROUND: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients. MATERIAL AND METHODS: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP. RESULTS: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP. CONCLUSIONS: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP.

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La neurofibromatosis tipo 1 es uno de los trastornos genéticos neurocutáneos más frecuentes. La característica de esta enfermedad es la afectación cutánea en forma de manchas «café con leche», efélides y los característicos neurofibromas cutáneos. Otras manifestaciones frecuentes incluyen las alteraciones óseas, la «vasculopatía por neurofibromatosis tipo 1» y los problemas neurocognitivos. Además, los pacientes tienen más riesgo de padecer una gran variedad de neoplasias malignas, incluida la transformación maligna de neurofibromas plexiformes. Para ser capaces de brindar una atención óptima a estos pacientes, que presentan una afectación multisistémica y potencialmente grave, es necesario conocer las diversas características clínicas de este trastorno, así como propiciar un seguimiento y abordaje terapéutico precoz y multidisciplinar. En esta revisión, resumimos el diagnóstico, las principales características clínicas y proponemos un protocolo de cribado y seguimiento de pacientes adultos con neurofibromatosis tipo 1 (AU)

Neurofibromatosis type 1 is one of the most common genetic neurocutaneous disorders. The hallmark of this disease is skin lesions in the form of café-au-lait spots, ephelides, and the characteristic cutaneous neurofibromas. Other common manifestations include bone abnormalities, «neurofibromatosis type 1 vasculopathy», and neurocognitive disorders. In addition, patients are at an increased risk for a wide variety of malignant neoplasms, including the malignant transformation of plexiform neurofibromas. It is necessary to know the various clinical characteristics of this disorder and to provide an early, multidisciplinary follow-up and treatment approach in order to provide optimal care to these patients, who present with a multisystemic disease that is potentially severe. This review summarizes the diagnosis and main clinical characteristics and suggests a protocol for screening and follow-up of adult patients with neurofibromatosis type 1 (AU)

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Neurofibromatosis type 1 (NF1) is one of the most common genetic neurocutaneous disorders. The hallmark of this disease is skin lesions in the form of café-au-lait spots, ephelides, and the characteristic cutaneous neurofibromas. Other common manifestations include bone abnormalities, "NF1 vasculopathy," and neurocognitive disorders. In addition, patients are at an increased risk for a wide variety of malignant neoplasms, including the malignant transformation of plexiform neurofibromas. It is necessary to know the various clinical characteristics of this disorder and to provide an early, multidisciplinary follow-up and treatment approach in order to provide optimal care to these patients, who present with a multisystemic disease that is potentially severe. This review summarizes the diagnosis and main clinical characteristics and suggests a protocol for screening and follow-up of adult patients with NF1.

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Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible. Systemic therapies had not succeeded to reduce PN tumor volume until 2016 when the first trial with an MAPK/extracellular-signal-regulated kinase (MEK) inhibitor was published. We performed a systematic research on novel targeted therapies for patients with NF1 and PNs in PubMed, EMBASE, and conference abstracts with the last update in February 2021. Since 2016, seven trials have reported positive results with MEK inhibitors and other molecular targeted therapies (cabozantinib). Selumetinib has shown an overall response rate of 68% in children with NF1 and symptomatic inoperable PNs, and was associated with pain improvement and a manageable adverse events profile. This led to Food and Drug Administration (FDA) approval of selumetinib in May 2020. Recently, cabozantinib and mirdametinib have also proven their efficacy in adult population. Other MEK inhibitors such as trametinib and binimetinib have also communicated promising preliminary results. Ongoing trials in different populations and with intermittent dosing strategies are underway.

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Las porfirias son errores congénitos del metabolismo de las porfirinas o ruta biosintética del hemo. El acúmulo de los precursores de las porfirinas, ácido delta aminolevulínico (ALA) y/o porfobilinógeno (PBG) es responsable de las crisis neuroviscerales de las porfirias agudas que cuando se expresan clínicamente se inician con intenso dolor abdominal. Durante las crisis la eliminación urinaria de PBG y ALA siempre es muy elevada. La excesiva concentración de PBG en orina es fácilmente identificable mediante el sencillo test de Hoesch. Un test negativo descarta crisis porfírica actual. El protocolo de actuación en pacientes con dolor abdominal agudo no filiado en los que el test de Hoesch positivo permite la sospecha de porfiria aguda se basa en los siguientes aspectos: valoración clínica inicial en el servicio de urgencias, supresión de los posibles factores desencadenantes, tratamiento específico de la crisis con hemina y/o sobrecarga de glucosa y tratamiento sintomático

Porphyrias are a group of congenital errors in porphyrin metabolism and in the heme biosynthetic pathway. Accumulation of porphyrin precursors (delta-aminolaevulinic acid and porphobilinogen) is responsible for the neurovisceral crises of acute porphyria, which, when expressed clinically, start with intense abdominal pain. During crises, the urinary elimination of porphobilinogen and delta-aminolaevulinic acid is always very high. Excessive porphobilinogen concentration in urine is easily identified using the simple Hoesch test. A negative test rules out a current porphyric crisis. The clinical protocol for patients with acute abdominal pain of unknown origin in whom a positive Hoesch test leads to the suspicion of acute porphyria is based on the following aspects: initial clinical assessment in the emergency department, suppression of potential triggers, specific treatment for the crisis with hemin and/or glucose overload and symptomatic treatment

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Porphyrias are a group of congenital errors in porphyrin metabolism and in the heme biosynthetic pathway. Accumulation of porphyrin precursors (delta-aminolaevulinic acid and porphobilinogen) is responsible for the neurovisceral crises of acute porphyria, which, when expressed clinically, start with intense abdominal pain. During crises, the urinary elimination of porphobilinogen and delta-aminolaevulinic acid is always very high. Excessive porphobilinogen concentration in urine is easily identified using the simple Hoesch test. A negative test rules out a current porphyric crisis. The clinical protocol for patients with acute abdominal pain of unknown origin in whom a positive Hoesch test leads to the suspicion of acute porphyria is based on the following aspects: initial clinical assessment in the emergency department, suppression of potential triggers, specific treatment for the crisis with hemin and/or glucose overload and symptomatic treatment.

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BACKGROUND: Enzyme replacement therapy (ERT) has been shown to decrease urine glycosaminoglycans (uGAGs) and liver and spleen volumes, and to improve clinical symptoms in mucopolysaccharidosis type II (MPS-II) patients. METHODS: A systematic search of the literature, from inception to August 2017, was conducted to identify randomized trials or observational studies including ≥1 MPS-II patients with ERT initiated in adult age (≥16 years) and evaluating ERT efficacy. Evidence was rated according to GRADE criteria. Common efficacy outcomes of the clinical studies were analyzed. Case reports were separately evaluated. RESULTS: One randomized clinical trial, 4 observational studies and 5 case reports were selected. ERT decreased uGAG levels and liver and spleen size with moderate evidence level and led to anti-ERT antibody and IRRS development in a significant proportion of patients with moderate evidence level. There were no conclusive results for beneficial effects on 6MWT, respiratory, cardiac and neurological function, joint mobility, sleep disorders of respiratory origin, and quality of life. LIMITATIONS: Excluding one observational study, all others were not conducted specifically in the target population (ERT ≥16 years). Data were from subgroup analyses of selected studies. There was a great heterogeneity between study designs and clinical outcomes evaluated. CONCLUSIONS: ERT improves uGAGs and liver/spleen volume with a moderate evidence level in MPS-II patients initiating therapy as adults, although the putative associated clinical benefit is unclear.

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Patients with inborn errors of metabolism (IEMs) have become an emerging and challenging group in the adult healthcare system whose needs should be known in order to implement appropriate policies and to adapt adult clinical departments. We aimed to analyze the clinical characteristics of adult patients with IEMs who attend the most important Spanish hospitals caring for these conditions. A cohort study was conducted in 500 patients, categorized by metabolic subtype according to pathophysiological classification. The most prevalent group of IEMs was amino acid disorders, with 108 (21.6%) patients diagnosed with phenylketonuria. Lysosomal storage disorders were the second group, in which 32 (6.4%) and 25 (5%) patients had Fabry disease and Gaucher disease respectively. The great clinical heterogeneity, the significant delay in diagnosis after symptom onset, the existence of some degree of physical dependence in a great number of patients, the need for a multidisciplinary and coordinated approach, and the lack of specific drug treatment are common features in this group of conditions.

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La Unidad Pediátrica de Enfermedades Mitocondriales y Enfermedades Metabólicas Hereditarias (EM-EMH) presta atención a pacientes afectos de errores congénitos del metabolismo (ECM). Asimismo, realiza consejo genético, diagnóstico prenatal y el diagnóstico en sus familiares. Nuestro Hospital dispone de todas las especialidades médicas, pediátricas y de adultos, así como infraestructuras necesarias para proporcionar una atención de calidad. Por el trabajo realizado hemos recibido algunos premios y reconocimientos, otorgados por asociaciones de pacientes (Federación Española de Enfermedades Raras -FEDER-, Asociación Española de Enfermedades Raras -ACME-IM-). Hemos sido denominados Centro Experto de Referencia para centro del diagnóstico y seguimiento clínico de los casos sospechosos de enfermedades metabólicas congénitas detectados en el programa de cribado neonatal universal que se realiza en la Comunidad de Madrid y Centro de Referencia para enfermedades metabólicas congénitas para niños y adultos (CSUR) por el Ministerio de Sanidad, Servicios Sociales e. Igualdad. Recientemente hemos sido nominados dentro de la Red Europea de Referencia de enfermedades metabólicas hereditarias (metabERN) (AU)

The Pediatric Mitochondrial and Hereditary Mctabolic Diseases Unit (MD-IMD) provides care for patients affected by Inborn Errors of Metabolism (IMD). It also provides genetic advice, prenatal diagnosis and diagnosis in their family members. Our hospital has all the medical, pediatric and adult specialities, as well as the necessary infrastructure to provide quality care. We have received some awards and acknowledgments for our work, granted by the associations of patients (Spanish Federation of Rare Diseases-FEDER-, Spanish Association of Rare Diseases -ACMEIM-). We have been named as an Expert Center of Reference for HMD detected in extended neonatal screening of the community of Madrid and a Reference Center for lnborn Err0rs of Metabolism for children and adults (CSUR -Centers, Services and Units of Reference) by the National Health Service. Actually we are working in the European Reference Network for Rare Hereditary Metabolic Disorders (metabERN) (AU)

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Fundamento y objetivo. Los fármacosantirretrovirales pueden ser causa de interaccionesmedicamentosas.Material y métodos. Se describen tres casosclínicos de pacientes infectados por VIH en los quedebido a una interacción farmacocinética se produjoun efecto adverso clínicamente relevante.Resultados. Caso 1: mujer de 43 años en tratamientocon tenofovir DF, emtricitabina y lopinavir/ritonavirque presenta isquemia de ambos miembros superioressecundaria a síndrome ergotamínico. Caso 2: varón de54 años en tratamiento con zidovudina, lamivudina ylopinavir/ritonavir que presenta síndrome de Cushingsecundario al uso de fluticasona inhalada. Caso 3:varón de 45 años en tratamiento con tenofovir DF,emtricitabina y atazanavir/ritonavir que presenta unfracaso virológico como consecuencia del consumoconcomitante de omeprazol.Conclusiones. Se deben considerar las potencialesinteracciones medicamentosas de los fármacosantirretrovirales cuando se administra otro fármacoconcomitantemente, especialmente cuando algunode éstos es inductor o inhibidor enzimático delcitocromo P-450

Background and aim. Antiretroviral drugs cancause drug interactions.Material and methods. Three clinical cases aredescribed regarding HIV-infected patients in whicha clinically relevant adverse effect occurred due to apharmacokinetic interaction.Results. Case 1: A 43-year old woman being treatedwith tenofovir DF, emtricitabine andlopinavir/ritonavir who presents ischemia in bothupper extremities following an ergotaminesyndrome. Case 2: A 54-year old man being treatedwith zidovudine, lamivudine and lopinavir/ritonavirwho presents Cushing syndrome following to use ofinhaled fluticasone. Case 3: A 45-year old manbeing treated with tenofovir DF, emtricitabine andatazanavir/ritonavir who presents a virologicalfailure as consequence of concomitant use ofomeprazole.Conclusions. Potential drug interactions must beconsidered when other concomitant drugs are usedwith antiretroviral therapy especially when one ofthese is a P 450 cytochrome enzymatic inductor orinhibitor

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Two new antiretroviral drugs belonging to a new drug family have recently been marketed in Spain. These are maraviroc (CCR5 correceptor inhibitor) and raltegravir (integrase inhibitor). These have the advantage of not presenting crossed resistance with other previously administered antiretroviral drugs, converting them into the cornerstone of the rescue treatment in the patient infected by a multiresistant viral strain. The scientific evidence available on these two drugs is reviewed in this work and its indications in the HIV infected patient are discussed.

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Recientemente se han comercializado en Españados fármacos antirretrovirales que pertenecen anuevas familias farmacológicas: maraviroc (inhibidordel correceptor CCR5) y raltegravir (inhibidor de laintegrasa). Tienen la ventaja de no presentarresistencia cruzada con otros fármacosantirretrovirales administrados previamente, lo quelos convierte en la piedra angular del tratamiento derescate en el paciente infectado por una cepa viralmultirresistente. En este trabajo se revisa laevidencia científica disponible de estos dosfármacos, y se comentan cuáles son sus indicacionesen el paciente infectado por el virus de lainmunodeficiencia humana (VIH)

Two new antiretroviral drugs belonging to a newdrug family have recently been marketed in Spain.These are maraviroc (CCR5 correceptor inhibitor)and raltegravir (integrase inhibitor). These have theadvantage of not presenting crossed resistance withother previously administered antiretroviral drugs,converting them into the cornerstone of the rescuetreatment in the patient infected by a multiresistantviral strain. The scientific evidence available onthese two drugs is reviewed in this work and its indications in the HIV infected patient are discussed (AU)

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Recientemente se han comercializado en Españados fármacos antirretrovirales que pertenecen anuevas familias farmacológicas: maraviroc (inhibidordel correceptor CCR5) y raltegravir (inhibidor de laintegrasa). Tienen la ventaja de no presentarresistencia cruzada con otros fármacosantirretrovirales administrados previamente, lo quelos convierte en la piedra angular del tratamiento derescate en el paciente infectado por una cepa viralmultirresistente. En este trabajo se revisa laevidencia científica disponible de estos dosfármacos, y se comentan cuáles son sus indicacionesen el paciente infectado por el virus de lainmunodeficiencia humana (VIH)

Two new antiretroviral drugs belonging to a newdrug family have recently been marketed in Spain.These are maraviroc (CCR5 correceptor inhibitor)and raltegravir (integrase inhibitor). These have theadvantage of not presenting crossed resistance withother previously administered antiretroviral drugs,converting them into the cornerstone of the rescuetreatment in the patient infected by a multiresistantviral strain. The scientific evidence available onthese two drugs is reviewed in this work and its indications in the HIV infected patient are discussed (AU)

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BACKGROUND AND AIM: Antiretroviral drugs can cause drug interactions. MATERIAL AND METHODS: Three clinical cases are described regarding HIV-infected patients in which a clinically relevant adverse effect occurred due to a pharmacokinetic interaction. RESULTS: Case 1: A 43-year old woman being treated with tenofovir DF, emtricitabine and lopinavir/ritonavir who presents ischemia in both upper extremities following an ergotamine syndrome. Case 2: A 54-year old man being treated with zidovudine, lamivudine and lopinavir/ritonavir who presents Cushing syndrome following to use of inhaled fluticasone. Case 3: A 45-year old man being treated with tenofovir DF, emtricitabine and atazanavir/ritonavir who presents a virological failure as consequence of concomitant use of omeprazole. CONCLUSIONS: Potential drug interactions must be considered when other concomitant drugs are used with antiretroviral therapy especially when one of these is a P 450 cytochrome enzymatic inductor or inhibitor.

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BACKGROUND AND OBJECTIVE: Tuberculosis is an infectious disease currently having great importance in the daily clinical practice in Spain. Some cases of active tuberculosis are not identified until after the patient had died and an autopsy has been performed. This study has analyzed the clinical and pathological characteristics of patients diagnosed with active tuberculosis in the autopsy. MATERIAL AND METHOD: We reviewed all the autopsies performed in the University Hospital 12 de Octubre of Madrid between 1974 and 2002. The autopsy reports and clinical records were examined in those cases in which active tuberculosis was found. RESULTS: We found 92 cases of active tuberculosis, 57% corresponding to men. Mean age of this group was 64 years. A total of 20% of the patients died within 48 hours after admission. Predisposing factors were identified in 90% of the cases. Dyspnea (24% of cases) and wasting syndrome (23%) were the main symptoms that motivated patients to request medical attention. Up to 30% of cases had normal chest X-ray. Tuberculosis was suspected in only 46% of patients before death. Principal cause of death was tuberculosis in 61% of patients, 52% of patients had pulmonary tuberculosis, 28% suffered from miliary tuberculosis and 20% from extra-pulmonary tuberculosis. The lungs were the most frequently affected organ. Epithelioid granulomas were found in all patients. CONCLUSIONS: Tuberculosis is an uncommon finding in the autopsy as the cause of death. The presence of unspecific symptomatology, insufficient cost-effectiveness of the diagnostic tests and precocious death, are identified as the most frequent causes of undiagnosed tuberculosis.

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Fundamento y objetivo. En España, la tuberculosis es una enfermedad con importante relevancia en la práctica clínica diaria. En ocasiones su diagnóstico sorprende como hallazgo en la necropsia. El objetivo de este trabajo ha sido analizar las características clínico-anatomopatológicas que presentan los pacientes diagnosticados de tuberculosis activa en la necropsia. Material y método. Se revisaron retrospectivamente todas las autopsias de adultos realizadas en el Hospital Universitario 12 de Octubre de Madrid entre los años 1974 y 2002. En aquellos pacientes en los que se llegó al diagnóstico de tuberculosis activa se revisó la historia clínica y el informe anatomopatológico según protocolo establecido previamente. Resultados. Se encontraron 92 casos de tuberculosis activa. El 57% correspondía a hombres. La edad media de los pacientes era de 64 años. El 90% de los casos presentaba alguno de los factores predisponentes controlados. El 20% falleció en las primeras 48 horas tras el ingreso. Los motivos de consulta más frecuentes fueron la disnea (24% de los casos) y el síndrome constitucional (23%). Hasta el 30% de los casos presentaba una radiografía de tórax normal a su ingreso. Sólo en el 46% de los casos se sospechó la tuberculosis previa al fallecimiento y en el 61% fue ésta la causa del éxitus. El 52% presentaba una tuberculosis pulmonar, el 28% una tuberculosis miliar y el 20% extrapulmonar. El órgano más frecuentemente afectado fue el pulmón. En los 92 casos se encontraron granulomas epitelioides. Conclusiones. La tuberculosis es en España una causa poco frecuente de muerte en la autopsia. La presencia de sintomatología inespecífica, la escasa rentabilidad de las pruebas diagnósticas y el fallecimiento precoz hacen que un importante porcentaje de casos de tuberculosis lleguen sin diagnóstico a la necropsia (AU)

Background and objective. Tuberculosis is an infectious disease currently having great importance in the daily clinical practice in Spain. Some cases of active tuberculosis are not identified until after the patient had died and an autopsy has been performed. This study has analyzed the clinical and pathological characteristics of patients diagnosed with active tuberculosis in the autopsy. Material and method. We reviewed all the autopsies performed in the University Hospital 12 de Octubre of Madrid between 1974 and 2002. The autopsy reports and clinical records were examined in those cases in which active tuberculosis was found. Results. We found 92 cases of active tuberculosis, 57% corresponding to men. Mean age of this group was 64 years. A total of 20% of the patients died within 48 hours after admission. Predisposing factors were identified in 90% of the cases. Dyspnea (24% of cases) and wasting syndrome (23%) were the main symptoms that motivated patients to request medical attention. Up to 30% of cases had normal chest X-ray. Tuberculosis was suspected in only 46% of patients before death. Principal cause of death was tuberculosis in 61% of patients, 52% of patients had pulmonary tuberculosis, 28% suffered from miliary tuberculosis and 20% from extra-pulmonary tuberculosis. The lungs were the most frequently affected organ. Epithelioid granulomas were found in all patients. Conclusions. Tuberculosis is an uncommon finding in the autopsy as the cause of death. The presence of unspecific symptomatology, insufficient cost-effectiveness of the diagnostic tests and precocious death, are identified as the most frequent causes of undiagnosed tuberculosis (AU)

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