Summary
Prevention of major physical malformations would represent a significant reduction in the burden of mortality and morbidity in infants and young children. However, preventive and therapeutic approaches must be based on a clear understanding of underlying pathogenic mechanisms. While it is estimated that single gene defects account for up to 10% of cases of major malformation, relatively few of these have been identified and analysed in detail. The recognition of characteristic patterns of developmental anomalies associated with specific enzyme defects has highlighted the important role of the metabolic environment in normal development and offers the possibility of correlating biochemical abnormalities with particular teratogenic effects. Once it is generally appreciated that some forms of structural malformation have a specific biochemical basis, metabolic studies should be performed more often in patients with major developmental anomalies. This should lead to identification of other examples of diseases of this type and the elucidation of molecular mechanisms of human teratogenesis.
Similar content being viewed by others
References
Booth RFG, Patel TB, Clark JB (1980) The development of enzymes of energy metabolism in the brain of a precocial (guinea pig) and non-precocial (rat) species.J Neurochem 34: 17–25.
Brown GK (1992) Pyruvate dehydrogenase E1α deficiency.J Inher Metab Dis 15: 625–633.
Brown GK, Hunt SM, Scholem RD et al (1982) β-Hydroxyisobutyryl CoA deacylase deficiency — a defect in valine metabolism associated with physical malformations.Pediatrics 70: 532–538.
Chow CW, Anderson RMcD, Kenny GCT (1987) Neuropathology in cerebral lactic acidosis.Acta Neuropathol (Berl) 74: 393–396.
Clough JR, Whittingham DG (1983) Metabolism of [14C]glucose by postimplantation mouse embryosin vitro.J Embryol Exp Morphol 74: 133–142.
Cockroft DL, Coppola PT (1977) Teratogenic effects of excess glucose on head-fold rat embryos in culture.Teratology 16: 141–146.
Davison AN, Dobbing J (1966) Myelination as a vulnerable period in brain development.Br Med Bull 22: 40–44.
Denno KM, Sadler TW (1990) Phenylalanine and its metabolites induce embryopathies in mouse embryos in culture.Teratology 42: 565–570.
DiLiberti JH, Farndon PA, Dennis NR, Curry CJ (1984) The fetal valproate syndrome.Am J Med Genet 19: 473–481.
Eriksson UJ, Borg LA (1993) Diabetes and embryonic malformations. Role of substrate-induced free-oxygen radical production for dysmorphogenesis in cultured rat embryos.Diabetes 42: 411–419.
Fadel RA, Persaud TV (1992) Effects of alcohol and caffeine on cultured whole rat embryos.Acta Anat Basel 144: 114–119.
Freinkel N (1988) Diabetic embryopathy and fuel-mediated organ teratogenesis: lessons from animal models.Horm Metab Res 20: 463–475.
Giavini E, Broccia ML, Prati M, Bellomo D, Menegola E (1992) Effects of ethanol and acetaldehyde on rat embryos developing in vitro.In Vitro Cell Dev Biol 3: 205–210.
Goldman AS, Baker L, Piddington R, Marx B, Herold R, Egler J (1985) Hyperglycaemia-induced teratogenesis is mediated by a functional deficiency of arachidonic acid.Proc Natl Acad Sci USA 82: 8227–8231.
Goto MP, Goldman AS, Uhing MR (1992) PGE2 prevents anomalies induced by hyperglycemia or diabetic serum in mouse embryos.Diabetes 41: 1644–1650.
Hanson JW, Smith DW (1975) The fetal hydantoin syndrome.J Pediatr 87: 285–290.
Hod M, Star S, Passonneau J, Unterman TG, Freinkel N (1990) Glucose-induced dysmorphogenesis in the cultured rat conceptus: prevention by supplementation with myo-inositol.Isr J Med Sci 26: 541–544.
Hoth CF, Milunsky A, Lipsky N, Sheffer R, Clarren SK, Baldwin CT (1993) Mutations in the paired domain of the human PAX3 gene cause Klein-Wardenberg syndrome (WS-III) as well as Wardenberg syndrome Type I (WS-I).Am J Hum Genet 52: 455–462.
Kalter H, Warkany J (1983) Congenital malformations: etiologic factors and their role in prevention.N Engl J Med 308: 425–431.
Kay ED, Goldman AS, Daniel JC (1990) Common biochemical pathway of dysmorphogenesis in murine embryos: use of the glucocorticoid pathway by phenytoin.Teratogen Carcinog Mutagen 10: 31–39.
Khera KS (1987) Maternal toxicity of drugs and metabolic disorders — a possible etiologic factor in the intrauterine death and congenital malformation: a critique on human data.Crit Rev Toxicol 17: 345–375.
Kucera J (1971) Rate and type of congenital abnormalities among offspring of diabetic women.Lancet 1: 61–70.
Lenke RR, Levy HL (1980) Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies.N Engl J Med 303: 1202–1208.
Lewis NJ, Akazawa S, Freinkel N (1983) Teratogenesis from β-hydroxybutyrate during organogenesis in rat embryo organ culture and enhancement by subteratogenic glucose.Diabetes 32 (suppl): 11A.
MRC Vitamin Study Research Group (1991) Prevention of neural tube defects.Lancet 338: 131–137.
New DAT (1978) Whole-embryo culture and the study of mammalian embryos during organogenesis.Biol Rev 53: 81–122.
Reece EA, Gabrielli S, Abdallah M (1988) The prevention of diabetes-associated birth defects.Semin Perinatol 12: 292–301.
Schorah CJ, Habibzadah N, Wild J, Smithells RW (1993) Possible abnormalities of folate and vitamin b12 metabolism associated with neural tube defects.Ann NY Acad Sci 678: 81–91.
Schram AWS, Goldfischer S, van Roermund CWT et al (1987) Human peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency.Proc Natl Acad Sci USA 84: 2494–2496.
Shanks MJ, Wiley MJ, Kubow S, Wells PG (1989) Phenytoin embryotoxicity: role of enzymatic bioactivation in a murine embryo culture model.Teratology 40: 311–320.
Shepard TH, Tanimura T, Robkin MA (1970) Energy metabolism in early mammalian embryos.Symp Soc Dev Biol 29: 42–58.
Simpson JL, Elias S, Martin AO, Palmer MS, Ogata ES, Radvany RA (1983) Diabetes in pregnancy, Northwestern University series (1977–1981). I. Prospective study of anomalies in offspring of mothers with diabetes mellitus.Am J Obstet Gynecol 146: 263–270.
Singh RR, Lawrence WH, Autian J (1972) Embryonic-fetal toxicity and teratogenic effects of a group of methacrylate esters in rats.J Dent Res 51: 1632–1638.
Smeaton TC, Owens JA, Kind KL, Robinson JS (1989) The placenta releases branched-chain keto acids into the umbilical and uterine circulations in the pregnant sheep.J Dev Physiol 12: 95–99.
Smith I, Glossop J, Beasley M (1990) Fetal damage due to maternal phenylketonuria: effects of dietary treatment and maternal phenylalanine concentrations around the time of conception.J Inher Metab Dis 13: 651–657.
Smithells RW (1979) Fetal alcohol syndrome.Dev Med Child Neurol 21: 244–248.
Vandenberg P (1993) Molecular basis of heritable connective tissue disease.Biochem Med Metab Biol 49: 1–12.
Walker V, Mills GA, Hall MA, Millward-Sadler GH, English NR, Chalmers RA (1989) A fourth case of fumarase deficiency.J Inher Metab Dis 12: 331–332.
Wanders RJA, Heymans HSA, Schutgens RBH, Barth PG, van den Bosch H, Tager JM (1988) Peroxisomal disorders in neurology.J Neurol Sci 88: 1–39.
Wegner C, Nau H (1992) Alteration of embryonic folate metabolism by valproic acid during organogenesis: implications for mechanism of teratogenesis.Neurology 42: 17–24.
Wells PG, Vo HP (1989) Effects of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate on phenytoin-induced embryopathy in mice.Toxicol Appl Pharmacol 97: 398–405.
Wells PG, Zubovits JT, Wong ST, Molinari LM, Ali S (1989) Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid, and alpha-phenyl-N-t-butylnitrone: implications for bioactivation by prostaglandin synthetase.Toxicol Appl Pharmacol 97: 192–202.
Wilson GN, de-Chadarevian JP, Kaplan P, Loehr JP, Frerman FE, Goodman SI (1989) Glutaric aciduria type II: review of the phenotype and report of an unusual glomerulopathy.Am J Med Genet 32: 395–401.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brown, G.K. Metabolic disorders of embryogenesis. J Inherit Metab Dis 17, 448–458 (1994). https://doi.org/10.1007/BF00711360
Issue Date:
DOI: https://doi.org/10.1007/BF00711360