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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
GALT deficiency can present as: Classic galactosemia (CG) where enzyme activity is absent or barely detectable due to pathogenic mutations on both allelesClinical variant galactosemia where enzyme activity is close to or above 1% of control values but probably never >10%–15% with pathogenic mutation on one or both allelesDuarte galactosemia resulting in residual enzyme activity of 14%–25% due to one pathogenic classical mutation that severely impairs GALT activity and another mutation that is partially impaired
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 gene has been assigned to the short arm of chromosome 9, at 9p13 [12]. In classic galactosemia, the classic mutation is a nucleotide change which leads to a p.Q188R change in the enzyme [13]. In patients with Duarte variant detected by newborn screening but not manifesting clinical illness, the mutation is expressed as p.N314D [13].
Metabolic Disorders II
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Galactosemia is a disorder of galactose metabolism that can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and sepsis in untreated infants. Galactose metabolism is important for energy production, glycogen stores, and galactosylation of glycolipids and glycoproteins. This chapter will focus on classic galactosemia (OMIM 230400), a potentially lethal inherited disorder caused by the deficiency of galactose-1-phosphate-uridyltransferase (GALT). Despite adequate treatment with a lactose/galactose restricted diet, children with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function.
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.
Repurposing drugs for the treatment of galactosemia
Published in Expert Opinion on Orphan Drugs, 2019
Galactosemia is a term which describes four diseases resulting from mutations in the genes encoding enzymes of galactose metabolism [1,2]. The Leloir pathway facilitates the conversion of galactose to the glycolytic intermediate glucose 6-phosphate (Figure 1) [3]. It is also important in the synthesis of UDP-sugars, which are important precursors for the synthesis of glycolipids and glycoproteins. The disaccharide lactose is a significant source of galactose in the diets of babies and Caucasian adults. This disaccharide, which occurs in milk, is hydrolyzed releasing d-glucose and β-d-galactose. In aqueous solution, the two anomers of d-galactose (α-d-galactose and β-d-galactose) interconvert at an appreciable rate [4]. However, this rate is not enough to supply the Leloir pathway whose first enzyme, galactokinase (GALK1; EC 2.7.1.6), only recognizes the α-anomer of d-galactose. Galactose mutarotase (aldose 1-epimerase, GALM; EC 5.1.3.3) catalyses the interconversion of the d-galactose anomers [5,6]. Mutations in the GALM gene can result in the most recently discovered form of the disease, Type IV galactosemia, which appears to behave more like a complex genetic disorder than a simple, Mendelian disease [7,8]. The Leloir pathway is generally considered to begin with the phosphorylation of α-d-galactose at the expense of ATP in a reaction catalyzed by galactokinase [9,10]. Type II galactosemia (OMIM #230200) is caused by mutations in the GALK1 gene [11,12]. The product of this reaction α-d-galactose 1-phosphate participates in an exchange reaction with UDP-glucose, generating α-d-glucose 1-phosphate and UDP-galactose. This reaction is catalyzed by galactose 1-phosphate uridylyltranferase (GALT; EC 2.7.7.10) and mutations in the corresponding gene are associated with type I galactosemia (or classic galactosemia; OMIM #230400) [13–15]. UDP-glucose is regenerated in an isomerization reaction catalyzed by UDP-galactose 4ʹ-epimerase (GALE; EC 5.1.3.2). This enzyme can also catalyze the epimerisation of the N-acetyl derivatives of d-glucose and d-galactose [16]. Type III galactosemia (OMIM #230350) is caused by mutations in the GALE gene [17,18]. The production of α-d-glucose 1-phosphate is generally considered to complete the Leloir pathway. However, one final reaction is required before the carbon atoms in the original galactose molecule can enter glycolysis: α-d-glucose 1-phosphate is isomerized to d-glucose 6-phosphate in a reaction catalyzed by phosphoglucomutase (PGM; EC 5.4.2.2) [19]. To date, no form of galactosemia has been associated with this enzyme. However, congenital disorder of glycosylation, type It (OMIM #614921) is associated with PGM1 deficiency. The glycosylation disorders have some similarity with those seen in galactosemia types I and III [20].