Man made disease: Clinical manifestations of low phenylalanine levels in an inadequately treated phenylketonuria patient and mouse study

Pode‐Shakked, Ben; Shemer-Meiri, Lilach; Harmelin, Alon; Stettner, Noa; Brenner, Ori; Abraham, Smadar; Schwartz, Gerard; Anikster, Yair

doi:10.1016/j.ymgme.2013.10.006

Cited by 15 publications

(11 citation statements)

References 12 publications

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“…This results in both high tyrosine and low phenylalanine concentrations (De Laet et al 2011;Daly et al 2012;Wilson et al 2000), with dietary treatment being primarily monitored based on tyrosine concentrations. In phenylketonuria, too strict dietary treatment, resulting in "low" phenylalanine concentrations, has shown to be related to impaired growth and development (Teissier et al 2012;Rouse 1966;Smith et al 1990;Pode-Shakked et al 2013). In tyrosinemia type II, high tyrosine concentrations are associated with mental retardation.…”

Section: Introductionmentioning

confidence: 99%

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

et al. 2014

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Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism caused by fumarylacetoacetase deficiency. Biochemically, this results in accumulation of toxic metabolites including succinylacetone. Clinically, HT1 is characterized by severe liver, kidney, and neurological problems. Treatment with NTBC and dietary restriction of tyrosine and phenylalanine have strongly improved outcome, but impaired neurocognitive development has been reported. Whether impaired neurocognitive outcome results from high blood tyrosine or low blood phenylalanine concentrations is currently unknown. In this report, two HT1 newborns, diagnosed by neonatal screening, are presented. The first patient showed low phenylalanine concentrations, growth retardation, neurological impairments, and skin problems, clearly improving after institution of phenylalanine supplementation (~30 mg/kg/ day) at age 6 months, while both blood phenylalanine and tyrosine concentrations increased. In the second patient, phenylalanine supplementation (~20 mg/kg/day) was initiated as soon as low phenylalanine concentrations were observed at age 19 days. On this regimen, blood phenylalanine concentrations increased, and hypophenylalaninemia was less frequently observed than in the first patient, whereas blood tyrosine concentrations tended to increase. Clinically, no growth, neurological, or skin problems have been observed. The combination of knowledge obtained from these cases suggests that hypophenylalaninemia rather than hypertyrosinemia during the first months of life may impair neurocognitive development in young HT1 infants. Phenylalanine supplementation should really be considered in HT1 patients with consistently low blood phenylalanine concentrations during the first months of life. However, the minimal phenylalanine concentrations acceptable and the optimal phenylalanine supplementation regimen require further investigation.

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Section: Introductionmentioning

confidence: 99%

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

et al. 2014

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“…This demonstrates that the maximum recommended intake of natural protein is well fulfilled, providing a maximal possible daily amount of high quality protein [23], [24]. However, the rate of Phe > limit is significantly higher under these regimes.…”

Section: Discussionmentioning

confidence: 73%

Effect of dietary regime on metabolic control in phenylketonuria: Is exact calculation of phenylalanine intake really necessary?

Rohde

Thiele

Och

et al. 2015

Molecular Genetics and Metabolism Reports

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BackgroundA phenylalanine (Phe) restricted dietary management is required in phenylketonuria (PKU) to maintain good metabolic control. Nevertheless, five different models of dietary regimes, which differ in their accuracy of Phe documentation, are used. To investigate the effect of the dietary regime on metabolic control, a multicenter evaluation was performed.Patients/Methods149 patients (max. 800 mg Phe-intake/day; 108 children aged 1–9 years and 41 adolescents aged 10–15 years) could be included. They were separated according to age and dietary regime, revealed by a questionnaire on dietary habits. Dietary regimes vary from daily strict calculation of all Phe-intake (group 1) to a rather loose regime only estimating Phe-intake and including high protein food (group 5). Data were analyzed with respect to metabolic control (Phe-concentrations, Phe-concentrations above upper recommended limit during 6 months before the interview), Phe-intake (mg/day) and age (years).ResultsMedian Phe-concentrations in children did not differ significantly among diet groups (group 1: 161; 2: 229, 3: 236, 4: 249, 5: 288 μmol/l, p = 0.175). However, exact daily Phe calculation led to significantly lower percentage of Phe concentrations above the upper recommended limit (group 1: 17, 2: 50, 3: 42, 4: 50, 5: 75%, p = 0.035). All included patients showed good to acceptable metabolic control. Patients on the dietary regime with the least accuracy, consuming also high protein foods, showed the poorest metabolic control. Median Phe concentrations of all other groups remained within recommended ranges, including from groups not calculating special low protein foods, fruit and vegetables and using a simplified system of recording Phe-intake.In adolescents no significant differences among diet groups were revealed.ConclusionExact calculation of Phe content of all food is not necessary to achieve good metabolic control in children and adolescents with PKU. Excluding special low protein food, as well as fruit and vegetables from calculation of Phe-intake has no impact on metabolic control. However including protein rich food into the diet and simply estimating all Phe-intake appears insufficient. The simplification of dietary regime may be helpful in enhancing acceptability and feasibility.

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“…The total long-term Phe elimination results in death, and an excessive restriction may cause growth failure, weight loss or poor weight gain, erythema, skin desquamation, alopecia, aminoaciduria, hypoproteinemia, anemia, changes in bone tissue, mental retardation, severe malnutrition, keratomalacia, prolonged diarrhea, immunosuppression, and, in extreme cases, ulcers or corneal perforation, among others. 11,12 Some treatment protocols suggest, at the beginning of the diagnosis, to eliminate Phe depending on its initial plasma concentration; usually, higher levels will require longer time to reduce, but this should be closely monitored day to day with blood samples in order to achieve and maintain target blood Phe levels (2-6 mg%). 13,14 Other authors suggest that only with initial blood Phe levels of 1500 μmol/L or higher, Phe should be eliminated for 48 hours.…”

Section: Phenylalanine Requirements and Dietary Sourcesmentioning

confidence: 99%

“…44 It is common to find vitamin B 12 deficiency in patients with PKU. Low blood levels of vitamin B 12 have been reported, especially in those who were not compliant with the nutritional treatment and do not include in their diet a Phe-free medical formula or animal protein, which are the main sources of this vitamin. Also, low serum levels of ferritin and transferrin receptors, which suggest iron deficiency, have been found.…”

Section: Vitamin and Mineral Supplementation In Pkumentioning

confidence: 99%

Section: Phenylalanine Requirements and Dietary Sourcesmentioning

confidence: 99%

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Conventional Phenylketonuria Treatment

Guillén-López

López-Mejía

Ibarra-González

et al. 2016

Journal of Inborn Errors of Metabolism and Screening

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Phenylketonuria (PKU) is caused by a deficient activity of enzyme phenylalanine (Phe) hydroxylase, which results in high Phe blood concentration, which is toxic to the central nervous system. The fundamental purpose of nutritional treatment is to reduce and maintain blood Phe between 2 mg/dL (120 mmol/L) and 6 mg/dL (360 mmol/L) in order to prevent neuropathogenic complications. At the same time, nutrition support must provide enough energy and nutrients to promote normal growth and development and also to avoid vitamin and mineral deficiencies. Phenylketonuria treatment must be maintained long-life and its adherence must be frequently assessed. The amount of Phe required by patients with PKU varies throughout life and must be adjusted according to individual tolerance, residual phenylalanine hydroxylase enzymatic activity, age, sex, growth rate, protein intake, and nutritional and biochemical status among others. Treatment must be done by trained personnel. It is necessary to unify treatment criteria and further research must be done.

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Man made disease: Clinical manifestations of low phenylalanine levels in an inadequately treated phenylketonuria patient and mouse study

Cited by 15 publications

References 12 publications

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Effect of dietary regime on metabolic control in phenylketonuria: Is exact calculation of phenylalanine intake really necessary?

Conventional Phenylketonuria Treatment

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