Dietary management for pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency, a follow-on from the international consortium guidelines.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a neurometabolic disorder in the lysine metabolism pathway. In 2014 and 2021, the International PDE consortium published consensus guidelines about diagnosis and management. In this follow-on, a literature review was performed and nutrition management was evaluated through an international dietary questionnaire with 40 respondents. This manuscript discusses consensus dietary statements and the practical provision of lysine reduction therapies. Results from the questionnaire, statements from the PDE consensus guidelines, new data from the literature, as well as clinical practice experience of the metabolic dietitian group form the basis of these updated practical diet recommendations. These dietary management recommendations can support dietitians, nutritionists, and physicians in initiation and monitoring of lysine reduction therapies for PDE-ALDH7A1 patients and families.

Development of a practical dietitian road map for the nutritional management of phenylketonuria (PKU) patients on pegvaliase.

Background: The metabolic dietitian/nutritionist (hereafter 'dietitian') plays an essential role in the nutritional management of patients with phenylketonuria (PKU), including those on pegvaliase. Currently, more educational support and clinical experience is needed to ensure that dietitians are prepared to provide optimal nutritional management and counselling of pegvaliase-treated patients. Methods: Via a face-to-face data-review meeting, followed by a virtual consolidation meeting, a group of expert dietitians and one paediatrician discussed and developed a series of recommendations on the nutritional evaluation and management of patients receiving pegvaliase. The consensus group consisted of 10 PKU experts: six dietitians and one paediatrician from Europe and three dietitians from the US. One European and three US dietitians had experience with pegvaliase-treated patients. Results: The consensus group recommended that a physician, dietitian and nurse are part of the pegvaliase treatment team. Additionally, a psychologist/counsellor should be included if available. Practical proposals for the nutritional evaluation of pegvaliase-treated patients at baseline, during the induction and titration phases and for long-term maintenance were developed. The consensus group suggested assessment of blood Phe at least monthly or every 2 weeks in the event of low blood Phe (i.e., blood Phe <30 µmol/L). It may be appropriate to increase blood Phe monitoring when adjusting protein intake and/or pegvaliase dose. It was recommended that natural protein intake is increased by 10-20 g increments if blood Phe concentrations decrease to <240 µmol/L in patients who are not meeting the dietary reference intake for natural protein of 0.8 g/kg. It was proposed that with pegvaliase treatment blood Phe levels could be maintained <240 µmol/L but more evidence on the safety of achieving physiological blood Phe levels is necessary before any recommendation on the lower blood Phe target can be given. Finally, both patients and dietitians should have access to educational resources to optimally support patients receiving pegvaliase. Conclusion: This practical road map aims to provide initial recommendations for dietitians monitoring patients with PKU prescribed pegvaliase. Given that practical experience with pegvaliase is still limited, nutritional recommendations will require regular updating once more evidence is available and clinical experience evolves.

REVIEW: Practical strategies to maintain anabolism by intravenous nutritional management in children with inborn metabolic diseases.

One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.

Inconsistencies in the Nutrition Management of Glutaric Aciduria Type 1: An International Survey.

Glutaric aciduria type 1 (GA-1) is a cerebral organic aciduria characterized by striatal injury and progressive movement disorder. Nutrition management shifted from a general restriction of intact protein to targeted restriction of lysine and tryptophan. Recent guidelines advocate for a low-lysine diet using lysine-free, tryptophan-reduced medical foods. GA-1 guideline recommendations for dietary management of patients over the age of six are unclear, ranging from avoiding excessive intake of intact protein to counting milligrams of lysine intake. A 22-question survey on the nutrition management of GA-1 was developed with the goal of understanding approaches to diet management for patients identified by newborn screening under age six years compared to management after diet liberalization, as well as to gain insight into how clinicians define diet liberalization. Seventy-six responses (25% of possible responses) to the survey were received. Nutrition management with GA-1 is divergent among surveyed clinicians. There was congruency among survey responses to the guidelines, but there is still uncertainty about how to counsel patients on diet optimization and when diet liberalization should occur. Ongoing clinical research and better understanding of the natural history of this disease will help establish stronger recommendations from which clinicians can best counsel families.

Simplified Diet for nutrition management of phenylketonuria: A survey of U.S. metabolic dietitians.

BACKGROUND: Phenylketonuria (PKU) is an inherited metabolic disorder affecting the conversion of phenylalanine (Phe) to tyrosine. Medical nutrition therapy, consisting of a Phe-restricted diet with medical formula, is the primary treatment for PKU. The Simplified Diet is an approach to PKU nutrition management that allows certain fruits, vegetables, and low-protein foods to be eaten without measuring or tracking, referred to as free/uncounted foods. There is no consensus on how to implement this approach in metabolic centers in the United States (U.S.), and clinical practice varies. AIM: This study describes the clinical experience of metabolic dietitians in U.S.-based metabolic centers related to the use and implementation of the Simplified Diet. METHODS: A survey was developed and sent out to metabolic dietitians to query current clinical practices related to the Simplified Diet. Descriptive statistics were used to analyze responses. RESULTS: Sixty-three dietitians managing ≥5 patients with PKU in U.S.-based metabolic centers responded to the survey. Ninety-eight percent of survey respondents reported using some version of the Simplified Diet in clinical practice. The survey identified areas of strong agreement, including introduction of the Simplified Diet at 6 to 12 months of age. The survey also identified areas of widespread variability, including specific Phe or protein thresholds for free/uncounted foods, and whether or not to set daily quantity limits on these foods. CONCLUSIONS: Significant variability related to implementation of the Simplified Diet exists across U.S.-based metabolic centers. This practice variability may contribute to differences in the patient experience across centers and may indicate a need for development of clinical guidelines.

Impact on Isoleucine and Valine Supplementation When Decreasing Use of Medical Food in the Nutritional Management of Methylmalonic Acidemia.

BACKGROUND: Methylmalonic acidemia (MMA) is an autosomal recessive disorder treated with precursor-free medical food while limiting natural protein. This retrospective chart review was to determine if there was a relationship between medical food, valine (VAL) and/or isoleucine (ILE) supplementation, total protein intake, and plasma amino acid profiles. Methods: A chart review, of patients aged 31 days or older with MMA treated with dietary intervention and supplementation of VAL and/or ILE and followed at the Children's Hospital Colorado Inherited Metabolic Diseases Clinic. Dietary prescriptions and plasma amino acid concentrations were obtained at multiple time points. RESULTS: Baseline mean total protein intake for five patients was 198% of Recommended Dietary Allowance (RDA) with 107% natural protein and 91% medical food. Following intervention, total protein intake (p = 0.0357), protein from medical food (p = 0.0142), and leucine (LEU) from medical food (p = 0.0276) were lower, with no significant change in natural protein intake (p = 0.2036). At baseline, 80% of patients received VAL supplementation and 100% received ILE supplementation. After intervention, only one of the cohort remained on supplementation. There was no statistically significant difference in plasma propiogenic amino acid concentrations. CONCLUSIONS: Decreased intake of LEU from medical food allowed for discontinuation of amino acid supplementation, while meeting the RDA for protein.

Multiclinic Observations on the Simplified Diet in PKU.

Phenylketonuria is an inborn error of metabolism that historically has been treated with a strict phenylalanine-restricted diet where all foods are weighed and measured. This is cumbersome and difficult for patients and caregivers, especially patients with high phenylalanine blood concentrations who often have neurocognitive deficits. The Simplified Diet is an alternative approach that allows for increased flexibility, promotes healthy food choices, and is easier to manage than a traditional diet for PKU. This paper describes the implementation of the Simplified Diet and outlines education, counseling strategies, and challenges encountered by three metabolic clinics in the United States.

International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up.

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up.

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.

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.

Impact of geographic access to care on compliance and metabolic control in phenylketonuria.

OBJECTIVE: To study the impact of geographic access to care on metabolic control and compliance in phenylketonuria (PKU). STUDY DESIGN: Phenylalanine (Phe) levels and number of samples obtained were abstracted from a data base of 76 patients age <21 years and compared for age, sex, and distance to clinic. Levels and number of samples were compared to the clinic guidelines for age. RESULTS: There was a strong positive correlation between age and Phe levels in adolescents and young adults while age and number of samples submitted were negatively correlated. There was not a significant correlation between Phe levels and distance to clinic, nor was there a significant difference in the Phe levels by distant categories (Denver metro, Front Range, distant area). However, there was a decrease in number of samples sent compared to clinic guidelines by distance, with patients residing in distant areas (>100 miles) sending significantly less samples. CONCLUSION: Geographic access to care does not impact control of Phe levels, but it does affect the number of monitoring samples sent to the clinic. Age groups of adolescents and young adults have a strong impact on both control of Phe levels and number of monitoring samples compared to clinic guidelines.

Nutritional therapy improves growth and protein status of children with a urea cycle enzyme defect.

BACKGROUND: Poor growth has been described in patients with urea cycle enzyme defects treated with protein-restricted diets, while protein status is seldom reported. OBJECTIVE: To assess the effects of nutritional therapy with a medical food on growth and protein status of patients with a urea cycle enzyme defect. METHODS: A 6-mo multicenter outpatient study was conducted with infants and toddlers managed by nutrition therapy with Cyclinex-1 Amino Acid-Modified Medical Food with Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome variables were anthropometrics and plasma amino acids (selected), albumin, and transthyretin concentrations. RESULTS: Seventeen patients completed the study. Mean (+/-SE) baseline age was 11.30+/-3.20 months (median 4.40 months; range 0.22-38.84 months). Length and weight z-scores increased significantly during the 6-month study. Head circumference increased, but not significantly. Three patients were stunted and two were wasted (-2.0 z-score) at baseline while at study end, only one patient was both stunted and wasted. The majority of patients increased in length, head circumference, and weight z-scores during study. Mean (+/-SE) plasma albumin concentration increased from 34+/-2g/L at baseline to 38+/-1g/L at study end. Plasma transthyretin increased from a mean (+/-SE) of 177+/-13 mg/L at baseline to 231+/-15 mg/L at study end. No correlation was found between plasma NH(3) concentrations and medical food intake. Plasma NH(3) concentration was positively correlated with the percentage of Food and Agriculture Organization/World Health Organization/United Nations recommended protein ingested. CONCLUSIONS: Intakes of adequate protein and energy for age result in anabolism and linear growth without increasing plasma NH(3) concentrations. Medical food intakes did not correlate with plasma NH(3) concentrations.

Improved growth and nutrition status in children with methylmalonic or propionic acidemia fed an elemental medical food.

BACKGROUND: Failure-to-thrive (FTT) has been described in patients with organic acidemias treated with low protein diets. OBJECTIVE: To determine if patients with methylmalonic (MMA) or propionic acidemia (PA) can achieve normal growth and nutrition status. METHODS: A 6-month multicenter outpatient study was conducted with infants and toddlers treated with Propimex-1 Amino Acid-Modified Medical Food With Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome measures were anthropometrics, protein status indices, plasma retinol, and alpha-tocopherol. RESULTS: Sixteen patients completed the study. Mean baseline age was 0.54 +/- 0.02 years (range 0.03-3.00 years). By study end, mean National Center for Health Statistics (NCHS) weight centile increased from 26 to 49%; mean crown-heel length centile from 25 to 33%; and mean head circumference centile from 43 to 54%. Mean (+/- SE) protein and energy intakes by <6-month-old, 6<12-month-old, and 1<4-year-old patients were 15.3 +/- 0.9 g and 645 +/- 10 kcal; 18.3 +/- 1.1 g and 741 +/- 92 kcal; and 25.1 +/- 2.46 g and 1062 +/- 100 kcal, respectively. Plasma glycine concentrations were significantly and negatively correlated with energy intake (r=-0.77, p<0.0005). No correlation was found between dietary protein intakes and plasma ammonia concentrations. Protein status indices, retinol and alpha-tocopherol concentrations were within reference ranges at study end. CONCLUSIONS: Propimex-1 improved growth and nutrition status in patients with MMA or PA in just 6 months when fed in sufficient amounts. Providing energy and protein for patients with FTT at intakes recommended for catch-up growth may have resulted in even better growth.

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. Children's 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. Tukey's 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.