Management
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PKU Nutrition Management Guidelines
First Edition
March 2015, v.1.12
Updated: August 2016
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Nutrition Recommendations
Question
4. For individuals with PKU monitoring of which parameters is associated with positive outcomes?
Conclusion Statement
Derived from evidence and consensus based clinical practice

Regular monitoring of clinical and nutritional status to determine adequacy of nutrient intake, and to guide modifications in the dietary prescription appropriately, is central to management of individuals with PKU. It is important to monitor growth and development, as well as status of micronutrients that are impacted by limited intake of intact protein and adherence with medical food consumption. Hence, clinical monitoring includes assessment of dietary intake, nutrient analysis, growth, and evaluation of clinical signs and symptoms. Biochemical monitoring includes frequent measurements of blood PHE, TYR and PRO status; as well as additional biochemical tests to determine status of at risk nutrients when indicated. This additional testing includes: assessment of essential fatty acids, vitamin D, B12, folate, iron, trace mineral status, and bone status as indicated. The individual's outcome measures are also informed by assessments of neurocognition and quality of life.

Recommendation 4.1

Monitor dietary records to assess adequacy of nutrient intake in supporting appropriate growth and nutritional status. If intake is suboptimal, modify individual dietary recommendations and counseling to improve adherence. See TABLE #8, Monitoring Nutritional Management of PKU for monitoring of nutrition management.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Monitoring dietary intake of PHE, PRO, and energy is a widely accepted practice for assessing and assuring adequacy of dietary therapy recommendations (F.2629). Assessment of intake of nutrients at risk for being low in individuals on a PHE restricted diet such as: iron, vitamin D, vitamin B12, folate, zinc, selenium and essential fatty acids is also recommended throughout life (F.2626,F.2627, F.2629F.1180). Increased availability of medical food choices and improvement in product composition (see TABLE #6, Classification of Medical Foods for PKU for classification of medical foods), availability of modified low protein foods and recipes, and advances in education and counseling tools to support dietary control and optimize nutritional status are all found to enhance adherence (F.1180F.2605).

Consensus based on clinical practice

In Delphi 1, 86% of all the respondents agreed a review of both dietary intake and laboratory monitoring is needed in order to determine need for nutrient supplementation.

Recommendation 4.2

Monitor age-specific anthropometrics. See Table TABLE #8, Monitoring Nutritional Management of PKU for monitoring of nutrition management.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Study reports of anthropometric assessments in individuals with PKU vary and are sometimes contradictory. Poor linear growth has been reported as a consequence of strict adherence to the restrictive dietary therapy required to achieve blood PHE concentrations within treatment range. Poor head circumference growth has been reported, but normal head circumference has also been documented with strict dietary adherence at least until age 10 (F.910). Normal growth patterns and body composition have been reported when individuals with PKU are compared to the healthy population (F.910F.2629). Monitoring individual growth and adjusting the dietary prescription accordingly is key for positive outcome (F.1344). 

Normal linear growth through early childhood has been noted with slightly higher weight for age until at least 4 years, despite the restrictive diet. Individuals with strict dietary adherence until 10 years of age were able to achieve weight, height, and head circumference appropriate for age (F.910).

IUGR has been reported in newborns with PKU, evidenced by reduced length and head circumference measurements, however, all data was collected in one location (F.1296). Growth retardation has also been described in the PKU population, with the causative factor not thought to be due to inadequate energy intake or hormonal function (F.2239). Evaluation and monitoring of nutrient supplementation, especially zinc, was recommended (F.2239). 

In individuals with PKU, overweight and obesity have been historically reported (F.910F.1344F.1464). More recent studies, in which intact protein intake is added as a variable, are inconsistent but do not support this finding (F.2629F.2239). Non-adherence with medical food recommendations seems to be associated with higher BMIs (F.1464). Higher blood PHE was associated with increased weight, more in girls than boys (F.910). Prevalence of obesity was found to be higher in individuals with PKU aged 10-16 years compared to controls (F.1476). Mean body fat (using Bod Pod technology) was reported to increase with body weight, which was significantly higher in individuals with PKU than in controls (F.1320). Prevalence of overweight and obesity was described as higher in individuals with poor metabolic control (42.9%) than in those with good metabolic control (27.9%), and those with central obesity exhibited higher BMI and percent body fat (F.1476). Recent studies looking at growth and body composition (measured by bioelectrical impedance), and specifically fat-free mass (FFM), found no significant difference between individuals with PKU and controls (F.2629F.2239). However, a significant correlation was noted between FFM and intact protein intake, indicating the nutritional value of higher tolerance of natural PRO (F.2629). Longitudinal studies are required to determine if overweight and obesity as variously reported are related to PKU management practices or are independent of PKU.

Consensus based on clinical practice

This topic was not addressed in the consensus process.

Recommendation 4.3

Routinely monitor clinical indicators and biochemical markers for deficiency or excess of nutrients whose intake may not be optimal in an individual on a PHE-restricted diet (PHE, TYR, PRO, iron and vitamin D). See TABLE #8, Monitoring Nutritional Management of PKU for monitoring of nutrition management.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Monitoring of blood PHE concentration is the hallmark of PKU management (F.2626F.2627, F.2629). Use of blood PHE to monitor metabolic status and to determine tolerance and appropriate dietary PHE prescription has been shown to be a reliable predictor of clinical outcome (F.2627L.33).

Results of blood PHE monitoring differ depending on the technique used for analysis, and consistency in the method utilized is recommended. Analysis of whole blood spots on filter paper is reported to yield blood PHE results 15% lower than analysis of plasma (F.2482).

Frequent monitoring of blood PHE during times of increased growth such as infancy, childhood, and pregnancy is recommended. Frequent monitoring allows appropriate dietary prescription modification in order to support growth and maintain blood PHE in the treatment range (F.1129). During infancy, weekly adjustments in PHE intake prescription may be needed, based on assessment of growth and blood PHE concentrations. Subsequently, blood PHE may be assessed once or twice monthly, depending on age and clinical status of the individual (F.1129).

Consensus based on clinical practice

This topic was not addressed in the consensus process.

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Evidence

TYR becomes a conditionally essential amino acid in individuals with PKU and is usually supplemented in PKU specific medical foods. Monitoring of blood TYR is recommended, as low blood TYR has been reported in some individuals on dietary therapy (F.1316). Several studies have reported the importance of monitoring both PHE and TYR concentrations, in addition to the PHE:TYR ratio, in order to characterize level of metabolic control (F.2626, F.2629F.905F.2605). See Question 2 for further information.

Consensus based on clinical practice

In Delphi 1, 100% of respondents agreed TYR supplementation is necessary only when blood TYR concentrations are consistently below the normal range, assuming the prescribed amount of medical food is consumed.

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Evidence

Normal PRO status, as measured by plasma amino acids and prealbumin (transthyretin), is achievable when total PRO intake is provided in appropriate amounts (F.2627F.2629). Assessment of PRO status is reported to be inadequate when only blood PHE is measured, and measurement of other amino acid concentrations is warranted at selected intervals. For example, low leucine concentrations can impair brain protein synthesis and may account for deficits in individuals with PKU (F.2445).

Chronic catabolism, resulting in elevated blood PHE and branched chain amino acids (BCAA) has been reported. Monitoring BCAA as a marker to distinguish elevation of blood PHE due to poor adherence from elevation of blood PHE due to catabolism, which can be resolved with subsequent increase in energy intake, has been suggested (F.2195).  Because a prealbumin (transthyretin) concentration of <20 mg/dl has been associated with decreased linear growth, a level of ≥20 mg/dl is recommended to indicate adequate PRO status (F.2629).

Consensus based on clinical practice

In Delphi 2, 71% of all respondents reported use of transthyretin (prealbumim) to monitor PRO status. During infancy, 43% of all respondents agreed that monitoring PRO status should include regular full amino acid panel evaluation, and 57% stated monitoring growth, dietary intake, and blood PHE concentrations was sufficient. However, 86% of all respondents agreed with monitoring PRO status by regular full amino acid assays after infancy.

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Evidence

Low iron stores have been seen in some individuals with PKU (L.200). However, improvement in iron status has been reported when children with PKU were adherent to dietary therapy (F.2627). Routine evaluation of iron status, including complete blood count (CBC) and ferritin, is recommended (F.2629).

Consensus based on clinical practice

In Delphi 2, 81% of all respondents agreed that both CBC and ferritin assays are appropriate for monitoring iron status every 6-12 months. There was little agreement for monitoring of CBC or ferritin concentrations alone to assess iron status.

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Evidence

Vitamin D is a fat-soluble vitamin that plays several important roles in the body, including involvement with bone health and immune function. Vitamin D promotes calcium absorption and enables normal bone mineralization (L.196). 

Vitamin D is limited in foods appropriate for the restrictive PKU diet. Vitamin D can be obtained from supplementation or absorbed via sun exposure. Individuals with PKU have been found to have lower vitamin D status despite sufficient calcium and vitamin D intake (F.2333). Supplementation with both calcium and vitamin D in individuals with early signs of poor bone mineralization was noted to result in improvement (F.1210).

Consensus based on clinical practice

In Delphi 2, 90% of all respondents agreed that 25-OH vitamin D should be monitored every 6-12 months, and 100% agreed that supplementation with vitamin D3 should be started if blood concentrations are low. There was no agreement regarding appropriateness of preemptive supplementation for individuals receiving low sun exposure. Comments noted that this statement applies to the pediatric population in general as well.

Recommendation 4.4

Monitor clinical indicators and biochemical markers when indicated by circumstances such as rapid growth, pregnancy, poor compliance with management recommendations, or consumption of an incomplete medical food.  See TABLE #8, Monitoring Nutritional Management of PKU for monitoring of nutrition management.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Vitamin B12 deficiency has been reported in adults with PKU (F.2627F.1283). Vitamin B12 deficiency is more common in individuals with PKU who are non-adherent or off-diet (F.2280). As vitamin B12 deficiency causes neurological impairment, detection prior to appearance of clinical signs is critical (F.2629). The importance of maintaining contact with all individuals with PKU so that vitamin B12 status can be monitored has been suggested, regardless of severity of dietary restriction or level of diet adherence, and especially for those on a relaxed diet (F.2280).

Folate deficiency has not been described in individuals with PKU (F.1172). However, the impact of PKU on folate metabolism has been studied, as folate and biopterin pathway enzymes have structural and functional similarities (F.1287). The possible impact of PKU on folate metabolism has been studied, but needs further investigation (F.1287).

Homocysteine (HCY), a sulfur containing amino acid, is recycled into methionine by a transmethylation reaction requiring folate and B12. Studies indicate that elevated blood HCY is associated with increased risk of premature occlusive vascular disease, and is an independent risk factor for the onset of coronary artery disease (CAD). Low blood folate is also associated with increased CAD, largely mediated through its effect on blood HCY concentration (F.1283). Total blood HCY has been shown to be lower in some individuals with PKU, possibly as a result of higher blood folate and B12 concentrations (F.1329F.2502). It is unclear if higher blood folate levels in individuals with PKU have a protective effect against vascular disease (F.2502).

Measurement of serum methylmalonic acid (MMA) or plasma homocysteine may function as a marker to differentiate and diagnose functional B12 deficiency (F.2629).

Consensus based on clinical practice

In Delphi 2, there was poor and varying agreement (38-52% of all participants) as to whether vitamin B12, RBC folate, or trace minerals should be monitored routinely at annual visits, or only when clinically indicated. Most comments suggested concern only for individuals who are not adherent to dietary therapy. 

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Evidence

The role of long-chain polyunsaturated fatty acids (LCPUFA), particularly arachidonic acid (ARA; C20:4n-6) and docosahexaenoic acid (DHA; C22:6n-3), in neurological development has been well documented. Studies show failure to provide a dietary source of DHA adversely affects cognitive and visual development (L.152F.2228F.2200). Adequate intake of LCPUFA, specifically DHA, is particularly beneficial in individuals with PKU because they are more exposed to neural damage caused by elevated blood PHE concentrations (F.1180). Abnormally low blood concentrations of DHA and ARA have been reported in children (L.201), adolescents, and adults (F.978F.1304) with PKU; with recommendations for supplementation, especially for individuals adhering to a PHE restricted diet. Previous studies have shown improved plasma and red blood cell (RBC) DHA with supplementation, as well as improved visual evoked responses (F.1345). A positive relationship between RBC DHA status and performance on verbal ability testing was reported, but testing failed to detect a relationship between biomarkers of DHA and performance on tasks of processing speed and executive function (F.2407). Improvements in fine motor skills have been noted with fish oil supplements (F.1348).

Consensus based on clinical practice

In Delphi 1, 93% of all participants had some degree of agreement with recommending essential fatty acid supplements when laboratory testing indicates deficiency. 

In Delphi 2, there was lack of agreement for whether essential fatty acid concentrations should be monitored at regular yearly visits, or only when clinically indicated. Comments primarily suggested concern for individuals who are not adherent to dietary therapy.

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Evidence

Trace mineral status has been studied in individuals with PKU, with several case reports of deficiencies resulting in subsequent symptoms (F.2627, F.2629F.1180). Zinc (F.1314F.2239) and selenium (F.1314, L.202) have been studied in particular.

Trace mineral content of medical foods varies greatly and adequate supplementation of specific trace minerals in this primary dietary source is important to achieve normal blood concentrations. Monitoring of erythrocyte zinc, serum copper, and serum selenium (+ erythrocyte glutathione peroxidase) has been recommended in order to assure adequate intake (L.202, F.1314F.1475). Molybdenum supplementation in German medical foods was reported to result in excessive retention and plasma concentration of molybdenum in early infancy. This supplementation was discontinued as excess intake of molybdenum may affect copper metabolism (F.2522).

Consensus based on clinical practice

In Delphi 2, there was poor and varying agreement of all participants as to whether trace minerals should be monitored routinely at annual visits, or only when clinically indicated. Comments primarily suggested concern for individuals who are not adherent to dietary therapy.

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Evidence

Compromised peak bone mass has been reported in individuals with PKU (F.2627, F.2629F.1180), although the mechanism of bone mineral disease (BMD) in this population remains unclear. Different and contradictory mechanisms have been suggested. A relationship between intake of calcium and vitamin D, level of physical activity, blood PHE concentrations, and development of BMD was not observed (F.1403). A correlation between dietary adherence and BMD has not been reported, although the benefit of yearly dual x-ray absorptiometry (DXA) was suggested for early detection (F.1210). In another study, quantitative ultrasound was used as a non-invasive method to reveal bone impairment in children with PKU (F.2447). High blood PHE was considered the causative mechanism for decreased bone density due to its strong relationship with bone deterioration (F.2447). Increased bone resorption, together with increased urinary calcium excretion, is believed to lead to increased osteopenia in adults with PKU, even though bone formation was reported as similar to that of control subjects (F.2333). In prepubertal children with PKU, markers for bone formation and resorption suggested decreased bone turnover, and the possibility that these children may not achieve optimal bone mineral content and remain at risk for bone abnormalities (F.2405).

Adolescence is a critical period for bone formation, as rapid increase in height and bone mineralization occurs. Necessary components for achieving optimal peak bone mass are adequate: energy and calcium intake, weight gain, sexual maturation, and physical exercise (L.195).  Adequate vitamin D intake, which has been reported to be reduced in individuals with PKU, is also essential for promoting calcium absorption and enabling normal bone mineralization (F.2333). In children, increase in height indicates appropriate nutritional support for physical growth. However, in adolescence bone maturation takes place when the final stage of growth has been reached. Poor adherence to treatment and the consequent imbalance in nutrient intake from inconsistent consumption of medical food may be partially responsible for growth delay in children and low bone mineralization in adolescents with PKU (F.1525).

Measurements of bone mineral density reflect only bone mineral status, and not the dynamics of bone turnover (F.2405). Measuring osteoclast precursors and the activation of T cells may be an early assessment tool for determining presence of bone resorption, which can lead to bone demineralization (F.1146).

Consensus based on clinical practice

In Delphi 2, 67% of all respondents agreed an initial DXA is appropriate at 5 years of age, with further monitoring scans done every 5 years after this baseline scan.

Recommendation 4.5

Monitor neurocognitive development. See Table TABLE #9, Recommendations for Neurocognitive Testing in PKU for recommended neurocognitive testing for individuals with PKU.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

The overall goal for dietary management of individuals with PKU is to lower blood PHE concentrations for optimal cognitive outcome. Adherence to a nutritionally balanced diet that supports normal growth and development while maintaining metabolic control is the mainstay of the treatment. Cognitive outcomes are significantly correlated inversely to blood PHE concentrations (F.1477) and developmental progress should be assessed periodically to identify neurocognitive deficits and offer appropriate therapies (F.2626). See Question 2.1 for further description, and TABLE #9, Recommendations for Neurocognitive Testing in PKU for recommendations for psychological testing.

Consensus based on clinical practice

This topic was not addressed in the consensus process.

Recommendation 4.6

Assess quality of life using age- and disorder-specific instruments when possible. See TABLE #8, Monitoring Nutritional Management of PKU for monitoring of nutrition management.

Strength of Recommendation:
Insufficient EvidenceConsensusWeakFairStrong
Clinical Action:
ConditionalImperative
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Evidence

Quality of life (QoL) or adjustment scores have been found to be higher for individuals with PKU who received early and continuous treatment, or who had early treatment, and then returned to treatment after a period of relaxed dietary adherence (F.2348F.2372F.2535). Some, but not all, who relaxed or discontinued PHE-restriction report problems such as depression and anxiety (F.2302). QoL measures improved in those individuals who experienced "distress" in the form of depression, when they returned to a PHE-restricted diet sufficient to lower blood PHE concentrations (F.2555). Improved QoL (specifically feeling calmer, quieter and less easily upset) was reported in adults who resumed a PHE restricted diet after a period of discontinuation (F.2245). Individuals with PKU can exhibit lower or delayed autonomy and increased difficulty forming adult relationships or stable marriages, even when compared to individuals with similar educational levels and labor status in the general population (F.2448). Healthy emotional adjustment is possible when PKU is diagnosed early and is well treated (F.2626F.2627, F.2629F.2448). Optimal metabolic control resulting from early and strict dietary treatment, specifically through childhood and adolescence, may allow for normal health related QoL and psychological adjustment (F.1300). The metabolic team should identify and empower individuals with PKU and their care-givers to seek and maintain social support for best outcome. See Recommendation 3.7 for more information.

Consensus based on clinical practice

In Delphi 2, 81% of all respondents agreed assessing QoL is important in monitoring of individuals with PKU, and 71% agreed presently available QoL assessment instruments are not adequately sensitive to specific issues pertinent to PKU.

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