Galactosemia results from an impaired ability to metabolize galactose.
Humans encounter the monosaccharide galactose from both dietary and endogenous sources. The predominant source of dietary galactose, especially for infants, is the disaccharide lactose, which is abundant in milk and milk products. Lactose is hydrolyzed to its constituent monosaccharides, glucose and galactose, prior to absorption from the intestine. Galactose is also found at significant levels in some nondairy foods.
"Free" dietary galactose may exist in either the alpha or beta conformation. "Bound" dietary galactose is released in the beta conformation from the breakdown of lactose, complex sugars, or glycoconjugates.
Once absorbed, dietary galactose may be converted into glucose-1-phosphate (Glc-1-P), as described below, and metabolized to release energy. Alternatively, galactose may be converted into UDP-galactose (UDP-Gal) and its derivatives, which serve as key substrate donors for the biosynthesis of glycoproteins and glycolipids.
The conversion of β-D-galactose to Glc-1-P is a four-step process that has been conserved from bacteria to mammals. In the first step, galactose mutarotase (EC 18.104.22.168) catalyzes the conversion of β-D-galactose to α-D-galactose. In the second step, galactokinase (GALK, EC 22.214.171.124) phosphorylates α-D-galactose to produce galactose-1-phosphate (Gal-1-P). In the third step, galactose-1-phosphate uridylyltransferase (GALT, EC 126.96.36.199) transfers a UMP group from UDP-glucose (UDP-Glc) to Gal-1-P, releasing Glc-1-P and producing UDP-Gal. In the final step, uridine diphosphate galactose 4′-epimerase (GALE, EC 188.8.131.52) epimerizes the 4′ carbon of UDP-Gal to form UDP-Glc. There are autosomal recessive genetic diseases resulting from impairment of each of the GALK, GALT, and GALE enzymes.
The biochemical consequences of impaired galactose metabolism are abnormally high concentrations of galactose and its derivative metabolites in body tissues and fluids. Abnormal glycosylation of glycoproteins and/or glycolipids also may occur. The severity of clinical features spans a broad range, with outcome a function of which enzyme is impaired, the degree of functional impairment, and environmental or other factors, many of which remain poorly understood.
The gene encoding human galactokinase (Reference Assembly NC_000017.9) maps to chromosome 17p24; it consists of 8 exons spanning about 7.3 kb of genomic DNA and shows many of the features of a housekeeping gene. At least 25 different mutations have now been identified in the GALK loci of galactokinase-deficient patients. The human enzyme includes 392 amino acids with a subunit molecular mass of 42 kDa; structural coordinates as determined by x-ray crystallography are publicly available (1WUU; Protein Data Bank).
Profound galactokinase deficiency occurs with a frequency of fewer than 1 in 100,000 live births. A hallmark of galactokinase deficiency is cataracts that are usually bilateral and detectable in the early weeks of life. Pseudotumor cerebri, or elevated intracranial pressure, also has been described in several cases of galactokinase deficiency. The clinical symptoms of galactokinase deficiency generally will self-resolve on dietary restriction of galactose.
The gene encoding human galactose-1-phosphate uridylyltransferase (Reference Assembly NC_000009.10) maps to chromosome 9p13 and includes 11 exons that span about 4 kb of genomic DNA. The cDNA is approximately 1.3 kb in length and encodes a polypeptide of 379 amino acids with an estimated subunit molecular mass of 44 kDa. The active enzyme is a homodimer of molecular mass 88 kDa. Structures have been solved for the Escherichia coli enzyme by high-resolution x-ray crystallography and are publicly available (1GUP and 1GUQ, Protein Data Bank). More than 200 different mutations have now been identified in the GALT loci of patients, although the functional significance of most mutations remains unconfirmed. A few of these mutations are common, although most are rare. Of those mutations that have been characterized in vitro or through whole-body galactose oxidation studies of homozygotes, it is clear that some are true nulls, whereas others are hypomorphs.
Profound GALT deficiency, termed classic galactosemia, occurs with a frequency of approximately 1 in 30,000 to 1 in 60,000 live births, although this frequency varies over a wide range between among geographic populations. Acute symptoms of classic galactosemia generally appear in the first weeks of life and include poor feeding and weight loss, vomiting, diarrhea, lethargy, and hypotonia; liver dysfunction, bleeding tendencies, cataracts, and septicemia also may occur. These symptoms generally will self-resolve on stringent dietary restriction of galactose and may be prevented altogether by presymptomatic diagnosis via newborn screening. Unfortunately, many affected individuals go on to suffer serious long-term cognitive, female reproductive, and/or neurologic complications despite early detection and careful intervention. Whether the long-term complications observed result from subtle developmental abnormalities initiated in utero, chronic exposure to endogenously produced galactose, or other factors remains unknown.
The gene encoding human uridine diphosphate galactose 4′-epimerase (GALE, Reference Assembly NG_007068.1) maps to chromosome 1p36. The gene includes 12 exons that span about 4 kb of genomic DNA. The cDNA is approximately 1.5 kb in length and encodes a polypeptide of 348 amino acids; the predicted subunit molecular mass is 38 kDa. The active enzyme is a homodimer. At least 20 distinct mutations have now been reported in the GALE loci of affected individuals. Structures of the human epimerase enzyme have been solved by high-resolution x-ray crystallography and are available in the Protein Data Bank (1ek5, 1ek6).
The population frequency of GALE deficiency remains unknown, largely owing to variable expressivity and inconsistent newborn screening protocols, many of which are inadequate for identifying patients with GALE deficiency. The majority of patients described with GALE deficiency appear to have an enzyme defect restricted to their erythrocytes and circulating white blood cells; these patients are said to have peripheral epimerase deficiency and are believed to be asymptomatic. A generalized, severe form of GALE deficiency with a clinical presentation similar to classic galactosemia also has been described; this condition is extremely rare. Finally, recent data demonstrate that even clinically well infants diagnosed with hemolysate GALE deficiency may not be entirely peripheral in their enzyme impairment; these individuals are said to have an intermediate form of GALE deficiency. The clinical significance of intermediate GALE deficiency remains unclear.