Evolución y seguimiento de pacientes detectados en el nuevo cribado de la Comunidad de Madrid: nuestra experiencia

El cribado neonatal por espectrometría de masas en tandem permite la detección de algunos errores congénitos del metabolismo (ECM) con el fin de iniciar un tratamiento precoz y así poder evitar morbimortalidad y discapacidades asociadas. Así mismo, permite conocer la incidencia real de los ECM que puede variar entre los diferentes países y regiones geográficas. Algunos estudios han demostrado una mejoría en la evolución clínica de algunos ECM. No obstante, algunas cuestiones quedan por aclarar. En la Comunidad de Madrid se inició el cribado ampliado en el año 2011. Objetivos: Conocer la incidencia de los ECM y la evolución clínica de los pacientes detectados mediante el nuevo cribado ampliado en la Comunidad de Madrid durante los primeros dos años desde su inicio. Pacientes y métodos: Estudio prospectivo, observacional, descriptivo. Recién nacidos derivados al Hospital Universitario 12 de Octubre, tras detectar niveles fuera de rango en el cribado neonatal ampliado desde abril del año 2011 hasta mayo de 2013. Se han recogido datos bioquímicos, genéticos, tratamiento, síntomas clínicos, episodios intercurrentes y de descompensación metabólica y valoración de neurodesarrollo. Resultados: Se ha realizado el cribado neonatal a 83.774 recién nacidos durante el periodo de estudio. 98 casos fueron remitidos por presentar alteraciones. 30 casos han sido diagnosticados de ECM. La incidencia global de ECM es 1/2.792 recién nacidos. La incidencia de aminoacidopatías es de 1/9.308 recién nacidos vivos, 1/5.235 de los trastornos de la oxidación de los ácidos grasos (FAO) y 1/16.754 de las acidurias orgánicas. Los ECM diagnosticados con más frecuencia han sido el déficit de acil-CoA deshidrogenasa de cadena media (MCADD) con una incidencia de 1/11.967, seguidos del déficit de acil-CoA deshidrogenasa de cadena muy larga (VLCADD) con 1/16.754 y la aciduria glutárica (AG1) con 1/20.943. La especificidad del cribado es del 99,92 %, y el valor predictivo positivo de la prueba es del 30,61%. Un 20% de los pacientes con ECM (6/30) presentaron algún síntoma o alteración analítica previa al resultado del cribado. El inicio del tratamiento es significativamente precoz en los pacientes diagnosticados por cribado con un mediana de 18 días (rango intercuartil: 11-31) con respecto al grupo de pacientes diagnosticados en la Unidad previo a su implantación 365 días (213-2190); p <0,001. El 83% de nuestros pacientes precisan tratamiento nutricional. Las medidas antropométricas de los pacientes estaban dentro de lo normal al inicio del tratamiento pero mejoraron durante el seguimiento. Ningún caso diagnosticado de MCADD presentó descompensación metabólica mientras que algunos pacientes con AG1 y con FAO de cadena larga presentaron descompensaciones. No exisen diferencias significativas en cuanto al número de descompensaciones ni a la edad de la primera descompensación entre ambos grupos. El 80 % de los pacientes con ECM se encontraban asintomáticos en la última visita con un periodo de seguimiento (mediana y rango) de 2,03 años (1,40-2,53). Dos pacientes (1 CACT y 1 LCHADD) fallecieron durante el primer año de vida tras una descompensación metabólica. Los casos con AG1 presentan una puntuación peor en las escalas del neurodesarrollo. Se han diagnosticado algunos ECM en las madres de recién nacidos así como en otros miembros de la familia..

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

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

The homozygous R504C mutation in MTO1 gene is responsible for ONCE syndrome

We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative phosphorylation deficiency) syndrome. Whole-exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant.post-print712 K

Identification of clinical variants beyond the exome in inborn errors of metabolism

Inborn errors of metabolism (IEM) constitute a huge group of rare diseases affecting 1 in every 1000 newborns. Next-generation sequencing has transformed the diagnosis of IEM, leading to its proposed use as a second-tier technology for confirming cases detected by clinical/biochemical studies or newborn screening. The diagnosis rate is, however, still not 100%. This paper reports the use of a personalized multi-omics (metabolomic, genomic and transcriptomic) pipeline plus functional genomics to aid in the genetic diagnosis of six unsolved cases, with a clinical and/or biochemical diagnosis of galactosemia, mucopolysaccharidosis type I (MPS I), maple syrup urine disease (MSUD), hyperphenylalaninemia (HPA), citrullinemia, or urea cycle deficiency. Eight novel variants in six genes were identified: six (four of them deep intronic) located in GALE, IDUA, PTS, ASS1 and OTC, all affecting the splicing process, and two located in the promoters of IDUA and PTS, thus affecting these genes’ expression. All the new variants were subjected to functional analysis to verify their pathogenic effects. This work underscores how the combination of different omics technologies and functional analysis can solve elusive cases in clinical practic

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