Guiametabolica.org: empowerment through internet tools in inherited metabolic diseases.

Web-based interventions are effective on the patient empowerment. Guiametabolica.org constitutes an interface for people involved in inherited metabolic diseases, trying to facilitate access to information and contact with professionals and other patients, offering a platform to develop support groups. Guiametabolica.org is widely considered for Spanish-speaking patients and caregivers with inherited metabolic diseases. Preliminary evaluations show changes in their habits, decrease in their senses of isolation and improvement regarding self-efficacy. Specific inherited metabolic diseases websites, especially participative websites, should be considered as a complement to more traditional clinical approaches. Their contribution lies in patient's general well-being, without interfering with traditional care.

Evolución neurológica, neuropsicológica y oftalmológica tras un año de suplementación con ácido docosahexaenoico en pacientes fenilcetonúricos / Neurological, neuropsychological, and ophtalmological evolution after one year of docosahexaenoic acid supplementation in phenylketonuric patients

Introducción. La fenilcetonuria (PKU) es una enfermedad metabólica autosómica recesiva causada por la deficiencia defenilalanina hidroxilasa. El tratamiento dietético de la PKU consiste en la restricción de alimentos ricos en proteínas, loque afecta la ingestión de lípidos de los pacientes y distorsiona la relación n-3:n-6 de ácidos grasos esenciales en la dieta. Esta deficiencia puede contribuir al deterioro neurológico y visual de los pacientes. Objetivo. Evaluar los cambios en las alteraciones de la sustancia blanca, potenciales evocados visuales (PEV) y rendimiento en funciones ejecutivas y motrices en pacientes con PKU tratados precozmente tras la suplementación con ácidodocosahexaenoico (DHA).Pacientes y métodos. Se seleccionaron 21 pacientes con PKU (edad: 9-25 años), con dieta restringida en fenilalanina. Loscriterios de inclusión fueron: valores bajos de DHA eritrocitaria, retraso de latencias de la onda P100 en PEV o presencia dehiperintensidad de sustancia blanca en la resonancia magnética (RM) cerebral, y cociente intelectual > 80. Los pacientes se suplementaron con DHA (10 mg/kg/día) durante 12 meses. La evaluación se realizó al inicio del estudio y a los 12 mesesde tratamiento, e incluyó parámetros bioquímicos, RM, PEV, evaluación oftalmológica y pruebas neuropsicológicas. Resultados y conclusión. Los pacientes normalizaron los niveles de DHA tras la suplementación. La mejora en las latencias de la onda P100 y la motricidad fina fue significativa. No se evidenciaron cambios en las otras exploraciones tras el tratamiento. Es necesario proseguir la investigación para establecer una relación causa-efecto entre el tratamiento con DHA y la mejoría observada en algunas funciones neurológicas (AU)

Introduction. Phenylketonuria (PKU) is an autosomal recessive metabolic disease caused by a deficiency of phenylalanine hydroxylase. The dietary therapy for the effective management of PKU, in particular the restriction of high-protein foodsof animal-origin, compromises patients’ intake of fat and distorts the n-3:n-6 ratio of essential fatty acids in the diet. This deficiency can contribute to neurological and visual impairment. Aim. To evaluate changes in white matter alterations, visual evoked potential (VEP) latences and performance in executive and motor functions in a group of early and continuously treated PKU patients after supplementation with docosahexaneoic acid (DHA).Patients and methods. We selected 21 PKU patients with early diagnosis (age range: 9-25 years), on a Phe-restricted diet and supplemented with PKU formula. Inclusion criteria were: low erythrocyte DHA values, prolonged P100 wave latencies in VEP and/or presence of white matter hyperintensities on brain magnetic resonance imaging (MRI), and intellectual quotient > 80. All patients were treated with DHA (10 mg/kg/day) for 12 months. Assessment was conducted at baseline and after 12 months of treatment, and included biochemical parameters, brain MRI, VEP, ophthalmologic evaluation andneuropsychological tests.Results and conclusion. All the patients normalized the DHA levels after supplementation. Improvement in the P100 wavelatencies, and fine motor skills was significant. No significant improvement in the other explorations was evident aftersupplementation. Further investigations seem advisable to establish a cause-effect relationship between DHA treatmentand the slight improvement observed in some neurological functions (AU)

[Neurological, neuropsychological, and ophthalmological evolution after one year of docosahexaenoic acid supplementation in phenylketonuric patients]. / Evolucion neurologica, neuropsicologica y oftalmologica tras un ano de suplementacion con acido docosahexaenoico en pacientes fenilcetonuricos.

INTRODUCTION. Phenylketonuria (PKU) is an autosomal recessive metabolic disease caused by a deficiency of phenylalanine hydroxylase. The dietary therapy for the effective management of PKU, in particular the restriction of high-protein foods of animal-origin, compromises patients' intake of fat and distorts the n-3:n-6 ratio of essential fatty acids in the diet. This deficiency can contribute to neurological and visual impairment. AIM. To evaluate changes in white matter alterations, visual evoked potential (VEP) latencies and performance in executive and motor functions in a group of early and continuously treated PKU patients after supplementation with docosahexaneoic acid (DHA). PATIENTS AND METHODS. We selected 21 PKU patients with early diagnosis (age range: 9-25 years), on a Phe-restricted diet and supplemented with PKU formula. Inclusion criteria were: low erythrocyte DHA values, prolonged P100 wave latencies in VEP and/or presence of white matter hyperintensities on brain magnetic resonance imaging (MRI), and intellectual quotient > 80. All patients were treated with DHA (10 mg/kg/day) for 12 months. Assessment was conducted at baseline and after 12 months of treatment, and included biochemical parameters, brain MRI, VEP, ophthalmologic evaluation and neuropsychological tests. RESULTS AND CONCLUSION. All the patients normalized the DHA levels after supplementation. Improvement in the P100 wave latencies, and fine motor skills was significant. No significant improvement in the other explorations was evident after supplementation. Further investigations seem advisable to establish a cause-effect relationship between DHA treatment and the slight improvement observed in some neurological functions.

Errores congénitos del metabolismo y práctica deportiva / Inborn errors of metabolism and sports

Los errores congénitos del metabolismo son enfermedades poco frecuentes y muy diferentes entre sí. Muchas de ellas (la mayoría) se presentan en la edad pediátrica y repercuten en diversas esferas de la vida del niño dando lugar, en muchos casos, a situaciones de desigualdad frente a los otros niños. Recomendar la práctica deportiva (práctica deportiva adaptada según el caso), tal y como se hace con el resto de los niños, es importante no sólo desde el punto de vista físico y psíquico, sino también para su desarrollo personal y social. Acercar el deporte a este grupo de pacientes constituye una maniobra más para su integración con el resto de los niños. No obstante, no es fácil realizar recomendaciones generales para un grupo de pacientes tan heterogéneo. En este trabajo intentamos realizar unas recomendaciones y observaciones particulares para algunos de los errores congénitos del metabolismo de mayor frecuencia(AU)

Inborn errors of metabolism are a rare and very diverse group of disorders. The majority of them present at paediatric age and have an effect on the child in many spheres of life, often leading to inequalities with other children. To recommend practicing a sport (adapted depending on the condition), like the rest of the children, it is very important, not only from a physical and psychological point of view, but also for their personal and social development. To bring sport nearer to this group of patients is one more manoeuvre for their integration with the other children. However, it is not easy to make general recommendations for such a heterogeneous group of patients. In this article we attempt to make particular recommendations and observations for some of the more common inborn errors of metabolism(AU)

Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle. With the exception of the French-Canadian founder effect, no common mutation has been detected in other populations. In this study, we collected 16 additional HHH cases and expanded the spectrum of SLC25A15/ORC1 mutations. Eleven novel mutations were identified including six new missense and one microrearrangement. We also measured the transport properties of the recombinant purified proteins in reconstituted liposomes for four new and two previously reported missense mutations and proved that the transport activities of these mutant forms of ORC1 were reduced as compared with the wild-type protein; residual activity ranged between 4% and 19%. Furthermore, we designed three-dimensional (3D)-modeling of mutant ORC1 proteins. While modeling the changes in silico allowed us to obtain new information on the pathomechanisms underlying HHH syndrome, we found no clear-cut genotype-phenotype correlations. Although patient metabolic alterations responded well to low-protein therapy, predictions concerning the long-term evolution of HHH syndrome remain uncertain. The preference for a hepatic rather than a neurological presentation at onset also continues, largely, to elude us. Neither modifications in oxidative metabolism-related energy, such as those expected in different mtDNA haplogroups, nor sequence variants in SLC25A2/ORC2 seem to be crucial. Other factors, including protein stability and function, and ORC1-ORC2 structural interactions should be further investigated.

Is deoxypyridinoline a good resorption marker to detect osteopenia in phenylketonuria?

OBJECTIVES: To evaluate deoxypyridinoline as a resorption marker in phenylketonuria (PKU) and to search for a relationship between deoxypyridinoline, calcium/creatinine index (Ca/Cr I), osteocalcin and bone alkaline phosphatase (BAP). METHODS: This was a transversal analytical study of 46 PKU patients [17.5 (4-38) years]. Deoxypyridinoline and osteocalcin were measured with a chemiluminescent assay and BAP was measured with an immunoradiometric assay. RESULTS: Deoxypyridinoline was significantly increased in patients aged 7-14 and >18 years old, being associated with age (r=-0.724, P<0.001). Adult patients showed significantly higher Ca/Cr I, which correlates with Phe values for the year prior to the study (P=0.014). Serum BAP was significantly increased in pediatric patients (9-13 years), while it was decreased in adult patients (P=0.003). Decreased osteocalcin levels were found in patients>15 years (P=0.028). Altered deoxypyridinoline and BAP values were related (P=0.042). CONCLUSION: PKU patients excreted increased D-Pyr, suggesting high bone resorption. Bone formation seems active in childhood but deteriorates in adult PKU patients. Periodic measurement of D-Pyr and BAP may be useful in the prevention of osteopenia in PKU patients.

A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations.

Background & Aims: At least 500 mug of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy) concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 mug of folate or with one 500 mug capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (p<0.001) and plasma tHcy decreased (p<0.001) with both therapies. Folate-rich foods decreased tHcy by 8.6% (95% CI: -15.9 to -1.2) and synthetic folic acid capsules by 8% (95% CI: -13.3 to -2.7). Conclusions: This study shows, for the first time in the literature, that a folate-rich diet is as effective as folic acid capsules in decreasing plasma tHcy concentrations and adds further support to the recommendation of those diets to prevent cardiovascular disease.

Polymorphisms of genes involved in homocysteine metabolism in preeclampsia and in uncomplicated pregnancies.

OBJECTIVE: To evaluate the possible relationship between preeclampsia and polymorphisms in the main genes involved in folate-homocysteine metabolism. STUDY DESIGN: Case-control study: 43 patients with preeclampsia and 122 controls without pregnancy complications. Laboratory studies: tHcy and other amino acids, folate and vitamin B(12) and polymorphisms: 677C > T and 1298A > C (MTHFR); 699C > T, 844ins68 and 1080C > T (CBS); 2756A > G (MTR); and 66G > A, IVS1+766G > A and IVS1+754A > C (MTRR). RESULTS: Plasma tHcy and folate values were significantly higher (P = 0.004 and P = 0.019), while Met/tHcy ratios were lower (P < 0.001) in the patients compared with controls. No association was observed between polymorphisms tested and preeclampsia. In the control group, four such associations were found: the 1298A > C polymorphism (MTHFR) with the ratio Met/tHcy (P = 0.014); the 699C > T polymorphism (CBS) with the ratio tHcy/SigmaAA (P = 0.013); the 2756A > G polymorphism (MTR) with tHcy (P = 0.034); and the IVS1+766G > A polymorphism (MTRR) with hyperhomocysteinemia (P = 0.012). CONCLUSION: An association between the polymorphisms analysed and preeclampsia could not be demonstrated.

cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression.

The cblE type of homocystinuria is a rare autosomal recessive disorder caused by impaired reductive activation of methionine synthase. Although earlier biochemical studies proposed that the methionine synthase enzyme might be activated by two different reducing systems, mutations were reported in only the methionine synthase reductase gene (MTRR) in cblE patients. The pathogenicity of MTRR mutations, however, has not yet been tested functionally. We report on nine patients of European origin affected by the cblE type of homocystinuria. They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases. Bone marrow examination performed in seven patients showed megaloblastic changes in all but one of them. All patients exhibited moderate to severe hyperhomocysteinemia (median plasma total homocysteine [Hcy] 92 mumol/L, range 44-169), while clearly reduced methionine was observed only in four cases. Pathogenic mutations were identified in both parental alleles of the MTRR gene in all patients. Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected. Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect. Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C>T mutation, but no other obvious genotype-phenotype correlation. The identification of mutations in the MTRR gene, together with restoration of methionine synthesis following MTRR minigene expression in cblE cells confirms that this disease is caused by defects in the MTRR gene.

Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals.

OBJECTIVE: Exposure to nucleoside analogues in fetal or early life has been associated with rare clinically significant mitochondrial toxic effects, mainly neurologic symptoms. Lactate (LA) measurements have been used to monitor nucleoside-related mitochondrial toxicity. Our aim was to determine the prevalence, clinical evolution, and risk factors for hyperlactatemia in our cohort of human immunodeficiency virus (HIV)-uninfected children who were exposed to antiretrovirals. METHODS: We conducted a prospective observational study of 127 HIV-uninfected infants who were born to HIV-infected women. Clinical symptoms suggesting mitochondrial dysfunction were analyzed in routine follow-up, and LA and alanine plasma levels were obtained at 6 weeks, 3 months, 6 months, and 12 months in all patients. Elevated alanine levels, together with hyperlactatemia, suggest chronic mitochondrial injury. RESULTS: Most (85%) women received highly active antiretroviral therapy (HAART) during pregnancy (mean duration: 31 weeks) and zidovudine during labor (93%). Most (96%) children received zidovudine alone. Hyperlactatemia with hyperalaninemia was detected in 63 children in at least 1 of the measurements. Mean LA levels were significantly higher in children who were exposed to nucleoside analogue reverse transcriptase inhibitors than in control subjects (2.88 vs 1.61 at 6 weeks, 2.78 vs 1.49 at 3 months, 1.89 vs 1.39 at 6 months, and 1.71 vs 1.24 at 12 months; peak levels: 8.06, 10.1, 7.28, and 4.48 mmol/L, respectively). In 44 patients, LA levels progressed spontaneously to normality within the first year of life. Three girls presented a slight and self-limited delay in psychomotor development, with LA peak levels of 7.3, 4.0, and 4.6 mmol/L. Only the gestational use of didanosine was associated with a higher risk of hyperlactatemia. CONCLUSIONS: In our series, almost half of the children (63 of 127) who were exposed to nucleoside analogues developed benign and self-limited hyperlactatemia. When symptomatic, nucleoside analogue-induced toxicity affected neurologic development.

Perinatal outcome prediction by maternal homocysteine and uterine artery Doppler velocimetry.

OBJECTIVES: (a) To evaluate the predictive value of uterine Doppler velocimetry for pregnancy complications, (b) to study the relationship between abnormal uterine Doppler velocimetry and plasma homocysteine, and (c) to determine whether homocysteine measurement improves the predictive value of uterine Doppler screening. STUDY DESIGN: Prospective study including 94 pregnant women without previous risk factors. Total homocysteine, folate and Vitamin B(12) were analysed. Uterine Doppler velocimetry at weeks 24-25 was performed. RESULTS: The presence of any uterine Doppler alteration had a sensitivity of 66.7%, and a specificity of 81.2%, in predicting obstetric complications. The likelihood ratio was 3.6. The positive and negative predictive values were 27.3 and 95.8%, respectively. The global efficiency was 83.0%. The addition of hyperhomocysteinemia to Doppler alterations increased the sensitivity from 66.7 to 77.8%. CONCLUSIONS: The addition of homocysteine determination to uterine Doppler evaluation in the second trimester does not usefully improve its predictive value.

[Hyperhomocysteinemia during pregnancy as a risk factor of preeclampsia]. / Hiperhomocisteinemia durante el embarazo como factor de riesgo de preeclampsia.

A revision about the role of hyperhomocysteinemia in the development of preeclampsia is presented, which summarises our experience in different biochemical and genetic points in relation to this possible association. Plasma total homocysteine concentrations (tHcy) during pregnancy were significantly lower than those of non-pregnant women: 2nd trimester (median, 5.3 micromol/l; range, 3.1-10.0 micromol/l); 3rd trimester (median, 6.3 micromol/l; range, 3.2-13.0 micromol/l). Hyperhomocysteinemia (tHcy>P95) was established as values higher than 7.7 micromol/l in the 2nd trimester, and as values higher than 10.5 micromol/l in the 3rd trimester of pregnancy. We found an association between hyperhomocysteinemia and preeclampsia: tHcy values were significantly higher in the preeclamptic group than in uncomplicated pregnancies; the OR for preeclampsia in hyperhomocysteinemic patients was 7.7 (CI 95%, 1.7-34.8). The other amino acid concentrations were also higher in preeclamptic women. The negative correlation observed between homocysteine and folate in the control group, was not present in preeclamptic women. An association between homocysteine concentrations in preeclampsia and glucose intolerance was not observed. The Doppler study of uterine artery flow velocity waveforms seems to be a good screening method to identify pregnancies at high risk of preeclampsia. The addition of homocysteine determination did not usefully improve its predictive value. The polymorphisms in the main genes involved in folate-homocysteine metabolism studied could not be considered as the determinants of the hyperhomocysteinemia observed in preeclamptic pregnants.

Hiperhomocisteinemia durante el embarazo como factor de riesgo de preeclampsia / Hyperhomocysteinemia during pregnancy as a risk factor of preeclampsia

Se presenta una revisión sobre el papel que la hiperhomocisteinemia tiene en el desarrollo de preeclampsia, aportando nuestra experiencia en diferentes aspectos bioquímicos y genéticos relacionados con el tema. Las concentraciones de homocisteína plasmática total (Hct) observadas en gestantes son inferiores a las de mujeres fértiles no gestantes: 2.o trimestre (mediana, 5,3 µmol/l; rango, 3,1-10 µmol/l); 3.er trimestre (mediana, 6,3 µmol/l; rango, 3,2-13,0 µmol/l). Definimos hiperhomocisteinemia (Hct > P95) durante el embarazo toda concentración > 7,7 µmol/l (2.o trimestre) y >10,5 µmol/l (3.er trimestre).Encontramos asociación entre hiperhomocisteinemia y preeclampsia: la Hct es significativamente superior en el grupo de preeclampsias que en los controles; odds ratio (OR) para preeclampsia en hiperhomocisteinémicas = 7,7 (intervalo de confianza [IC] 95 por ciento, 1,7-34,8). Las preeclampsias muestran también un aumento generalizado del resto de los aminoácidos. La correlación negativa observada en gestantes controles entre homocisteína y folato no se observa en las preeclámpticas. No hemos encontrado asociación entre las concentraciones de homocisteína en las preeclámpticas y la intolerancia a la glucosa. La velocimetría Doppler de arterias uterinas en el 2.o trimestre es un método que puede ser útil para identificar a gestantes con riesgo de preeclampsia. La adición de la determinación de Hct no mejora significativamente su predictibilidad. Los polimorfismos en los genes implicados en el metabolismo de la homocisteína estudiados no pueden ser considerados como determinantes de la hiperhomocisteinemia observada en las gestantes con preeclampsia (AU)

Plasma total homocysteine in uncomplicated pregnancy and in preeclampsia.

OBJECTIVES: (a) To establish the reference values for plasma total homocysteine in our pregnant population. (b) To determine the possible association between hyperhomocysteinemia and preeclampsia in our geographical area. STUDY DESIGN: Control-case study with 32 preeclamptic patients and 64 controls without pregnancy complications. Plasma total homocysteine, determined by HPLC (fluorescence detection), was correlated with serum folate and Vitamin B(12) (analyzed by competitive protein binding chemiluminescent assay). STATISTICAL ANALYSES: Mann-Whitney, Wilcoxon and Spearman test (SPSS, 10.0). RESULTS: Homocysteine concentrations in the controls were significantly higher while folate was significantly lower in the third trimester of pregnancy when compared with the second (P<0.0001). Homocysteine and folate values were significantly higher in patients compared with controls in the third trimester (P=0.005 and 0.005, respectively). The OR for preeclampsia in hyperhomocysteinemia was 7.7 (95% CI: 1.7-34.8). CONCLUSION: Pregnant women with hyperhomocysteinemia have a 7.7-fold risk for preeclampsia (CI 95%: 1.7-34.8) compared with normal controls.

Homocisteína y gestación / Homocysteine and pregnancy

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Errores congénitos del metabolismo: ¿causa de estrés oxidativo? / Inborn errors of metabolism: cause of oxidative stress?

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