BackgroundHereditary Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the enzyme Fumarylacetoacetate Hydrolase. Due to this defect, toxic products accumulate which, in turn, cause liver and kidney dysfunction. Treatment with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and diet has diminished these problems, but recent data indicate that HT1 patients have neurocognitive problems. However, the neuropsychological profile of these patients is unknown. Therefore, this study aimed to investigate this neuropsychological profile by comparing HT1 patients with healthy controls.MethodsNeurocognitive testing was performed in a heterogeneous group of 19 NTBC and dietary treated HT1 patients (five female, fourteen male; mean age 12.9 ± 4.8 years; range 7.9–23.6 years) and 19 age and gender matched controls (five female, fourteen male; mean age 13.2 ± 4.6 years; range 8.1–24.8 years). IQ scores were estimated and all participants performed the Amsterdam Neuropsychological Tasks, measuring executive functions (inhibition, cognitive flexibility and working memory) and social cognition (face recognition and identification of facial emotions).ResultsHT1 patients showed poorer estimated IQ, executive functioning (working memory and cognitive flexibility), and social cognition compared to healthy controls. Lower IQ scores in HT1 patients were mostly unrelated to scores on executive function- and social cognition tasks and therefore did not account for group differences in these domains. Further analyses within the HT1 patient group (comparing different groups of patients based on the age at diagnosis and the clinical symptoms at diagnosis) did not reveal any significant results. The duration of NTBC treatment was negatively correlated with IQ.ConclusionsDespite the heterogeneity of the patient group, these data clearly show that IQ, executive functioning and social cognition are affected in HT1 patients, and that IQ screening is not sufficient for cognitive monitoring of these patients. Further research should focus on the underlying pathophysiological mechanisms of these impairments to consequently try to improve treatment strategies.

There are few data to support the use of follow-on formulas in infants from the age of 6 months. In a prospective trial in a deprived inner city area of Birmingham 100 infants who were already receiving pasteurised cows' milk by 6 months of age were enrolled and randomised either to receive a follow-on formula or to continue on cows' milk from 6 months until 18 months. At 18 months of age the follow-on formula group returned to cows' milk and both groups were followed up until 24 months. Iron status, growth, and nutritional status were analysed at intervals of six months. At enrolment, no differences in haematological status were evident. However, by 12 months of age, 31% of the cows' milk group were anaemic (haemoglobin concentration < 110 gIl) compared with only 3% of those receiving follow-on formulas. At 18 months, 33% of the cows' milk group were anaemic compared with only 2% of the follow-on formula group and by 24 months of age none of the follow-on formula group was anaemic, whereas 26% in the cows' milk group still had a haemoglobin of < 110 gIl. Mean corpuscular volume was significantly smaller and ferritin significantly lower in the cows' milk group at 12, 18, and 24 months. Dietary iron intake was higher in the follow-on formula group at 12 and 18 months but not at 24 months, when both groups were back on cows' milk. Infants and toddlers at high risk of iron deficiency are therefore unlikely to become anaemic if receiving a follow-on formula, although the relative merits of follow-on formula compared with an ordinary infant formula remain uncertain. (Arch Dis Child 1996;75:9-16)

No abstract

Blood phenylalanine control within the first 3 years of age, poor parental educational achievement at school level, and unsatisfactory maternal dietary knowledge may all influence longer-term blood phenylalanine control in children.

Background: In phenylketonuria (PKU), phenylalanine-free L-amino acid supplements are the major source of dietary micronutrients. Methods: Four hundred fifty-two retrospective annual/bi-annual non-fasting blood samples for nutritional markers (plasma zinc, selenium, and serum folate) from 78 subjects aged 1-16 years (median number of blood samples: 6, range 1-14) were analysed over 12 years. Longitudinal blood result data were available for 51 subjects (65%). The dietary intake from supplements was calculated. Results: The median intakes of all of the micronutrients studied were >200% of the reference nutrient intakes (RNI). There was no statistical correlation between dietary intake and nutritional markers outside of the normal reference range (RR) except for selenium, but there was a correlation between a lower plasma zinc, plasma selenium and haemoglobin status and better blood phenylalanine control in 1- to 4-year-old children. On at least one occasion, the individual plasma concentrations of zinc (71%, n = 54/76) and selenium (21%, n = 16/75) were below the RR; however, the concentrations of selenium (41%, n = 31/75) and serum folate (83%, n = 34/41) were also above the RR. Dietary intakes exceeded the upper tolerable intakes for zinc and copper (32%, n = 25) and folate (65%, n = 51). Individual longitudinal data demonstrated little change in micronutrient status over time. Conclusions: In PKU, biochemical micronutrient deficiencies are common despite micronutrient intakes above the RNI. Further study of the nutritional profiling of L-amino acid supplements in PKU is needed.

Blood phenylalanine concentrations were consistently lower in the afternoon. Taking blood samples at variable time points in the day may lead to variation in interpreting dietary control. A detailed study is necessary to examine the 24-h diurnal variation of plasma phenylalanine and tyrosine in HT1. It is possible that phenylalanine concentrations may be very low for a substantive time over 24 h and the potential impact that this may have on cognitive development and growth in children is unknown.

Lactose and casein synthesis by rabbit mammary explants in organ culture was inhibited when fractions of goat milk were included in the culture medium. Inhibition was dose-dependent, and readily reversed when milk fractions were removed. The pattern of effects obtained with various fractions of milk indicated that inhibition was caused by a protein of 10,000-30,000 Da, which was present in the milk serum or whey fraction. The inhibitor fraction decreased milk accumulation when injected into lactating rabbit mammary glands via the teat ducts, whereas other milk proteins had no effect. Results are discussed in terms of autocrine regulation of milk synthesis through negative feedback by milk constituents.

Background: The optimal dose of protein substitute has not been determined in children with phenylketonuria (PKU). Aim: To determine if a lower dose of protein substitute could achieve the same or better degree of blood phenylalanine control when compared to the dosage recommended by the UK MRC.