Table S1. International Standard Classification of Education (ISCED). ISCED 0 Early childhood edu... more Table S1. International Standard Classification of Education (ISCED). ISCED 0 Early childhood education; ISCED 1 Primary education; ISCED 2 Lower secondary education; ISCED 3 Upper secondary education; ISCED 4 Post-secondary non-tertiary education; ISCED 5 Short-cycle tertiary education; ISCED 6 Bachelor's or equivalent level; ISCED 7 Master's or equivalent level; ISCED 8 Doctoral or equivalent level. *Included patients have all completed education. **82.9% of the siblings are still in education. (PDF 173 kb)
Table S3. Bone health. BMD was measured by dual energy x-ray photometry (DXA) using T- or Z-score... more Table S3. Bone health. BMD was measured by dual energy x-ray photometry (DXA) using T- or Z-scores of the lumbar spine, depending on age and gender. T-scores were used in post-menopausal women and men ≥ 50 years. Z-scores, considering age, gender, and ethnicity, were used in pre-menopausal women and men
This study aims to quantify concentrations of minerals and trace elements in human milk (HM) and ... more This study aims to quantify concentrations of minerals and trace elements in human milk (HM) and infant formula (IF) and evaluate associations with medical, social, environmental, and demographic variables. A prospective, case series study of 170 nursing mothers was made. HM samples were obtained from full-term (colostrum, intermediate and mature HM) and preterm (mature HM) mothers. Variables of interest were assessed by a questionnaire. For comparison, IF samples (n = 30) were analyzed in a cross-sectional study. Concentrations of 35 minerals, essential and toxic trace elements were quantified, 5 for the first time: thallium in HM and IF; strontium in preterm HM; and gallium, lithium and uranium in IF. In preterm and full-term HM, levels of selenium (p < 0.001) were significantly lower than recommended and were associated with low birth weight (p < 0.002). Cesium and strontium concentrations were significantly higher than recommended (p < 0.001). Associations were observed...
BACKGROUND AND OBJECTIVES: There are conflicting views as to whether testing for biotinidase defi... more BACKGROUND AND OBJECTIVES: There are conflicting views as to whether testing for biotinidase deficiency (BD) ought to be incorporated into universal newborn screening (NBS) programs. The aim of this study was to evaluate the cost-effectiveness of adding BD to the panel of conditions currently screened under the national NBS program in Spain. METHODS: We used information from the regional NBS program for BD that has been in place in the Spanish region of Galicia since 1987. These data, along with other sources, were used to develop a cost-effectiveness decision model that compared lifetime costs and health outcomes of a national birth cohort of newborns with and without an early detection program. The analysis took the perspective of the Spanish National Health Service. Effectiveness was measured in terms of quality-adjusted life years (QALYs). We undertook extensive sensitivity analyses around the main model assumptions, including a probabilistic sensitivity analysis. RESULTS: In th...
Homocystinuria due to cystathionine β-synthase deficiency or "classical homocystinuria"... more Homocystinuria due to cystathionine β-synthase deficiency or "classical homocystinuria" is a rare autosomal recessive condition resulting in altered sulfur metabolism with elevated methionine and homocysteine in plasma and homocystine in urine. This condition is characterized by a high clinical heterogeneity, which contributes to late clinical diagnosis, usually only made after irreversible damage has occurred. Treatment is effective if started before clinical symptoms. The analysis of methionine levels by tandem mass spectrometry (MS/MS) allows the newborn screening for homocystinuria, but false-positive results can be frequently obtained and lead to the unwanted identification of methionine adenosyl transferase (MAT I/III) deficiency. This latter condition is biochemically characterized by isolated persistent hypermethioninemia, accompanied in some individuals with slightly elevated levels of homocysteine in plasma. A dominant form of MAT I/III deficiency, associated wit...
Journal of Pediatric Gastroenterology & Nutrition, 1999
Aluminum toxicity is well documented and contamination of milk formulas has been implicated as th... more Aluminum toxicity is well documented and contamination of milk formulas has been implicated as the source of accumulation in bone and brain tissues. The purpose of the current study was to evaluate the aluminum contents of human milk, cow&amp;amp;amp;amp;#39;s milk, and infant formulas. Aluminum contents were determined by atomic absorption spectrometry in samples of human milk in the colostrum, intermediate, and mature stages; infant formulas from eight manufacturers; and various types and brands of commercially available cow&amp;amp;amp;amp;#39;s milk. Mean aluminum concentration was lowest in human milk (23.4 +/- 9.6 microg/l), and did not differ significantly between colostrum, intermediate-stage and mature-stage milk. Mean aluminum concentration was 70 microg/l in cow&amp;amp;amp;amp;#39;s milk, and 226 microg/l in reconstituted infant formulas. Aluminum concentrations in infant formulas differed markedly among manufacturers; concentration in milk from one of the manufacturers was particularly high (mean, 551 microg/l; range, 302-1149 microg/l). These values are for milk reconstituted with aluminum-free water under laboratory conditions; formulas prepared with tap water in the University Hospital&amp;amp;amp;amp;#39;s infant-feeding unit had even higher aluminum content. Experiments showed that aluminum concentration in the high-aluminum milk could be reduced by more than 70% at the manufacturing stage, by using low aluminum components. The results of the present study support the recommendations for infant formula manufacturers to strive to reduce aluminum concentration in their products.
BH4 therapy is an advancement in the treatment of phenylketonuria, reducing blood phenylalanine (... more BH4 therapy is an advancement in the treatment of phenylketonuria, reducing blood phenylalanine (phe) levels and increasing tolerance to natural proteins of responding patients. We report the results of 16 patients undergoing long-term BH4 treatment. Responding patients to BH4 was usually based on 24-h loading tests; a ≥30% decrease in blood phe was considered a positive response. Weekly loading made it possible to identify an additional "slow responder." The 16 responders constitute 24.6% of patients who completed the trial (87.5% of responders in mild hyperphenylalaninemia, 38.1% in mild PKU, and 2.8% in classical PKU).Mean dose of BH4 used was 9.75 ± 0.9 mg/kg per day, during a mean of 62 months. Age at treatment start was below 4 years in seven patients; five of which begun treatment during their first month since birth. All but one patient showed good treatment compliance; six continue on BH4 monotherapy without dietary phe restriction; six showed an increase in phe t...
Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importan... more Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importance due to the significant morbidity and mortality in undiagnosed patients. MCADD screening has been performed routinely in Galicia since July 2000, and until now 199,943 newborns have been screened. We identified 11 cases of MCADD, which gives an incidence of 1/18,134. During this period, no false negative screens have been detected. At diagnosis, all identified newborns were asymptomatic. Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. C8 was increased in all patients and C8/C10 was increased in all but one patient.The common mutation, c.985A &amp;amp;gt; G, was found in homozygosity in seven newborns and in compound heterozygosity in three, while one patient did not carry the common mutation at all. In addition, two novel mutations c.245G &amp;amp;gt; C (p.W82S) and c.542A &amp;amp;gt; G (p.D181G) were identified. Ten of the 11 identified newborns did not experience any episodes of decompensation. The patient with the highest level of medium chain acylcarnitines at diagnosis, who was homozygous for the c.985A &amp;amp;gt; G mutation, died at the age of 2 years due to a severe infection.This is the first report of the results from neonatal screening for MCADD in Spain. Our data provide further evidence of the benefits of MCADD screening and contribute to better understanding of this disease.
Knowledge of hyperphenylalaninemia (HPA) mutational spectrum in a population allows in many cases... more Knowledge of hyperphenylalaninemia (HPA) mutational spectrum in a population allows in many cases an accurate prediction of the phenotype and tetrahydrobiopterin (BH4) responsiveness, thus selecting an adequate treatment. In this work, we have performed the molecular characterization of 105 HPA patients from Galicia, in the northwest region of Spain, evaluating their phenotype and BH4 response. The mutational spectrum analysis showed 47 distinct mutations in 89 families, 37 of them (78.7%) corresponding to missense mutations. Six mutations account for 47.2% of all the investigated alleles, each one with a frequency ≥ 5% (IVS10-11G&amp;amp;gt;A, p.R261Q, p.V388M, p.R176L, p.E280K, p.A300S). The most prevalent HPA mutations in Galicia are the common Mediterranean mutation IVS10-11G&amp;amp;gt;A and p.R261Q, with frequencies of 13.8% and 10.5%, respectively. One novel mutation (p.K361Q; c.1081A&amp;amp;gt;C) was also reported. Although a good genotype-phenotype correlation is observed, there is no exact correlation for some genotypes involving mutations p.R261Q, p.I65T or IVS10-11G&amp;amp;gt;A. Forty seven patients were monitored for post-challenge BH4, establishing genotype-based predictions of BH4-responsiveness in all of them. All phenylketonuric patients with 2 nonresponsive mutations were unresponsive to BH4 and patients with mutations previously associated with BH4 responsiveness in the two alleles had a clear positive response to the test, with the exception of 5 patients with mutations p.R261Q, p.I65T and p.R68S. Our study supports a similar degree of heterogeneity of the HPA mutation spectrum in Galicia compared to reported data from Southern Europe. Patients carrying null mutations in both alleles showed the highest degree of concordance with the most severe phenotypes. Genotype is a good predictor of BH4 response.
The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) popu... more The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) population of Andalusia, assessing the correlation with the phenotype and the usefulness in predicting the response to treatment with tetrahydrobiopterin. We conducted a retrospective observational study between January 1980 and January 2010 in 147 Andalusian PKU patients assessing phenotype, genotype and response to a 24-h BH4 loading test. Our cohort of patients exhibited 65 different mutations, 69.2% corresponding to the missense type, in a total of 123 different genotypes. IVS10nt-11g&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;a was the most common mutation (10.9%). Four novel missense mutations were identified: p.L258P; p.E66K, p.R155C and p.P122S. Although generally there is a good genotype-phenotype correlation, for eight of the repeated genotypes a slightly different phenotype was observed. In 96 PKU subjects BH4 challenge was carried out. Patients with previously reported unresponsive mutations on both alleles showed a negative response, while 95.5% (28/29) of the responsive patients carry at least one missense mutation previously associated to the BH4. Our data reveal a great genetic heterogeneity in the Andalusian population. Genotype is quite a good predictor of the phenotype and of the responsiveness to tetrahydrobiopterin, which is relevant for patient management and follow-up.
Table S1. International Standard Classification of Education (ISCED). ISCED 0 Early childhood edu... more Table S1. International Standard Classification of Education (ISCED). ISCED 0 Early childhood education; ISCED 1 Primary education; ISCED 2 Lower secondary education; ISCED 3 Upper secondary education; ISCED 4 Post-secondary non-tertiary education; ISCED 5 Short-cycle tertiary education; ISCED 6 Bachelor's or equivalent level; ISCED 7 Master's or equivalent level; ISCED 8 Doctoral or equivalent level. *Included patients have all completed education. **82.9% of the siblings are still in education. (PDF 173 kb)
Table S3. Bone health. BMD was measured by dual energy x-ray photometry (DXA) using T- or Z-score... more Table S3. Bone health. BMD was measured by dual energy x-ray photometry (DXA) using T- or Z-scores of the lumbar spine, depending on age and gender. T-scores were used in post-menopausal women and men ≥ 50 years. Z-scores, considering age, gender, and ethnicity, were used in pre-menopausal women and men
This study aims to quantify concentrations of minerals and trace elements in human milk (HM) and ... more This study aims to quantify concentrations of minerals and trace elements in human milk (HM) and infant formula (IF) and evaluate associations with medical, social, environmental, and demographic variables. A prospective, case series study of 170 nursing mothers was made. HM samples were obtained from full-term (colostrum, intermediate and mature HM) and preterm (mature HM) mothers. Variables of interest were assessed by a questionnaire. For comparison, IF samples (n = 30) were analyzed in a cross-sectional study. Concentrations of 35 minerals, essential and toxic trace elements were quantified, 5 for the first time: thallium in HM and IF; strontium in preterm HM; and gallium, lithium and uranium in IF. In preterm and full-term HM, levels of selenium (p < 0.001) were significantly lower than recommended and were associated with low birth weight (p < 0.002). Cesium and strontium concentrations were significantly higher than recommended (p < 0.001). Associations were observed...
BACKGROUND AND OBJECTIVES: There are conflicting views as to whether testing for biotinidase defi... more BACKGROUND AND OBJECTIVES: There are conflicting views as to whether testing for biotinidase deficiency (BD) ought to be incorporated into universal newborn screening (NBS) programs. The aim of this study was to evaluate the cost-effectiveness of adding BD to the panel of conditions currently screened under the national NBS program in Spain. METHODS: We used information from the regional NBS program for BD that has been in place in the Spanish region of Galicia since 1987. These data, along with other sources, were used to develop a cost-effectiveness decision model that compared lifetime costs and health outcomes of a national birth cohort of newborns with and without an early detection program. The analysis took the perspective of the Spanish National Health Service. Effectiveness was measured in terms of quality-adjusted life years (QALYs). We undertook extensive sensitivity analyses around the main model assumptions, including a probabilistic sensitivity analysis. RESULTS: In th...
Homocystinuria due to cystathionine β-synthase deficiency or "classical homocystinuria"... more Homocystinuria due to cystathionine β-synthase deficiency or "classical homocystinuria" is a rare autosomal recessive condition resulting in altered sulfur metabolism with elevated methionine and homocysteine in plasma and homocystine in urine. This condition is characterized by a high clinical heterogeneity, which contributes to late clinical diagnosis, usually only made after irreversible damage has occurred. Treatment is effective if started before clinical symptoms. The analysis of methionine levels by tandem mass spectrometry (MS/MS) allows the newborn screening for homocystinuria, but false-positive results can be frequently obtained and lead to the unwanted identification of methionine adenosyl transferase (MAT I/III) deficiency. This latter condition is biochemically characterized by isolated persistent hypermethioninemia, accompanied in some individuals with slightly elevated levels of homocysteine in plasma. A dominant form of MAT I/III deficiency, associated wit...
Journal of Pediatric Gastroenterology & Nutrition, 1999
Aluminum toxicity is well documented and contamination of milk formulas has been implicated as th... more Aluminum toxicity is well documented and contamination of milk formulas has been implicated as the source of accumulation in bone and brain tissues. The purpose of the current study was to evaluate the aluminum contents of human milk, cow&amp;amp;amp;amp;#39;s milk, and infant formulas. Aluminum contents were determined by atomic absorption spectrometry in samples of human milk in the colostrum, intermediate, and mature stages; infant formulas from eight manufacturers; and various types and brands of commercially available cow&amp;amp;amp;amp;#39;s milk. Mean aluminum concentration was lowest in human milk (23.4 +/- 9.6 microg/l), and did not differ significantly between colostrum, intermediate-stage and mature-stage milk. Mean aluminum concentration was 70 microg/l in cow&amp;amp;amp;amp;#39;s milk, and 226 microg/l in reconstituted infant formulas. Aluminum concentrations in infant formulas differed markedly among manufacturers; concentration in milk from one of the manufacturers was particularly high (mean, 551 microg/l; range, 302-1149 microg/l). These values are for milk reconstituted with aluminum-free water under laboratory conditions; formulas prepared with tap water in the University Hospital&amp;amp;amp;amp;#39;s infant-feeding unit had even higher aluminum content. Experiments showed that aluminum concentration in the high-aluminum milk could be reduced by more than 70% at the manufacturing stage, by using low aluminum components. The results of the present study support the recommendations for infant formula manufacturers to strive to reduce aluminum concentration in their products.
BH4 therapy is an advancement in the treatment of phenylketonuria, reducing blood phenylalanine (... more BH4 therapy is an advancement in the treatment of phenylketonuria, reducing blood phenylalanine (phe) levels and increasing tolerance to natural proteins of responding patients. We report the results of 16 patients undergoing long-term BH4 treatment. Responding patients to BH4 was usually based on 24-h loading tests; a ≥30% decrease in blood phe was considered a positive response. Weekly loading made it possible to identify an additional "slow responder." The 16 responders constitute 24.6% of patients who completed the trial (87.5% of responders in mild hyperphenylalaninemia, 38.1% in mild PKU, and 2.8% in classical PKU).Mean dose of BH4 used was 9.75 ± 0.9 mg/kg per day, during a mean of 62 months. Age at treatment start was below 4 years in seven patients; five of which begun treatment during their first month since birth. All but one patient showed good treatment compliance; six continue on BH4 monotherapy without dietary phe restriction; six showed an increase in phe t...
Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importan... more Neonatal screening of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is of major importance due to the significant morbidity and mortality in undiagnosed patients. MCADD screening has been performed routinely in Galicia since July 2000, and until now 199,943 newborns have been screened. We identified 11 cases of MCADD, which gives an incidence of 1/18,134. During this period, no false negative screens have been detected. At diagnosis, all identified newborns were asymptomatic. Our data showed that octanoylcarnitine (C8) and C8/C10 ratio are the best markers for screening of MCADD. C8 was increased in all patients and C8/C10 was increased in all but one patient.The common mutation, c.985A &amp;amp;gt; G, was found in homozygosity in seven newborns and in compound heterozygosity in three, while one patient did not carry the common mutation at all. In addition, two novel mutations c.245G &amp;amp;gt; C (p.W82S) and c.542A &amp;amp;gt; G (p.D181G) were identified. Ten of the 11 identified newborns did not experience any episodes of decompensation. The patient with the highest level of medium chain acylcarnitines at diagnosis, who was homozygous for the c.985A &amp;amp;gt; G mutation, died at the age of 2 years due to a severe infection.This is the first report of the results from neonatal screening for MCADD in Spain. Our data provide further evidence of the benefits of MCADD screening and contribute to better understanding of this disease.
Knowledge of hyperphenylalaninemia (HPA) mutational spectrum in a population allows in many cases... more Knowledge of hyperphenylalaninemia (HPA) mutational spectrum in a population allows in many cases an accurate prediction of the phenotype and tetrahydrobiopterin (BH4) responsiveness, thus selecting an adequate treatment. In this work, we have performed the molecular characterization of 105 HPA patients from Galicia, in the northwest region of Spain, evaluating their phenotype and BH4 response. The mutational spectrum analysis showed 47 distinct mutations in 89 families, 37 of them (78.7%) corresponding to missense mutations. Six mutations account for 47.2% of all the investigated alleles, each one with a frequency ≥ 5% (IVS10-11G&amp;amp;gt;A, p.R261Q, p.V388M, p.R176L, p.E280K, p.A300S). The most prevalent HPA mutations in Galicia are the common Mediterranean mutation IVS10-11G&amp;amp;gt;A and p.R261Q, with frequencies of 13.8% and 10.5%, respectively. One novel mutation (p.K361Q; c.1081A&amp;amp;gt;C) was also reported. Although a good genotype-phenotype correlation is observed, there is no exact correlation for some genotypes involving mutations p.R261Q, p.I65T or IVS10-11G&amp;amp;gt;A. Forty seven patients were monitored for post-challenge BH4, establishing genotype-based predictions of BH4-responsiveness in all of them. All phenylketonuric patients with 2 nonresponsive mutations were unresponsive to BH4 and patients with mutations previously associated with BH4 responsiveness in the two alleles had a clear positive response to the test, with the exception of 5 patients with mutations p.R261Q, p.I65T and p.R68S. Our study supports a similar degree of heterogeneity of the HPA mutation spectrum in Galicia compared to reported data from Southern Europe. Patients carrying null mutations in both alleles showed the highest degree of concordance with the most severe phenotypes. Genotype is a good predictor of BH4 response.
The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) popu... more The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) population of Andalusia, assessing the correlation with the phenotype and the usefulness in predicting the response to treatment with tetrahydrobiopterin. We conducted a retrospective observational study between January 1980 and January 2010 in 147 Andalusian PKU patients assessing phenotype, genotype and response to a 24-h BH4 loading test. Our cohort of patients exhibited 65 different mutations, 69.2% corresponding to the missense type, in a total of 123 different genotypes. IVS10nt-11g&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;a was the most common mutation (10.9%). Four novel missense mutations were identified: p.L258P; p.E66K, p.R155C and p.P122S. Although generally there is a good genotype-phenotype correlation, for eight of the repeated genotypes a slightly different phenotype was observed. In 96 PKU subjects BH4 challenge was carried out. Patients with previously reported unresponsive mutations on both alleles showed a negative response, while 95.5% (28/29) of the responsive patients carry at least one missense mutation previously associated to the BH4. Our data reveal a great genetic heterogeneity in the Andalusian population. Genotype is quite a good predictor of the phenotype and of the responsiveness to tetrahydrobiopterin, which is relevant for patient management and follow-up.
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