Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia?
Classic Galactosemia due to galactose-1-phosphate uridyltransferase (GALT) deficiency is associated with apparent diet-independent complications including cognitive impairment, learning problems and speech defects. As both galactose-1-phosphate and galactitol may be elevated in cord blood erythrocytes and amniotic fluid despite a maternal lactose-free diet, endogenous production of galactose may be responsible for the elevated fetal galactose metabolites, as well as postnatal CNS complications. A prenatal deficiency of myo-inositol due to an accumulation of both galactose-1- phosphate and galactitol may play a role in the production of the postnatal CNS dysfunction. Two independent mechanisms may result in fetal myo-inositol deficiency: competitive inhibition of the inositol monophosphatase1 (IMPA1)-mediated hydrolysis of inositol monophosphate by high galactose-1- phosphate levels leading to a sequestration of cellular myo-inositol as inositol monophosphate and galactitol-induced reduction in SMIT1-mediated myo-inositol transport. The subsequent reduction of myo-inositol within fetal brain cells could lead to inositide deficiencies with resultant perturbations in calcium and protein kinase C signaling, the AKT/mTOR/ cell growth and development pathway, cell migration, insulin sensitivity, vescular trafficking, endocytosis and exocytosis, actin cytoskeletal remodeling, nuclear metabolism, mRNA export and nuclear pore complex regulation, phosphatidylinositol-anchored proteins, protein phosphorylation and/or endogenous iron "chelation". Using a knockout animal model we have shown that a marked deficiency of myo-inositol in utero is lethal but the phenotype can be rescued by supplementing the drinking water of the pregnant mouse. If myo-inositol deficiency is found to exist in the GALT-deficient fetal brain, then the use of myo-inositol to treat the fetus via oral supplementation of the pregnant female may warrant consideration.
Division of Genetics, Children's Hospital Boston, Center for Life Sciences Building, Boston, MA, 02115, USA. Gerard.Berry@childrens.harvard.edu
Gerard T
GT
Berry
D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000175:diagnosis*; D002614:Chelating Agents / Q000494:pharmacology; D005260:Female; D005690:Galactose / Q000378:metabolism; D005693:Galactosemias / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000378:metabolism; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase / Q000172:deficiency* / Q000235:genetics
D002614:Chelating Agents; D012333:RNA, Messenger; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D005690:Galactose
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