Elevated plasma phenylalanine concentrations may adversely affect bone status of phenylketonuric mice.

Children with phenylketonuric (PKU) are at risk for fractures. This study used a PKU murine model (PAH(enu-2)) to evaluate effects of moderate dietary protein restriction and elevated plasma phenylalanine concentration impact upon bone status. Fifty-four male weanling PKU and control mice were assigned to either an elemental phenylalanine (Phe)-restricted diet (treated) or Phe-unrestricted diet (untreated) with low or normal protein levels for 56 days. Untreated mice and control mice received equal amounts of dietary Phe; treated mice consumed prescribed dietary Phe to maintain plasma Phe concentrations between 120 and 480micromol/L. Plasma Phe, osteocalcin, and urine deoxypyridinoline (DPD)/creatinine were analysed at baseline and at days 28 and 56. Femur strength, bone mineral density (BMD) and bone mineral content (BMC) were analysed at day 56. Moderate protein restriction did not significantly affect bone status. Mean plasma Phe concentrations were significantly greater in untreated vs treated and control mice (p < 0.0001). Total body weight was significantly less in untreated vs control mice (p < 0.01). Mean femur weight was reduced in untreated mice vs both treated and control mice (p < 0.03). Untreated mice had smaller mean femur length than control mice (p < 0.002). Femur strength was greater in treated mice compared to control mice (p < 0.01) but not compared to untreated mice. No significant difference among groups was found in BMD and BMC. At day 56 there was a statistical trend (p < 0.056) towards higher urine DPD/creatinine excretion in untreated mice than in treated mice. Plasma Phe concentration was positively correlated with urine DPD/creatinine. These data suggested that hyperphenylalaninaemia may adversely affect bone status in PKU mice.

Intake and blood levels of fatty acids in treated patients with phenylketonuria.

BACKGROUND: Investigators in Italy and Spain have suggested that therapy for patients with phenylketonuria (PKU) may result in essential fatty acid (EFA) deficiency. Objectives of this study were to determine if the diets of patients with PKU in the United States provided adequate EFA intakes and whether patients could form long-chain polyunsaturated fatty acids. METHODS: Patients (1-13 years of age) with classic PKU undergoing therapy and their non-PKU sibling closest in age were compared. Nutrient intakes were calculated from 3-day diet diaries. Fatty acids in plasma and erythrocytes were identified and quantified. Paired t tests compared results for the patients and their non-PKU siblings. RESULTS: Twenty-eight patients and 26 siblings were studied. Mean fat intake was greatest by siblings (34.8 +/- 1.3% of energy) and lowest by Phenyl-Free-fed patients (19.5 +/- 1.2% of energy; P < 0.05). Fat intake (30.4 +/- 1.8% of energy) by Phenex-fed patients did not differ from that of siblings. Percentage of energy ingested as C18:2n-6 and C18:3n-3 did not differ significantly between patients and siblings. No clinically significant, consistent differences were found in fatty acid levels (wt%) in plasma or erythrocytes between patients with PKU and siblings. CONCLUSIONS: No patient in this study exhibited a Holman index of EFA deficiency. Siblings ingested animal protein containing C20:5n-3 and C22:6n-3 fatty acids, and this may account for their greater wt% of these plasma and erythrocyte fatty acids. Because patients with PKU do not ingest fatty acids >C18 but C20:4n-6, C20:5n-3, and C22:6n-3 were found in their plasma and erythrocytes, in vivo synthesis from C18:2n-6 and C18:3n-3 appears to occur. Lack of EFA deficiency in patients in this study may be the result of the use of canola and soy oils containing C18:2n-6 and C18:3n-3 rather than olive oil in the diets.

Protein status of infants with phenylketonuria undergoing nutrition management.

OBJECTIVES: The objectives of this study were to determine if Phenex-1, amino-acid modified medical food with iron maintained normal indices of protein status in infants with phenylketonuria (PKU) and to investigate factors that influence plasma amino acid concentrations. METHODS: A study was conducted for six months in 35 infants with classical PKU diagnosed in the neonatal period. Diet diaries and plasma amino acid concentrations were obtained monthly. Blood for analysis of plasma albumin, blood urea nitrogen (BUN), retinol binding protein (RBP) and transthyretin was obtained at one, three and six months of study. RESULTS: Mean (+/-SEM) total daily intake of medical food and nutrients was 79+/-4 g; 17.3+/-0.6 g protein, 660+/-18 kcal, 255+/-10 mg phenylalanine (Phe), and 1423+/-56 mg tyrosine (Tyr). Mean concentrations of plasma amino acids, except cystine (during entire study), glycine (first month) and Phe were in the normal range. Mean concentrations of plasma Phe were in the treatment range (120 to 360 micromol/L). Plasma concentrations of arginine, methionine, Phe, tryptophan, Tyr, and valine were positively correlated with intakes at various months of study. Concentrations of aspartic and glutamic acids, Phe, and Tyr were positively correlated and 17 amino acids were negatively correlated with the interval between feeding and blood draw. At six months of study, concentration of plasma albumin was 4.1+/-0.1 g/dL, RBP was 3.74+/-0.2 mg/dL, transthyretin was 17.9+/-0.9 mg/dL, and urea nitrogen was 11.9+/-0.5 mg/dL. CONCLUSION: During study, all mean plasma indices of protein status were in normal reference ranges. Phenex-1 supports normal mean plasma amino acid, albumin, RBP, transthyretin, and BUN concentrations when fed in adequate amounts.

Plasma micronutrient concentrations in infants undergoing therapy for phenylketonuria.

Twenty-seven infants with classical phenylketonuria were evaluated longitudinally for 6 mo while ingesting Phenex-1 Amino Acid Modified Medical Food With Iron as their primary protein source. Intake of selected nutrients and biochemical indices of trace and ultratrace mineral status and plasma retinol and alpha-tocopherol concentrations were evaluated. The means of iron status indices (complete blood count, plasma ferritin, iron, transferrin saturation, total iron binding capacity) and the plasma concentrations of trace and ultratrace minerals (copper, manganese, molybdenum, selenium, zinc) and plasma retinol and alpha-tocopherol were in the reference ranges. Vitamin A intakes (r = 0.49, p < 0.05) and plasma retinol-binding protein concentrations (r = 0.42, p < 0.05) were positively correlated with plasma retinol concentrations at 3 mo of study. At 6 mo, concentrations of plasma transthyretin (r = 0.72, p < 0.01) and retinol-binding protein (r = 0.48, p < 0.05) were positively correlated with plasma retinol concentrations. At 6 mo, concentrations of plasma transthyretin (r = 0.52, p < 0.05) were positively correlated with retinol-binding protein concentrations. Phenex-1 supports normal mean iron status indices and mean concentrations of trace and ultratrace minerals, retinol, and alpha-tocopherol when fed in adequate amounts.

Nutrient intake and growth of infants with phenylketonuria undergoing therapy.

BACKGROUND: Because of reports of poor growth, a study was conducted for 6 months in 35 infants with classic phenylketonuria diagnosed during the neonatal period who were fed Phenex-1 Amino Acid Modified Medical Food With Iron (Ross Products Division, Columbus, OH, U.S.A.).as their primary protein source. METHODS: Diet diaries and anthropometric measures were obtained monthly as part of a larger study in which nutrition status was evaluated. RESULTS: In 6-month-old infants, mean percentiles for crown-heel length (59.14+/-4.31 SEM), head circumference (63.88+/-4.50) and weight (71.51+/-4.25) were normal. Mean (+/- SEM) daily intake of medical food was 79+/-4 g; protein and energy intakes were 17.3+/-0.6 g and 2772+/-75.6 kJ (660+/-18 kcal). Mean daily phenylalanine and tyrosine intakes per kilogram of body weight were 40+/-1 mg and 219+/-9 mg. Intakes of protein, energy, and tyrosine were positively correlated with crown-heel length, head circumference, and weight at 3 months of study. Overall plasma phenylalanine and tyrosine concentrations during the 6-month study were 297+/-41 micromol/l and 58+/-5 micromol/l, respectively. Neither plasma phenylalanine nor tyrosine concentration was correlated with growth. CONCLUSION: Phenex-1 supports normal growth when fed in adequate amounts. These data support those of the Medical Research Council Working Party on Phenylketonuria for 3 g/kg per day of amino acids from medical food.

Protein intake affects phenylalanine requirements and growth of infants with phenylketonuria.

Growth and metabolic status of 25 infants with PKU were evaluated based on protein intake. Food A-fed infants received a medical food containing 3.12 g protein equivalent per 100 kcal and Food B-fed infants received a medical food containing 2.74 g protein equivalent per 100 kcal. Growth percentiles of infants in the Food A group were significantly greater than those for infants in the Food B group at 6 months of age (Food A percentiles: crown-heel length 55, head circumference 60, weight 73. Food B percentiles: crown-heel length 28; head circumference 29, weight 39). At study entrance, only crown-heel length of the two groups differed; Food B infants had a significantly greater mean crown-heel length percentile (p < 0.05). Mean phenylalanine (PHE) intake was 38% greater by Food A-fed infants than by Food B-fed infants. Plasma PHE concentrations and mean energy intakes of the two groups did not differ. Mean protein intake of Food A-fed infants was greater during the first three months of life and significantly greater (p < 0.05) during the second three months of life than by Food B-fed infants. Mean protein intake 24% greater than Recommended Dietary Allowances (RDA) was associated with better PHE tolerance and growth than was found when mean protein intake was 9% greater than RDA.

Nutrition support for glutaric acidemia type I.

Glutaric acidemia type I is a rare, autosomal recessive, inborn error of lysine and tryptophan metabolism. This disorder is caused by a defect in the mitochondrial enzyme glutaryl-coenzyme A dehydrogenase, resulting in permanent or episodic elevations of glutaric acid. Despite clinical variability, untreated children often experience progressive neurologic damage that frequently leads to death. Recent evidence suggests that a lysine- and tryptophan-restricted diet and pharmacologic therapy with oral riboflavin and L-carnitine may arrest the neurologic deterioration. Several cases of normal growth and development have been reported in children diagnosed and treated before neurologic insult. In this article, we review previously published experience with dietary and pharmacologic therapy and provide guidelines for nutrition support based on our experience of treating four affected children. We suggest that dietary restriction of lysine and tryptophan is a safe and potentially effective therapy for individuals with glutaric acidemia type I.

Plasma molybdenum concentrations in children with and without phenylketonuria.

Plasma molybdenum concentrations were determined in children, ages two to 12 yr, with and without phenylketonuria (PKU). Mean plasma molybdenum concentrations did not differ significantly between the children with PKU (1.33 +/- 0.5 microgram/L) and without PKU (1.75 +/- 0.8 microgram/L). Plasma molybdenum concentrations in both groups of children ranged from < 1 to 3 micrograms/L. When data from all children were combined and then separated based on gender, mean plasma molybdenum levels did not differ significantly between 9 females (1.56 +/- 0.68 microgram/L) and 12 males (1.58 +/- 0.76 microgram/L). Data were also combined and mean (+/- SD) plasma molybdenum concentrations calculated for age groups. Two children aged 1 to < 4 yr had plasma molybdenum concentrations of 1.0 micrograms/L, and six children aged 4 to < 7 yr had mean (+/- SD) plasma molybdenum concentrations of 1.5 +/- 0.8 microgram/L. Eleven children aged 7 to < 11 yr had a mean plasma molybdenum concentration of 1.7 +/- 0.7 microgram/L, and two children 11 to < 14 yr had plasma molybdenum of 1 microgram/L and 2 micrograms/L. Plasma molybdenum concentrations did not differ significantly among children in the age groups.

Nutrient intakes of adolescents with phenylketonuria and infants and children with maple syrup urine disease on semisynthetic diets.

Adequacy of nutrient intakes of adolescents with and without phenylketonuria (PKU) and infants and children with and without maple syrup urine disease (MSUD) were assessed using 3-day diet records sorted by disease and by age of the subject. Mean intakes of all nutrients were greater than two-thirds of the Recommended Dietary Allowances (RDA) or Estimated Safe and Adequate Daily Dietary Intakes (ESADDI) for all adolescents studied, with the exception of selenium (Se) in PKU adolescents, which averaged 27.8 micrograms. For adolescents with PKU, > 50% of the RDA or ESADDI for all nutrients was provided by elemental or modified protein hydrolysate medical foods, except for vitamin A in children aged 11-15 years and Se in children 11-18 years. Mean nutrient intakes of all infants and children were greater than two-thirds of the RDA or ESADDI for all nutrients except Se in MSUD children aged 1-11 years, where intakes ranged from 6.4 to 13.2 micrograms (21-66% of the RDA). The medical foods provided for most of the RDA and ESADDI recommendations, with the exception of Se in MSUD children.

Decreased selenium intake and low plasma selenium concentrations leading to clinical symptoms in a child with propionic acidaemia.

A child with biotin-non-responsive propionic acidaemia treated with a propiogenic amino acid-restricted diet presented with an elevated blood mean corpuscular volume (MCV) of 93.1 fl, indicative of macrocytosis, and unusual hair texture with hypopigmentation. Plasma selenium concentration at this time was subnormal (45.9 micrograms/L), and calculated dietary selenium intake was 4.7 micrograms/day. After 4 months of selenium supplementation (50 micrograms/day) plasma selenium concentration normalized (97.7 micrograms/L) in conjunction with a reduced MCV (84.0 fl) and a dramatic improvement in hair growth, colour and length. Two additional periods off and on selenium supplementation, of varying time intervals, resulted in similar clinical changes. We conclude that these clinical changes were due to a deficient intake of dietary selenium.

The management of breast feeding among infants with phenylketonuria.

Treatment for phenylketonuria (PKU) involves using low phenylalanine-free or phenylalanine-free formulas and supplementation with sufficient phenylalanine for normal growth and development. Eighteen infants with phenylketonuria who received breast milk as their primary phenylalanine source were compared with ten other infants with PKU who received their phenylalanine primarily from infant formulas. There were no significant differences between breast-fed and formula-fed infants for serum phenylalanine, serum tyrosine, length, weight, head circumference, haematocrit, haemoglobin, serum iron, total iron binding capacity, percentage iron saturation, ferritin, plasma zinc and total calorie intake. Breast-fed infants did show lower mean corpuscular volume at 3 months and 6 months of age. Breast-fed infants had lower phenylalanine intake at 2, 4, 5 and 6 months of age. Breast-fed infants at 1, 2, 3, 4, 5 and 6 months of age had lower protein intake. Breast feeding may be continued in the newly diagnosed phenylketonuric infant without any apparent adverse nutritional consequences.

Normal growth and development with unrestricted protein intake after severe infantile propionic acidaemia.

A child with propionic acidaemia, after a stormy infantile course complicated by microcephaly, has shown normal subsequent growth and development without dietary protein restriction.