Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia?

J Inherit Metab Dis. 2011 Apr;34(2):345-55. doi: 10.1007/s10545-010-9260-x. Epub 2011 Jan 19.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain / embryology
  • Brain / metabolism
  • Central Nervous System Diseases / diagnosis*
  • Chelating Agents / pharmacology
  • Female
  • Galactose / metabolism
  • Galactosemias / diagnosis*
  • Galactosemias / genetics*
  • Humans
  • Hydrolysis
  • Mice
  • Phosphoric Monoester Hydrolases / metabolism
  • Pregnancy
  • Pregnancy, Animal
  • RNA, Messenger / metabolism
  • UTP-Hexose-1-Phosphate Uridylyltransferase / deficiency*
  • UTP-Hexose-1-Phosphate Uridylyltransferase / genetics

Substances

  • Chelating Agents
  • RNA, Messenger
  • UTP-Hexose-1-Phosphate Uridylyltransferase
  • Phosphoric Monoester Hydrolases
  • myo-inositol-1 (or 4)-monophosphatase
  • Galactose