Maternal glutamine supplementation in murine succinic semialdehyde dehydrogenase deficiency, a disorder of γ-aminobutyric acid metabolism.

Murine succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with high concentrations of γ-aminobutyric acid (GABA) and γ-hydroxybutyrate (GHB) and low glutamine in the brain. To understand the pathogenic contribution of central glutamine deficiency, we exposed aldh5a1-/- (SSADHD) mice and their genetic controls (aldh5a1+/+ ) to either a 4% (w/w) glutamine-containing diet or a glutamine-free diet from conception until postnatal day 30. Endpoints included brain, liver and blood amino acids, brain GHB, ataxia scores, and open field testing. Glutamine supplementation did not improve aldh5a1-/- brain glutamine deficiency nor brain GABA and GHB. It decreased brain glutamate but did not change the ratio of excitatory (glutamate) to inhibitory (GABA) neurotransmitters. In contrast, glutamine supplementation significantly increased brain arginine (30% for aldh5a1+/+ and 18% for aldh5a1-/- mice), and leucine (12% and 18%). Glutamine deficiency was confirmed in the liver. The test diet increased hepatic glutamate in both genotypes, decreased glutamine in aldh5a1+/+ but not in aldh5a1-/- , but had no effect on GABA. Dried bloodspot analyses showed significantly elevated GABA in mutants (approximately 800% above controls) and decreased glutamate (approximately 25%), but no glutamine difference with controls. Glutamine supplementation did not impact blood GABA but significantly increased glutamine and glutamate in both genotypes indicating systemic exposure to dietary glutamine. Ataxia and pronounced hyperactivity were observed in aldh5a1-/- mice but remained unchanged by the diet intervention. The study suggests that glutamine supplementation improves peripheral but not central glutamine deficiency in experimental SSADHD. Future studies are needed to fully understand the pathogenic role of brain glutamine deficiency in SSADHD.

The association of malaria morbidity with linear growth, hemoglobin, iron status, and development in young Malawian children: a prospective cohort study.

BACKGROUND: Although poor complementary feeding is associated with poor child growth, nutrition interventions only have modest impact on child growth, due to high burden of infections. We aimed to assess the association of malaria with linear growth, hemoglobin, iron status, and development in children aged 6-18 months in a setting of high malaria and undernutrition prevalence. METHODS: Prospective cohort study, conducted in Mangochi district, Malawi. We enrolled six-months-old infants and collected weekly data for 'presumed' malaria, diarrhea, and acute respiratory infections (ARI) until age 18 months. Change in length-for-age z-scores (LAZ), stunting, hemoglobin, iron status, and development were assessed at age 18 months. We used ordinary least squares regression for continuous outcomes and modified Poisson regression for categorical outcomes. RESULTS: Of the 2723 children enrolled, 2016 (74.0%) had complete measurements. The mean (standard deviation) incidences of 'presumed' malaria, diarrhea, and ARI, respectively were: 1.4 (2.0), 4.6 (10.1), and 8.3 (5.0) episodes/child year. Prevalence of stunting increased from 27.4 to 41.5% from 6 to 18 months. 'Presumed' malaria incidence was associated with higher risk of stunting (risk ratio [RR] = 1.04, 95% confidence interval [CI] = 1.01 to 1.07, p = 0.023), anemia (RR = 1.02, 95%CI = 1.00 to 1.04, p = 0.014) and better socio-emotional scores (B = - 0.21, 95%CI = - 0.39 to - 0.03, p = 0.041), but not with change in LAZ, haemoglobin, iron status or other developmental outcomes. Diarrhea incidence was associated with change in LAZ (B = - 0.02; 95% CI = - 0.03 to - 0.01; p = 0.009), stunting (RR = 1.02; 95% CI = 1.01 to 1.03; p = 0.005), and slower motor development. ARI incidence was not associated with any outcome except for poorer socio-emotional scores. CONCLUSION: In this population of young children living in a malaria-endemic setting, with active surveillance and treatment, 'presumed' malaria is not associated with change in LAZ, hemoglobin, or iron status, but could be associated with stunting and anemia. Diarrhea was more consistently associated with growth than was malaria or ARI. The findings may be different in contexts where active malaria surveillance and treatment is not provided. TRIAL REGISTRATION: NCT00945698 (July 24, 2009) and NCT01239693 (November 11, 2010).

Associations between prenatal mercury exposure and early child development in the ALSPAC study.

INTRODUCTION: There is evidence that high levels of mercury exposure to the pregnant woman can result in damage to the brain of the developing fetus. However there is uncertainty as to whether lower levels of the metal have adverse effects on the development of the infant and whether components of fish consumption and/or the selenium status of the woman is protective. METHODS: In this study we analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=2875-3264) to determine whether levels of total blood mercury of pregnant women collected in the first half of pregnancy are associated with the development of the offspring at ages 6, 18, 30 and 42 months. The developmental measures used maternal self-reported scales for individual types of development (fine and gross motor, social and communication skills) and total scores. Multiple and logistic regression analyses treated the outcomes both as continuous and as suboptimal (the lowest 15th centile). The statistical analyses first examined the association of prenatal mercury exposure with these developmental endpoints and then adjusted each for a number of social and maternal lifestyle factors; finally this model was adjusted for the blood selenium level. RESULTS: Total maternal prenatal blood mercury and selenium ranged from 0.17 to 12.76 and 17.0 to 324µg/L respectively. We found no evidence to suggest that prenatal levels of maternal blood mercury were associated with adverse development of the child, even when the mother had consumed no fish during pregnancy. In general, the higher the mercury level the more advanced the development of the child within the range of exposure studied. For example, the fully adjusted effect sizes for total development at 6 and 42 months were +0.51 [95%CI +0.05, +1.00] and +0.43 [95%CI +0.08, +0.78] points per SD of mercury. For the risk of suboptimal development the ORs at these ages were 0.90 [95%CI 0.80, 1.02] and 0.88 [95%CI 0.77, 1.02]. In regard to the associations between blood mercury and child development there were no differences between the mothers who ate fish and those who did not, thus implying that the benefits were not solely due to the beneficial nutrients in fish. CONCLUSIONS: We found no evidence of adverse associations between maternal prenatal blood mercury and child development between 6 and 42 months of age. The significant associations that were present were all in the beneficial direction.

Emphasizing the health benefits of vitamin D for those with neurodevelopmental disorders and intellectual disabilities.

People with neurodevelopmental disorders and intellectual disabilities have much greater health care needs. Mainly staying indoors, such people generally have low 25-hydroxyvitamin D (25(OH)D) concentrations. The Vitamin D Task Force of the American Academy of Developmental Medicine and Dentistry (AADMD) reviewed the evidence of 25(OH)D concentrations that benefit the health of persons with developmental disabilities. Maintaining recommended optimal serum 25(OH)D concentrations year long will benefit skeletal development in infants, children, and adolescents, and benefit musculoskeletal health and neuromuscular coordination in adult patients, and decrease risk of falls. Maintaining optimal concentrations decreases risks and severities of autoimmune diseases, cardiovascular disease, many types of cancer, dementia, types 1 and 2 diabetes mellitus, and respiratory tract infections. Other benefits include improved dental and oral health and improved physical performance. The Task Force recommends that 25(OH)D concentrations for optimal health to be in the range of 75 to 125 nmol/L, which can be achieved using between 800 and 4000 IU/day vitamin D3 and sensible exposure to solar UVB radiation. The paper also discusses the potential risks of higher 25(OH)D concentrations, the evidence from and limitations of randomized controlled trials, and the recommendations by various groups and agencies.

Maternal supplementation of nucleotides improves the behavioral development of prenatal ethanol-exposed mice.

Maternal ethanol consumption during pregnancy can induce learning deficits in the offspring. The objective of this study was to assess whether supplementation of exogenous nucleotides during pregnancy and lactation would ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, and to explore the possible mechanisms. In the present study, pregnant C57BL/6J mice were exposed to ethanol (5 g/kg body weight) intragastrically from gestational day (GD) 6 to GD15. The dams in exogenous nucleotide intervention groups were fed with feed containing 0.01%, 0.04%, or 0.16% nucleotide powder, with control and ethanol groups receiving normal feed. The dams were allowed to deliver naturally and to breast feed their offspring. After weaning, behavioral tests were carried out in the offspring of each group. Serum oxidation indexes were analyzed, and the hippocampus of each offspring was collected and detected for acetyl cholinesterase (AChE) activity and the expression of p-CREB, CREB, and BDNF. The results showed that maternal supplementation with exogenous nucleotides during pregnancy could ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, through improving their antioxidant capacity, reversing hippocampus AChE levels, and allowing the expression of some proteins related to learning and memory. However, different sensitivities were found between the two sexes.

Acute kernicterus in a neonate with O/B blood group incompatibility and a mutation in SLC4A1.

We cared for a term female newborn, who at 108 hours of age, with a total serum bilirubin of 15.4 mg/dL, was discharged from the hospital on home phototherapy. At a return appointment 44 hours later, her total serum bilirubin was 41.7 mg/dL and signs of acute kernicterus were present. Maternal/fetal blood group O/B incompatibility was identified, with a negative direct antiglobulin test, which was positive on retesting. She had abundant spherocytes on blood smear, and these persisted at follow-up, but neither parent had spherocytes identified. A heterozygous SLC4A1(E508K) mutation (gene encoding erythrocyte membrane protein band 3) was found, and in silico predicted to result in damaged erythrocyte cytoskeletal protein function. No mutations were identified in other red cell cytoskeleton genes (ANK1, SPTA1, SPTB, EPB41, EPB42) and the UGT1A1 promoter region was normal. Neurologic follow-up at 2 and 4 months showed developmental delays consistent with mild kernicterus.

Docosahexaenoic acid status at 9 months is inversely associated with communicative skills in 3-year-old girls.

The objective of the present observational study was to investigate if the docosahexaenoic acid (DHA) status assessed in infant erythrocytes (RBC) at 9 months was associated with the age when the infants reach developmental milestones and their psychomotor function at 3 years of age. Three hundred eleven healthy Danish children were followed from 9 months to 3 years of age (the SKOT cohort). RBC fatty acid composition was analysed by gas chromatography in 272 of the children. Milestone age was collected by questionnaires at 9 and 18 months and psychomotor development at 3 years of age was assessed by the parents using third edition of the Ages and Stages Questionnaire (ASQ-3). RBC DHA levels ranged from 2.2% to 12.6% of the RBC fatty acids. The age of reaching milestones correlated with psychomotor development, particularly with gross motor function at 3 years. An association between milestones and later personal and social skills was also observed, but only for girls. In girls, RBC-DHA was found to be inversely correlated with communication at 3 years of age (odds ratio = 0.69, 95% confidence interval: 0.56-0.86, P = 0.001), but no other associations with psychomotor development or milestones were found. The results from study indicate that DHA status at 9 months may not have a pronounced beneficial effect on psychomotor development in early childhood and that communicative skills at 3 years of age may even be inversely associated with early RBC-DHA levels in girls.

Reduced platelet aggregation in a boy with scurvy.

Pediatric scurvy is a rare condition characterized by perifollicular petechiae and bruising, hemorrhagic gingivitis and musculoskeletal symptoms, all assumed to be predominantly related to abnormal collagen structure. We report on a 9-year-old autistic boy with vitamin C deficiency due to a highly limited food range presenting with multiple petechiae, gum bleeding and debilitating bone pain, in whom platelet aggregometry revealed a distinctly reduced thrombocyte aggregation, normalizing after vitamin C supplementation. This observation indicates that platelet dysfunction may additionally contribute to the hemorrhagic diathesis in scurvy, and demonstrates that ascorbic acid deficiency should be considered in children with an otherwise unexplained acquired thrombocytopathy.

Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.

BACKGROUND: Arginine:glycineamidinotransferase (AGAT/GATM) deficiency has been described in 9 patients across 4 families. Here we describe the clinical outcome and response to creatine supplementation in a patient of the second family affected with AGAT deficiency-a 9-year-old girl. PATIENT AND METHODS: Delayed motor milestones were noticed from 4 months of age and at 14 months moderate hypotonia, developmental delay and failure to thrive. Laboratory studies revealed low plasma creatine as well as extremely low levels of guanidinoacetic acid in urine and plasma. Proton magnetic resonance spectroscopy (MRS) of the brain showed absence of creatine. DNA sequence analysis revealed a homozygous mutation (c.484+1G>T) in the AGAT/GATM gene. AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay. At 16 months, Bayley's Infant Development Scale (BIDS) showed functioning at 43% of chronologic age. Oral creatine supplementation (up to 800 mg/kg/day) was begun. RESULTS: At age 9 years she demonstrated advanced academic performance. Partial recovery of cerebral creatine levels was demonstrated on MRS at 25 months of age. Brain MRS at 40 months of age revealed a creatine/NAA ratio of about 80% of that in age-matched controls. CONCLUSIONS: 8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills. We emphasize that early diagnosis combined with early treatment onset of AGAT deficiency may lead to improvement of developmental outcome.

Increasing supplemental thyroid hormone use among premature infants born at 23 to 32 weeks' gestation.

We assessed the pattern of levo-thyroxine (l-thyroxine) therapy in very premature newborns over a 10-year period. We analyzed the electronic database of a large private neonatal practice group (Pediatrix, Ft. Lauderdale, FL) for 23- to 32-week gestation neonates ( N = 96,813) managed during 1997 to 2006. L-thyroxine use was analyzed by birth year and by gestational age (GA). L-thyroxine use increased with decreasing GA (nadir 0.3% at 32 weeks, peak 8.4% at 24 weeks). L-thyroxine supplementation increased 2.6-fold over time among infants ≤26 weeks' GA (3.4% in 1997 to 1999 to 8.7% in 2004 to 2006), but did not change among infants born at ≥29 weeks' GA. The highest rate of l-thyroxine supplementation (12.8%) occurred among 24-week GA infants in 2006. Median age at start of l-thyroxine was 23 days (25 to 75%, 15 to 38 days). Only 2% of treated infants were started on day of life 1. Despite no clear evidence from randomized trials supporting thyroid supplementation, l-thyroxine treatment of very preterm infants has significantly increased over the past decade. As l-thyroxine treatment was not consistent with protocols from published randomized trials, new focused randomized controlled trials are needed.

The fatty acid compositions of erythrocyte and plasma polar lipids in children with autism, developmental delay or typically developing controls and the effect of fish oil intake.

The erythrocyte and plasma fatty acid compositions of children with autism were compared in a case-control study with typically developing (TD) children and with children showing developmental delay (DD). Forty-five autism subjects were age-matched with TD controls and thirty-eight with DD controls. Fatty acid data were compared using paired t tests. In addition, blood fatty acids from treatment-naive autism subjects were compared with autism subjects who had consumed fish oil supplements by two-sample t tests. Relatively few differences were seen between erythrocyte fatty acids in autism and TD subjects although the former had an increased arachidonic acid (ARA):EPA ratio. This ratio was also increased in plasma samples from the same children. No changes in n-3 fatty acids or ARA:EPA ratio were seen when comparing autism with DD subjects but some SFA and MUFA were decreased in the DD subjects, most notably 24 : 0 and 24 : 1, which are essential components of axonal myelin sheaths. However, if multiple comparisons are taken into account, and a stricter level of significance applied, most of these values would not be significant. Autism subjects consuming fish oil showed reduced erythrocyte ARA, 22 : 4n-6, 22 : 5n-6 and total n-6 fatty acids and increased EPA, 22 : 5n-3, 22 : 6n-3 and total n-3 fatty acids along with reduced n-6:n-3 and ARA:EPA ratios. Collectively, the autism subjects did not have an underlying phospholipid disorder, based on erythrocyte fatty acid compositions, although the increased ARA:EPA ratio observed suggested that an imbalance of essential highly unsaturated fatty acids may be present in a cohort of autism subjects.

[Iron biochemical screening and development in infants from 6 to 24 month, by socioeconomic background, Cordoba Argentina]. / Hierro hemático y desarrollo, en niños de 6 a 24 meses de edad, según su origen social, Córdoba Argentina.

AIMS: To correlate the iron biochemical screening with cognitive and motor development, related to social background, in 6 to 24 month infants. METHODS: a population - based study of 276 children. The iron deficiency was determine by the modified criterion of Hillman (1996), combining three different screenings tests: serum ferritin, hemoglobin and erythrocyte protoporphyrin. To analyse development we used Bayley II Scale. RESULTS AND CONCLUSIONS: the anaemia was significative different (p< 0,05) between social levels, 36% in children with low socioeconomic background, 8% for the high one and iron deficiency without anaemia 42% in the total population. The motor development was homogeneous by social groups, showed 1% significative delay, 8% light delay. But the mental development shows significative differences (p<0,05) in both light and significative delay, been the must affected children with low socioeconomic background.

Hierro hemático y desarrollo en niños de 6 a 24 meses de edad, según su origen social, Córdoba, Argentina / Iron biochemical screening and development, in infants from 6 to 24 month, by socioeconomic background, Cordoba Argentina

Objetivo: Correlacionar parámetros bioquímicos de hierro y desarrollo psicomotríz, en relación al origen social, en niños de 6 a 24 meses de Córdoba, Argentina. Material y Métodos: En 276 niños se determino el estado nutricional del hierro con el criterio de Hillman, combinando ferritina, hemoglobina y protoporfirina eritrocitaria, para desarrollo Escala de Bayley 11, y variables socioeconómicas. Resultados y Conclusiones: La anemia presento diferencias (p<0.05) entre los niveles soci21es, la depleción fue 42 % en la población total. El desarrollo motor fue homogéneo en los grupos sociales; mientras que el mental presento diferencias ( p< 0.05) en retraso leve y significativo, siendo los mas afectados los niños del nivel bajo. En desarrollo y parámetros bioquímicos, el 19 % de los niños con anemia y depleción, presentaron retraso motor leve, mientras que en desarrollo mental, el retraso leve y significativo afecto en doble proporción a los niños con depleción y anemia en comparación con los niños normales.

Aims: To correlate the iron biochemical screening with cognitive and motor development, related to social background, in 6 to 24 month infants. Methods: a population - based study of 276 children. The iron deficiency was determine by the modified criterion of Hillman ( 1996), combining three different screenings tests: serum ferritin, hemoglobin and erythrocyte protoporphyrin. To analyse development we used Bayley 11 Scale. Results and conclusions: the anaemia was significative different (p< 0,05) between social levels, 36% in children with low socioeconomic background, 8% for the high one and iron deficiency without anaemia 42% in the total population. The motor development was homogeneous by social groups, showed 1 % significative delay, 8% light delay. But the mental development shows significative differences (p<0,05) in both light and significative delay, been the must affected children with low socioeconomic background.

Hierro hemático y desarrollo en niños de 6 a 24 meses de edad, según su origen social, Córdoba, Argentina / Iron biochemical screening and development, in infants from 6 to 24 month, by socioeconomic background, Cordoba Argentina

Objetivo: Correlacionar parámetros bioquímicos de hierro y desarrollo psicomotríz, en relación al origen social, en niños de 6 a 24 meses de Córdoba, Argentina. Material y Métodos: En 276 niños se determino el estado nutricional del hierro con el criterio de Hillman, combinando ferritina, hemoglobina y protoporfirina eritrocitaria, para desarrollo Escala de Bayley 11, y variables socioeconómicas. Resultados y Conclusiones: La anemia presento diferencias (p<0.05) entre los niveles soci21es, la depleción fue 42 % en la población total. El desarrollo motor fue homogéneo en los grupos sociales; mientras que el mental presento diferencias ( p< 0.05) en retraso leve y significativo, siendo los mas afectados los niños del nivel bajo. En desarrollo y parámetros bioquímicos, el 19 % de los niños con anemia y depleción, presentaron retraso motor leve, mientras que en desarrollo mental, el retraso leve y significativo afecto en doble proporción a los niños con depleción y anemia en comparación con los niños normales.(AU)

Aims: To correlate the iron biochemical screening with cognitive and motor development, related to social background, in 6 to 24 month infants. Methods: a population - based study of 276 children. The iron deficiency was determine by the modified criterion of Hillman ( 1996), combining three different screenings tests: serum ferritin, hemoglobin and erythrocyte protoporphyrin. To analyse development we used Bayley 11 Scale. Results and conclusions: the anaemia was significative different (p< 0,05) between social levels, 36% in children with low socioeconomic background, 8% for the high one and iron deficiency without anaemia 42% in the total population. The motor development was homogeneous by social groups, showed 1 % significative delay, 8% light delay. But the mental development shows significative differences (p<0,05) in both light and significative delay, been the must affected children with low socioeconomic background.(AU)

Iron supplemented formula milk related to reduction in psychomotor decline in infants from inner city areas: randomised study.

OBJECTIVE: To compare the effect of unmodified cows' milk and iron supplemented formula milk on psychomotor development in infants from inner city areas when used as the main milk source. DESIGN: Double blind, randomised intervention trial. SETTING: Birmingham health centre. SUBJECTS: 100 infants, mean age 7.8 months (range 5.7 to 8.6 months), whose mothers had already elected to use unmodified cows' milk as their infant's milk source. INTERVENTION: Changing to an iron supplemented formula milk from enrolment to 18 months of age, or continuing with unmodified cows' milk. MAIN OUTCOME MEASURES: Developmental assessments using Griffiths scales at enrolment and at 18 and 24 months. RESULTS: 85 participants completed the trial. There were no significant differences in haemoglobin concentration between the two groups at enrolment, but by 18 months of age 33% of the unmodified cows' milk group, but only 2% of the iron supplemented group, were anaemic (P<0.001). The experimental groups had Griffiths general quotient scores that were not significantly different at enrolment, but the scores in both groups declined during the study. By 24 months the decrease in the mean scores in the unmodified cows' milk group was 14.7 whereas the decrease in the mean scores in the iron supplemented group was 9.3 (P<0.02, 95% confidence interval 0.4 to 10.4). Mean subquotient scores were considerably lower in the unmodified cows' milk group at 24 months; significantly so for personal and social scores (P<0.02, 1.2 to 16.8 [corrected]). CONCLUSION: Replacing unmodified cows' milk with an iron supplemented formula milk up to 18 months of age in infants from inner city areas prevents iron deficiency anaemia and reduces the decline in psychomotor development seen in such infants from the second half of the first year.

Vitamin D, calcium, and bone status in children with developmental delay in relation to anticonvulsant use and ambulatory status.

Reports of abnormalities in vitamin D, calcium, and bone status associated with anticonvulsant use are inconsistent and difficult to interpret because of widely varying study designs, particularly for ambulatory status. We examined the relative effects of anticonvulsant use and ambulatory status on vitamin D, calcium, and bone status in a large group (n = 338) of children who had either normal motor function (ambulatory) or were nonambulatory and either receiving anticonvulsants or not; all had developmental delays. Data included diet records, serum analyses (calcium and calcidiol), and hand-wrist radiographs evaluated for bone maturation and quality. Data were analyzed by using a general linear models (GLM) procedure. Dietary and biochemical data were compared with those of a group of 34 normal children. There were no differences in calcium or vitamin D intakes among the four study groups; however, a high percentage of intakes was below the recommended dietary allowances for calcium (56%) and vitamin D (70%). Vitamin D intakes were positively associated with serum calcium (P < 0.005) and calcidiol (P < 0.01) concentrations. Analysis of covariance indicated that ambulatory status but neither anticonvulsant use nor their interaction contributed significantly to the prediction of serum calcium (P < 0.009) and calcidiol (P < 0.0001), the Z scores for number of ossified centers (P < 0.008), bone age (P < 0.0001), and bone area (P < 0.003). A strong interaction between anticonvulsant use and ambulatory status was seen for percentage cortical area (P < 0.0008), which was entirely due to anticonvulsant use in nonambulatory children (effect size = 0.98). Results suggest that ambulatory status is more important than was recognized previously in relation to abnormalities in vitamin D, calcium, and bone statuses; that all nonambulatory children may be at risk for low serum calcidiol and osteopenia; and that routine monitoring of risk and consideration of prophylactic vitamin D supplementation are warranted.