Delayed Leukoencephalopathy: Three Case Reports and a Literature Review

Background: Delayed leukoencephalopathy (DL) is a rare entity associated with cerebral hypoxia and heroin consumption. We describe the clinical course of three cases of DL due to non-heroin drug use. Material and methods: We describe the cases of three DL patients admitted to our hospital in 2012. Discussion: These cases contribute to the aetiological spectrum of DL since multifactorial causes could account for the clinical symptoms

Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.Fac. de MedicinaTRUEUnión EuropeaInstituto de Salud Carlos IIIFundación Mutua Madrileña de Investigación Médicapu

Diagnosis and Management of Inborn Errors of Metabolism in Adult Patients in the Emergency Department

Inborn errors of metabolism (IEM) constitute an important group of conditions characterized by an altered metabolic pathway. There are numerous guidelines for the diagnosis and management of IEMs in the pediatric population but not for adults. Given the increasing frequency of this group of conditions in adulthood, other clinicians in addition to pediatricians should be aware of them and learn to identify their characteristic manifestations. Early recognition and implementation of an appropriate therapeutic approach would improve the clinical outcome of many of these patients. This review presents when and how to investigate a metabolic disorder with the aim of encouraging physicians not to overlook a treatable disorder.Depto. de MedicinaFac. de MedicinaTRUEUnión EuropeaInstituto de Salud Carlos IIIFundación Mutua Madrileña de Investigación Médicapu

Understanding the ecosystem of patients with lysosomal storage diseases in Spain: a qualitative research with patients and health care professionals

Background Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients' quality of life. Methods Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people's views and actions. The study was conducted through in-depth face-to-face semi-structured interviews. Results In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers. Conclusions Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life

High Prevalence of Insulin Resistance in Asymptomatic Patients with Acute Intermittent Porphyria and Liver-Targeted Insulin as a Novel Therapeutic Approach

Acute porphyria attacks are associated with the strong up-regulation of hepatic heme synthesis and over-production of neurotoxic heme precursors. First-line therapy is based on carbohydrate loading. However, altered glucose homeostasis could affect its efficacy. Our first aim was to investigate the prevalence of insulin resistance (IR) in an observational case-control study including 44 Spanish patients with acute intermittent porphyria (AIP) and 55 age-, gender- and BMI-matched control volunteers. Eight patients (18.2%) and one control (2.3%, p = 0.01) showed a high HOMA-IR index (cut-off ≥ 3.4). Patients with IR and hyperinsulinemia showed clinically stable disease. Thus, the second aim was to evaluate the effect of the co-administration of glucose and a fast-acting or new liver-targeted insulin (the fusion protein of insulin and apolipoprotein A-I, Ins-ApoAI) in AIP mice. The combination of glucose and the Ins-ApoAI promoted partial but sustained protection against hepatic heme synthesis up-regulation compared with glucose alone or co-injected with fast-acting insulin. In a prevention study, Ins-ApoAI improved symptoms associated with a phenobarbital-induced attack but maintained high porphyrin precursor excretion, probably due to the induction of hepatic mitochondrial biogenesis mediated by apolipoprotein A-I. In conclusion, a high prevalence of IR and hyperinsulinemia was observed in patients with AIP. The experimental data provide proof-of-concept for liver-targeted insulin as a way of enhancing glucose therapy for AIP

Plasma Gelsolin Reinforces the Diagnostic Value of FGF-21 and GDF-15 for Mitochondrial Disorders

Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is highly relevant. Previous studies identified Gelsolin as a regulator of cell survival adaptations triggered by mitochondrial defects. Gelsolin presents a circulating plasma isoform (pGSN), whose altered levels could be a hallmark of mitochondrial dysfunction. Therefore, we investigated the diagnostic performance of pGSN for MD relative to FGF-21 and GDF-15. Using ELISA assays, we quantified plasma levels of pGSN, FGF-21, and GDF-15 in three age- and gender-matched adult cohorts: 60 genetically diagnosed MD patients, 56 healthy donors, and 41 patients with unrelated neuromuscular pathologies (non-MD). Clinical variables and biomarkers’ plasma levels were compared between groups. Discrimination ability was calculated using the area under the ROC curve (AUC). Optimal cut-offs and the following diagnostic parameters were determined: sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and efficiency. Comprehensive statistical analyses revealed significant discrimination ability for the three biomarkers to classify between MD and healthy individuals, with the best diagnostic performance for the GDF-15/pGSN combination. pGSN and GDF-15 preferentially discriminated between MD and non-MD patients under 50 years, whereas FGF-21 best classified older subjects. Conclusion: pGSN improves the diagnosis accuracy for MD provided by FGF-21 and GDF-15

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

Background 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

El cribado metabólico del recién nacido como modelo asistencial de la medicina de precisión. Perspectiva desde la Asociación Española para el Estudio de los Errores Congénitos del Metabolismo (AECOM)

Los programas de cribado de enfermedades congénitas en los recién nacidos tienen como objetivo lograr un diagnóstico presintomático y temprano de trastornos tratables, con el fin de prevenir o reducir significativamente la morbilidad y/o mortalidad. Muchas de las condiciones incluidas en es estos programas son errores innatos del metabolismo (EIM); sin embargo, la detección de enfermedades endocrinas, hematológicas, inmunológicas, cardiovasculares, y la hipoacusia congénita también se incluyen en muchos de ellos. Las pruebas de detección de recién nacidos no son diagnósticas y, por tanto, se necesitan pruebas complementarias para con firmar o excluir la sospecha diagnóstica. La demanda social y profesional de la mano de los avances tecnológicos y de nuevas opciones de tratamiento, permiten la expansión continua del cribado neonatal; este progreso conlleva un claro beneficio para los pacientes, pues gracias al diagnóstico y al tratamiento precoz de su enfermedad pueden tener un mejor pronóstico y una mejor calidad de vida. Los criterios de inclusión de las diferentes enfermedades no deben ser valorados exclusivamente con el prisma del momento en que se realiza la evaluación, es necesario aplicar una visión de oportunidad a largo plazo basada en las fortalezas del sistema sanitario. Hoy en día, tras 50 años de recorrido, podemos asegurar que los programas de cribado neonatal constituyen uno de los avances más significativos que se han producido en salud pública, su práctica generalizada ha significado uno de los grandes logros asistenciales en pediatría y están marcando la organización asistencial de muchas unidades de adultos. De la mano de los avances en genética y genómica, los programas de cribado del recién nacido continuarán expandiéndose para aquellos trastornos en los que una intervención temprana pueda modificar significativamente el curso de la enfermedad