Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

Abstract

Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.

The Importance of Neonatal Screening for Galactosemia

“…However, this type of test lacks sensitivity and specificity, leading to false positive results in the case of fructosuria, lactosuria (caused by intestinal lactase deficiency), or conditions that affect the clearance of blood galactose, such as severe liver disease or antimicrobial therapy. On the other hand, if the infant is receiving intravenous nutrition, galactosuria may be absent, thus leading to false negative results [ 25 , 26 ].…”

Galactosemia a Disease that you Need to know

“…The main one of them, jaundice, is a frequent manifestation in newborns since about 2/3 present it; however, it is a transient situation called habitual or physiological jaundice [19]. The jaundice that occurs in cases of galactosemia has special characteristics, it can begin as an unconjugated hyperbilirubinemia that can reach very high levels [13], or can become a cholestasis with high levels of conjugated bilirubin, so with the presentation of jaundice in newborns, with indirect bilirubin pattern or with cholestasis pattern, galactosemia should be included within the possible etiologies [1,13,18]; in addition, there is alteration of liver function until early failure, sometimes with hyperammonemia [11]. The medical history (interrogation and physical examination) is essential to find difficulties in feeding, the presence of vomiting, failure to thrive, the finding of hepatomegaly and hypotonia; in the interrogation, the history of consanguinity between the parents or neonatal death without diagnosis is an important issue.…”

“…The latest enzyme galactose 4-epimerase (GALE) catalyzes the reversible conversion of UDP-Gal into UDP-Glc having as cofactor NAD + . Galactosemia may be due to deficiency of any of the 4 enzymes [1]. In galactosemia, galactose accumulates in the cells and alternate metabolic pathways are activated causing the accumulation of toxic metabolites such as galactitol and galactonate that cause tissue damage [2].…”

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

“…Recently, genome wide association studies conducted in Argentina [ 139 ] identified 14 different mutations among 72 unrelated alleles and similar studies conducted in Sweden [ 140 ], Greece [ 141 ], Korea [ 142 ], Turkey [ 143 ], Lithuania [ 144 ] and India [ 145 ] have reported mutations that are confined to specific regions and populations. Current approaches for the treatment of galactosemia include neonatal screening [ 146 ] followed by dietary management via the reduction or substitution of galactose and lactose; however, long-term therapy required additional interventions such as molecular chaperones to correct the misfolded [ 147 ] GALT enzyme [ 148 ] and the reliance on animal models to characterize the genetic association between GALT mutations and galactosemia [ 149 ]. Replacement of the GALT gene in the murine model [ 150 ] has shown promise, and the recombinant adeno-associated virus-mediated gene therapy [ 151 ] has proven to be effective in human cell lines.…”