Disease relevance of Galactosemias

• Brain edema may occur in infants with galactosemia and has been associated with accumulation of galactitol [1].
• Retinal microvessels, the main site of lesions in diabetic retinopathy, likewise showed elevated activity of PKC and inhibition of ATPases in diabetes and in experimental galactosemia, and administration of LY333531 to diabetic animals prevented these abnormalities [2].
• An oral dose of galactose, 1 g/kg of body weight, was administered to 24 children with the Duarte variant/classical galactosemia genetic compound (GtD/gt) and to 16 controls ranging in age from 0.3 to 10.7 years [3].
• Neither infant had evidence of congenital infection, galactosemia, alpha 1-antitrypsin deficiency, tyrosinemia, Zellweger syndrome, or hemophagocytic lymphohistiocytosis [4].
• They are commonly used in infants with immunoglobulin E-mediated cow's milk allergy (at least 86% effective), lactose intolerance, galactosemia, and as a vegetarian human milk substitute [5].

High impact information on Galactosemias

• Hypergonadotropic hypogonadism in female patients with galactosemia [6].
• Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor [7].
• Prenatal exposure to galactose or its metabolites may contribute to the premature ovarian failure characteristic of human galactosemia [8].
• This metabolic alteration, occurring in response to galactose exposure, may be related to the pathophysiology of classical galactosemia [9].
• Galactosemia: alterations in sulfate metabolism secondary to galactose-1-phosphate uridyltransferase deficiency [9].

Chemical compound and disease context of Galactosemias

• Dulcitol similarly accumulates in the presence of galactosemia [10].
• Epimerase-deficiency galactosemia results from the impairment of UDP-galactose 4'-epimerase (GALE), the third enzyme in the Leloir pathway of galactose metabolism [11].
• The arginine 188 mutation is the most common galactosemia mutation characterized to date [12].
• The requirement of oxygen for pentosidine formation suggests that oxidative stress associated with glutathione depletion and ascorbate oxidation are plausible mechanisms for rapid pentosidine formation upon onset of galactosemia [13].
• Actual pentosidine levels increased shortly after onset of galactosemia [13].
• Four weeks later, this patient was switched to a galactose-free formula (as recommended in citrin deficiency with galactosemia) and her pathological status returned to normal [14].

Biological context of Galactosemias

• An outstanding question relates to the response of AR gene expression to diet-induced galactosemia in extrarenal tissues [15].
• We conclude that the codon change N314D in cis with the base-pair transition 1721C-->T produces the LA variant of galactosemia and that this nucleotide change increases GALT activity by increasing GALT protein abundance without increasing transcription or decreasing thermal lability [16].
• Thus, it appears that extracellular matrix changes in chronic galactosemia are complex, being partly attributable to advanced glycosylation and partly to polyol-pathway activation [17].
• The structure of galactokinase described here serves as a model for understanding the functional consequences of point mutations known to result in Type II galactosemia in humans [18].
• To study the molecular genetics of classical and Duarte galactosemia, we analyzed the GALT mutations in 30 families with classical galactosemia, in 10 families with the D-2 variant and in 3 individuals carrying the D-1 allele by denaturing gradient gel electrophoresis (DGGE) [19].

Anatomical context of Galactosemias

• Erythrocyte (RBC) galactokinase (GALK) and galactose-1-phosphate uridylyl-transferase (GALT) activities were measured in a random sample of 1,700 (1.082 black and 618 white) pregnant women from the Philadelphia area to estimate the frequency of the genes GALKG and GALTG responsible for the two biochemically distinct forms of galactosemia [20].
• The isogenic liver cell lines described here can also serve as model systems for studying galactosemias, which are inherited disorders of galactose metabolism in humans [21].
• To determine whether the elimination of galactosemia can also reduce the progression of retinal lesions, the galactose diet was removed from the galactosemic dogs after either the appearance of pericyte ghosts or formation of microaneurysms [22].
• We review various causes for galactosemia and point out that transfer of galactose through the cell wall and into the erythrocyte is markedly reduced in certain cats and, although unreported, may possibly be a cause for galactosemia in humans [23].
• This stable isotope dilution assay is a rapid accurate method for measurement of galactitol in amniotic fluid for prenatal diagnosis of galactosemia [24].

Gene context of Galactosemias

• Galactosemia is an autosomal recessive disorder of human galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT) [12].
• Finally, the structure has enabled us to further our understanding on the functional consequences of mutations in human GalK which cause galactosemia [25].
• Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia [26].
• Approximately 20 mutations have now been identified in human galactokinase, which result in the diseased state referred to as Type II galactosemia [27].
• Impairment of the human enzyme galactose-1-phosphate uridylyltransferase (hGALT) results in the potentially lethal disorder classic galactosemia [28].

Analytical, diagnostic and therapeutic context of Galactosemias

• Neonatal screening for galactosemia by quantitative analysis of hexose monophosphates using tandem mass spectrometry: a retrospective study [29].
• In July 1983, the Manitoba Perinatal Screening Programme modified its existing procedure for neonatal screening for galactosemia by introducing quantitation of total galactose plus galactose-1-phosphate from dried blood spots using the Multistat centrifugal analyzer [30].
• This method of galactosemia screening has proven to be rapid, sensitive, efficient, and the method of choice for mass screening of disorders of galactose metabolism [30].
• Newborn galactosemia screening programs using the fluorescence spot test to detect red cell galactose-1-phosphate uridyltransferase activity are prone to inaccuracy if the screened infants have received blood transfusions [31].
• Molecular cloning and characterization of all three human galactose-metabolic genes have led to the identification of a number of mutations which result in three forms of galactosemia which are caused by kinase (GALK), transferase (GALT), or epimerase (GALE) deficiency [32].

References