Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain

Nephrocalcinosis; Phenotype; Severe liver dysfunctionNefrocalcinosis; Fenotipo; Disfunción hepática graveNefrocalcinosi; Fenotip; Disfunció hepàtica greuTreatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 ± 4.9 and 10.6 ± 5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity

Problem-Based Learning in Plant Biology (Poster)

Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEsubmitte

Epidemiología y clínica de las infecciones y colonizaciones causadas por enterobacterias productoras de carbapenemasas en un hospital de tercer nivel

Objective. To describe the epidemiology of Enterobactera-les producing carbapenemases (EPC) in a tertiary hospital. Material and methods. A retrospective observational study, all patients with a positive sample for EPC treated in hospitalization or in the Emergency Department were included, between January 1, 2014 and December 31, 2016. Results. A total of 272 patients (316 samples) were in-cluded: 155 (57%) male. Mean age of 70.4 years (95% CI 68.2-72.7). Mean Charlson index was 3.6 (95% CI 3.4-3.8). In 63.2% the acquisition was nosocomial, in 35.3% it was health-care associated (HA). 55.1% presented infection, the most frequent infection was urinary tract infection (UTI) (58.7%). The most frequent species were Klebsiella pneumoniae (62.7%) and Enterobacter cloacae (10.1%). The most frequent types of carbapenemase were OXA-48 (53.8%) and VIM (43%). The nosocomial acquisition was associated with the male gender, transplantation, immunosuppression, admission to the Intensi-ve Care Unit (ICU) or surgical service, prior antibiotic treatment, Enterobacter, VIM, respiratory and intra-abdominal infections. The HA acquisition was associated with age and comorbidity, nursery home origin, bladder catheterization, greater number of outpatient procedures, previous hospital admission, K. pneu-moniae and E. coli, OXA-48, coproduction of extended spectrum betalactamases, UTI and sepsis. Conclusions. Patients who acquire EPC in nursery homes frequently have an infection. Patients with nosocomial acquisition are colonized by EPC in the ICU, in relation to invasive procedures and transplantation. This population has a higher mortality due to developing respiratory infections by EPC

Clinical features and health-related quality of life in adult patients with mucopolysaccharidosis IVA: the Spanish experience

Elosulfasa alfa; Qualitat de vida relacionada amb la salut; Síndrome de Morquio AElosulfasa alfa; Calidad de vida relacionada con la salud; Síndrome de Morquio AElosulfase alfa; Health-related quality of life; Morquio A syndromeBackground Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is a progressive and disabling disease characterized by a deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulphatase. Its clinical presentation is very heterogeneous and poorly understood in adults. The aim of this study was to describe the clinical manifestations of MPS IVA in adult patients in Spain and to assess their health-related quality of life (HRQoL). Results Thirty-three patients from nine reference centres participated in the study. The median age was 32 (interquartile range [IQR]: 20.5–40.5) years. The phenotype was classical in 54.5% of patients, intermediate in 33.3% of patients, and non-classical in 12.1% of patients. The most common clinical manifestation was bone dysplasia, with a median height of 118 (IQR: 106–136) cm. Other frequent clinical manifestations were hearing loss (75.7%), ligamentous laxity (72.7%), odontoid dysplasia (69.7%), limb deformities that required orthopaedic aids (mainly hip dysplasia and genu valgus) (63.6%), and corneal clouding (60.6%). In addition, 36.0% of patients had obstructive sleep apnoea/hypopnoea syndrome and 33.3% needed non-invasive ventilation. Cervical surgery and varisation osteotomy were the most common surgical interventions (36.4% each). Almost 80% of patients had mobility problems and 36.4% used a wheelchair at all times. Furthermore, 87.9% needed help with self-care, 33.3% were fully dependent, and 78.8% had some degree of pain. HRQoL according to the health assessment questionnaire was 1.43 (IQR: 1.03–2.00) in patients with the non-classical phenotype, but 2.5 (IQR: 1.68–3.00) in those with the classical phenotype. Seven patients were initiated on enzyme replacement therapy (ERT), but two of them were lost to follow-up. Lung function improved in four patients and slightly worsened in one patient. The distance achieved in the six-minute walk test increased in the four patients who could perform it. HRQoL was better in patients treated with elosulfase alfa, with a median (IQR) of 1.75 (1.25–2.34) versus 2.25 (1.62–3.00) in patients not treated with ERT. Conclusions The study provides real-world data on patients with MPS IVA. Limited mobility, difficulties with self-care, dependence, and pain were common, together with poor HRQoL. The severity and heterogeneity of clinical manifestations require the combined efforts of multidisciplinary teams.BioMarin Pharmaceuticals España SL. funded the writing of this paper

Acylcarnitine profile in neonatal hypoxic-ischemic encephalopathy: The value of butyrylcarnitine as a prognostic marker

Optimal prognostic markers evaluating early neuroprotective interventions in neonatal hypoxic-ischemic encephalopathy (HIE) are lacking. This study was designed to assess the prognostic value of acylcarnitines in neonatal HIE.An observational cohort study was conducted over 10 years in 67 HIE. Variables analyzed included sex, blood cord pH, Apgar score, hypothermia treatment (yes/no), neuron-specific enolase (NSE) levels, and clinical outcome (neurological examination, brain magnetic resonance imaging [MRI], and electroencephalogram) before discharge and at 6 months. Acylcarnitine profiles were analyzed by tandem-mass spectrometry on dried-blood spots collected on day 3 for newborn screening. A cohort of healthy newborns was used as control group.HIE patients had significantly increased C4, C5, C5:1, C6, C6-OH, C8 levels (all P < .01) and decreased long-chain acylcarnitine levels (P < .03). Hypothermia treatment was associated with a decrease in C4 levels (p = 0.005) and an increase in most long-chain acylcarnitine levels (P < .01). A significant association was found between C4 levels and NSE on day 1 of hypothermia treatment (P = .002) and abnormal brain magnetic resonance imaging (MRI) at discharge (P = .037). In the hypothermia group, C4 levels decreased in patients with favorable outcomes but remained high in those who progressed unfavorably.C4 appears to be a good prognostic marker in HIE, as blood levels correlated with NSE levels and abnormal MRI findings. Furthermore, hypothermia did not lead to decreased levels in patients with adverse outcomes

Inflammatory myopathy in the context of an unusual overlapping laminopathy

Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery–Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot–Marie–Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff–Parkinson– White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.This work was funded by the Instituto de Salud Carlos III (grant number: PI081449) and the European Regional Development Fund, FEDER. In addition, SRG was awarded a Research Fellowship granted by the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP)S

Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain

Clinical practice; Glycerol phenylbutyrate; Urea cycle disordersPráctica clinica; Fenilbutirato de glicerol; Trastornos del ciclo de la ureaPràctica clínica; Fenilbutirat de glicerol; Trastorns del cicle de la ureaBackground and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 μmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 μmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments.This study was funded by AECOM (Spanish Association for the Study of Inborn Errors of Metabolism). Immedica Pharma Spain funded medical writing support and article processing charges

Efficacy and safety of preoperative preparation with Lugol's iodine solution in euthyroid patients with Graves’ disease (LIGRADIS Trial): Study protocol for a multicenter randomized trial

Background: Currently, both the American Thyroid Association and the European Thyroid Association recom mend preoperative preparation with Lugol's Solution (LS) for patients undergoing thyroidectomy for Graves’ Disease (GD), but their recommendations are based on low-quality evidence. The LIGRADIS trial aims to pro vide evidence either to support or refute the systematic use of LS in euthyroid patients undergoing thyroidec tomy for GD. Methods: A multicenter randomized controlled trial will be performed. Patients ≥18 years of age, diagnosed with GD, treated with antithyroid drugs, euthyroid and proposed for total thyroidectomy will be eligible for inclusion. Exclusion criteria will be prior thyroid or parathyroid surgery, hyperparathyroidism that requires associated parathyroidectomy, thyroid cancer that requires adding a lymph node dissection, iodine allergy, consumption of lithium or amiodarone, medically unfit patients (ASA-IV), breastfeeding women, preoperative vocal cord palsy and planned endoscopic, video-assisted or remote access surgery. Between January 2020 and January 2022, 270 patients will be randomized for either receiving or not preoper ative preparation with LS. Researchers will be blinded to treatment assignment. The primary outcome will be the rate of postoperative complications: hypoparathyroidism, recurrent laryngeal nerve injury, hematoma, surgical site infection or death. Secondary outcomes will be intraoperative events (Thyroidectomy Difficulty Scale score, blood loss, recurrent laryngeal nerve neuromonitoring signal loss), operative time, postoperative length of stay, hospital readmissions, permanent complications and adverse events associated to LS. Conclusions: There is no conclusive evidence supporting the benefits of preoperative treatment with LS in this set ting. This trial aims to provide new insights into future Clinical Practice Guidelines recommendations. Trial registration: ClinicalTrials.gov identifier: NCT03980132

Rol del amamantamiento en el desarrollo del sistema estomatognático

La lactancia materna, permite al infante, ingerir elementos nutricios y relacionarse con el medio. La succión es relevante, no solo asegura la obtención del alimento y el normal desarrollo psico- emocional del lactante, sino que además, genera fuerzas activas que actúan sobre las estructuras del sistema estomatognático. El ejercicio muscular en cada mamada, actúa como estímulo significativo en la conformación de los maxilares y estructuras adyacentes. La lactancia artificial, implica una función mecánica disminuida, lo que redunda en un deficiente desarrollo. El objetivo de este trabajo, es valorar el rol que la lactancia materna juega en el desarrollo armónico del sistema estomatognático