Galactosemia Disorder: Causes, Forms and Treatments


Carbohydrates are vital for energy in all living organism and also in the biosynthesis of essential glycoconjugates. One of these carbohydrates is a monosaccharide called galactose which is broken-down in humans by the Leloir pathway of the galactose metabolism.[1] Within this pathway, there are three main enzymes that is responsible for modifying galactose in order to convert it into glycolysis for the production of energy – galactokinase (GALK1), galactose-1-phosohate uridyl transferase (GALT), and galactose-6-phosphate epimerase (GALE). A deficiency in any of these enzymes results in a disorder in the human called galactosemia. The second enzyme of this pathway, GALT which produces uridine diphosphogalactose (UPD-gal) from galactose-1-phosphate (gal-1P), a deficiency in this is the most severe of the three galactosemia disorders. GALK1 is rare and the symptoms are much milder than that of GALT with the rarest of the disorder being GALE. Galactosemia is established shortly after an infant starts feeding and even though a strict galactose-free diet is introduced promptly eliminating any acute symptoms, the long-term complications unfortunately has already taken place. While early detection can lead to relatively normal life, this inherited disorder is unable to break down simple sugar called galactose and with excessive buildup causes liver, brain, and eye damages.

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All living organism make use of carbohydrates or sugars for the formation of cellular energy along with the synthesis of essential cellular glycoconjugates. In humans, we not only consume carbohydrates but we’re also able to synthesize altered carbohydrate monomers by means of reversible metabolic pathways. Galactose is typically in many of our dairy products that we consume as a carbohydrate monomer which is part of the disaccharide lactose. The human body is able to break down galactose using the Leloir pathway of galactose metabolism. This pathway consists of three enzymes, each structuring a different metabolic intermediate functioning together to accomplish one objective and that is to modify galactose into glucose in order to release it into glycolysis for the production of energy. The three enzymes are, Galactokinase (GALK1), galactose-1-phosohate uridyl transferase (GALT), and galactose-4-phosphate epimerase (GALE). An absence or mutations in any of these enzymes results in a disorder in the human called galactosemia. The second enzyme of this pathway, GALT which produces uridine diphosphogalactose (UPD-gal) from galactose-1-phosphate (gal-1P), a deficiency in this enzyme is the most severe of the three galactosemia disorders. GALK1 is rare and the symptoms are much milder than that of GALT causing cataracts of the eye with the rarest of the disorder being GALE with acute symptoms as in GALT. UDP-gal in the Leloir’s pathway plays crucial role in synthesizing several essential glycoconjugates along with ultimately being used for energy production. GALT deficiency in humans’ results in a disorder called galactosemia, a potentially fatal disorder if left untreated immediately after birth.

Galactose Metabolism (Leloir Pathway):

Figure 1. Galactose Metabolism (Leloir Pathway) in the Liver.

The galactose metabolic pathway, also known as Leloir pathway named after Luis Federico Leloir who revealed the principal mechanisms of galactose metabolism and defining the cause of galactosemia.[2] This is the only mechanism of galactose metabolism in humans which contains three enzymes, galactokinase (GALK1), galactose-1-phosphate uridyl transferase (GALT), and galactose-4-phosphate epimerase (GALE) which are responsible for their respective role in the Leloir pathway.[3]

Upon entrance of the cell, galactose is first phosphorylated by GALK to yield galactose-1-phosphate, which is one of the two substrates of GALT. From here, GALT modifies it further to one uridine diphosphogalactose and one glucose-1-phosphate from one uridine diphosphoglucose and one galactose-1-phosphate. The expected product of GALT, UDP-gal, is the substance of GALE. As GALE epimerizes UDP-gal to produce UDP-glu, which is modified furthermore to enter glycolysis or be used as UDP-glu to synthesize necessary glycoconjugates in the cell.[4] [5] Further modification of UDP-glu consist of the loss of uridine monophosphate in order to produce glucose-1-phosphate. The mutase enzyme then yields glucose-6-phosphate, a glycolytic intermediate that moves into glycolysis to harvest energy in the form of ATP.[6] Since galactose is an essential component of many glycoconjugates, some UDP-gal is used for the synthesis of these sugar moieties which highlights the significance of GALT in the metabolism and cellular consumption of galactose.[7]


Galactosemia is an autosomal recessive inborn error in the metabolism which affects how the body breakdown the sugar galactose with a rate of about 1 in 62,000 individuals.[8] As a result, those individuals with galactosemia has difficulty digesting this simple sugar that are often found in many foods which is primarily part of a larger sugar called lactose. Lactose produces one molecule each of the simple sugar glucose and galactose which is nearly found in all dairy products and baby formulas.[9] The disorder is typically diagnosed soon after birth, as infants are either breast-fed or formula-fed. However these newborn starts to express characteristic complications that tend to develop after the consumption of milk over a short period of time like nausea, vomiting, jaundice, and lethargy.[10] The accumulation of galactose is toxic to the body if not digested by the appropriate enzyme quickly causes serious health complications to the newborn. Treatments currently involves management of galactose-free diet, although some drug tests in the disorder process have been proposed.

Laboratory tests are available to confirm of the disease by measuring the enzyme activity of galactose-1-phosphate uridyl transferase or GALT which is the second step in the pathway of galactose metabolism.[11] There are 3 forms of this disorder: galactose-1-phosphate uridyl transferase (GALT), galactose kinase (GALK1), and galactose-4-phosphate epimerase (GALE) with each form having a relative differences in severity. Those individuals who expresses any of these disorders will have elevated levels of galactose in their blood along with high levels of galactose in the urine. For this reason, hospitals now carry out galactose tolerance tests which are now considered essential for the identification of the disease.

Once confirmation of this disorder has been done, the newborn is treated using a dietary galactose restriction by replacing breast or milk base-formula with soy base-formula. Although most of the prominent features of this disease will improve such as nausea, diarrhea, cataracts, or enlarged liver and spleen will gradually regress once placed on the dietary restriction there is one chief symptom which does not show much improvement which is mental retardation due to the damage of the central nervous system.[12] It’s for this reason, that early diagnosis and prompt therapy are crucial.

Cause of Disorder:

Galactosemia means “galactose in the blood”, since these individuals are not able to break down galactose to produce energy, this sugar therefore builds up in their blood resulting in high levels of galactose-1-phosphate in the tissues. The pathway for galactose is more complex than most other simple sugars with three enzymes that are essential to convert a molecule of galactose into glucose-6-phosphate. Therefore, any type of genetic mutations in any part of the galactose pathway will cause severe life altering changes effecting organs and intellectual capacity if not treated right away.

We can see from Fig. 1 that there are multiple steps in the breakdown of galactose into glucose-1-phosphate and be able to enter into glycolysis where it is broken down into glucose our main energy source. The GALK1 is the first enzyme in the galactose pathway and from this figure we can clearly see how by a mutation in GALK1 could cause so much chaos in the breakdown of galactose. The ability for our bodies to breakdown galactose into glucose plays a crucial for life. As a result, individuals with galactosemia, the GALT enzyme is either missing or not working properly and therefore unable to digest galactose into glucose causing large buildups in the blood. Overtime, this buildup if remain untreated will develop into fatality and although certain damages are able to regress a few of the many will not be irreversible.

Forms of Disorder:

There are several forms of galactosemia which are caused by mutations of a specific gene affecting different enzymes that are involved in the process of breaking down galactose. The classic galactosemia or galactose-1-phosphate uridyl transferase (GALT) is also known as galactosemia type I, is the most common and severe form of this disorder. Classical galactosemia affects 1 out of 60,000 newborns.

In the classic galactosemia, infants are born without the GALT enzyme and are either fed breast-milk or milk-base formulas. In newborns nearly 90% of their carbohydrates comes from lactose, human breast milk comprises of nearly 6% to 8% lactose and most infant formulas comprises of 7% lactose.[13] Therefore all these milk-based products are immediately substituted with lactose free formulas such as soy-based formulas to lessen any further damage to the newborn. Fortunately, most cases of classic galactosemia are detected early enough by newborn screenings and a galactose-free diet is quickly put in place.

Within galactosemia type I, there is a rare type of galactosemia called “Duarte variant”, it is often but not always detected during newborn screening since this is a milder form requiring less treatment or in most cases, no treatment but an erythrocyte GALT enzyme activity test may be performed to confirm this variant form of the disease.

Galactokinase deficiency (GALK1) is also known as galactosemia type II which is rare genetic causing cataract damage due to a lack of galactokinase.[14] Galactosemia type II affects fewer than 1 out of 100,000 newborns. GALK1, is responsible for one step in the galactose metabolic pathway that converts galactose to galactose-1-phosphate which is then converted to glucose. A mutation in this gene results in galactose and an associated sugar called galactitol to buildup in the cells that constructs the lens of the eye.[15] With high level of these accumulations in the blood will damage the lens which will cause cataract and lead to blurred vision – a characteristic in galactosemia type II.

Galactose-4-phosphate epimerase deficiency (GALE) is also known as galactosemia type III and the rarest of the three forms of galactosemia. Those who have this may have mild to severe symptoms which may include cataracts, delayed growth and development, along with liver disease, and liver problems. There has not been many reported with the GALE mutations as this is the fewest of the galactosemia disorders.

GALE, is an enzyme that instructs the production of an enzyme called UPD-galactose-4-epimerase and responsible for converting UDP-galactose to UDP-glucose. Since GALE is the rarest of the disorder, those affected with galactosemia type III may or may not have any of the complications characteristically related to galactosemia and often do not require treatment. In general, those who have this disorder whose had high level of these enzymes in the blood will still lead to complications such as damaged tissues or organs, cataract, to intellectual disabilities and damages to the liver, kidneys and brain.[16]

Newborn Screening:

With the high rate of associated with untreated individuals, newborn screening for galactosemia and other inherited genetic disorders are available in all of the 50 states and provinces of the United States. To screen for galactosemia, infant blood and urine samples are screened for the presence of GALT and any galactose metabolites.[17] The samples are first tested for the concentration of galactose and GALT activity, and if galactose levels are high and/or GALT activity is low, then the samples are then assayed for galactose-1-phosphate and further tested of the more common DNA mutations associated with galactosemia.[18] . GALT enzyme presence of less than 32 µmol/L (normal 150-500 µmol/L) is usually indicative of GALT-deficient galactosemia.[19]

Newborn screening is essential in early detection and treatment of galactosemia patients efficiently. It is vital to their physical and mental health to avoid as much damage to the individual as possible. Studies has shown that approximately 80% of children given newborn screening for galactosemia were diagnosed within 2 weeks of age, compared to approximately 35% of whom were not screened. From those whom were screened 20% were free of GALT deficiency symptoms at the time of diagnosis.[20]

Although nutritional therapy is frequently used which gradually improves the symptoms in patients with galactosemia disorders by introducing these individuals to a galactose-free diet.[21] In most cases, as long as the disease has not advanced too much, most of all acute symptoms gradually regress and often times completely disappear with dietary restriction alone. Many newborns will show rapid weight gain along with no more nauseating or vomiting. The organs like the liver and spleen that would be enlarged due to excess galactose in the body also returns to normal size along with cataracts, if present, will start to regress and most of the time will disappear completely.[22] Unfortunately, there is one significant symptom that shows no signs of improvement – mental retardation or intellectual disability like speech defects and other neurological or physiological abnormalities.[23] Since newborn screening is not performed until at least 24 hours after an infant has begun feeding, galactosemia infants will consume galactose before being diagnosis. A more efficient and timely screening methods are necessary to decrease the cases of infants who are already exhibiting disease symptoms at the time of diagnosis.


The most common and most effective form of treatment so far for galactosemia is dietary restriction of galactose consumption. By having galactosemia patient avoid lactose or ingesting food containing galactose they are able to minimize any further damage to their body. For infants, it’s particularly imperative as lactose is present in all milk-base products and studies has now shown that there are some free-galactose in some fruits and vegetables. A study by Gross and Acosta in 1991 indicated monomeric galactose contents in approximately 45 different fruits and vegetables. For example, artichoke, mushrooms, olives, and peanuts all contained less than 0.1 mg of free galactose per 100 mg of plant tissue. In persimmon and tomato contained approximately 34.5 mg of free galactose per 100 g of plant tissue. Fruits and vegetables like dates, papaya, bell pepper, and watermelon were found to have upwards of 10 mg of free galactose per 100 g of plant tissues.[24]


Although uncommon due to the effective newborn screening, undiagnosed galactosemia can lead to liver cirrhosis, mental retardation, and even death. [25] Girls with galactosemia have been found in later years to have higher rates of ovarian failure even with dietary intake. It’s important to understand that with acute symptoms at birth can managed with diet but the long-term affect involving impaired sexual and mental function are still prevalent among galactosemia individuals.


Antshel, K. M., Epstein, I. O., & Waisbren, S. E. (2004). Cognitive strengths and weaknesses in children and adolescents homozygous for the galactosemia Q188R mutation: a descriptive study. Neuropsychology, 18(4), 658-664.

Hardin, J., Bertoni, G., Kleinsmith, L.J., (2012) Becker’s World of the Cell, 8th Ed, International Edition. Pearson Education, Inc. Glenview. pp. 242

Isselbacher, K.J. (1957), Clinical and Biochemical Observations in Galactosemia. The American Journal of Clinical Nutrition. Vol. 5, No. 5, pp. 527-532.

Grossiord, B. P., Luesink, E. J., Vaughan, E. E., Arnaud, A., & de Vos, W. M. (2003).

Characterization, Expression, and Mutation of the Lactococcus lactis galPMKTE Genes, Involved in Galactose Utilization via the Leloir Pathway. Journal of Bacteriology. Vol. 185, No. 3, pp. 870-878.

Kalckar, H. M., Kurahashi, K., & Jordan, E. (1959). “Hereditary Defects in Galactose

Metabolism in Escherichia Coli Mutants, I. Determination of Enzyme Activities”. Proceedings of the National Academy of Sciences of the United States of America, Vol. 45, No. 12, pp. 1776-1786.

Asada, M., Okano, Y., Imamura, T., Suyama, I., Hase, Y., Isshiki, G., (1999). Molecular characterization of galactokinase deficiency in Japanese patients. Journal of Human Genetics. Vol. 44: 377-382.

Lai, K., Langley, S. D., Khwaja, F. W., Schmitt, E. W., & Elsas, L. J. (2003). GALT Deficiency Causes UDP-Hexose Deficit in Human Galactosemic Cells. Glycobiology. Vol. 13, No. 4, pp. 285-294.

Berry, G.T., Classic Galactosemia and Clinical Variant Galactosemia. 2000 Feb 4 [Updated 2014 Apr 3]. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Ai, Y., Zheng, Z., O’Brien-Jenkins, A., Bernard, D.J., Wynshaw-Boris, T., Ning, C., Reynolds, R., Segal, S., Huang, K., and Dwight Stambolian. (2000), A Mouse Model of Galactose-Induced Cataracts. Human Molecular Genetics. Vol. 9, No. 12, pp. 1821-1827.

Fridovich-Keil, J.,Bean, L., He, M., andRichard Schroer., Epimerase Deficiency Galactosemia. 2011 Jan 25 [Updated 2013 Oct 24]. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Freer, D. E., Ficicioglu, C., & Finegold, D. (2010). Newborn Screening for Galactosemia: A Review of 5 Years of Data and Audit of a Revised Reporting Approach. Clinical Chemistry, Vol. 56, No. 3, pp. 437-444.

Waggoner, D. D., Buist, N. R., & Donnell, G. N. (1990). Long-term Prognosis in Galactosaemia: Results of a Survey of 350 Cases. Journal of Inherited Metabolism Disorder., Vol. 13, No. 6, pp.802-818.

Gross, K. C., & Acosta, P. B. (1991). Fruits and Vegetables are a Source of Galactose: Implications in Planning the Diets of Patients with Galactosemia. Journal of Inherited Metabolism Disorder, Vol. 14, No.2 253-258.

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