Protein Metabolism in Phenylketonuria and Lesch-Nyhan Syndrome

Abstract

ABSTRACT. Animal and in vitro studies have implicated decreased protein synthesis in the pathogenesis of tissue damage in phenylketonuria (PKU) and of growth failure in Lesch-Nyhan syndrome. Protein turnover was measured in vivo in ten young adult subjects with classical PKU, two subjects with hyperphenylalaninemia, and three children with Lesch-Nyhan syndrome using techniques based on continuous infusions of ['3C]leucine and, in Lesch-Nyhan subjects, [2Hs]phenylalanine. The PKU subjects had various degrees of dietary phenylalanine restriction and plasma phenylalanine levels at the time of study ranged from 450-1540 pmol/L (mean 1106). Plasma phenylalanine in the two hyperphenylalaninemic subjects was 533 and 402 pmol/L. Rates of protein synthesis in all PKU subjects (mean 3.71 g/kg/24 h, range 2.68-5.10, ['3C]leucine as tracer) were in a range similar to or above control values (mean 2.97, range 2.78-3.22, n = 6), as were rates of protein catabolism (PKU mean 4.23 g/kg/24 h, range 3.15-5.45; controls 3.64, 3.50-3.91). Protein turnover values in hyperphenylalaninemia were also similar to those in controls. With ['3C]leucine as tracer, both mean protein synthesis and catabolism values in Lesch-Nyhan subjects (mean 4.80 and 5.64 g/kg/24 h, respectively) were higher than values in control children matched for protein intake (synthesis 4.32 + 0.74 (SD) and catabolism 4.85 + 0.57 (g/kg/24 h, n = 5). Similar results were obtained in LeschNyhan subjects using [2Hs]phenylalanine as tracer. These results suggest that protein turnover is not decreased in either PKU or Lesch-Nyhan syndrome. This conclusion is inconsistent with the hypothesis that tissue damage in PKU results from impaired protein synthesis. The findings also indicate that growth failure in Lesch-Nyhan syndrome is unlikely to be due to decreased protein synthesis resulting from impaired energy metabolism. (Pediatr Res 28: 240-246,1990) Abbreviations PKU, phenylketonuria HPRT, hypoxanthine-guanine phosphoribosyltransferase KIC, a-ketoisocaproic acid BMI, body mass index GTP, guanosine 5'-triphosphate APE, atoms percent excessThe cause of tissue damage in PKU is still a matter of debate.A number of studies have demonstrated reduced protein synthe-

Lesch‐Nyhan syndrome and its pathogenesis: Normal nicotinamide‐adenine dinucleotide but reduced ATP concentrations that correlate with reduced poly (ADP‐ribose) synthetase activity in HPRT‐deficient lymphoblasts

“…In HPRT deficiency, very small and short-lived alterations in metabolic rates and patterns may be important in pathogenesis, as shown by normal function in the mouse model, even in testes (Ansell et al 1991). Overall protein turnover in man appears normal (Thompson et al 1990).…”

The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study

“…These abnormalities were initially reported in a few patients suffering from neurological deterioration after lowphenylalanine diet discontinuation and were partially reversed by the reintroduction of a strict dietary regimen [2][3][4][5]. Thereafter similar alterations were detected in untreated, late-treated and also in early and continuously treated PKU patients that did not show any neurological symptom [1,6,7].…”

Comparison of Glycomacropeptide with Phenylalanine Free-Synthetic Amino Acids in Test Meals to PKU Patients: No Significant Differences in Biomarkers, Including Plasma Phe Levels

“…Participants in the project were invited to participate if they met the following inclusion criteria: diagnosis of classical PKU confirmed by mutation analysis and a known phe tolerance (12–20 mg/kg) [ 18 – 20 ], age ≥ 15 years at inclusion, had received treatment with a protein-restricted diet since the neonatal period, and were willing and able to visit the PKU clinic four times. The period between visits varied from 24 hours to 1 month, since we estimated this to be sufficient time for a wash-out period [ 21 , 22 ]. Exclusion criteria were (1) <15 years at inclusion, (2) had not followed the dietary treatment continuously, (3) had a second chronic disease or condition, which potentially could influence the PKU treatment and outcome, (4) treated with BH4, or (5) pregnant, nursing, or planning to become pregnant.…”