International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Dietary practices in pyridoxine non-responsive homocystinuria: a European survey.

BACKGROUND: Within Europe, the management of pyridoxine (B6) non-responsive homocystinuria (HCU) may vary but there is limited knowledge about treatment practice. AIM: A comparison of dietetic management practices of patients with B6 non-responsive HCU in European centres. METHODS: A cross-sectional audit by questionnaire was completed by 29 inherited metabolic disorder (IMD) centres: (14 UK, 5 Germany, 3 Netherlands, 2 Switzerland, 2 Portugal, 1 France, 1 Norway, 1 Belgium). RESULTS: 181 patients (73% >16 years of age) with HCU were identified. The majority (66%; n=119) were on dietary treatment (1-10 years, 90%; 11-16 years, 82%; and >16 years, 58%) with or without betaine and 34% (n=62) were on betaine alone. The median natural protein intake (g/day) on diet only was, by age: 1-10 years, 12 g; 11-16 years, 11 g; and >16 years, 45 g. With diet and betaine, median natural protein intake (g/day) by age was: 1-10 years, 13 g; 11-16 years, 20 g; and >16 years, 38 g. Fifty-two percent (n=15) of centres allocated natural protein by calculating methionine rather than a protein exchange system. A methionine-free l-amino acid supplement was prescribed for 86% of diet treated patients. Fifty-two percent of centres recommended cystine supplements for low plasma concentrations. Target treatment concentrations for homocystine/homocysteine (free/total) and frequency of biochemical monitoring varied. CONCLUSION: In B6 non-responsive HCU the prescription of dietary restriction by IMD centres declined with age, potentially associated with poor adherence in older patients. Inconsistencies in biochemical monitoring and treatment indicate the need for international consensus guidelines.

Micronutrient status in phenylketonuria.

Patients with phenylketonuria (PKU) encompass an 'at risk' group for micronutrient imbalances. Optimal nutrient status is challenging particularly when a substantial proportion of nutrient intake is from non-natural sources. In PKU patients following dietary treatment, supplementation with micronutrients is a necessity and vitamins and minerals should either be added to supplement phenylalanine-free l-amino acids or given separately. In this literature review of papers published since 1990, the prevalence of vitamin and mineral deficiency is described, with reference to age of treatment commencement, type of treatment, dietary compliance, and dietary practices. Biological micronutrient inadequacies have been mainly reported for zinc, selenium, iron, vitamin B12 and folate. The aetiology of these results and possible clinical and biological implications are discussed. In PKU there is not a simple relationship between the dietary intake and nutritional status, and there are many independent and interrelated complex factors that should be considered other than quantitative nutritional intake.

Dietary management of urea cycle disorders: European practice.

BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Main issues in micronutrient supplementation in phenylketonuria.

For almost all patients with PKU, a low phenylalanine diet is the basis of the treatment despite a widely varying natural protein tolerance. A vitamin and mineral supplement is essential and it is commonly added to a phenylalanine-free (phe-free) source of L-amino acids. In PKU, many phe-free L-amino acid supplements have age-specific vitamin and mineral profiles to meet individual requirements. The main micronutrient sources are chemically derived and their delivery dosage is usually advised in three or more doses throughout the day. Within the EU, the composition of VM (vitamin and mineral) phe-free L-amino acid supplements is governed by the Foods for Special Medical Purposes (FSMP) directive (European Commission Directive number 1999/21/EC and amended by Directive 2006/141/EC). However the micronutrient composition of the majority fails to remain within FSMP micronutrient maximum limits per 100 kcal due to their low energy content and so compositional exceptions to the FSMP directive have to be granted for each supplement. All patients with PKU require an annual nutritional follow-up, until it has been proven that they are not at risk of any vitamin and mineral imbalances. When non-dietary treatments are used to either replace or act as an adjunct to diet therapy, the quality of micronutrient intake should still be considered important and monitored systematically. European guidelines are required about which micronutrients should be measured and the conditions (fasting status) for monitoring.

Adherence issues in inherited metabolic disorders treated by low natural protein diets.

Common inborn errors of metabolism treated by low natural protein diets [amino acid (AA) disorders, organic acidemias and urea cycle disorders] are responsible for a collection of diverse clinical symptoms, each condition presenting at different ages with variable severity. Precursor-free or essential L-AAs are important in all these conditions. Optimal long-term outcome depends on early diagnosis and good metabolic control, but because of the rarity and severity of conditions, randomized controlled trials are scarce. In all of these disorders, it is commonly described that dietary adherence deteriorates from the age of 10 years onwards, at least in part representing the transition of responsibility from the principal caregivers to the patients. However, patients may have particular difficulties in managing the complexity of their treatment because of the impact of the condition on their neuropsychological profile. There are little data about their ability to self-manage their own diet or the success of any formal educational programs that may have been implemented. Trials conducted in non-phenylketonuria (PKU) patients are rare, and the development of specialist L-AAs for non-PKU AA disorders has usually shadowed that of PKU. There remains much work to be done in refining dietary treatments for all conditions and gaining acceptable dietary adherence and concordance, which is crucial for an optimal outcome.

The 48-hour tetrahydrobiopterin loading test in patients with phenylketonuria: evaluation of protocol and influence of baseline phenylalanine concentration.

BACKGROUND: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 µmol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and the necessity of the 400 µmol/l minimum baseline phenylalanine concentration. METHODS: Data on 186 phenylketonuria patients were collected. Patients were supplemented with phenylalanine if phenylalanine was <400 µmol/l. BH4 20mg/kg was administered at T = 0 and T = 24. Blood samples were taken at T=0, 8, 16, 24 and 48 h. Responsiveness was defined as ≥ 30% reduction in phenylalanine concentration at ≥ 1 time point. RESULTS: Eighty-six (46.2%) patients were responsive. Among responders 84% showed a ≥ 30% response at T = 48. Fifty-three percent had their maximal decrease at T = 48. Fourteen patients had ≥ 30% phenylalanine decrease not before T = 48. A ≥ 30% decrease was also seen in patients with phenylalanine concentrations <400 µmol/l. CONCLUSION: In the 48-hour BLT, T = 48 seems more informative than T = 24. Sampling at T = 32, and T = 40 may have additional value. BH4 responsiveness can also be predicted with baseline blood phenylalanine <400 µmol/l, when the BLT is positive. Therefore, if these results are confirmed by data on long-term BH4 responsiveness, we advise to first perform a BLT without phenylalanine loading and re-test at higher phenylalanine concentrations when no response is seen. Most likely, the 48-hour BLT is a good indicator for BH4 responsiveness, but comparison with long term responsiveness is necessary.

Phenylketonuria: tyrosine supplementation in phenylalanine-restricted diets.

Treatment of phenylketonuria (PKU) consists of restriction of natural protein and provision of a protein substitute that lacks phenylalanine but is enriched in tyrosine. Large and unexplained differences exist, however, in the tyrosine enrichment of the protein substitutes. Furthermore, some investigators advise providing extra free tyrosine in addition to the tyrosine-enriched protein substitute, especially in the treatment of maternal PKU. In this article, we discuss tyrosine concentrations in blood during low-phenylalanine, tyrosine-enriched diets and the implications of these blood tyrosine concentrations for supplementation with tyrosine. We conclude that the present method of tyrosine supplementation during the day is far from optimal because it does not prevent low blood tyrosine concentrations, especially after an overnight fast, and may result in largely increased blood tyrosine concentrations during the rest of the day. Both high tyrosine enrichment of protein substitutes and extra free tyrosine supplementation may not be as safe as considered at present, especially to the fetus of a woman with PKU. The development of dietary compounds that release tyrosine more slowly could be beneficial. We advocate decreasing the tyrosine content of protein substitutes to approximately 6% by wt (6 g/100 g protein equivalent) at most and not giving extra free tyrosine without knowing the diurnal variations in the blood tyrosine concentration and having biochemical evidence of a tyrosine deficiency. We further advocate that a better daily distribution of the protein substitute be achieved by improving the palatability of these products.

Large daily fluctuations in plasma tyrosine in treated patients with phenylketonuria.

In patients with phenylketonuria (PKU), extra tyrosine supplementation is advocated in addition to tyrosine-enriched amino acid mixtures. PKU patients have low fasting plasma tyrosine concentrations, but little is known about tyrosine fluctuations during the day. Plasma tyrosine concentrations were studied in 12 PKU patients in response to a test without breakfast and to three tests with different tyrosine contents in breakfast and lunch: 0%/30%, 25%/30%, 50%/10%, and 75%/10% tests, reflecting the protein consumption at breakfast and lunch, respectively. Prolonged fasting resulted in a small decrease in the already low overnight fasting plasma tyrosine concentrations. Breakfast and lunch with 25% and 30% of the daily tyrosine intake resulted in both lower than normal and higher than normal tyrosine concentrations. The 50%/10% and 75%/10% tests resulted in excessively high plasma tyrosine concentrations in most patients. Therefore, both lower than normal and higher than normal postprandial plasma tyrosine concentrations were found in treated PKU patients, even if the daily tyrosine intake was distributed evenly. When there was a large fractional tyrosine intake from one meal, very high plasma tyrosine concentrations were found. Therefore, strict control of plasma tyrosine is necessary if tyrosine supplementation is considered in addition to the tyrosine-enriched amino acid mixtures.

Phenylketonuria: plasma phenylalanine responses to different distributions of the daily phenylalanine allowance over the day.

OBJECTIVE: To achieve smooth control of plasma phenylalanine concentrations in phenylketonuric patients, it is advocated to divide the daily intake of natural protein and amino acid supplements equally over the meals. However, this may be quite an encumbrance for the patient. We, therefore, investigated whether a breakfast with an unequal daily distribution results in an undue rise in the plasma phenylalanine concentration. DESIGN: Plasma phenylalanine concentrations were measured in seven patients with phenylketonuria in response to three tests with breakfast and lunch, representing an equally or unequally divided daily distribution of the individually tailored phenylalanine intake. Breakfast contained 25%, 50%, or 75%, whereas lunch contained 30% or 10% of the individual daily phenylalanine allowance, respectively. RESULTS: Plasma phenylalanine concentrations showed postprandial increases of up to 26% above baseline. Generally, phenylalanine returned to baseline during the test and remained within the target range if baseline phenylalanine was within that range. Two patients having values in the upper target range showed a rise just above the target range for 60 minutes on an unequal daily distribution of phenylalanine. In another patient treated similarly, plasma phenylalanine did not return to baseline during the test. CONCLUSIONS: Unequal distributions of the daily phenylalanine allowance are justified, provided that the patient is in good clinical condition, adjusted to the diet adequately, and the daily allowance is not exceeded. At this time, however, we cannot recommend this unequal daily distribution for daily practice.