Dietary Considerations in Tyrosinemia Type I.

Since the introduction of 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1, 3-cyclohexanedione (NTBC), life expectancy of HT1 patients greatly improved. However, due to treatment with NTBC, tyrosine concentrations greatly increase. As a consequence to possible neurocognitive problems, the main objective of dietary therapy in HT1 is to provide adequate nutrition allowing normal growth and development while strictly controlling tyrosine levels in blood (and tissues). Although no well-defined target levels exist, tyrosine concentrations below 400 µmol/L are considered to be safe. To achieve this aim a diet restricted in natural protein and supplemented with a special tyrosine and phenylalanine-free amino acid mixture is necessary.Dietary management could be strenuous at diagnosis due to several different problems. If vomiting and diarrhea are a major issue at diagnosis, frequent feeding with additional energy from low protein food is needed for catch-up growth. Initiation of dietary treatment is usually easier if diagnosis is directly after birth. Based on newborn screening when infants are still reasonable healthy. If presenting clinically infants may experience serious difficulties in taking the amino acid mixtures probably due to feeding problems while when presenting after some 2-3 months taste development and the difference in the taste of amino acid mixtures compared to regular formula and breast milk increase difficulties with the treatment.Following a dietary treatment is even harder than taking some medicine. Older children and adolescents often relax the diet and at some age become reluctant to stick to a strict regimen. Therefore, adequate training and information should be given to the patients and the family at regular intervals. To achieve this, a multidisciplinary approach involving pediatricians/physicians, dieticians, psychologists and social workers is an asset for the care of patients with HT1.

Weight Management in Phenylketonuria: What Should Be Monitored.

BACKGROUND: Severe intellectual disability and growth impairment have been overcome by the success of early and continuous treatment of patients with phenylketonuria (PKU). However, there are some reports of obesity, particularly in women, suggesting that this may be an important comorbidity in PKU. It is becoming evident that in addition to acceptable blood phenylalanine control, metabolic dieticians should regard weight management as part of routine clinical practice. SUMMARY: It is important for practitioners to differentiate the 3 levels for overweight interpretation: anthropometry, body composition and frequency and severity of associated metabolic comorbidities. The main objectives of this review are to suggest proposals for the minimal standard and gold standard for the assessment of weight management in PKU. While the former aims to underline the importance of nutritional status evaluation in every specialized clinic, the second objective is important in establishing an understanding of the breadth of overweight and obesity in PKU in Europe. KEY MESSAGES: In PKU, the importance of adopting a European nutritional management strategy on weight management is highlighted in order to optimize long-term health outcomes in patients with PKU.

Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions.

Hepatic glycogen storage diseases (GSD) underscore the intimate relationship between carbohydrate and lipid metabolism. The hyperlipidemias in hepatic GSD reflect perturbed intracellular metabolism, providing biomarkers in blood to monitor dietary management. In different types of GSD, hyperlipidemias are of a different origin. Hypertriglyceridemia is most prominent in GSD type Ia and associated with long-term outcome morbidity, like pancreatitis and hepatic adenomas. In the ketotic subtypes of GSD, hypertriglyceridemia reflects the age-dependent fasting intolerance, secondary lipolysis and increased mitochondrial fatty acid oxidation. The role of high protein diets is established for ketotic types of GSD, but non-traditional dietary interventions (like medium-chain triglycerides and the ketogenic diet) in hepatic GSD are still controversial and necessitate further studies. Patients with these rare inherited disorders of carbohydrate metabolism meet several criteria of the metabolic syndrome, therefore close monitoring for cardiovascular diseases in ageing GSD patients may be justified.

In vitro digestion of starches in a dynamic gastrointestinal model: an innovative study to optimize dietary management of patients with hepatic glycogen storage diseases.

Uncooked cornstarch (UCCS) is a widely used treatment strategy for patients with hepatic glycogen storage disease (GSD). It has been observed that GSD-patients display different metabolic responses to different cornstarches. The objective was to characterize starch fractions and analyze the digestion of different starches in a dynamic gastrointestinal in vitro model. The following brands of UCCS were studied: Argo and Great Value from the United States of America; Brazilian Maizena Duryea and Yoki from Brazil; Dutch Maizena Duryea from the Netherlands. Glycosade, a modified starch, and sweet polvilho, a Brazilian starch extracted from cassava, were also studied. The starch fractions were analyzed by glycemic TNO index method and digestion analyses were determined by the TIM-1 system, a dynamic, computer-controlled, in vitro gastrointestinal model, which simulates the stomach and small intestine. The final digested amounts were between 84 and 86% for the UCCS and Glycosade, but was 75.5% for sweet povilho. At 180 min of the experiment, an important time-point for GSD patients, the digested amount of the starches corresponded to 67.9-71.5 for the UCCS and Glycosade, while it was 55.5% for sweet povilho. In an experiment with a mixture of sweet polvilho and Brazilian Maizena Duryea, a final digested amount of 78.4% was found, while the value at 180 min was 61.7%. Sweet polvilho seems to have a slower and extended release of glucose and looks like an interesting product to be further studied as it might lead to extended normoglycemia in GSD-patients.

Relationships between lumbar bone mineral density and biochemical parameters in phenylketonuria patients.

BACKGROUND: The etiology of reduced bone mineral density (BMD) in phenylketonuria (PKU) is unknown. Reduced BMD may be inherent to PKU and/or secondary to its dietary treatment. MATERIALS AND METHODS: Lumbar BMD was measured by dual-energy X-ray absorptiometry in 53 early and continuously treated PKU patients (median age 16, range 2-35 years). First, Z-scores of BMD were correlated to age group, clinical severity of PKU, mean phenylalanine (Phe) concentration and Phe variation in the year prior to DXA scanning, as well as to blood vitamin, mineral, and alkaline phosphatase concentrations. Second, parameters were compared between subjects with reduced BMD (Z-score<-2 SD) and subjects with normal BMD. RESULTS: BMD was significantly reduced in our cohort (p=0.000). Z-scores of BMD were neither significantly correlated to age group, nor clinical severity of PKU. Both mean Phe concentration and Phe variation in the year prior to DXA scanning did not significantly correlate with Z-scores of BMD. Higher blood calcium concentrations were significantly associated with lower BMD (r(2)=-0.485, p=0.004). Other biochemical parameters, including vitamin B12 availability markers, did not show significant correlations with Z-score of BMD. Subjects with reduced BMD had significantly higher blood phosphorus concentrations than subjects with normal BMD (p=0.009). No other significant differences were found between both BMD groups. CONCLUSION: Reduced BMD in PKU is present from early age onward and does not progress with age. Therefore, BMD deserves attention from early age onward in PKU patients. Our findings are consistent with increased bone turnover in PKU. It remains unclear whether reduced BMD is inherent to PKU and/or secondary to its dietary treatment.

Serum vitamin B12 concentrations within reference values do not exclude functional vitamin B12 deficiency in PKU patients of various ages.

UNLABELLED: Homocysteine (Hcy) and in particular methylmalonic acid (MMA) are considered reliable parameters for vitamin B(12) status in healthy individuals. Phenylketonuria (PKU) patients are at risk for functional vitamin B(12) deficiency based on their diet. OBJECTIVE: The aim of this study was to investigate the prevalence of functional vitamin B(12) deficiency in continuously treated PKU patients and the association of parameters of vitamin B(12) and metabolic control. METHODS: In 75 continuously treated PKU patients of 1-37 years of age, serum vitamin B(12) concentrations, plasma Hcy, MMA, and phenylalanine concentrations were studied. RESULTS: Eight patients had vitamin B(12) concentrations below normal. Out of these eight patients, two had elevated MMA and/or Hcy concentrations. Ten other patients with normal vitamin B(12) concentrations had elevated concentrations of MMA and/or Hcy. CONCLUSIONS: A vitamin B(12) concentration within the reference range does not automatically imply a sufficient vitamin B(12) status. We recommend measuring serum MMA, or alternatively plasma Hcy, yearly in all PKU patients to diagnose functional vitamin B(12) deficiency.

PKU: high plasma phenylalanine concentrations are associated with increased prevalence of mood swings.

UNLABELLED: In phenylketonuria, knowledge about the relation between behavior and plasma phenylalanine is scarce. The aim of this study was to determine whether high phenylalanine is associated with disturbed behavior noticed by the patient and or close environment (parents or partners). 48 early treated PKU patients (median age 8.5, range 0-35 years) participated (median phenylalanine concentration in total sample 277 (range 89-1171) µmol/l; and in patients <12 years 238 (range 89-521) µmol/l). After sending blood samples, patients or close environment were interviewed with a standardized questionnaire whether they noticed hyperactivity, annoying behavior, mood swings and introvert or extravert behavior. The interviewer as well as the respondents were blinded with regard to the phenylalanine concentration. RESULTS: Patients reported less deviant behavior compared to close environment. Mood swings were positively associated with phenylalanine concentrations in the total group (P=0.039) and patients <12 years (P=0.042). The relationships between temporary high phenylalanine concentrations and hyperactivity, annoying behavior, introvert and extravert behavior were not statistically significant. CONCLUSION: there is a positive association between phenylalanine concentrations and mood swings.

Diurnal variations in blood phenylalanine of PKU infants under different feeding regimes.

UNLABELLED: In phenylketonuria (PKU) patients, diurnal fluctuations of blood phenylalanine (Phe) are different from healthy individuals. Until now this pattern has been studied in PKU patients over one year of age. OBJECTIVE: The aim of this observational study was to investigate diurnal patterns in PKU infants under one year of age receiving both the natural protein and Phe-free formula at the same time or in an alternating feeding scheme. METHODS: In 7 PKU infants (aged 3-8 months), diurnal variations in blood Phe concentrations were recorded: on day A they received natural protein and Phe-free formula combined in each feeding; on day B they received these in an alternating feeding scheme. The number of feedings, total protein, and energy intake was similar on both study days. Blood samples were taken before each feeding. RESULTS: The means (± SD) of the difference between the individual minimum and maximum blood Phe concentrations were 81(± 50) µmol/L and 104(± 26) µmol/L on days A and B, respectively (n.s.). Fifty and 30% of the samples were below target range for age (120 µmol/L), while only 3% and 6% were above target range (360 µmol/L) on days A and B respectively (n.s.). CONCLUSION: Both feeding regimes, i.e. the natural protein and Phe-free formula combined in each feeding or alternating, resulted in comparable diurnal fluctuations of blood Phe concentrations.

Adjusting diet with sapropterin in phenylketonuria: what factors should be considered?

The usual treatment for phenylketonuria (PKU) is a phenylalanine-restricted diet. Following this diet is challenging, and long-term adherence (and hence metabolic control) is commonly poor. Patients with PKU (usually, but not exclusively, with a relatively mild form of the disorder) who are responsive to treatment with pharmacological doses of tetrahydrobiopterin (BH4) have either lower concentrations of blood phenylalanine or improved dietary phenylalanine tolerance. The availability of a registered formulation of BH4 (sapropterin dihydrochloride, Kuvan®) has raised many practical issues and new questions in the dietary management of these patients. Initially, patients and carers must understand clearly the likely benefits (and limitations) of sapropterin therapy. A minority of patients who respond to sapropterin are able to discontinue the phenylalanine-restricted diet completely, while others are able to relax the diet to some extent. Care is required when altering the phenylalanine-restricted diet, as this may have unintended nutritional consequences and must be undertaken with caution. New clinical protocols are required for managing any dietary change while maintaining control of blood phenylalanine, ensuring adequate nutrition and preventing nutritional deficiencies, overweight or obesity. An accurate initial evaluation of pre-sapropterin phenylalanine tolerance is essential, and the desired outcome from treatment with sapropterin (e.g. reduction in blood phenylalanine or relaxation in diet) must also be understood by the patient and carers from the outset. Continuing education and support will be required thereafter, with further adjustment of diet and sapropterin dosage as a young patient grows.

Adult patients with well-controlled phenylketonuria tolerate incidental additional intake of phenylalanine.

BACKGROUND/AIMS: In patients with phenylketonuria (PKU), target ranges of blood phenylalanine (Phe) concentrations have been tightened in order to improve long-term outcomes. We investigated day-to-day and week-to-week variations in blood Phe concentration and the effect of an additional Phe load. METHODS: We performed a longitudinal study in 6 adult PKU patients. The study was divided in five 7-day periods: 1 period without any intervention (period I) and 4 periods with a Phe load on day 3 equivalent to 100% (periods II and III) and to 200% (periods IV and V) of each patient's individual daily Phe intake. Phe loading was given as encapsulated L-Phe. Blood spots to measure blood Phe concentration were taken each morning before breakfast in all periods. RESULTS: Day-to-day and week-to-week blood Phe concentrations varied considerably with and without intervention in Phe intake. Equal loads of Phe did not result in comparable effects in blood Phe concentrations in all patients. In periods II-IV, mean blood Phe concentrations of days 1-3 (pre-load) were not significantly different from days 4-7 (post-load). The 200% load resulted in a significantly larger variation. CONCLUSION: These results showed that patients with well-controlled PKU can incidentally tolerate 100% - and in some cases 200% - of their normal daily Phe intake.

The reality of dietary compliance in the management of phenylketonuria.

In phenylketonuria (PKU), it is common for blood phenylalanine (Phe) concentrations to be outside optimal target ranges, particularly in teenagers and adults, indicating inadequate compliance. It is well known that significant noncompliance exists, and the situation in PKU would appear no different than other chronic conditions. In PKU, compliance is complex, being subject to diverse definitions, and factors influencing compliance include the nature and nurture of the patient, as well as the inconvenience, cost and availability of dietary treatment. It is also a dynamic process, with many patients changing between a state of compliance and partial and noncompliance. In PKU, compliance has received little rigorous study, and there have been few observational reports identifying barriers and behaviors impacting dietary compliance. Compliance assessment measures remain inadequately defined. The direct assessment of blood Phe concentration is perhaps the best overall measure, but there is no universal agreement about the number of Phe concentrations that should be within target range and frequency or timing of measurement. Although no one strategy for improving compliance is universally effective, and an individualized approach to noncompliance is essential, it is important to have clear evidence about the most effective strategies in achieving long-term dietary adherence in PKU.

Large neutral amino acids in the treatment of PKU: from theory to practice.

Notwithstanding the success of the traditional dietary phenylalanine restriction treatment in phenylketonuria (PKU), the use of large neutral amino acid (LNAA) supplementation rather than phenylalanine restriction has been suggested. This treatment modality deserves attention as it might improve cognitive outcome and quality of life in patients with PKU. Following various theories about the pathogenesis of cognitive dysfunction in PKU, LNAA supplementation may have multiple treatment targets: a specific reduction in brain phenylalanine concentrations, a reduction in blood (and consequently brain) phenylalanine concentrations, an increase in brain neurotransmitter concentrations, and an increase in brain essential amino acid concentrations. These treatment targets imply different treatment regimes. This review summarizes the treatment targets and the treatment regimens of LNAA supplementation and discusses the differences in LNAA intake between the classical dietary phenylalanine-restricted diet and several LNAA treatment forms.

A survey of natural protein intake in Dutch phenylketonuria patients: insight into estimation or measurement of dietary intake.

This study investigated which methods patients and parents used to determine phenylalanine (Phe) intake and the relationship between the methods applied, age, and blood Phe concentration, as this practice had not been studied before in relation to metabolic control. A questionnaire was sent to 327 Dutch phenylketonuria patients (age 0-29 years) to investigate the method used to determine Phe intake (either by estimation, exact measurement, or a combination of both). Mean blood Phe concentration of each individual patient was related to the method reported to be used. Three different age groups (<10 years, > or =10-15 years, and > or =16 years) were distinguished. The response rate for the questionnaires was 73%. In these 188 patients, data for both Phe concentrations and questionnaires could be used. Of these, 75 used exact measurement, 75 used estimation, and 38 used both methods. The number of patients that estimated Phe intake clearly increased with age. Whatever method was used, an increase in Phe concentrations was seen with age. During childhood, exact measurement was used more frequently, and from adolescence on estimation was used more frequently. The method (exact measurement and/or estimation) did not result in statistically different Phe concentrations in any of the three age groups, although blood Phe concentration tended to be lower in adolescence using exact measurement. Data suggest that estimation and exact measurement of Phe intake are both reliable methods. Therefore, in addition to exact measurement, patients should be instructed in both methods at an early age, so that both methods can be used adequately.

Ketogenic Diet in Refractory Childhood Epilepsy: Starting With a Liquid Formulation in an Outpatient Setting.

BACKGROUND: Ketogenic diet in children with epilepsy has a considerable impact on daily life and is usually adopted for at least 3 months. Our aim was to evaluate whether the introduction of an all-liquid ketogenic diet in an outpatient setting is feasible, and if an earlier assessment of its efficacy can be achieved. METHODS: The authors conducted a prospective, observational study in a consecutive group of children with refractory epilepsy aged 2 to 14 years indicated for ketogenic diet. Ketogenic diet was started as an all-liquid formulation of the classical ketogenic diet, KetoCal 4:1 LQ, taken orally or by tube. After 6 weeks, the liquid diet was converted into solid meals. The primary outcome parameter was time-to-response (>50% seizure reduction). Secondary outcome parameters were time to achieve stable ketosis, the number of children showing a positive response, and the retention rate at 26 weeks. RESULTS: Sixteen children were included. Four of them responded well with respect to seizure frequency, the median time-to-response was 14 days (range 7-28 days). The mean time to achieve stable ketosis was 7 days. The retention rate at 26 weeks was 50%. Of the 8 children who started this protocol orally fed, 6 completed it without requiring a nasogastric tube. CONCLUSIONS: Introduction of ketogenic diet with a liquid formulation can be accomplished in orally fed children without major complications. It allowed for fast and stable ketosis.

Protein metabolism in adult patients with phenylketonuria.

OBJECTIVE: Protein intake recommendations in phenylketonuria (PKU) are frequently the subject of discussion. For healthy adults, the recommended daily allowance (RDA) is 0.8 g.kg(-1).d(-1), which is generally lower than that observed in the general Western population. We investigated whether whole-body protein metabolism in patients with PKU is comparable to that of healthy controls at a RDA rate of protein intake. METHODS: Six adult patients with well-controlled PKU and six healthy subjects of comparable age, height, and weight were studied using a primed continuous infusion of [1-(13)C]-valine for 8 h after an overnight fast before and during frequent meals. Normal protein was given to controls, whereas patients with PKU received a combination of an amino acid mixture and natural protein. RESULTS: No significant differences were observed between patients with PKU and controls in preprandial and prandial rates of valine appearance and oxidation and protein breakdown, protein synthesis, and net protein balance. Feeding resulted in a significant (P < 0.01) decrease in protein breakdown (PKU: 94 +/- 15 micromol.kg(-1).h(-1) preprandial to 49 +/- 10 micromol.kg(-1).h(-1) prandial; controls: 97 +/- 10 micromol.kg(-1).h(-1) preprandial to 55 +/- 10 micromol.kg(-1).h(-1) prandial), whereas no effects were observed in protein synthesis (PKU: 77 +/- 10 micromol.kg(-1).h(-1) preprandial to 73 +/- 7 micromol.kg(-1).h(-1) prandial; controls: 76 +/- 8 micromol.kg(-1).h(-1) preprandial to 71 +/- 5 micromol.kg(-1).h(-1) prandial). Net protein balance increased from negative prandial to positive preprandial values (PKU: -17 +/- 6 micromol.kg(-1).h(-1) preprandial to +23 +/- 8 micromol.kg(-1).h(-1) prandial; controls: -21 +/- 4 micromol.kg(-1).h(-1) preprandial to +16 +/- 9 micromol.kg(-1).h(-1) prandial). CONCLUSION: Whole-body protein metabolism in adult patients with PKU is fully comparable to that in healthy controls at the RDA level of protein intake.

What Is the Best Blood Sampling Time for Metabolic Control of Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients?

BACKGROUND: Treatment of hereditary tyrosinemia type 1 with nitisinone and phenylalanine and tyrosine restricted diet has largely improved outcome, but the best blood sampling time for assessment of metabolic control is not known. AIM: To study diurnal and day-to-day variation of phenylalanine and tyrosine concentrations in tyrosinemia type 1 patients. METHODS: Eighteen tyrosinemia type 1 patients aged >1 year (median age 7.9 years; range 1.6-20.7) were studied. Capillary blood samples were collected 4 times a day (T1: pre-breakfast, T2: pre-midday meal, T3: before evening meal, and T4: bedtime) for 3 days. Linear mixed-effect models were used to investigate diurnal and day-to-day variation of both phenylalanine and tyrosine. RESULTS: The coefficients of variation of phenylalanine and tyrosine concentrations were the lowest on T1 (13.8% and 14.1%, respectively). Tyrosine concentrations did not significantly differ between the different time points, but phenylalanine concentrations were significantly lower at T2 and T3 compared to T1 (50.1 µmol/L, 29.8 µmol/L, and 37.3 µmol/L, respectively). CONCLUSION: Our results indicated that for prevention of too low phenylalanine and too high tyrosine concentrations, measurement of phenylalanine and tyrosine pre-midday meal would be best, since phenylalanine concentrations are the lowest on that time point. Our results also indicated that whilst blood tyrosine concentrations were stable over 24 h, phenylalanine fluctuated. Day-to-day variation was most stable after an overnight fast for both phenylalanine and tyrosine. Therefore, in tyrosinemia type 1 patients the most reliable time point for measuring phenylalanine and tyrosine concentrations to enable interpretation of metabolic control is pre-breakfast.

The efficacy of the modified Atkins diet in North Sea Progressive Myoclonus Epilepsy: an observational prospective open-label study.

BACKGROUND: North Sea Progressive Myoclonus Epilepsy is a rare and severe disorder caused by mutations in the GOSR2 gene. It is clinically characterized by progressive myoclonus, seizures, early-onset ataxia and areflexia. As in other progressive myoclonus epilepsies, the efficacy of antiepileptic drugs is disappointingly limited in North Sea Progressive Myoclonus Epilepsy. The ketogenic diet and the less restrictive modified Atkins diet have been proven to be effective in other drug-resistant epilepsy syndromes, including those with myoclonic seizures. Our aim was to evaluate the efficacy of the modified Atkins diet in patients with North Sea Progressive Myoclonus Epilepsy. RESULTS: Four North Sea Progressive Myoclonus Epilepsy patients (aged 7-20 years) participated in an observational, prospective, open-label study on the efficacy of the modified Atkins diet. Several clinical parameters were assessed at baseline and again after participants had been on the diet for 3 months. The primary outcome measure was health-related quality of life, with seizure frequency and blinded rated myoclonus severity as secondary outcome measures. Ketosis was achieved within 2 weeks and all patients completed the 3 months on the modified Atkins diet. The diet was well tolerated by all four patients. Health-related quality of life improved considerably in one patient and showed sustained improvement during long-term follow-up, despite the progressive nature of the disorder. Health-related quality of life remained broadly unchanged in the other three patients and they did not continue the diet. Seizure frequency remained stable and blinded rating of their myoclonus showed improvement, albeit modest, in all patients. CONCLUSIONS: This observational, prospective study shows that some North Sea Progressive Myoclonus Epilepsy patients may benefit from the modified Atkins diet with sustained health-related quality of life improvement. Not all our patients continued on the diet, but nonetheless we show that the modified Atkins diet might be considered as a possible treatment in this devastating disorder.

Key European guidelines for the diagnosis and management of patients with phenylketonuria.

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 µmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 µmol/L and 600 µmol/L, and lifelong treatment is recommended if the concentration is more than 600 µmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 µmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 µmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 µmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy.