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.

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.

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.

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.

Phenylketonuria: High plasma phenylalanine decreases cerebral protein synthesis.

Left untreated, phenylketonuria biochemically results in high phenylalanine concentrations in blood and tissues, and clinically especially in severe mental retardation. Treatment consists of severe dietary restriction of phenylalanine with more or less normal intellectual outcome as result when started early enough. It is unclear whether treatment for life is necessary. A clear relationship between plasma phenylalanine concentrations and cerebral outcome exists, but the precise pathophysiological mechanism is not understood. In studies in mice with phenylketonuria, the cerebral protein synthesis rate is decreased when compared to controls. The aim of the present study was to determine the protein synthesis rate in relation to the plasma phenylalanine concentrations in-vivo in patients with phenylketonuria by positron emission tomography brain studies after an intravenous l-[1-(11)C]-tyrosine bolus. Results showed a significant negative relationship (R(2)=0.40, p<0.01) between plasma phenylalanine concentration and the cerebral protein synthesis rate in 19 patients with phenylketonuria. At increased plasma phenylalanine concentrations, i.e. above 600-800micromol/l, the cerebral protein synthesis rate is clearly decreased compared to lower phenylalanine concentrations. These data suggest that cerebral protein metabolism in untreated adults with phenylketonuria can be abnormal due to high plasma phenylalanine concentrations. Hence, we speculate that it is important to continue dietary treatment into adulthood, aiming at plasma phenylalanine concentrations <600-800micromol/l.

Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause?

In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.

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.

Phenylketonuria: reduced tyrosine brain influx relates to reduced cerebral protein synthesis.

BACKGROUND: In phenylketonuria (PKU), elevated blood phenylalanine (Phe) concentrations are considered to impair transport of large neutral amino acids (LNAAs) from blood to brain. This impairment is believed to underlie cognitive deficits in PKU via different mechanisms, including reduced cerebral protein synthesis. In this study, we investigated the hypothesis that impaired LNAA influx relates to reduced cerebral protein synthesis. METHODS: Using positron emission tomography, L-[1-11C]-tyrosine (11C-Tyr) brain influx and incorporation into cerebral protein were studied in 16 PKU patients (median age 24, range 16 - 47 years), most of whom were early and continuously treated. Data were analyzed by regression analyses, using either 11C-Tyr brain influx or 11C-Tyr cerebral protein incorporation as outcome variable. Predictor variables were baseline plasma Phe concentration, Phe tolerance, age, and 11C-Tyr brain efflux. For the modelling of cerebral protein incorporation, 11C-Tyr brain influx was added as a predictor variable. RESULTS: 11C-Tyr brain influx was inversely associated with plasma Phe concentrations (median 512, range 233 - 1362 µmol/L; delta adjusted R2=0.571, p=0.013). In addition, 11C-Tyr brain influx was positively associated with 11C-Tyr brain efflux (delta adjusted R2=0.098, p=0.041). Cerebral protein incorporation was positively associated with 11C-Tyr brain influx (adjusted R2=0.567, p<0.001). All additional associations between predictor and outcome variables were statistically nonsignificant. CONCLUSIONS: Our data favour the hypothesis that an elevated concentration of Phe in blood reduces cerebral protein synthesis by impairing LNAA transport from blood to brain. Considering the importance of cerebral protein synthesis for adequate brain development and functioning, our results support the notion that PKU treatment be continued in adulthood. Future studies investigating the effects of impaired LNAA transport on cerebral protein synthesis in more detail are indicated.

Isolated elevated serum transaminases leading to the diagnosis of asymptomatic Pompe disease.

An asymptomatic boy, aged 1.5 years, was referred with presumed liver disease because of persistently increased transaminase. Ultimately Pompe disease was confirmed, without specific abnormalities in muscle biopsy. This case demonstrates that increased transaminases do not always suggest liver disease. It is hard to determine prognosis and to decide whether enzyme replacement therapy should be started in asymptomatic patients with Pompe disease.