Effect of Experimental Phenylketonuria on the Bone of Pregnant Mothers and their young during Perinatal Life and after Delivered Newborn of Albino Rats

  • Hassan I. Elsayyad Zoology Department, Faculty of Science, EL Mansoura University, Egypt.
  • Mahmoud E. Mohallal Zoology Department, Faculty of Science, Suez Canal University, Egypt.
  • Hany A. Hefny Biology Department, University College, Umm Al Qura University, Al-Jomoum, KSA.
  • Hala M. Ebied Zoology Department, Faculty of Science, Suez Canal University, Egypt.
Keywords: PKU, Bone, Pregnant, Rat

Abstract

Phenylketonuria (PKU) is a genetic disorder that is characterized by an inability of the body to utilize the essential amino acid, phenylalanine. The disease results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine to tyrosine. Although, this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known about the mechanisms involved in the pathology of PKU during neonatal development. Elevated concentrations of plasma phenylalanine were induced in pregnant rats by oral administration of 50mg/100g body weight alpha-methylphenylalanine plus phenylalanine supplementation at a dosage of 60mg/100g body weight two times daily after the 6th day of onset of gestation till 14 & 16 days of gestation as well as at parturition. Treatment with alpha-methylphenylalanine/ phenylalanine resulted in a significant decrease of accumulated body weight gain during pregnancy as well as exhibited marked growth retardation of prenatal fetuses and delivered newborn. The growth retarded fetuses was manifested by decreased body weight, malformed both fore- & hindlimb, oedematous skin & superficial hematomas widely spread in different parts of the body. Ossification of bones was greatly altered. Skeletal abnormalities restricted mainly in skull, sternebrae, lumbar, caudal vertebrae and distal phalanx of both fore- & hindlimb. Histological examination of femoral bone revealed varieties of histopathological abnormalities which illustrated and discussed. These results suggested that exposure of the fetus to high plasma concentrations of phenylalanine cause deformities of bone.

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References

[1]. Fölling, A. (1934). Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität. Hoppe Seylers Z. Physiol. Chem., 227:169—176.
[2]. Pietz, J. (1998). Neurological aspects of adult Phenylketonuria. Curr. Opin. Neurol., 11: 679-88.
[3]. Roberts, S.A., Thorpe, J.M., Ball, R.O. and Pencharz, P.B. (2001). Tyrosine requirement of healthy men receiving a fixed phenylalanine intake determined by using indicator amino acid oxidation. Am. J. Clin. Nutr.,73(2):276-82.
[4]. Tam, S.Y. and Roth, R.H. (1997). Mesoprefrontal dopaminergic neurons: can tyrosine availability influence their functions? Biochem. Pharmacol., 53(4):441-53.
[5]. Recommendations on the dietary management of phenylketonuria. Report of Medical Research Council Working Party on Phenylketonuria (1993). Archives of Disease in Childhood, 68(3), 426-7.
[6]. Kaufman, S., Kapatos, G., Rizzo, W.B., Schulman, J.D., Tamarkin, L., Van Loon, G.R. (1983). Tetrahydropterin therapy for hyperphenylalaninemia caused by defective synthesis of tetrahydrobiopterin. Ann. Neurol., 14(3): 308-15.
[7]. Zschocke, J. (2003). Phenylketonuria mutations in Europe. Hum. Mutat., 21(4):345-56.
[8]. Scriver, C.R., Hurtubise, M., Konecki, D., Phommarinh, M., Prevost, L., Erlandsen, H., Stevens, R., Waters, P.J., Ryan, S., McDonald, D., Sarkissian, C. (2003). PAHdb 2003: what a locus-specific knowledgebase can do. Hum. Mutat., 21:333-44.
[9]. Brenton, D.P. and Lilburn, M. (1996). Maternal phenylketonuria. A study from the United Kingdom. Eur. J. Pediatr., 155 Suppl 1:S177-80.
[10]. Levy, H.L. and Ghavami, M. (1996). Maternal Phenylketonuria: a metabolic teratogen. Teratology, 53: 176-84.
[11]. Koch, R., Hanley, W., Levy, H., Matalon, R., Rouse, B., Trefz, F., Guttler, F., Azen, C., Friedman, E., Platt, L., de la Cruz, F. (2000). Maternal phenylketonuria: An international study. Mol. Genet. Metab., 71(1-2):233-9.
[12]. Cechak, P., Hejcmanova, L. and Rupp, A. (1996). Long-term follow-up of patients treated for Phenylketonuria (PKU). Results from the Prague PKU Center. Eur. J. Pediatr., 155 Suppl. l: S59-63.
[13]. Riva, E., Agostoni, C., Biasucci, G., Trojan, S., Luotti, D., Fiori, L., Giovannini, M. (1996). Early breastfeeding is linked to higher intelligence quotient scores in dietary treated phenylketonuric children. Acta Paediatr., 85: 56-8.
[14]. Rouse, B., Azen, C., Koch, R., Matalon, R., Hanley, W., de la Cruz, F., Trefz, F., Friedman, E., Shifrin, H. (1997). Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae. Am. J. Med. Genet., 69(1): 89-95.
[15]. Rohr, F.J., Lobbregt, D. and Levy, H.L. (1998). Tyrosine supplementation in the treatment of Maternal Phenylketonuria. Am. J. Clin. Nutr., 67: 473-6.
[16]. Pietz, J., Dunckelmann, R., Rupp, A., Rating, D., Meinck, H.M., Schmidt, H., Bremer, H.J. (1998). Neurological outcome in adult patients with early-treated Phenylketonuria. Eur. J. Pediatr., 157(10):824-30.
[17]. Williams, K. (1998). Benefits of normalizing plasma phenylalanine: impact on behavior and health. A case report. J. Inherit. Metab. Dis., 21: 785-90.
[18]. Christen, S.D., Hill, T.M., Williams, M.S. (1996). Effects of tempered barley on milk yield, intake, and digestion kinetics of lactating Holstein cows. J. Dairy Sci., 79: 1394-1399.
[19]. Spero, D.A. and Yu, M.C. (1983). Effects of maternal hyperphenylalaninemia on fetal brain development: a morphological study. Exp. Neurol., 79(3): 655-665.
[20]. Rech, V.C., Feksa, L.R., Dutra-Filho, C.S., Wyse, A.T., Wajner, M. and Wannmacher, C.M. (2002). Inhibition of the mitochondrial respiratory chain by phenylalanine in rat cerebral cortex. Neurochem. Res., 27: 353–357.
[21]. Bancroft, J. D. & Stevens, A. (1977). Theory and Practice of Histological Techniques. Edinburgh: Churchill Livingstone.
[22]. Drury, R.A. and Wallington, E.A. (1980). Carleton's Histological Technique. 5th Edition, Oxford University Press, New York.
[23]. Field, A.P. (2000). Discovering statistics using SPSS for Windows: Advanced techniques for the beginner. London: Sage Publications.
[24]. Robinson, B.H., MacMillan, H., Petrova-Benedict, R., Sherwood, W.G., (1987). Variable clinical presentation in patients with defective E1 component of pyruvate dehydrogenase complex. J. Pediatr., 111(4): 525-533.
[25]. Diamond, A. (1996). Evidence for the importance of dopamine for prefrontal cortex functions early in life. Philos. Trans. R. Soc. Lond. B. Biol. Sci., 351(1346):1483-93.
[26]. Gazit, V., Ben-Abraham, R., Pick, C.G., Katz, Y. (2003). beta-Phenylpyruvate induces long-term neurobehavioral damage and brain necrosis in neonatal mice. Behav. Brain Res., 143(1):1-5.
[27]. Belloso, L.M. and Lowitt, M.H. (2003). Cutaneous findings in a 51-year-old man with Phenylketonuria. J. Am. Acad. Dermatol., 49(2 Suppl Case Reports):S190-2.
[28]. Brass, C.A., Isaacs, C.E., McChesney, R., Greengard, O. (1982). The effects of hyperphenylalaninemia on fetal development: a new animal model of Maternal Phenylketonuria. Pediatr. Res., 16:388-394.
[29]. Sadava, D. and Sutcliffe, D. (1988). The effects of maternal hyperphenylalaninemia on learning in mature rats. Life Sci., 43(14):1119-23.
[30]. Gadallah, A.A. (2004). Molecular and developmental studies on the effect of experimental Phenylketonuria on the differentiation of some organs of Albino rats during postnatal life. Ph.D. Thesis, Mansoura Faculty of Science, Mansoura University, Egypt.
[31]. MacDonald, A., Daly, A., Chakrapani, A., Rylance, G., Asplin, D., Hall, S.K., Booth, I.W. (2004). What is the ideal dose of protein substitute in Phenylketonuria (Pku)? Arch. Dis. Child., 89:A58-A59.
[32]. Halliwell, B. and Chirico, S. (1993). Lipid peroxidation: its mechanism, measurement, and significance. Am. J. Clin. Nutr., 57(5 Suppl):715S-724S.
[33]. Lee, P.J., Ridout, D., Walter, J.H., Cockburn, F. (2005). Maternal Phenylketonuria: report from the United Kingdom registry 1978-97. Arch. Dis. Child., 90(2): 143-6.
[34]. Fisch, R.O. and Stassart, J.P. (2004). Normal infant by a gestational carrier for a Phenylketonuria mother: alternative therapy. Mol. Genet. Metab., 82(1):83-6.
[35]. Matalon, K.M., Acosta, P.B., and Azen, C. (2003). Role of nutrition in pregnancy with phenylketonuria and birth defects. Pediatrics, 112(6 Pt. 2):1534–1536.
[36]. Brenton, D.P. (1988). Maternal phenylketonuria. Eur. J. Clin. Nutr., 43: 13-17.
[37]. Jones, K.L. (1986). Fetal alcohol syndrome. Pediatr. Rev., 8:122-126.
[38]. Autti-Rämö, I., Gaily, E., Granström, M.L. (1992). Dysmorphic features in offspring of alcoholic mothers. Arch. Dis. Child., 67: 712-716.
[39]. Aragón, M.C., Giménez, C., Valdivieso, F. (1982). Inhibition by L-phenylalanine of tyrosine transport by synaptosomal plasma membrane vesicles: implications in the pathogenesis of phenylketonuria. J. Neurochem., 39:1185-7.
[40]. Krause, W., Epstein, C., Averbook, A., Dembure, P., Elsas, L. (1986). Phenylalanine alters the mean power frequency of electroencephalograms and plasma L-dopa in treated patients with phenylketonuria. Pediatr. Res., 20: 1112-1116.
[41]. Greeves, L.G., Thomas, P.S. and Carson, D.J. (1995). Radiological assessment of the hand and wrist in phenylketonuria and hyperphenylalaninaemia. Pediatr. Radiol., 25(5): 353-5.
[42]. Al-Qadreh, A., Schulpis, K.H., Athanasopoulou, H., Mengreli, C., Skarpalezou, A., Voskaki, I. (1998). Bone mineral status in children with Phenylketonuria under treatment. Acta Paediatr., 87(11): 1162-6.
[43]. Schwahn, B., Mokov, E., Scheidhauer, K., Lettgen, B., Schönau, E. (1998). Decreased trabecular bone mineral density in patients with phenylketonuria measured by peripheral quantitative computed tomography. Acta Paediatr., 87(1):61-3.
[44]. Pérez-Dueñas, B., Cambra, F.J., Vilaseca, M.A., Lambruschini, N., Campistol, J., Camacho, J.A. (2002). New approach to osteopenia in Phenylketonuric patients. Acta Paediatr., 91(8): 899-904.
[45]. Yannicelli, S., Medeiros, D.M. (2002). Elevated plasma phenylalanine concentrations may adversely affect bone status of phenylketonuric mice. J. Inherit. Metab. Dis., 25(5): 347-61.
[46]. Ambroszkiewicz, J., Gajewska, J., Laskowska-Klita, T. (2003). Markers of bone formation and resorption in prepubertal children with Phenylketonuria. Med. Wieku Rozwoj., 7(1): 89-95.
[47]. Mallette, L.E., Patten, B., Cook, J.D., Engel, W.K. (1977). Calcium metabolism in amyotrophic lateral sclerosis. Dis. Nerv. Syst., 38(6): 457-61.
[48]. Schaefer, F., Burgard, P., Batzler, U., Rupp, A., Schmidt, H., Gilli, G., Bickel, H., Bremer, H.J. (1994). Growth and skeletal maturation in children with phenylketonuria. Acta Paediatr., 83(5): 534-41.
[49]. Andersen, A. (1976). Maternal hyperphenylalaninemia: an experimental model in rats. Dev. Psychobiol., 9(2): 157-66.
[50]. McDonald, J.D., Dyer, C.A., Gailis, L., Kirby, M.L. (1997). Cardiovascular defects among the progeny of mouse Phenylketonuria females. Pediatr Res., 42(1):103-7.
[51]. Smith, C.B. and Kang, J. (2000). Cerebral protein synthesis in a genetic mouse model of phenylketonuria. Proc. Natl. Acad. Sci. USA, 97: 11014-11019.
[52]. Jervis, G.A. (1939). The Genetics of Phenylpyruvic Oligophrenia: A Contribution to the Study of the Influence of Heredity on Mental Defect. Journal of Mental Science, (85): 719-762.
[53]. Fisch, R.O., Matalon, R., Weisberg, S., Michals, K. (1991). Children of fathers with phenylketonuria: An international survey. J. Pediatr., 118: 739-741.
Published
2015-10-01
How to Cite
Elsayyad, H., Mohallal, M., Hefny, H., & Ebied, H. (2015). Effect of Experimental Phenylketonuria on the Bone of Pregnant Mothers and their young during Perinatal Life and after Delivered Newborn of Albino Rats. Journal of Advanced Laboratory Research in Biology, 6(4), 129-143. Retrieved from https://e-journal.sospublication.co.in/index.php/jalrb/article/view/241
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