Galactosemia
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The pathogenesis of most of the clinical manifestations of galactosemia is the accumulation of Gal-1-P in tissues [71]. Among the best evidence for this is the observation that therapeutic measures that result in reduction of intracellular concentrations of Gal-1-P lead to prevention or disappearance of symptoms. It is clear that the manifestations of galactosemia do not occur in galactokinase deficiency, in which disease hepatic, renal, and cerebral damage is unknown. Thus, impaired mental development is not due to galactose itself. Cataracts and pseudotumor cerebri occur in patients with galactokinase deficiency [26, 72, 73], and these complications are due to galactitol. This byproduct of galactose accumulation occurs by its reduction at carbon-1 and is present in urine and tissues. In the lens, galactitol causes osmotic swelling and disruption of fibers. Osmotic swelling is also the mechanism of production of cerebral edema. In addition, cataracts that result from galactose treatment of rats are prevented by sorbinil, which inhibits aldose reductase, the enzyme that catalyzes the conversion of galactose to galactitol [74]. Galactitol has been demonstrated in vivo by proton magnetic resonance spectroscopy in the brain of an encephalopathic infant with galactosemia [75].
Nerve and Retinal Changes in Experimental Diabetes
John H. McNeill in Experimental Models of Diabetes, 2018
Similarly to the hyperglycemic conditions, in experimental galactosemia, galactitol accumulates in the tissue due to polyol pathway activation as it cannot be metabolized further. Loss of nerve conduction velocity in these animals is further assodated with myoinositol and taurine depletion.7,170,182–183 However, in contrast to diabetic animals, galactosemic rats show a high Na+-K+-ATPase activity,182,183 indicating that although the response to polyol pathway activation is different in this model it may lead to similar structural changes.
Lipids of Histoplasma Capsulatum
Rajendra Prasad, Mahmoud A. Ghannoum in Lipids of Pathogenic Fungi, 2017
Peak III, which eluted very close to peak II, exhibited a very different spectrum. The ion profile indicated that it was a derivative of a terminal hexose but one in which the hexose was unsubstituted at positions 2 and 3 and acetylated at carbon 4. The retention time of peak III matched the retention time of l,4-di-O-acetyl-2,3,5,6-tetra-0-methyl-galactitol prepared from authentic 1-β-O-methylgalactofuranoside and did not chromatograph with the partially methylated alditol acetate of β-mannofuranoside.30 These data are consistent with the designation of peak III as 1,4-di-O-acetyl-2,3,5,6-tetra-O-methylgalactitol or the derivative of a terminal galacto-furanose.
Repurposing drugs for the treatment of galactosemia
Published in Expert Opinion on Orphan Drugs, 2019
David J. Timson
The symptoms of galactosemia are highly variable [21–25]. The most severe forms result in significant cognitive and physical disability in childhood and can result in death of the infant if untreated. The mildest forms result in perturbations of blood chemistry which are not currently associated with any adverse effects on the patient. Almost all forms, except the very mildest, result in childhood onset cataracts. These result from the buildup of galactose in the lens. This is converted to the sugar alcohol galactitol (dulcitol) by the action of aldose reductase (EC 1.1.1.21). Unlike galactose, galactitol cannot be transported across the cell membrane and thus accumulates in the lens cells, upsetting the osmotic balance of these cells [26]. The most severe symptoms are associated with type I and some instances of type III galactosemia. Type III galactosemia probably has the widest phenotypic range [27]. In addition to severely disabling and life-threatening outcomes, it can also result in very mild symptoms which cause little of no harm. Types II and IV have similar symptoms. Typically patients with these types of galactosemia have early onset cataracts, normally in early childhood [8,28,29]. The severity of the symptoms depend on the exact mutation(s) present in the patient along with the patient’s environment. In this context, the environment includes the health care available to the patient: early identification of the disease and intervention can slow or prevent the development of some symptoms.
Two consecutive pregnancies in a patient with premature ovarian insufficiency in the course of classic galactosemia and a review of the literature
Published in Gynecological Endocrinology, 2022
Jagoda Kruszewska, Hanna Laudy-Wiaderny, Sandra Krzywdzinska, Monika Grymowicz, Roman Smolarczyk, Blazej Meczekalski
Classic galactosemia is usually diagnosed within the neonatal period after milk introduction due to the accumulation of large amounts of galactose and its toxic metabolites (e.g. galactitol, galactose-1-phosphate) [13,14]. The untreated disorder with its serious implications – jaundice, cirrhosis, renal tubular disease, cataract formation, failure to thrive – may lead to neonatal death, usually from E.coli sepsis [14]. It is generally considered that short-term health consequences observed in infancy reflect galactose toxicity and are reversed rapidly by avoidance of breastfeeding and administration of galactose-free soya milk, whereas long-term complications such as cognitive impairment, speech difficulties, low bone mineral density and POI are rather believed to be diet-independent [14,15]. Our patient avoided a neurological sequel. Nevertheless, features of hypogonadism were observed in adolescence and diagnostic process confirmed POI.
Centella asiatica prevents D-galactose-Induced cognitive deficits, oxidative stress and neurodegeneration in the adult rat brain
Published in Drug and Chemical Toxicology, 2022
Zeba Firdaus, Neha Singh, Santosh Kumar Prajapati, Sairam Krishnamurthy, Tryambak Deo Singh
A limited amount of D-gal is catabolized by D-galactokinase and galactose-1-phosphate uridyl transferase. The surplus D-gal is reduced to galactitol and stored inside the cell causing osmotic stress and generation of ROS (Hsieh et al. 2009, Li et al. 2016). The brain is very susceptible to oxidative stress owing to its higher oxygen consumption, iron content, polyunsaturated lipids, and poor antioxidant system. Hippocampal and cortical regions are particularly susceptible to oxidative damage, and cellular injury in these regions can decrease memory by compromising hippocampal synaptic plasticity (TERRY and PeÑa 1965). Thus, D-gal treatment induces oxidative stress and causes intolerable alterations in the cell that play a key role in aging, and ultimately ends with cell death (Finkel and Holbrook 2000).
Related Knowledge Centers
- Aldose Reductase
- Cataract
- Galactose
- Sugar Alcohol
- Galactosemia
- Redox
- Galactokinase Deficiency
- Lens
- Galactose-1-Phosphate Uridylyltransferase
- Dominance