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1.
J Hum Genet ; 61(8): 731-44, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27121329

RESUMEN

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.


Asunto(s)
Estudios de Asociación Genética , Genotipo , Mutación , Fenotipo , Fenilalanina Hidroxilasa/genética , Fenilcetonurias/epidemiología , Fenilcetonurias/genética , Alelos , Terapia de Reemplazo Enzimático , Frecuencia de los Genes , Heterogeneidad Genética , Humanos , Epidemiología Molecular , Fenilalanina Hidroxilasa/metabolismo , Fenilcetonurias/diagnóstico , Fenilcetonurias/terapia , España/epidemiología
2.
Mol Genet Metab ; 115(4): 145-50, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26123187

RESUMEN

Natural sources of protein and some vitamins and minerals are limited in phenylketonuria (PKU) treated patients, who should receive optimal supplementation although this is not yet fully established. We conducted a cross-sectional observational multicenter study including 156 patients with hyperphenylalaninemia. Patients were stratified by age, phenotype, disease detection and type of treatment. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, and biochemical parameters (total protein, prealbumin, electrolytes, selenium, zinc, B12, folic acid, ferritin, 25-OH vitamin D) were collected in all patients. 81.4% of patients had biochemical markers out of recommended range but no clinical symptoms. Total protein, calcium, phosphorus, B12, ferritin, and zinc levels were normal in most patients. Prealbumin was reduced in 34.6% of patients (74% with PKU phenotype and 94% below 18 years old), showing almost all (96.3%) an adequate adherence to diet. Selenium was diminished in 25% of patients (95% with PKU phenotype) and also 25-OHD in 14%. Surprisingly, folic acid levels were increased in 39% of patients, 66% with classic PKU. Phosphorus and B12 levels were found diminished in patients with low adherence to diet. Patients under BH4 therapy only showed significant lower levels of B12. This study shows a high percentage of prealbumin and selenium deficiencies as well as an increased level of folic acid in PKU treated patients, which should lead us to assess an adjustment for standards supplements formulated milks.


Asunto(s)
Minerales/metabolismo , Fenilcetonurias/metabolismo , Vitaminas/metabolismo , Adolescente , Adulto , Niño , Preescolar , Dieta , Suplementos Dietéticos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Prealbúmina/metabolismo , Adulto Joven
3.
Mol Genet Metab ; 115(1): 10-6, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25882749

RESUMEN

BACKGROUND AND AIMS: Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. METHODS: We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH4 responsiveness and growth outcome. RESULTS: No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial= -0.57 ± 1.54; final=-0.52 ± 1.29; BMI Z-score: initial=0.17 ± 1.05; final=0.18 ± 1.00) or the diet-only group (height Z-score: initial=-0.92 ± 0.96; final= -0.78 ± 1.08; BMI Z-score: initial=0.17 ± 0.97; final=-0.07 ± 1.03) over the 1-year observation period. Furthermore, we found no significant differences (p>0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6-60.3] to 56.5 [39.8-68.3] mgkg(-1)day(-1)) and natural protein intake (from 1.0 [0.8-1.7] to 1.5 [1.0-1.8] g kg(-1)day(-1)), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p<0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration. CONCLUSIONS: Our study indicates that treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes.


Asunto(s)
Biopterinas/análogos & derivados , Estatura , Peso Corporal , Estado Nutricional , Fenilcetonurias/tratamiento farmacológico , Biopterinas/administración & dosificación , Biopterinas/uso terapéutico , Preescolar , Dieta con Restricción de Proteínas , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Mutación , Fenilalanina/administración & dosificación , Fenilalanina/sangre , Fenilcetonurias/dietoterapia , Fenilcetonurias/genética , Fenilcetonurias/fisiopatología , Estudios Retrospectivos , España
4.
Eur J Nutr ; 54(1): 89-99, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24671237

RESUMEN

PURPOSE: Currently, there is no consensus concerning the possible beneficial colonic and systemic effects of prebiotic-containing infant formula. This study assesses whether the feeding of a galactooligosaccharides (GOS)-containing infant formula (0.44 g/dl of GOS) and the subsequent feeding of a GOS-containing follow-on formula (0.50 g/dl of GOS) have a prebiotic effect on intestinal microbiota that helps to decrease infections and allergy manifestations in healthy infants during the first year of life. METHODS: A multicentre, randomised, double-blind and placebo-controlled trial was carried out on 365 healthy term infants enrolled before 8 weeks of age and randomly assigned to a formula with or without GOS, until 12 months of age. The incidence of infections and allergy manifestations, the antibiotics prescribed and faecal characteristics were recorded up to 12 months of age, while faecal samples were collected up to 4 months for the measurement of secretory immunoglobulin A, short-chain fatty acids and microbiota. RESULTS: A prebiotic effect on the faecal analysis was observed at 4 months of life. The GOS group showed a lower faecal pH (P = 0.019), a lower decreasing trend in secretory immunoglobulin A (P = 0.078), lower butyric acid concentration (P = 0.040) and an increase in Bifidobacterium counts (P = 0.010). Changes in faecal characteristics involved greater frequency (P < 0.001) and softer consistency (P < 0.05). The incidence of infections or allergic manifestations during the first year of life was similar in both groups, with no statistical differences (P > 0.05). CONCLUSIONS: The feeding of GOS-containing infant formula produced a definite prebiotic effect consisting of changes in faecal composition and microbiota, and in faecal consistency and the frequency of defaecation. No changes in the incidence of infection or allergic manifestation during the first year of life were observed.


Asunto(s)
Antialérgicos/uso terapéutico , Hipersensibilidad/prevención & control , Inmunidad Innata , Factores Inmunológicos/uso terapéutico , Fórmulas Infantiles , Oligosacáridos/uso terapéutico , Prebióticos , Bifidobacterium/crecimiento & desarrollo , Bifidobacterium/aislamiento & purificación , Bifidobacterium/metabolismo , Estudios de Cohortes , Estreñimiento/epidemiología , Estreñimiento/prevención & control , Método Doble Ciego , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/metabolismo , Heces/química , Heces/microbiología , Humanos , Hipersensibilidad/epidemiología , Inmunoglobulina A Secretora/análisis , Incidencia , Lactante , Fórmulas Infantiles/química , Infecciones/epidemiología , Perdida de Seguimiento , Masculino , España/epidemiología , Trisacáridos/uso terapéutico
5.
Aten Primaria ; 47(1): 56-65, 2015 Jan.
Artículo en Español | MEDLINE | ID: mdl-24704195

RESUMEN

Familial hypercholesterolemia (FH) is a common genetic disorder, clinically manifested since birth, and associated with very high levels of plasma LDL-cholesterol (LDL-c), xanthomas, and premature coronary heart disease. Its early detection and treatment reduces coronary morbidity and mortality. Despite effective treatment being available, FH is under-diagnosed and under-treated. Identification of index cases and cascade screening using LDL-c levels and genetic testing are the most cost-effective strategies for detecting new cases and starting early treatment. Long-term treatment with statins has decreased the vascular risk to the levels of the general population. LDL-c targets are < 130 mg/dL for children and young adults, <100mg/dL for adults, and < 70 mg/dL for adults with known coronary heart disease or diabetes. Most patients do not to reach these goals, and combined treatments with ezetimibe or other drugs may be necessary. When the goals are not achieved with the maximum tolerated drug treatment, a reduction ≥ 50% in LDL-c levels can be acceptable. Lipoprotein apheresis can be useful in homozygous, and in treatment-resistant severe heterozygous, cases. This Consensus Paper gives recommendations on the diagnosis, screening, and treatment of FH in children and adults, and specific advice to specialists and general practitioners with the objective of improving the clinical management of these patients, in order to reduce the high burden of coronary heart disease.


Asunto(s)
Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Algoritmos , Humanos , Guías de Práctica Clínica como Asunto , España
6.
Mol Genet Metab ; 110(1-2): 181-3, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23835251

RESUMEN

We report citrin deficiency in a neonatal non-East-Asian patient, the ninth Caucasian reported with this disease. The association of intrahepatic cholestasis, galactosuria, very high alpha-fetoprotein and increased plasma and urine citrulline, tyrosine, methionine and threonine levels suggested citrin deficiency. Identification of a protein-truncating mutation (c.1078C>T; p.Arg360*) in the SLC25A13 gene confirmed the diagnosis. An immediate response to a high-protein, lactose-free, low-carbohydrate formula was observed. Our report illustrates the need for awareness on citrin deficiency in Western countries.


Asunto(s)
Proteínas de Unión al Calcio/deficiencia , Proteínas de Unión al Calcio/genética , Dietoterapia , Proteínas de Transporte de Membrana Mitocondrial/genética , Transportadores de Anión Orgánico/deficiencia , Transportadores de Anión Orgánico/genética , Pueblo Asiatico/genética , Proteínas de Unión al Calcio/sangre , Proteínas de Unión al Calcio/orina , Citrulina/sangre , Citrulina/orina , Humanos , Metionina/sangre , Metionina/orina , Mutación , Transportadores de Anión Orgánico/sangre , Transportadores de Anión Orgánico/orina , Rumanía , España , Treonina/sangre , Treonina/orina , Tirosina/sangre , Tirosina/orina , Población Blanca/genética
7.
Mol Genet Metab ; 109(4): 331-8, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23810227

RESUMEN

BACKGROUND: Treatment of phenylketonuria based upon strict vegetarian diets, with very low phenylalanine intake and supplemented by phenylalanine-free formula, has proven to be effective in preventing the development of long-term neurological sequelae due to phenylalanine accumulation. On the other hand, such diets have occasionally been reported to hinder normal development, some individuals presenting with growth retardation. Tetrahydrobiopterin therapy has opened up new treatment options for a significant proportion of phenylketonuric patients, enabling them to eat normal diets and be freed from the need to take synthetic supplements. However, little is known about how this therapy affects their physical development. METHODS: We conducted a retrospective longitudinal study examining anthropometric characteristics (height, weight, body mass index and growth speed Z-scores) in a cohort of phenylketonuric patients on tetrahydrobiopterin therapy (38 subjects) comparing their characteristics with those of a group of phenylketonuric patients on phenylalanine-restricted diets (76 subjects). Nutritional issues were also considered, to further explore the possibility of higher natural protein intake being associated with better physical development. Data were collected every six months over two different periods of time (two or five years). RESULTS: No improvement was observed in the aforementioned anthropometric variables in the cohort on tetrahydrobiopterin therapy, from prior to starting treatment to when they had been taking the drug for two or five years. Rather, in almost all cases there was a fall in the mean Z-score for the variables during these periods, although the changes were not significant in any case. Further, we found no statistically differences between the two groups at any considered time point. Growth impairment was also noted in the phenylketonuric patients on low-phenylalanine diets. Individuals on tetrahydrobiopterin therapy increased their natural protein intake and, in some instances, this treatment enabled individuals to eat normal diets, with protein intake meeting RDAs. No association was found, however, between higher protein intake and growth. CONCLUSION: Our study identified growth impairment in patients with phenylketonuria on tetrahydrobiopterin, despite higher intakes of natural proteins. In fact, individuals undergoing long-term tetrahydrobiopterin treatment seemed to achieve similar developmental outcomes to those attained by individuals on more restricted diets.


Asunto(s)
Biopterinas/análogos & derivados , Dieta , Fenilalanina/metabolismo , Fenilcetonurias/dietoterapia , Biopterinas/administración & dosificación , Composición Corporal/efectos de los fármacos , Estatura/efectos de los fármacos , Índice de Masa Corporal , Peso Corporal/efectos de los fármacos , Estudios de Seguimiento , Humanos , Fenilalanina/administración & dosificación , Fenilcetonurias/patología
8.
Hum Mutat ; 32(7): 835-42, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21520339

RESUMEN

Homocystinuria due to CBS deficiency is a rare autosomal recessive disorder characterized by elevated plasma levels of homocysteine (Hcy) and methionine (Met). Here we present the analysis of 22 unrelated patients of different geographical origins, mainly Spanish and Argentinian. Twenty-two different mutations were found, 10 of which were novel. Five new mutations were missense and five were deletions of different sizes, including a 794-bp deletion (c.532-37_736 + 438del794) detected by Southern blot analysis. To assess the pathogenicity of these mutations, seven were expressed heterologously in Escherichia coli and their enzyme activities were assayed in vitro, in the absence and presence of the CBS activators PLP and SAM. The presence of the mutant proteins was confirmed by Western blotting. Mutations p.M173del, p.I278S, p.D281N, and p.D321V showed null activity in all conditions tested, whereas mutations p.49L, p.P200L and p.A446S retained different degrees of activity and response to stimulation. Finally, a minigene strategy allowed us to demonstrate the pathogenicity of an 8-bp intronic deletion, which led to the skipping of exon 6. In general, frameshifting deletions correlated with a more severe phenotype, consistent with the concept that missense mutations may recover enzymatic activity under certain conditions.


Asunto(s)
Cistationina betasintasa/genética , Homocistinuria/genética , Eliminación de Secuencia/genética , Alelos , Argentina , Femenino , Mutación del Sistema de Lectura/genética , Expresión Génica , Homocisteína/genética , Homocistinuria/enzimología , Humanos , Intrones , Masculino , Mutagénesis Sitio-Dirigida , Sitios de Empalme de ARN/genética , España , Relación Estructura-Actividad
9.
Hum Mutat ; 32(6): E2189-210, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21394825

RESUMEN

Mutational analysis of the IDUA gene was performed in a cohort of 102 European patients with mucopolysaccharidosis type I. A total of 54 distinct mutant IDUA alleles were identified, 34 of which were novel including 12 missense mutations, 2 nonsense mutations, 12 splicing mutations, 5 micro-deletions, 1 micro-duplication 1 translational initiation site mutation, and 1 'no-stop' change (p.X654RextX62). Evidence for the pathological significance of all novel mutations identified was sought by means of a range of methodological approaches, including the assessment of evolutionary conservation, RT-PCR/in vitro splicing analysis, MutPred analysis and visual inspection of the 3D-model of the IDUA protein. Taken together, these data not only demonstrate the remarkable mutational heterogeneity characterizing type 1 mucopolysaccharidosis but also illustrate our increasing ability to make deductions pertaining to the genotype-phenotype relationship in disorders manifesting a high degree of allelic heterogeneity.


Asunto(s)
Iduronidasa/genética , Mucopolisacaridosis I/genética , Alelos , Empalme Alternativo/genética , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Europa (Continente) , Exones , Estudios de Asociación Genética , Humanos , Datos de Secuencia Molecular , Mutación Missense , Conformación Proteica , Población Blanca/genética
10.
Blood Cells Mol Dis ; 46(1): 115-8, 2011 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-20934891

RESUMEN

Recently, an acute restriction of imiglucerase has occurred as a result of viral contamination and manufacturing problems. A position statement from the European Working Group for Gaucher Disease and European Gaucher Alliance established a set of key recommendations for identifying and monitoring at-risk patients. In Spain, a profile of the shortage situation was obtained through follow-up of patients with Gaucher disease (GD) and compliance with the therapy recommendations. Here we describe a group of patients, with modified doses of imiglucerase, during the shortage. Fifty adult GD1 patients (25 males/25 females), previously on ERT, were analysed before and after the 6-month shortage. The mean age was 45.3 ± 15.3 years (range: 18-84). The mean Severity Score Index at diagnosis was 8.7 ± 3.8 (range: 3-19); 20% of patients were splenectomized; and 78% had bone disease. During the shortage, 23 patients (46%) discontinued therapy; as complications in this group only one patient suffered a bone crisis and another anaemia (Hb <10.0 g/dL). The mean reduction of haemoglobin level (-2.7%) and platelet counts (-5.4%) were non-significant. Chitotriosidase (CT) activity was increased 135% (p<0.03) and CCL18/PARC 8.2% (p<0.08) in this group. Imiglucerase was reduced by 50% in 17 patients (34%) in this group, seven patients (41.0%) suffered bone pain, three of them true bone crisis and four (23.5%) required support therapy. The mean reduction of haemoglobin (-2.8%) and platelet counts (-10.7%), CT activity was increased 48.2% (p<0.03) and no changes were observed in CCL18/PARC concentration. In both groups no significant changes in visceral size were observed. In 3 patients (6%), imiglucerase was reduced 75% and 7 patients (14%) needed to switch to another ERT (4 patients) or miglustat (3 patients) due to a restart of symptomatic disease. In Spain the 6 first months shortage of imiglucerase have produced a 20% incidence of bone pain, one case of anaemia, and a significant increase in CT activity. Fourteen percent of patients had to switch to another therapy. No significant changes in blood counts, visceral volumes and CCL18/PARC concentration were observed.


Asunto(s)
Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/patología , Glucosilceramidasa/provisión & distribución , Glucosilceramidasa/uso terapéutico , Adolescente , Adulto , Anciano de 80 o más Años , Terapia de Reemplazo Enzimático , Femenino , Estudios de Seguimiento , Enfermedad de Gaucher/enzimología , Humanos , Masculino , Persona de Mediana Edad , España , Resultado del Tratamiento , Adulto Joven
11.
Pediatr Int ; 53(6): 985-9, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21752152

RESUMEN

BACKGROUND: Tyrosinemia type 1 (HT1) is a rare but treatable disease. The aim of the present study was to review the efficacy of long-term treatment of HT1 with nitisinone, expand knowledge about the clinical spectrum of the disease and assess a possible genotype-phenotype correlation. METHODS: A retrospective multicenter study was carried out based on questionnaires on genotype, phenotype, therapy and outcome in 34 Spanish patients with HT1. RESULTS: The main manifestations that led to the diagnosis were acute liver failure (55.8%), asymptomatic hepatomegaly (44.1%) and renal tubular dysfunction (29.4%). Laboratory analysis indicated a marked increase of α-fetoprotein and coagulopathy. The most common mutation was IVS6-1(G > T; 66.6% of 24/34 patients for whom mutation analysis was available) and these patients presented less nephrocalcinosis and more hepatomegaly at diagnosis; two novel mutations (c.974C>T, c.398A>T) were found. The mean duration of treatment was 6.73 years. Dietary compliance was very good in 47.1% and good in 20.6%; nitisinone treatment adherence was very good in 85.2% of cases. Mean dose of nitisinone was 0.87 mg/kg per day with average plasma levels of 45.67 µmol/L. Only one patient required liver transplantation after nitisinone and none had hepatocellular carcinoma. CONCLUSIONS: Treatment with nitisinone has improved the prognosis of HT1, and compliance is good. In Spain, screening for HT1 by plasma tyrosine and urine succinylacetone determination may be implemented with IVS6-1(G > T) mutational analysis. A correlation between low frequency of nephrocalcinosis and IVS6-1(G > T) mutation was observed.


Asunto(s)
Ciclohexanonas/uso terapéutico , ADN/genética , Mutación , Nitrobenzoatos/uso terapéutico , Tirosina/genética , Tirosinemias/genética , 4-Hidroxifenilpiruvato Dioxigenasa/antagonistas & inhibidores , Niño , Preescolar , Análisis Mutacional de ADN , Inhibidores Enzimáticos/uso terapéutico , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Incidencia , Masculino , Estudios Retrospectivos , España/epidemiología , Factores de Tiempo , Resultado del Tratamiento , Tirosina/sangre , Tirosinemias/tratamiento farmacológico , Tirosinemias/epidemiología
13.
J Pediatr Endocrinol Metab ; 33(1): 147-155, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31846426

RESUMEN

Background The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim To describe the dietary management of patients with MMA across Europe. Methods A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0-6 months; 7-12 months; 1-10 years; 11-16 years; >16 years). Results Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Proteínas en la Dieta/administración & dosificación , Encuestas y Cuestionarios/normas , Adolescente , Errores Innatos del Metabolismo de los Aminoácidos/epidemiología , Niño , Preescolar , Estudios Transversales , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Apoyo Nutricional
14.
J Inherit Metab Dis ; 32 Suppl 1: S349-53, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20033293

RESUMEN

Uniparental isodisomy arises when an individual inherits two copies of a specific chromosome from a single parent, which can unmask a recessive mutation or cause a problem of genetic imprinting. Here we describe an exceptional case in which the patient simultaneously presents tyrosinemia type 1 and Angelman syndrome. The genetic studies showed that the patient presents paternal uniparental isodisomy of chromosome 15, with absence of the maternal homolog. As a consequence of this isodisomy, the patient is homozygous for the mutation IVS12+5G>A in the FAH gene, located in the chromosomal region 15q23-25, causing tyrosinemia type 1. The mutation was inherited from his father in double dosage, whereas the mother is not a carrier, which implies that the recurrence risk in the family is negligible. On the other hand, the lack of maternal contribution causes Angelman syndrome, a neurodevelopmental disorder associated with a loss of maternal gene expression in chromosome region 15q11-q13, and more specifically, of the UBE3A gene. This gene shows a tissue-specific imprinting, and only the maternally derived allele is expressed in certain areas of the brain. We observed through a literature review that uniparental disomy probably occurs more frequently than suspected, although it is more usually detected when the uniparental disomy implies the appearance of a disease because of the gene imprinting or by reduction to homozygosity of a recessive mutation. The conclusion is that uniparental disomy should always be considered when more than one genetic disease mapping to the same chromosome is present in a patient.


Asunto(s)
Síndrome de Angelman/complicaciones , Síndrome de Angelman/genética , Cromosomas Humanos Par 15 , Tirosinemias/complicaciones , Tirosinemias/genética , Disomía Uniparental , Adulto , Secuencia de Bases , Preescolar , Análisis Mutacional de ADN , Padre , Femenino , Impresión Genómica , Humanos , Lactante , Recién Nacido , Masculino , Linaje
15.
Orphanet J Rare Dis ; 14(1): 66, 2019 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-30871635

RESUMEN

BACKGROUND: The Registry of Adult and Paediatric Patients Treated with Cystadane® - Homocystinuria (RoCH) is a non-interventional, observational, multi-centre, post-authorization safety study that aimed to identify safety of betaine anhydrous (Cystadane®) in the treatment of patients with inborn errors of homocysteine metabolism (homocystinuria) in order to minimise the treatment associated risks and establish better knowledge on its clinical use. The registry included patients of all ages with homocystinuria who were treated with betaine anhydrous in conjunction with other therapies. Clinical data were collected retrospectively from 2007 to 2013, then prospectively up to February 2014. All adverse events (AEs) reported during the study were recorded. The clinical and biological status of patients was monitored at least once a year. RESULTS: A total of 125 patients with homocystinuria (adults [> 18 years]: 50; paediatric [≤18 years]: 75) were enrolled at 29 centres in France and Spain. Patients were treated with betaine anhydrous for a mean duration of 7.4 ± 4.3 years. The median total daily dose of betaine anhydrous at the first and last study visits was 6 g/day for cystathionine ß-synthase (CBS)-deficient vitamin B6 responders and 9 g/day for methylenetetrahydrofolate reductase-deficient patients, while the median daily dose increased in CBS-deficient B6 non-responders (from 6 to 9 g/day) and cobalamin metabolism-defective patients (from 3 to 6 g/day) between the first and last visits. Treatment caused a mean overall reduction of 29% in plasma homocysteine levels in the study population. A total of 277 AEs were reported during the study, of which two non-serious AEs (bad taste and headache) and one serious AE (interstitial lung disease) were considered to be drug related. Overall, betaine anhydrous was well tolerated with no major safety concerns. CONCLUSIONS: Data from the RoCH registry provided real-world evidence on the clinical safety and efficacy of betaine anhydrous in the management of homocystinuria in paediatric and adult patients.


Asunto(s)
Betaína/administración & dosificación , Homocistinuria/tratamiento farmacológico , Sistema de Registros , Adolescente , Adulto , Betaína/efectos adversos , Niño , Preescolar , Femenino , Francia , Homocisteína/sangre , Humanos , Lactante , Masculino , Estudios Retrospectivos , España , Resultado del Tratamiento , Adulto Joven
16.
Pediatr Allergy Immunol ; 19(2): 180-3, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17651378

RESUMEN

Children with short bowel syndrome (SBS) undergo frequent operations, so they are at risk for sensitizing to latex. There have been isolated reports of sensitization to food in these children. In a cross-sectional study, we assessed sensitization to latex, cow's milk, and egg with skin prick tests (SPT) and serum-specific immunoglobulin E (IgE) in 14 children with SBS. Data were collected about the number of operations with latex devices, serum total IgE, and history of feeding with milk formula. Ten children were sensitized to latex (specific IgE median: 6.7 kU/l, range: 0.5-33). Compared with those non-sensitized, sensitized children had significantly (p < 0.05) higher levels of serum total IgE in z-units (mean rank 3.25 vs. 9.2, respectively), and more operations with latex devices (mean rank 3.75 vs. 9). Eight children were sensitized to cow's milk, one with only positive SPT, the other seven with serum-specific IgE (median: 3.5, range: 0.5-21.1 kU/l), and five to egg (specific IgE median: 0.68, range: 0.58-2.17 kU/l). Except for some isolated days with cow's milk formula, the children had been initially fed with a diet without intact cow's milk proteins. Sensitization to latex, cow's milk, and egg is very frequent in children with SBS. They should be treated in a latex-free environment since the very early stages of the disease, and should be routinely studied regarding food sensitization, as this might contribute as an added factor in the chronic diarrhea of these patients.


Asunto(s)
Hipersensibilidad al Huevo/epidemiología , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Hipersensibilidad al Látex/epidemiología , Hipersensibilidad a la Leche/epidemiología , Síndrome del Intestino Corto/epidemiología , Preescolar , Comorbilidad , Estudios Transversales , Hipersensibilidad al Huevo/diagnóstico , Hipersensibilidad al Huevo/inmunología , Femenino , Humanos , Hipersensibilidad al Látex/diagnóstico , Hipersensibilidad al Látex/inmunología , Masculino , Hipersensibilidad a la Leche/diagnóstico , Hipersensibilidad a la Leche/inmunología , Factores de Riesgo , Síndrome del Intestino Corto/inmunología , Pruebas Cutáneas/estadística & datos numéricos
17.
Medicine (Baltimore) ; 97(29): e11246, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30024503

RESUMEN

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is a progressive multisystem X-linked lysosomal storage disease caused by mutations in the IDS gene that shows a wide spectrum of clinical symptoms and severity. Idursulfase, a specific enzyme replacement therapy (ERT) for MPSII, has been available since 2007. ERT, along with symptomatic management of patients, is fundamental for improving patient prognosis and quality of life. The aims of this study were to investigate whether Spanish pediatricians who are experts in managing the disease agreed with current international guidelines regarding MPSII patient diagnosis and follow-up; and to reach a consensus regarding which items are essential for the diagnosis, follow-up, and treatment of these patients in Spain.An advisory panel of 5 experts from the Hunter Spanish Working Group reviewed key studies, developed a questionnaire based on a modified Delphi method, sent the questionnaire to selected experts, and reviewed the responses. The final questionnaire had 83 items in the following categories: diagnosis, ERT considerations after diagnosis, Periodic assessments, and ERT considerations during follow-up. A total of 85 experts were invited to participate; 28 (35%) responded and showed a strong consensus for most items. The advisory panel decided not to perform a second Delphi round. There was strong agreement (>3.1 median value; range, 1 to 4) for 43/56 items in Diagnosis, for 4/6 items in "ERT considerations after diagnosis," for 6/16 items in "Periodic assessments," and for 3/5 items in "ERT considerations during follow-up." Most responses were in agreement with international guidelines, and controversial items were discussed by the advisory panel. Based on the results, on the key studies, and on clinical experience and opinions, the panel developed and scheduled recommendations for the diagnosis and follow-up of patients with MPSII.An expert 5-person panel oversaw a Delphi survey of 28 pediatricians and reached a consensus on recommendations for the diagnosis and follow-up of MPSII patients. This document will help guide clinicians involved in the diagnosis, management, and treatment of MPSII.


Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Adhesión a Directriz/estadística & datos numéricos , Mucopolisacaridosis II/diagnóstico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Consenso , Técnica Delphi , Estudios de Seguimiento , Humanos , Mucopolisacaridosis II/terapia , Pediatras , Guías de Práctica Clínica como Asunto , España , Encuestas y Cuestionarios
19.
Orphanet J Rare Dis ; 12(1): 84, 2017 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-28468677

RESUMEN

BACKGROUND: The enzymatic replacement therapy (ERT) availability for Gaucher disease (GD) has changed the landscape of the disease, several countries have screening programs. These actions have promoted the early diagnosis and avoided many complications in pediatric patients. In Spain ERT has been available since 1993 and 386 patients have been included in the Spanish Registry of Gaucher Disease (SpRGD). The aim of this study is to analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. AIM: To analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. METHODS: A review of data in SpRGD from patients' diagnosed before 18 years old was performed. The cohort was split according the year of diagnosis (≤1994, cohort A; ≥1995, cohort B). RESULTS: A total of 98 pediatric patients were included, GD1: 80, GD3: 18; mean age: 7.2 (0.17-16.5) years, 58 (59.2%) males and 40 (40.8%) females. Forty-five were diagnosed ≤ 1994 and 53 ≥ 1995. Genotype: N370S/N370S: 2 (2.0%), N370S/L444P: 27 (27.5%), N370S/other: 47 (48%), L444P/L444P: 7 (7.1%), L444P/D409H: 2 (2.0%), L444P/other: 3 (6.2%), other/other: 10 (10.2%). The mean age at diagnosis was earlier in patients diagnosed after 1995 (p < 0.001) and different between the subtypes, GD1: 8.2 (0.2-16.5) years and GD3: 2.8 (0.17-10.2) years (p < 0.001). There were more severe patients in the group diagnosed before 1994 (p = 0.045) carrying L444P (2), D409H (2), G377S (1), G195W (1) or the recombinant mutation. The patients' diagnosed ≤1994 showed worse cytopenias, higher chance of bone vascular complications at diagnosis and previous spleen removal. The patients started ERT at a median time after diagnosis of 5.2 years [cohort A] and 1.6 years [cohort B] (p < 0.001). CONCLUSIONS: The early diagnosis of Gaucher disease in the era of ERT availability has permitted to reduce the incidence of severe and irreversible initial complication in pediatric patients, and this has permitted better development of these patients. This is the largest pediatric cohort from a national registry.


Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad de Gaucher/diagnóstico , Adolescente , Niño , Preescolar , Terapia de Reemplazo Enzimático/estadística & datos numéricos , Femenino , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/epidemiología , Humanos , Lactante , Masculino , Sistema de Registros , España/epidemiología
20.
Pediatrics ; 137(2): e20152781, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26783325

RESUMEN

Scurvy is a rare disease in developed countries. Risk groups include children with restricted diets, mainly patients who are autistic or have cerebral palsy. Furthermore, consumption of plant-based beverages has increased in recent years, especially in developed countries. When plant-based beverages are the exclusive diet in the first year of life and not consumed as a supplement to formula or breastfeeding, it can result in severe nutritional problems. We report a case of scurvy after exclusive intake of almond beverages and almond flour from 2.5 to 11.0 months of life. The patient was referred for pathologic fractures of the femur, irritability, and failure to thrive. He had typical radiologic signs of scurvy, such as osteopenia, cortical thinning, Wimberger ring, Frankel line, fracture, and periosteal reaction. Moreover, his plasmatic vitamin C level was very low. The child was diagnosed with scurvy and was started on vitamin C replacement therapy at a dose of 300 mg per day. Over the following 3 months, his general condition, the pain in the legs, and the radiologic features improved; the plasmatic vitamin C level was normalized; and the child started walking. In summary, this case demonstrates that scurvy is a new and severe complication of improper use of almond drinks in the first year of life. Manufacturers should indicate that these beverages are inappropriate for infants who consume a vitamin C-deficient diet.


Asunto(s)
Dieta/efectos adversos , Escorbuto/etiología , Bebidas , Enfermedades Óseas Metabólicas/etiología , Insuficiencia de Crecimiento/etiología , Fracturas del Fémur/etiología , Harina , Humanos , Lactante , Genio Irritable , Masculino , Prunus dulcis , Deficiencia de Vitamina D/etiología
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