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Inborn Errors of Metabolism
Published in Praveen S. Goday, Cassandra L. S. Walia, Pediatric Nutrition for Dietitians, 2022
Surekha Pendyal, Areeg Hassan El-Gharbawy
Neonates with classic galactosemia develop life-threatening complications including feeding problems, malnutrition, hypoglycemia, hepatocellular damage, bleeding diathesis, jaundice, and bilateral cataracts (secondary to galactitol accumulation in the lens) within days of ingesting lactose from human milk or lactose-containing formula. The disease progresses rapidly, and if lactose is not removed from diet, it leads to liver failure, E. coli sepsis, and death. Symptoms and severity of GALE galactosemia type depend on whether the enzyme deficiency is confined to certain types of blood cells (peripheral) or is present in all tissues (generalized). Peripheral GALE deficiency is usually benign and asymptomatic whereas generalized GALE deficiency presents like and needs similar dietary intervention to classic galactosemia.
Galactosemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
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
Published in John H. McNeill, 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.
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).
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.
Metabolomics reveals the effect of valproic acid on MCF-7 and MDA-MB-231 cells
Published in Xenobiotica, 2020
Xingzhi Zhou, Zhen Li, Xuanyu Wang, Ge Jiang, Changliang Shan, Shuangping Liu
In this study, we examined the effects of VPA on metabolites in breast cancer cells and the potential relationship between differential metabolites to gain a deeper understanding of the mechanism of action of VPA. To evaluate the effect of metabolite changes on related metabolic pathways, and the effect of VPA on the metabolic pathway was further explored. We evaluated the stability and accuracy of the platform and the results were consistent with follow-up experimental requirements. We focused on analyzing the relationships between 63 differential metabolites (MCF-7 cells) and 61 differential metabolites (MDA-MB-231 cells) after VPA treatment (Figures 2 and 3). Most of the metabolites were down-regulated in response to VPA compared with control samples. This suggested that VPA may affect the metabolism of breast cancer cells through the down-regulation of certain metabolites or metabolic pathways. However, metabolites up-regulated by VPA had been shown to be associated with tumors. L-cystine, glutamine and terephthalic acid play an important role in inhibiting tumors growth (Chen et al., 2019; Cramer et al., 2017; Luciani-Torres et al., 2015). In addition, the modification products of up-regulated metabolites had also been shown to be involved in the suppression of cancer, such as furfural and galactitol (Jiang et al., 2017; Zhao et al., 2013). This reveals that metabolites were up-regulated by VPA may be one of its targets. It is worth noting that the association of 5-S-methyl-5-thioadenosine, N-acetyl-L-alanine and 2, 3, 4-trihydroxybutanoic acid with cancer remained unknown.