Clinical and molecular diagnosis of non-phosphomannomutase 2 N-linked congenital disorders of glycosylation in Spain.

The congenital disorders of glycosylation (CDG) are defects in glycoprotein and glycolipid glycan synthesis and attachment. They affect multiple organ/systems, but non-specific symptoms render the diagnosis of the different CDG very challenging. Phosphomannomutase 2 (PMM2)-CDG is the most common CDG, but advances in genetic analysis have shown others to occur more commonly than previously thought. The present work reports the clinical and mutational spectrum of 25 non-PMM2 CDG patients. The most common clinical symptoms were hypotonia (80%), motor or psychomotor disability (80%) and craniofacial dysmorphism (76%). Based on their serum transferrin isoform profile, 18 were classified as CDG-I and 7 as CDG-II. Pathogenic variations were found in 16 genes (ALG1, ALG6, ATP6V0A2, B4GALT1, CCDC115, COG7, DOLK, DPAGT1, DPM1, GFPT1, MPI, PGM1, RFT1, SLC35A2, SRD5A3, and SSR4). Overall, 27 variants were identified, 12 of which are novel. The results highlight the importance of combining genetic and biochemical analyses for the early diagnosis of this heterogeneous group of disorders.

Breastfeeding and Inborn Errors of Amino Acid and Protein Metabolism: A Spreadsheet to Calculate Optimal Intake of Human Milk and Disease-Specific Formulas.

Human milk (HM) offers important nutritional benefits. However, except for phenylketonuria (PKU), there are little data on optimal levels of consumption of HM and a special formula free of disease-related amino acids (SF-AA) in infants with inborn errors of metabolism of amino acids and proteins (IEM-AA-P). We designed a spreadsheet to calculate the amounts of SF-AA and HM required to cover amino acid, protein, and energy needs in patients with the nine main IEM-AA-P in infants aged under 6 months. Upon entering the infant's weight and the essential amino acid or intact protein requirements for the specific IEM, the spreadsheet calculates the corresponding required volume of HM based on the amino acid concentration in HM. Next, the theoretical daily fluid intake (typical range, 120-200 mL/kg/day) is entered, and the estimated daily fluid intake is calculated. The required daily volume of SF-AA is calculated as the difference between the total fluid intake value and the calculated volume of HM. The spreadsheet allows for the introduction of a range of requirements based on the patient's metabolic status, and includes the option to calculate the required volume of expressed HM, which may be necessary in certain conditions such as MMA/PA and UCD. In cases in which breastfeeding on demand is feasible, the spreadsheet determines the daily amount of SF-AA divided over 6-8 feeds, assuming that SF-AA is administered first, followed by HM as needed. Intake data calculated by the spreadsheet should be evaluated in conjunction with data from clinical and nutritional analyses, which provide a comprehensive understanding of the patient's nutritional status and help guide individualized dietary management for the specific IEM.

Hyperhomocysteinemia in Adult Patients: A Treatable Metabolic Condition.

Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for various significant medical conditions, yet controversy persists around its assessment and management. The diagnosis of disorders afffecting homocysteine (Hcy) metabolism faces delays due to insufficient awareness of its clinical presentation and unique biochemical characteristics. In cases of arterial or venous thrombotic vascular events, particularly with other comorbidities, it is crucial to consider moderate to severe HHcy. A nutritional approach to HHcy management involves implementing dietary strategies and targeted supplementation, emphasizing key nutrients like vitamin B6, B12, and folate that are crucial for Hcy conversion. Adequate intake of these vitamins, along with betaine supplementation, supports Hcy remethylation. Lifestyle modifications, such as smoking cessation and regular physical activity, complement the nutritional approach to enhance Hcy metabolism. For individuals with HHcy, maintaining a plasma Hcy concentration below 50 µmol/L consistently is vital to lowering the risk of vascular events. Collaboration with healthcare professionals and dietitians is essential for developing personalized dietary plans addressing the specific needs and underlying health conditions. This integrated approach aims to optimize metabolic processes and reduce the associated health risks.

Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project.

BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

Cross-cultural adaptation to Spanish and content validity of three nutritional risk scales.

INTRODUCTION: There are various scales designed to determine the risk of malnutrition at hospital admission in children. However, most of these instruments are developed and published in English. Their cross-cultural adaptation and validation being mandatory in order to be used in our country. OBJECTIVES: Cross-culturally adapt three scales designed to determine the risk of malnutrition linked to the disease and determine the validity of their content. MATERIAL AND METHODS: Cross-cultural adaptation using the translation-back-translation method in accordance with the recommendations of the International Test Commission Guidelines for Translating and Adapting Tests. Content validity was measured by a panel of experts (under seven basic selection criteria adapted from the Fehring model) who evaluated each item of the scales by measuring 4 criteria: ambiguity, simplicity, clarity and relevance. With the extracted score, Aiken's V statistic was obtained for each item and for the complete scales. RESULTS: Starting from three independent translations per scale, 3 definitive versions in Spanish of the PNRS, STRONGkids and STAMP scales were obtained semantically equivalent to their original versions. The PNRS and STRONGkids scales presented an Aiken's V greater than 0.75 in all their items, while the STAMP scale presented a value less than 0.75 for the item "weight and height". CONCLUSION: This study provides the transculturally adapted Spanish versions of the PNRS, STRONGkids and STAMP scales. The PNRS and STRONGkids scales present valid content to be applied in the state hospital context. STAMP requires the adaptation of its item "weight and height" to consider its use in a Spanish child population adequate.

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.

Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance.

Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = -0.386, p = 0.024) and FSS (R = -0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.

Implementation and results of a risk-sharing scheme for enzyme replacement therapy in lysosomal storage diseases.

OBJECTIVE: To describe a risk-sharing program's implementation and  results on enzyme replacement therapy for lysosomal diseases. METHOD: The program was designed and implemented in a referral hospital for congenital metabolic diseases. The conclusion of  agreements required the following phases: 1) To define and agree on  response variables and criteria to treatment; 2) to assign discount  percentage to each stage of effectiveness; 3) to prepare and sign the  agreement by all parties; 4) to implement the agreement; 5) to  individualize purchases management; 6) to evaluate clinical results, and  7) to issue an annual report. RESULTS: Eight patients were included in the program (four with Hurler's disease, two with Pompe and two with Gaucher), five of them  were women and three were men. After analyzing the defined variables  and response criteria, all patients presented full effectiveness after two  or three years of follow-up except one of them that could not be  evaluated. Given the effectiveness achieved, the hospital made full  payment of all administered therapies. CONCLUSIONS: The implanted risk-sharing program is Spain's first  published event of paying for clinical results using orphan drugs.  Economic impact has been limited, and program implementation has  gone through a complex process of formulation and management.  However, the greatest achievement has been to reduce the knowledge  gap between efficacy and effectiveness, stating that the therapies  administered have shown the optimal benefits for which the funder is  willing to pay.

Objetivo: Describir la implantación y los resultados de un programa de riesgo compartido para el tratamiento enzimático sustitutivo de  enfermedades lisosomales.Método: Se diseñó y aplicó el programa en un hospital de referencia para enfermedades congénitas del metabolismo. La  consecución de los acuerdos requirió las siguientes fases: 1) Definir y  consensuar las variables y criterios de respuesta al tratamiento; 2)  asignar el porcentaje de descuento a cada escalón de efectividad; 3)  elaborar y firmar el acuerdo por todas las partes; 4) implantar el  acuerdo; 5) individualizar la gestión de compras; 6) evaluar los  resultados clínicos, y 7) emitir un informe anual.Resultados: Se incluyeron ocho pacientes en el programa (cuatro con enfermedad de Hurler, dos con enfermedad de Pompe y dos con  enfermedad de Gaucher), siendo cinco de ellos mujeres y tres varones.  Tras analizar las variables y criterios de respuesta definidos, todos los  pacientes presentaron efectividad plena tras dos o tres años de  seguimiento, excepto uno de ellos que no se pudo evaluar. Dada la  efectividad alcanzada, el hospital realizó el pago íntegro de todos los  tratamientos administrados.Conclusiones: El programa de riesgo compartido implantado es la primera experiencia publicada de pago por resultados clínicos en  medicamentos huérfanos en España. El impacto económico ha sido  limitado y la implantación del programa no ha estado exenta de  complejidad de formulación y de gestión. Sin embargo, el mayor logro  ha sido reducir la brecha de conocimiento entre eficacia y efectividad,  constatando que las terapias administradas han mostrado los beneficios  óptimos por los que está dispuesto a pagar el financiador.

[The importance of water consumption in health and disease prevention: the current situation]. / Importancia del consumo de agua en la salud y la prevención de la enfermedad: situación actual.

INTRODUCTION: Water is an essential nutrient for life and the most abundant component in the human body. However, its dietary recommendations or clinical management guidelines do not receive as much attention as they deserve. In addition, there are some obstacles to establishing optimal values, both for the amount of water the body must contain and for water ingestion. Water intake and elimination depend on unsteady factors that are difficult to measure and, at the same time, compensated by the body's ability to regulate homeostasis. Since scientific evidence is lacking for establishing recommendations, "adequate intakes" (to maintain an adequate hydration state) have been estimated using data on water intake from groups of healthy people. The European Food Safety Authority (EFSA) also considers desirable the use of urine osmolarity to estimate the adequacy of water intake in adults. Clinical studies have generally shown the benefits of adequate hydration and the damage caused by water imbalance, whether quantitative (dehydration and overhydration) or qualitative (extracellular and intracellular water). Unfortunately, these studies are few and often have poor cross-sectional, case-control, or prospective designs, and use small samples or indirect methods to assess hydration status. This article presents up-to-date information on subjects such as: 1) compliance with water consumption recommendations and suggestions for improvement; 2) techniques available to measure hydration status and their clinical applications; 3) effects of hydration/dehydration on physical or cognitive activities and chronic diseases; and 4) existing Spanish regulations on the quality and salubrity of water.

INTRODUCCIÓN: Aunque el agua es un nutriente esencial para la vida y el componente más abundante de nuestro cuerpo, recibe escasa atención en las recomendaciones dietéticas y las guías clínicas. Existen inconvenientes para determinar las cifras óptimas, tanto para la cantidad de agua que debe contener el cuerpo como para su ingesta. La ingesta y eliminación del agua dependen de factores no constantes y difíciles de medir, a su vez compensados por la capacidad del organismo para la homeostasis. Dada la falta de evidencia científica para el establecimiento de recomendaciones, se han estimado las "ingestas adecuadas" (para mantener un estado de hidratación adecuado) utilizando datos de ingestas de agua en grupos de personas sanas. La Autoridad Europea de Seguridad Alimentaria (EFSA) también considera la osmolaridad deseable en la orina para estimar la ingesta adecuada de agua en los adultos. Los estudios clínicos han mostrado en general beneficios con una hidratación adecuada y perjuicios con sus desequilibrios, ya sean cuantitativos (deshidratación y sobrehidratación) o cualitativos (agua extracelular e intracelular). Desafortunadamente, estos estudios son escasos y suelen tener diseños deficientes, ya sean transversales, de casos y controles o prospectivos, utilizando muestras pequeñas o métodos indirectos para evaluar el estado de hidratación. En este artículo se presenta información de actualización respecto a: 1) la adherencia a las recomendaciones de consumo de agua y sugerencias para mejorarla; 2) técnicas disponibles para medir el estado de hidratación y sus aplicaciones clínicas; 3) efectos de la hidratación/deshidratación en las actividades físicas o cognitivas y en las enfermedades crónicas; y 4) normativa española sobre calidad y salubridad del agua.

Audiological findings in children with mucopolysaccharidoses type i-iv. / Hallazgos audiológicos en niños con mucopolisacaridosis tipos i-iv.

OBJECTIVE: The aim of our study is to reflect hearing impairment of 23children diagnosed with mucopolysaccharidosis (MPS) typeI, II, III and IV. METHODS: Retrospective study of the clinical, audiological and treatment (medical vs surgical) findings of 23children diagnosed with MPS typeI, II, III or IV followed at a Tertiary Referral Hospital between 1997 and 2015. RESULTS: Six cases of MPSI, 8 of MPSII, 4 of MPSIII and 5 of MPSIV were reviewed. 71.2% of patients had secretory otitis media (SOM) and 54% of patients had some type of hearing loss (HL). The behaviour of hearing loss was variable in each of the subgroups of MPS, finding greater involvement and variability in typesI and II. CONCLUSIONS: Children with MPS have a high risk of hearing loss. A significant percentage of transmissive HL progressing to mixed or sensorineural HL was observed. This was more common in typesI and II. Periodic follow up of these patients is mandatory because of hearing impairment and consequences for their development and quality of life.

Clinical response to long term enzyme replacement treatment in children, adolescent and adult patients with Hunter syndrome.

BACKGROUND AND OBJECTIVE: Since enzyme replacement treatment (ERT) with idursulfase is available for Hunter syndrome (HS; mucopolysaccharidosis type II), for the first time, disease progression can be limited and organ damage reduced or prevented. PATIENTS AND METHODS: We described retrospectively the clinical evolution of eight HS males, treated with ERT and followed in routine clinical practice in Hospital Infantil La Fe (Valencia, Spain). RESULTS: We studied three children, three adolescents and two adults. Time from diagnosis to ERT ranged from 13.7 to 0.2 years, and duration of ERT ranged from 24 to 77.1 months. From the start of ERT, weight and height increased in children and adolescents and remained stable in adults. Glycosaminoglycans (GAG) decreased in all patients; in patient 5 (aged 23 years), we observed the highest reduction (86%) with recovery of carpal tunnel syndrome, splenomegaly and a decrease in nocturnal oxygen dependence. CONCLUSION: Our results show that ERT improve respiratory impairment and organomegalies and decrease GAGs levels in all patients including children, adolescent and adults. While cardiac manifestations and facial features stabilized, responses in other parameters were heterogeneous.

Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases.

BACKGROUND: Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain. METHODS: Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities. RESULTS: 104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 µmol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid. CONCLUSIONS: Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care.

Teratomas sacrocoxígeos / Sacrococygeal teratoma

Se realiza una revisión acerca de los teratomas sacrocoxígeos en la que se hace una especial referencia a los aspectos anatomopatológicos, clínicos, diagnósticos, terapéuticos y pronósticos. Tiene una incidencia de 1 en 40000 nacimientos y predominan en el sexo femenino. La degeneración maligna puede ocurrir en un 18. El tratamiento es fundamentalmente quirúrgico y el pronóstico depende de dos factores: la edad de diagnóstico y su localización. Si el diagnóstico se realiza a edad superior a 2 años, la mortalidad es de un 55 mientras que los de localización tipo III de Altmman tienen una mortalidad de 28. Las recidivas posoperatorias son raras y son más probables en tumores con predominio de tejido nervioso o compuestos de tejidos de una sola hoja embrionaria