Postauthorization safety study of betaine anhydrous.

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 µmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

[50 years of the Neonatal Screening Program in Catalonia.] / 50 años del Programa de Cribado Neonatal en Cataluña.

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included.

El Programa de Cribado Neonatal de Cataluña (PCNC) se inició en el año 1969, en Barcelona, impulsado por el Dr. Juan Sabater Tobella y apoyado por la Diputación de Barcelona y la Fundación Juan March. Así nació el Instituto de Bioquímica Clínica para acometer funciones asistenciales, de investigación y docencia, con el espíritu de contribuir a la prevención del retraso mental. El PCNC se inició con la detección de la fenilcetonuria (PKU) y en el año 1982 se amplió con la detección del hipotiroidismo congénito. Hacia el año 1990 la cobertura territorial llegó casi al 100% de todos los recién nacidos en Cataluña. En 1999 se amplió el PCNC con la incorporación de la fibrosis quística y tras catorce años, en 2013, se realizó la ampliación más numerosa hasta ahora, con la incorporación de la detección de 19 enfermedades metabólicas hereditarias. En el año 2015 comenzó la detección de la enfermedad de células falciformes y en el 2017 la detección de la inmunodeficiencia combinada grave. Actualmente, el PCNC incluye la detección de 24 enfermedades. Desde su inicio en el año 1969, se han cribado 2.787.807 recién nacidos, de los cuales 1.724 han sido diagnosticados de alguna de las 24 enfermedades que componen nuestro panel principal y 252 por diagnóstico diferencial de las primeras. En total la prevalencia global es de 1:1.617 RN afectos de alguna de las enfermedades incluidas en el PCNC y de 1:1.140 RN si se incluyen los hallazgos incidentales encontrados.

50 años del Programa de Cribado Neonatal en Cataluña / 50 years of the Neonatal Screening Program in Catalonia

El Programa de Cribado Neonatal de Cataluña (PCNC) se inició en el año 1969, en Barcelona, impulsado por el Dr. Juan Sabater Tobella y apoyado por la Diputación de Barcelona y la Fundación Juan March. Así nació el Instituto de Bioquímica Clínica para acometer funciones asistenciales, de investigación y docencia, con el espíritu de contribuir a la prevención del retraso mental. El PCNC se inició con la detección de la fenilcetonuria (PKU) y en el año 1982 se amplió con la detección del hipotiroidismo congénito. Hacia el año 1990 la cobertura territorial llegó casi al 100% de todos los recién nacidos en Cataluña. En 1999 se amplió el PCNC con la incorporación de la fibrosis quística y tras catorce años, en 2013, se realizó la ampliación más numerosa hasta ahora, con la incorporación de la detección de 19 enfermedades metabólicas hereditarias. En el año 2015 comenzó la detección de la enfermedad de células falciformes y en el 2017 la detección de la inmunodeficiencia combinada grave. Actualmente, el PCNC incluye la detección de 24 enfermedades. Desde su inicio en el año 1969, se han cribado 2.787.807 recién nacidos, de los cuales 1.724 han sido diagnosticados de alguna de las 24 enfermedades que componen nuestro panel principal y 252 por diagnóstico diferencial de las primeras. En total la prevalencia global es de 1:1.617 RN afectos de alguna de las enfermedades incluidas en el PCNC y de 1:1.140 RN si se incluyen los hallazgos incidentales encontrados

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

[Excess weight in patients with cystic fibrosis: is it always beneficial?]

INTRODUCTION: The primary objective of this study was to find out the prevalence of overweight and obese status, as well as their association to pulmonary function, total cholesterol and vitamin D in patients with cystic fibrosis (CF). MATERIALS AND METHODS: This is a multicenter descriptive and cross-sectional study. Twelve Spanish hospitals participated. 451 patients with CF were included. Adults were classified according to body mass index (BMI) and children were classified according to BMI percentiles (WHO tables). Pearson's correlation, Anova, Student's t-test and multiple linear regression were conducted. RESULTS: Mean age was 12.3 (range 4-57) years old, 51% were male and 18% had pancreatic sufficiency. Participants were classified in five nutritional status categories: 12% were malnourished; 57%, at nutritional risk; 24%, normally nourished; 6%, overweight; and 1%, obese. Pulmonary function in overweight or obese patients (91 ± 19%) was better than in malnourished patients (77 ± 24%) (p = 0.017). However, no difference was observed between those at nutritional risk (86 ± 19%) or normally nourished (90 ± 22%) groups. Overweight and obese patients had higher levels of total cholesterol (p = 0.0049), a greater proportion of hypercholesterolemia (p = 0.001), as well as lower levels of 25 OH vitamin D (p = 0.058). CONCLUSIONS: Prevalence of overweight and obese was 6 and 1%. Excess weight status does not offer any benefit in pulmonary function in comparison to normally nourished patients.

Excess weight in patients with cystic fibrosis: is it always beneficial? / Incremento de peso en pacientes con fibrosisquística: ¿es siempre beneficioso?

Introduction: The primary objective of this study was to find out the prevalence of overweight and obese status, as well as their association to pulmonary function, total cholesterol and vitamin D in patients with cystic fibrosis (CF). Materials and methods: This is a multicenter descriptive and cross-sectional study. Twelve Spanish hospitals participated. 451 patients with CF were included. Adults were classified according to body mass index (BMI) and children were classified according to BMI percentiles (WHO tables). Pearson’s correlation, Anova, Student’s t-test and multiple linear regression were conducted. Results: Mean age was 12.3 (range 4-57) years old, 51% were male and 18% had pancreatic sufficiency. Participants were classified in five nutritional status categories: 12% were malnourished; 57%, at nutritional risk; 24%, normally nourished; 6%, overweight; and 1%, obese. Pulmonary function in overweight or obese patients (91 ± 19%) was better than in malnourished patients (77 ± 24%) (p = 0.017). However, no difference was observed between those at nutritional risk (86 ± 19%) or normally nourished (90 ± 22%) groups. Overweight and obese patients had higher levels of total cholesterol (p = 0.0049), a greater proportion of hypercholesterolemia (p = 0.001), as well as lower levels of 25 OH vitamin D (p = 0.058). Conclusions: Prevalence of overweight and obese was 6 and 1%. Excess weight status does not offer any benefit in pulmonary function in comparison to normally nourished patients (AU)

Introducción y objetivos: conocer la prevalencia de sobrepeso y obesidad, así como su asociación con la función pulmonar, el colesterol total y la vitamina D en pacientes con fibrosis quística (FQ). Material y métodos: estudio multicéntrico descriptivo y transversal. Participaron 12 hospitales españoles. Fueron incluidos 451 pacientes con FQ, clasificados según el índice de masa corporal (IMC) en adultos y el IMC percentilado (tablas OMS) en niños. Análisis estadístico: C.Pearson, Anova, t de Student y regresión lineal múltiple. Resultados: la mediana de edad fue 12,3 (rango 4-57) años. Un 51% eran varones y el 18%, suficientes pancreáticos (SP). El 12% estaba desnutrido; el 57%, en riesgo nutricional; el 24%, normonutrido; el 6% presentaba sobrepeso; y un 1%, obesidad. La función pulmonar en los pacientes con sobrepeso (91 ± 19%) era mejor que en los desnutridos (77 ± 24%) (p = 0,017), sin embargo, no se observaron diferencias con respecto a los que estaban en riesgo nutricional (86 ± 19%) o normonutridos (90 ± 22%). Los pacientes con sobrepeso tenían más elevado el colesterol total (p = 0,0049), mayor proporción de hipercolesterolemia (p = 0,001), así como niveles más bajos de 25 OH vitamina D (p = 0,058). Conclusiones: la prevalencia de sobrepeso y obesidad fue del 6 y el 1%. El sobrepeso y la obesidad no ofrecen beneficio sobre la función pulmonar en comparación con los normonutridos (AU)

Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders.

BACKGROUND: Inherited neurometabolic disorders (iNMDs) represent a group of almost seven hundred rare diseases whose common manifestations are clinical neurologic or cognitive symptoms that can appear at any time, in the first months/years of age or even later in adulthood. Early diagnosis and timely treatments are often pivotal for the favorable course of the disease. Thus, the elaboration of new evidence-based recommendations for iNMD diagnosis and management is increasingly requested by health care professionals and patients, even though the methodological quality of existing guidelines is largely unclear. InNerMeD-I-Network is the first European network on iNMDs that was created with the aim of sharing and increasing validated information about diagnosis and management of neurometabolic disorders. One of the goals of the project was to determine the number and the methodological quality of existing guidelines and recommendations for iNMDs. METHODS: We performed a systematic search on PubMed, the National Guideline Clearinghouse (NGC), the Guidelines International Network (G-I-N), the Scottish Intercollegiate Guideline Network (SIGN) and the National Institute for Health and Care Excellence (NICE) to identify all the published guidelines and recommendations for iNMDs from January 2000 to June 2015. The methodological quality of the selected documents was determined using the AGREE II instrument, an appraisal tool composed of 6 domains covering 23 key items. RESULTS: A total of 55 records met the inclusion criteria, 11 % were about groups of disorders, whereas the majority encompassed only one disorder. Lysosomal disorders, and in particular Fabry, Gaucher disease and mucopolysaccharidoses where the most studied. The overall methodological quality of the recommendation was acceptable and increased over time, with 25 % of the identified guidelines strongly recommended by the appraisers, 64 % recommended, and 11 % not recommended. However, heterogeneity in the obtained scores for each domain was observed among documents covering different groups of disorders and some domains like 'stakeholder involvement' and 'applicability' were generally scarcely addressed. CONCLUSIONS: Greater efforts should be devoted to improve the methodological quality of guidelines and recommendations for iNMDs and AGREE II instrument seems advisable for new guideline development. The elaboration of new guidelines encompassing still uncovered disorders is badly needed.

[VITAMIN D AND CHRONIC LUNG COLONIZATION IN PEDIATRIC AND YOUNG ADULTS CYSTIC FIBROSIS PATIENTS]. / VITAMINA D Y COLONIZACIONES PULMONARES CRÓNICAS EN PACIENTES PEDIÁTRICOS Y ADULTOS JÓVENES CON FIBROSIS QUÍSTICA.

INTRODUCTION AND OBJECTIVES: evaluate vitamin D status and its association with chronic lung colonisation in Cystic Fibrosis patients. MATERIAL AND METHODS: descriptive cross-sectional multicenter study. From November 2012 to April 2014, at 12 national hospitals, 377 patients with Cystic Fibrosis were included. Vitamin D levels < 30 ng/ml were classified as insufficient. Chronic colonisation was considered if they had at least two positive cultures in the past year. RESULTS: the median age was 8.9 years (2 months to 20 years). 65% had insufficient levels of vitamin D. There was an inverse correlation between age and vitamin D levels (r = -0.20 p < 0.001). Those diagnosed by screening, were younger and had higher levels of vitamin D. There was an inverse correlation between the number of colonisations and vitamin D levels (r = -0.16 p = 0.0015). Adjusting for age, pancreatic status and diagnosis by screening, colonization by S. aureus in 6 years, increased the risk of insufficient levels of vitamin D: OR 3.17 (95% CI 1.32 to 7.61) (p = 0.010) and OR 3.77 (95% CI 1.37 to 10 , 37) (p = 0.010), respectively. CONCLUSIONS: despite adequate supplementation, more than half of our patients did not achieve optimal levels of vitamin D. Regardless of age, diagnosis by screening or pancreatic status, chronic colonization by Pseudomonas sp. in children and adolescents and S. Aureus in infants and preschoolars increases the risk of developing vitamin D deficiency in these patients.

Introducción y objetivos: conocer la situación en la que se encuentran los pacientes con fibrosis quística en relación con sus niveles de vitamina D y su asociación con las colonizaciones pulmonares crónicas. Material y métodos: estudio multicéntrico transversal. Participaron 12 hospitales nacionales. De noviembre a abril del 2012 al 2014 se incluyeron 377 pacientes con fibrosis quística. Se consideraron insuficientes niveles de vitamina D < 30 ng/ml. Presentar al menos dos cultivos positivos en el último año fue considerado un criterio de colonización crónica. Resultados: los pacientes tenían una mediana de edad de 8,9 años (2 meses­20 años). Un 65% presentaban niveles insuficientes de vitamina D. Se observó una correlación inversa entre edad y niveles de vitamina D (r = -0,20 p < 0,001). Los diagnosticados por cribado eran más jóvenes y tenían niveles de vitamina D más altos. Los niveles de vitamina D presentaron una correlación inversa con el número de colonizaciones pulmonares (r = -0,16 p = 0,0015). Ajustando por edad, función pancreática y diagnóstico mediante cribado, la colonización por S. Aureus en menores de seis años y por Pseudomonas sp. en los mayores de esa edad, incrementaban el riesgo de presentar niveles insuficientes de vitamina D: OR 3,17 (IC95% 1,32-7,61) (p=0,010) y OR 3,77 (IC95% 1,37- 10,37)(p = 0,010), respectivamente. Conclusiones: a pesar de una suplementación adecuada, más de la mitad de nuestros pacientes no alcanzan niveles óptimos de vitamina D. La colonización crónica por Pseudomonas sp. en escolares y adolescentes y por S. Aureus en lactantes y preescolares se asocia de forma independiente con la deficiencia de vitamina D.

Vitamina D y colonizaciones pulmonares crónicas en pacientes pediátricos y adultos jóvenes con fibrosis quística / Vitamin D and chronic lung colonization in pediatric and young adults cystic fibrosis patients

Introducción y objetivos: conocer la situación en la que se encuentran los pacientes con fibrosis quística en relación con sus niveles de vitamina D y su asociación con las colonizaciones pulmonares crónicas. Material y métodos: estudio multicéntrico transversal. Participaron 12 hospitales nacionales. De noviembre a abril del 2012 al 2014 se incluyeron 377 pacientes con fibrosis quística. Se consideraron insuficientes niveles de vitamina D < 30 ng/ml. Presentar al menos dos cultivos positivos en el último año fue considerado un criterio de colonización crónica. Resultados: los pacientes tenían una mediana de edad de 8,9 años (2 meses-20 años). Un 65% presentaban niveles insuficientes de vitamina D. Se observó una correlación inversa entre edad y niveles de vitamina D (r = -0,20 p < 0,001). Los diagnosticados por cribado eran más jóvenes y tenían niveles de vitamina D más altos. Los niveles de vitamina D presentaron una correlación inversa con el número de colonizaciones pulmonares (r = -0,16 p = 0,0015). Ajustando por edad, función pancreática y diagnóstico mediante cribado, la colonización por S. Aureus en menores de seis años y por Pseudomonas sp. en los mayores de esa edad, incrementaban el riesgo de presentar niveles insuficientes de vitamina D: OR 3,17 (IC95% 1,32-7,61) (p=0,010) y OR 3,77 (IC95% 1,37- 10,37)(p = 0,010), respectivamente. Conclusiones: a pesar de una suplementación adecuada, más de la mitad de nuestros pacientes no alcanzan niveles óptimos de vitamina D. La colonización crónica por Pseudomonas sp. en escolares y adolescentes y por S. Aureus en lactantes y preescolares se asocia de forma independiente con la deficiencia de vitamina D (AU)

Introduction and objectives: evaluate vitamin D status and its association with chronic lung colonisation in Cystic Fibrosis patients. Material and methods: descriptive cross-sectional multicenter study. From November 2012 to April 2014, at 12 national hospitals, 377 patients with Cystic Fibrosis were included. Vitamin D levels < 30 ng/ml were classified as insufficient. Chronic colonisation was considered if they had at least two positive cultures in the past year. Results: the median age was 8.9 years (2 months to 20 years). 65% had insufficient levels of vitamin D. There was an inverse correlation between age and vitamin D levels (r = -0.20 p < 0.001). Those diagnosed by screening, were younger and had higher levels of vitamin D. There was an inverse correlation between the number of colonisations and vitamin D levels (r = -0.16 p = 0.0015). Adjusting for age, pancreatic status and diagnosis by screening, colonization by S. aureus in <6 years and Pseudomonas sp. in > 6 years, increased the risk of insufficient levels of vitamin D: OR 3.17 (95% CI 1.32 to 7.61) (p = 0.010) and OR 3.77 (95% CI 1.37 to 10,37) (p = 0.010), respectively. Conclusions: despite adequate supplementation, more than half of our patients did not achieve optimal levels of vitamin D. Regardless of age, diagnosis by screening or pancreatic status, chronic colonization by Pseudomonas sp. in children and adolescents and S. Aureus in infants and preschoolars increases the risk of developing vitamin D deficiency in these patients (AU)