Identification of very long-chain acyl-CoA dehydrogenase deficiency is possible in the expanded newborn screening (NBS) due to the increase in tetradecenoylcarnitine (C14:1) and in the C14:1/C2, ...C14:1/C16, C14:1/C12:1 ratios detected in dried blood spots. Nevertheless, different confirmatory tests must be performed to confirm the final diagnosis. We have revised the NBS results and the results of the confirmatory tests (plasma acylcarnitine profiles, molecular findings, and lymphocytes VLCAD activity) for 36 cases detected in three Spanish NBS centers during 4 years, correlating these with the clinical outcome and treatment. Our aim was to distinguish unambiguously true cases from disease carriers in order to obtain useful diagnostic information for clinicians that can be applied in the follow-up of neonates identified by NBS.
Increases in C14:1 and of the different ratios, the presence of two pathogenic mutations, and deficient enzyme activity in lymphocytes (<12% of the intra-assay control) identified 12 true-positive cases. These cases were given nutritional therapy and all of them are asymptomatic, except one. Seventeen individuals were considered disease carriers based on the mild increase in plasma C14:1, in conjunction with the presence of only one mutation and/or intermediate residual activity (18–57%). In addition, seven cases were classified as false positives, with normal biochemical parameters and no mutations in the exonic region of ACADVL. All these carriers and the false positive cases remained asymptomatic. The combined evaluation of the acylcarnitine profiles, genetic results, and residual enzyme activities have proven useful to definitively classify individuals with suspected VLCAD deficiency into true-positive cases and carriers, and to decide which cases need treatment.
Children with congenital hypothyroidism (CH) are at risk of developing mild cognitive impairment despite normal overall intellectual performance. These deficits may be caused by disease-related and ...treatment-related factors. This study explores the impact of abnormal thyroid function during the first 3 years of life on attention performance at school age.
We included 49 children diagnosed with CH and receiving treatment for the condition: 14 boys (mean age 9.5±2.8 years) and 35 girls (9.6±2.6 years). The number of episodes of normal, under-, and overtreatment were estimated based on TSH levels during their first 3 years of life (at 12, 18, 24, 30, and 36 months). Children were assessed using a computerised version of a Sustained attention test. General linear models were calculated with the attention index as the dependent variable and sex, aetiology, and number of episodes of normal, under-, and overtreatment as independent variables.
Higher numbers of episodes of overtreatment (low TSH level) were associated with poorer attention performance at school age (P=.005, r=-0.45).
Children with CH should be monitored closely during the first 3 years of life in order to prevent not only hypothyroidism but also any adverse effects of overtreatment that may affect attentional function at school age.
To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations.
Twenty-two of 32 NBS programmes from 18 countries screened for at least one ...form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres.
NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15,000 healthy newborns.
Due to the favourable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, e.g. birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.
Contradictory results regarding the optimal initial dose of levothyroxine in children with congenital hypothyroidism (CH) hamper the clinical management of these children during their early infancy. ...We explore the relationships between the initial dose of levothyroxine and endocrine control during the first 6 months and cognition at school age.
Fifty children with CH, 14 boys (10+/-3.1 years) and 36 girls (9.7+/-2.6 years), at the Pediatric Endocrine Unit of the Hospital Gregorio Marañón in Madrid were studied. Neurocognitive evaluation was carried out exploring alertness and inhibitory control. The number of episodes of overtreatment during the first 6 months, the initial dose of levothyroxine, etiology and sex were the predictor variables.
Inhibitory control was significantly lower in children with CH than in controls. An interaction with gender and etiology was obtained. Alertness had an inverse relationship with the number of episodes of overtreatment with no interaction with gender or etiology.
Episodes of overtreatment and not the initial dose of levothyroxine are a risk factor for deficit in alertness whereas subtle inhibitory control deficit seems to be a permanent problem with the current therapeutic approach.
Los niños con hipotiroidismo congénito (HC) están en riesgo de presentar déficit cognitivos sutiles, a pesar de tener un rendimiento intelectual global dentro de rangos normales. Estos déficits ...pueden ser consecuencia de condiciones inherentes a la enfermedad y a factores relacionados con el tratamiento. El presente estudio explora el efecto de las desviaciones del estado de eutiroidismo durante los primeros 3 años de vida en el rendimiento atencional durante la edad escolar.
Fueron evaluados 49 niños con HC diagnosticado y bajo tratamiento, de ellos 14 fueron niños (9,5±2,8 años de edad) y 35 niñas (9,6±2,6 años de edad). Se calculó el total de episodios de sobre, infra y normotratamiento a partir de los valores de TSH durante los primeros 3 años de vida (medidos a los 12, 18, 24, 30 y 36 meses de edad). Los niños fueron evaluados mediante una versión computarizada del Test de atención sostenida. Se calcularon los modelos lineales generales usando el índice de atención como variable dependiente y el género, la etiología y los episodios de sobre, infra y normotratamiento como independientes.
El número de episodios de sobretratamiento (TSH baja) se asoció a un peor rendimiento atencional en la edad escolar (p=0,005, r=–0,45).
Debe realizarse un seguimiento estrecho en los 3 primeros años en pacientes con HC para evitar no solo el hipotiroidismo, sino también los efectos adversos de episodios de hipertratamiento que pueden comprometer el procesamiento atencional en edad escolar.
Children with congenital hypothyroidism (CH) are at risk of developing mild cognitive impairment despite normal overall intellectual performance. These deficits may be caused by disease-related and treatment-related factors. This study explores the impact of abnormal thyroid function during the first 3 years of life on attention performance at school age.
We included 49 children diagnosed with CH and receiving treatment for the condition: 14 boys (mean age 9.5±2.8 years) and 35 girls (9.6±2.6 years). The number of episodes of normal, under-, and overtreatment were estimated based on TSH levels during their first 3 years of life (at 12, 18, 24, 30, and 36 months). Children were assessed using a computerised version of a Sustained attention test. General linear models were calculated with the attention index as the dependent variable and sex, aetiology, and number of episodes of normal, under-, and overtreatment as independent variables.
Higher numbers of episodes of overtreatment (low TSH level) were associated with poorer attention performance at school age (P=.005, r=–0.45).
Children with CH should be monitored closely during the first 3 years of life in order to prevent not only hypothyroidism but also any adverse effects of overtreatment that may affect attentional function at school age.
La anemia falciforme es una enfermedad hereditaria que como resultado de las migraciones, constituye una de las alteraciones genéticas más frecuentes en el noroeste de Europa. Las complicaciones ...secundarias a la enfermedad son frecuentes durante los primeros 3 años de vida, y se viene recomendando un diagnóstico precoz para disminuirlas. La Comunidad de Madrid (CM) inició el cribado universal neonatal de hemoglobinopatías en mayo de 2003. El objetivo de este trabajo es presentar los resultados de los primeros 32 meses de implantación de este programa.
Estudio prospectivo, descriptivo que incluye a toda la población de recién nacidos en cualquier centro de la CM desde mayo de 2003 a diciembre de 2005. La muestra de sangre fue la primera prueba del talón obtenida en las maternidades de forma sistemática a partir de las 48 h de vida del niño. Se analizó por cromatografía líquida de alta resolución (HPLC) para detectar hemoglobina (Hb) F, A, S, C, D y E.
Se analizaron 190.238 niños y se detectaron 1.060 variantes de hemoglobina (5,57 por cada 1.000 nacimientos). Un total de 31 de ellas fueron variantes de enfermedad falciforme (0,16 por cada 1.000 nacimientos), instaurándose antibioterapia profiláctica, vacunación apropiada y cuidados globales. El estudio de progenitores motivó la realización en embarazos posteriores de diagnóstico prenatal en 3 familias. El origen de los padres portadores de variantes de Hb abarcó 44 países.
Aunque la enfermedad de células falciformes ha sido considerada anecdótica en España hasta fechas recientes, el aumento en la inmigración ha supuesto un notable incremento en su diagnóstico. Se espera que el programa de cribado neonatal disminuya la morbilidad y mortalidad en los primeros años de vida.
Sickle cell anemia is a hereditary disease which, as a result of migration, constitutes one of the most frequent genetic disorders in northwest Europe. Complications secondary to this disease are common during the first 3 years of life and early diagnosis has been recommended to reduce their development. The autonomous community of Madrid began to perform universal neonatal screening for hemoglobinopathies in May 2003. This study presents the results of the first 32 months of this screening program.
A prospective, descriptive study was designed to include all the neonates born in centers in the autonomous community of Madrid from May 2003 to December 2005. A heel prick dried blood spot from the Guthrie card was analyzed by high-performance liquid chromatography to detect hemoglobin F, A, S, C, D and E.
A total of 190238 newborns were analyzed, and 1060 hemoglobin variants (5.57 for every 1000 births) were detected. Thirty-one were sickle cell diseases and appropriate antibiotics, vaccination and comprehensive care were initiated. Prenatal diagnosis of subsequent pregnancies was performed in three families after parental investigation. Carrier parents were from 44 countries of origin.
Although sickle cell disease was considered anecdotic in Spain until recently, the diagnosis of this entity has markedly increased as a result of immigration. The universal screening program is expected to reduce morbidity and mortality in the first years of life.
Abstract Objective To evaluate in an experimental model the effects of the PDE5 inhibitor sildenafil on kidney grafts autotransplanted after a period of 45 minutes of warm ischemia and 60 minutes of ...hypothermic pump perfusion. Methods Nine laboratory large-white pigs were divided into two groups. Group A ( n = 4): oral dose of 100 mg sildenafil was administered 1 hour before the surgery. Group B ( n = 5): no sildenafil given. Right single nephrectomy was completed after a 45-minute period of warm ischemia by complete vascular clamping. Before the autotransplant, all kidneys were submitted to a 60-minute period of hypothermic pulsatile perfusion. Renal flow, arterial pressure, and renal vascular resistance were recorded in real time for 60 minutes after autotransplant. Nitric oxide levels were determined in blood samples of the renal vein at predefined intervals. Optical and electronic microscopy was performed on all organs at the end of the procedure. Results Renal vascular flow was significantly higher and renal vascular resistance significantly lower in the sildenafil group compared with the non-sildenafil group. No significant differences were observed in systemic arterial pressure values between both groups. Nitric oxide levels were significantly higher for all periods in the sildenafil group. No differences were observed in histological studies. Conclusion Our experimental work suggested a positive effect of sildenafil on the immediate posttransplant outcome of warm-ischemic kidneys without systemic secondary effects.
Purpose
To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations.
Methods
Twenty‐two of 32 NBS programmes from 18 countries screened ...for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta‐synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres.
Results
NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second‐tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second‐tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns.
Conclusions
Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second‐tier markers.
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