Steven Yannicelli

Phenylketonuria Scientific Review Conference: State of the science and future research needs

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Nutrient intakes and physical growth of children with phenylketonuria undergoing nutrition therapy

OBJECTIVE To evaluate nutrient intakes, plasma phenylalanine (PHE) and tyrosine (TYR) concentrations, and physical growth of children with phenylketonuria undergoing nutrition management. DESIGN Children were fed three different medical foods during a one-year study. Subjects/setting Children were evaluated at baseline and every three months in metabolic clinics. Childrens diets were managed at home. Statistical analyses Intakes of medical foods and nutrients, number of diaries with nutrients <67% and <100% of Recommended Dietary Intakes (RDI), and mean plasma PHE and TYR concentrations were compared among groups using two-way ANOVA. chi-squared test compared the percentage of plasma PHE and TYR concentrations in each group in specific categories. Height and body mass index were plotted against National Center for Health Statistics reference data; means were compared among groups. Tukeys test compared groups with significant treatment effects. RESULTS Mean intakes of nutrients, except energy by all groups and vitamin B-12 by the Periflex-fed group, met or exceeded RDIs. The oldest children tended to have the highest PHE intakes and plasma PHE concentrations. Mean length or height z score indicated normal linear growth. Mean body mass index z scores at study end suggested many children were overweight. APPLICATIONS Dietitians should prescribe adequate medical food and encourage children with phenylketonuria to ingest all prescribed daily. Linear growth of children, where mean protein equivalent intakes ranged from 113% to 129% of RDI, was normal, demonstrating the need for a protein intake greater than RDIs when an elemental diet is the primary protein source. Dietitians should prescribe and carefully monitor energy intake, physical activity, and weight.

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.

Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors

Purpose: The purpose of the study was to determine the incidence of iron deficiency in children undergoing therapy for phenylketonuria using serum transferrin receptor and ferritin concentrations.Methods: A 1-year study was conducted in 37 children 2 < 13 years old with phenylketonuria (8 fed Periflex [Group I], 15 fed Phenex-2 Amino Acid-Modified Medical Food [Group II], and 14 fed Phenyl-Free [Group III]). Hemoglobin, hematocrit, serum transferrin receptor, and ferritin concentrations were assessed at baseline and 12 months and intakes of protein, iron, and vitamin C were evaluated at baseline and at 3-month intervals. Transferrin receptor and ferritin concentrations were analyzed for group differences by analysis of variance.Results: Mean protein, iron, and vitamin C intakes of all 3 groups of children were greater than Recommended Dietary Intakes for age. Only 2 of 60 3-day diet diaries of Group II children failed to contain 100% of Recommended Dietary Intakes for iron during study. The following number of children had iron status indices outside reference ranges at study end: 7 children, transferrin receptor/ferritin ratios; 4 children, transferrin receptors; 2 children, hematocrit; 1 child, ferritin. No correlation was found between iron intake and any index of iron status.Conclusions: The transferrin receptor/ferritin ratio appeared to be the most sensitive index of iron deficiency in this study. Reasons for iron deficiency with greater than recommended iron intakes by children with phenylketonuria may be multiple. Early assessment and therapy of iron deficiency may improve cognitive and behavioral outcomes of children with PKU.

A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia

The galactose-restricted diet is life-saving for infants with classic galactosemia. However, the benefit and extent of dietary galactose restriction required after infancy remain unclear and variation exists in practice. There is a need for evidence-based recommendations to better standardize treatment for this disorder. This paper reviews the association between diet treatment and outcomes in classic galactosemia and evaluates the contribution of food sources of free galactose in the diet. Recommendations include allowing all fruits, vegetables, legumes, soy products that are not fermented, various aged cheeses and foods containing caseinates. Further research directions are discussed.

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.

Galactose Content of Legumes, Caseinates, and Some Hard Cheeses: Implications for Diet Treatment of Classic Galactosemia

There are inconsistent reports on the lactose and/or galactose content of some foods traditionally restricted from the diet for classic galactosemia. Therefore, samples of cheeses, caseinates, and canned black, pinto, kidney, and garbanzo beans were analyzed for free galactose content using HPLC with refractive index or pulsed amperometric detection. Galactose concentrations in several hard and aged cheeses and three mild/medium Cheddars, produced by smaller local dairies, was <10 mg/100 g sample compared to 55.4 mg/100 g sample in four sharp Cheddars produced by a multinational producer. Galactose in sodium and calcium caseinate ranged from undetectable to 95.5 mg/100 g sample. Free galactose level in garbanzo beans was lower than previously reported at 24.6 mg/100 g sample; black beans contained 5.3 mg/100 g, and free galactose was not detected in red kidney or pinto beans. These data provide a basis for recommending inclusion of legumes, caseinate-containing foods, and some aged hard cheeses that had been previously restricted in the diet for individuals with galactosemia.

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 μg/L) and without PKU (1.75±0.8 μg/L). Plasma molybdenum concentrations in both groups of children ranged from <1 to 3 μg/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 μg/L) and 12 males (1.58±0.76 μg/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 μg/L, and six children aged 4 to <7 yr had mean (±SD) plasma molybdenum concentrations of 1.5±0.8 μg/L. Eleven children aged 7 to <11 yr had a mean plasma molybdenum concentration of 1.7±0.7 μg/L, and two children 11 to <14 yr had plasma molybdenum concentrations of 1 μg/L and 2 μg/L. Plasma molybdenum concentrations did not differ significantly among children in the age groups.

Role of medical food in MMA.

To the Editor: As senior metabolic dietitians who have provided nutritional management for individuals with methylmalonic acidemia (MMA), we wish to comment on the recent article by Manoli et al., “A Critical Reappraisal of Dietary Practices in Methylmalonic Acidemia Raises Concerns About the Safety of Medical Foods. Part 1: Isolated Methymalonic Acidemias”1, published online in this journal in August 2015. This title is misleading because it seems to imply that poor outcomes are due solely to the use of medical foods. We believe that their study does raise some concerns about some of the current management and monitoring practices2 in the context of a complex disease that, in many cases, cannot be optimized by diet alone. Medical food, a term created in 1988 by the Orphan Drug Amendments, is defined as “a food formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation” (http://medpolicy.ibx.com/policies/mpi. nsf/f12d23cb982d59b485257bad00552d87/85256aa800623d 7a85257bf2004f103f!OpenDocument). Although the authors refer to these products as incomplete proteins, they are technically not proteins but, rather, amino acid mixtures that are formulated to minimize the intake of those amino acids that are not catabolized in a specific metabolic disorder, e.g., the propiogenic amino acids in medical foods designed for MMA or propionic acidemia. Medical foods are never intended to be the sole source of nutrient intake for the individual. Limited intake of dietary intact protein (also referred to as natural protein, food protein, or complete protein) is titrated to provide the required essential amino acids, as well as carbohydrates and fat, to provide a nonprotein energy source. The authors suggest that individuals with MMA may be able to meet their protein needs solely with dietary intact protein. However, this overlooks the fact that many individuals with MMA are poor eaters. This may be due in part to chronic acidosis causing anorexia, neurological sequelae that limit the ability to chew and swallow, or aversion to certain textures and tastes. The use of medical foods (in combination with other dietary components containing the propiogenic amino acids) can provide a consistent energy and nutrient source for these poor eaters or for others during intercurrent illness or metabolic crisis. The authors also failed to address the issue of the biological value/quality3 of intact or dietary proteins. Proteins derived from plant sources are less likely to be of high biological value and contain limiting amounts of certain essential amino acids. Moreover, these are the very foods—fruits, vegetables, and some grains—that are the major source of intact dietary protein for individuals with MMA. Reliance solely on these sources can compromise protein status. There are some individuals with milder forms of MMA who can tolerate an intake of intact protein that meets the Dietary Reference Intake for age, but even for these individuals, addition of medical food can provide a “buffer” to allow some leeway in intact protein sources as well as provide an important source of nonprotein energy and micronutrients to meet individual needs. It is important to emphasize that nutritional intervention is not a panacea for the management of individuals with various forms of MMA; these are complex disorders with probable mitochondria dysfunction, chronic renal disease, and risk for decompensation during intercurrent illness. Therefore, it is difficult to equate growth parameters with nutrient intake. The subjects enrolled in this study had diverse nutritional, medical, and supportive interventions and illness histories. Some were identified only after significant decompensation. All of these factors can impact their growth and development, even if they had all followed similar dietary interventions. The authors raise important concerns about practices of increasing total protein intake by giving very large quantities of medical food and the negative impact of elevated leucine intake on the concentration of other essential amino acids. Medical foods available for use by individuals with MMA vary widely in their leucine content, as shown in Supplementary Table S2 online. The composition of some of these products deserves careful reevaluation. Attempts to establish normal plasma amino acid ratios have been shown to improve growth parameters in other inborn errors of metabolism, such as phenylketonuria,4 and may be an important goal for individuals with MMA. Short-term use of intact dietary protein alone may help establish appropriate plasma amino acid ratios, but the data are not available to show the long-term nutritional, anthropometric, and developmental outcomes of omitting medical foods in the management of individuals with MMA. We believe their data suggest that the use of close and frequent monitoring should guide the balance between the amount of medical food amino acids and intact protein in providing the total protein required for adequate growth and maintenance. Even when using amino acids (medical foods) as part of the nitrogen source, total protein intake more than 1.2–1.5 times the Dietary Reference Intake is probably unnecessary. The authors demonstrated this by comparing anthropometric data with total protein intake. If additional energy is needed to promote anabolism, then this should probably come from nonprotein sources, rather than from additional amino acid–based medical food. If plasma levels of valine and isoleucine are low, then additional intact protein sources can be used and an equivalent decrease in amino acids from medical food can be considered. Genet Med