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Definition: galactosaemia from Dictionary of Psychological Testing, Assessment and Treatment

Genetic disorder characterized by a failure to metabolize galactose (a sugar found in milk). Failure to treat the condition results in severe intellectual dysfunction, but early intervention (principally, adopting a rigidly lactose-free diet) should avoid this.

Summary Article: Nutrition and Health | Galactosemia from Encyclopedia of Dairy Sciences

Galactosemia is a rare autosomal recessive disorder due to a deficiency of galactose-1-P:uridyl transferase (GALT) (classical galactosemia), galactokinase (GALK), or UDP-galactose-4 epimerase (GALE). Of the three, GALT deficiency is the most severe and results in the accumulation of galactose-1-P in tissues, which damages the liver, eye, brain, ovary, and kidney. In GALK deficiency, ingested galactose may be converted into galactitol, which can cause cataract. Most patients with GALE deficiency have no clinical symptoms, but a minority have symptoms similar to classical galactosemia.

Significant advances have been made in recent years in understanding the genetics of galactosemia. However, clinical galactosemia is a complex trait and the phenotypic expression is often not predictable. Except for cataract, the pathophysiology of galactosemia is poorly understood. Despite the concept that there may be continuous endogenous production of galactose in affected individuals, the treatment remains a diet as devoid of galactose as possible, within the confines of adequate nutrition for normal growth and development. However, it is now recognized that this does not prevent long-term complications and there is a need for new approaches to treatment, in combination with diet therapy, that could improve the outcome of patients with galactosemia.


Galactose is an energy-providing nutrient and also a necessary basic substrate for the biosynthesis of many macromolecules in the body. Galactose is an important constituent of the complex polysaccharides, which are part of cell glycoconjugates, key elements of immunological determinants, hormones, cell membrane structures, endogenous lectins, and numerous other glycoproteins. In addition, galactose is incorporated into galactolipids, which are important structural elements of the central nervous system.

Metabolic pathways for galactose are important not only for the provision of these macromolecules but also to prevent the accumulation of galactose and galactose metabolites. Problems with galactose metabolism that result in galactosemia can cause a variety of clinical manifestations in humans.

Dietary Sources of Galactose

The principal dietary sources of galactose are milk and milk products, in which it occurs mainly as a component of lactose. Galactose can also be derived from lactose used as an extender in drugs.

Small amounts of galactose are present in cereals, fruits, legumes, nuts, organ meats, seeds, and vegetables in either the free form or bound in various glycosidic linkages and as a component of lipids. Considerable amounts of free galactose occur in some legumes (dried beans and peas), and bound galactose, in various glycosidic linkages, such as α-1,6, β-1,3, and β-1,4, and as a component of lipids, is ubiquitous in animals and plants. The bioavailability of these bound forms of galactose is unknown. Foods fermented by microorganisms for preparation or preservation purposes may contain free galactose.

Galactose Metabolism in Humans

Galactose is released (together with glucose) from lactose in the small intestine by the action of β-galactosidase (lactase) and both monosaccharides are absorbed by an active transport mechanism across the gut wall into the blood. The brush border of the human small intestine contains a sodium-dependent carrier, which is shared by glucose and galactose, and interaction between the carrier and a localized sodium pump allows the monosaccharides to be actively concentrated within the cell.

Hydrolysis of lactose by lactase is believed not to limit the rate of galactose absorption in lactose-tolerant humans. However, the absorption of both galactose and glucose is slower when ingested as lactose than when ingested as a mixture of monosaccharides. It is not clear why this should be so. In lactose-intolerant subjects, the absorption of galactose and glucose is much slower when ingested as lactose than when ingested as hydrolyzed lactose because lactose hydrolysis by intestinal lactase is rate-limiting.

The main route of metabolism of absorbed galactose is the Leloir pathway (Figure 1), which involves four enzymes and results in the overall conversion of galactose to glucose-1-phosphate. This metabolic pathway is critical for cellular energy production, modification of cellular macromolecules, for example, glycoproteins and glycolipids, and normal human development. UDP galactose is an important donor of galactose via galactosyl transferase reactions to form glycoproteins and glycolipids.

Figure 1 The Leloir pathway for galactose metabolism. 1, Galactokinase; 2, galactose-1-P:uridyl transferase; 3, UDP-galactose-4 epimerase; 4, UDP-glucose-pyrophosphorylase.

The liver is the primary site of the Leloir pathway but this pathway is also present in other tissues, including the kidney and erythrocytes. The congenital absence or inactivity of any of the first three enzymes of this pathway results in the clinical condition galactosemia.

There are three minor pathways for galactose metabolism in humans. The Isselbacher pathway involves conversion of galactose-1-P to UDP-galactose by the enzyme UDP-galactose pyrophosphorylase.

Reduction of galactose to the sugar alcohol galactitol is catalyzed by aldose reductase; this reaction is important in the development of cataracts in people suffering from galactosemia. Human tissues have only a limited capacity for further metabolism of galactitol.

Dehydrogenation of galactose produces galactonic acid, which can be detected in the urine of both galactosemic and nongalactosemic subjects after a galactose load.

Molecular cloning and characterization of all three human galactose metabolic genes have led to the identification of a number of mutations that result in three forms of galactosemia, which are caused by deficiency of the kinase (galactokinase (GALK)), the transferase (galactose-1-P:uridyl transferase (GALT)), or the epimerase (UDP-galactose-4 epimerase (GALE)). Of these, GALT deficiency, referred to as ‘classical galactosemia’, is the most widely studied. All forms occur as inborn errors of galactose metabolism. Tolerance of galactose is reduced and the ingestion of galactose results in a chronically elevated blood galactose concentration with the subsequent accumulation and/or excretion of galactose and galactose metabolites. All conditions can be treated by means of a galactose-free diet.

Classical Galactosemia

Classical galactosemia is an autosomal recessive disorder due to a deficiency of GALT; ingested galactose can be phosphorylated to galactose-1-P but not metabolized further, and this results in the accumulation of galactose and galactose-1-P in tissues. GALT is immunologically intact although enzymatically defective; thus, a structural gene mutation is involved. At the cellular level, galactose-1-P interferes with the metabolism of glucose and the synthesis of glycoproteins and glycolipids and reduces the level of ATP in the cell.


The worldwide incidence of classical galactosemia is estimated at about 1:70 000. However, the incidence varies between countries – Norway, 1:96 000; Sweden, 1:81 000; Switzerland, 1:58 000; Germany, 1:40 000; United States, 1:62 000 – varying from 1:30 000 to 1:191 000 in different populations. In Japan and China, only a few cases have been detected, and in Japan, classical galactosemia is thought to be only one-twentieth as frequent as it is in Caucasian populations of the United States. A high incidence of 1 in 480 has been reported in the Traveller group (an endogamous group of commercial industrial nomads within the Irish population) in Ireland, compared to 1 in 30 000 among non-Traveller communities in Ireland.


Galactose-1-P accumulates in the newborn in various tissues when lactose or galactose is ingested. Galactosemic infants appear normal at birth but subsequent to milk ingestion they develop symptoms, including liver malfunction (hepatomegaly, jaundice), cataract, cerebral edema, mental retardation, renal damage, failure to thrive, and susceptibility to sepsis. Failure to thrive is the most common initial clinical symptom of galactosemia. Vomiting or diarrhea usually begins within a few days of milk ingestion. Jaundice of intrinsic liver disease may be accentuated by the severe hemolysis occurring in some patients. Cataracts have been observed within a few days of birth. There appears to be a high frequency of neonatal death due to Escherichia coli sepsis, with a fulminant course. Except for cataract (see later), the underlying pathophysiology of these effects is poorly understood.


Early introduction of a galactose-free diet restores normal growth and can prevent permanent liver damage and halt (or sometimes reverse) cataract development. However, mental retardation is irreversible if a galactose-free diet is not introduced within 2–3 months.

While a galactose-restricted diet free of lactose is lifesaving in patients with GALT deficiency, it is now recognized that this does not prevent long-term complications such as developmental delay, mental disability and neurological syndromes, speech defects, poor growth, and, in females, ovarian failure. Most subjects have cognitive impairment.

The cause of the unsatisfactory outcome of seemingly good control of galactose intake and the disturbances in long-term development despite treatment is unclear. Possibilities include chronic intoxication by galactose metabolites, deficiency of galactose-containing glycoproteins and/or glycolipids as a result of an overrestrictive galactose-free diet, or alteration in the glycosylation process of glycoproteins and glycolipids.

Well-treated galactosemics retain a low level of red cell galactose-1-P, which is nevertheless much higher than the almost undetectable levels in normal subjects, and which increases if the patient departs from the prescribed diet. It is unknown how the galactosemic individual maintains this base level of galactose-1-P, whether from hidden galactose in the diet or through galactose biosynthesis from glucose, or both.

Lactose, found in dairy products and as an extender in drugs, has been considered to be the primary source of galactose in the diet. However, small amounts of galactose are present in organ meats and many plant foods, including cereals, fruits, legumes, nuts, and seeds. The role of free and bound galactose in these foods in the poor outcome seen in some patients with GALT deficiency is unknown. However, since galactose is widespread in foods, it is unlikely that the lactose restriction for patients with GALT deficiency ensures a galactose-free diet.

It is also possible that endogenous production of galactose may contribute to the base level of galactose-1-P. There is evidence that galactosemic patients, as well as normal subjects, synthesize gram quantities of galactose per day and it has been suggested that this may be an important factor in the pathogenesis of the complications of the brain and ovary in treated galactosemics.

Ovarian Failure

It has been found that the mammalian ovary is particularly susceptible to damage from the accumulation of galactose and galactose metabolites. Gonadal dysfunction, specifically hypergonadotropic hypogonadism with ovarian atrophy, in female galactosemics is an almost universal symptom and because of this, pregnancy is rare in women with classical galactosemia. The consequences range from failure of pubertal development, through primary amenorrhea or premature menopause. In contrast, male galactosemics have a relatively low risk of gonadal dysfunction.

Several candidate toxic states may be involved, including the galactose metabolites galactose-1-P and galactitol, and proposed mechanisms include interference with ovarian apoptosis and gonadotropin signaling. It has also been suggested that this complication may be at least partly prenatal in origin and studies in animal models suggest that ovarian dysfunction may have been caused in utero. Current dietary restrictions of galactose are inadequate to prevent ovarian failure.


The mechanism by which cataract develops in subjects with galactosemia has been elucidated by studies in experimental rats. The primary cause of cataract is the chronic elevation of plasma galactose concentration resulting in a high concentration of galactose in the lens of the eye. Galactitol, formed in the lens from galactose by the action of aldose reductase, accumulates to high concentrations and this exerts a strong osmotic effect. Sugar alcohols do not diffuse readily through biological membranes, so the retention of galactitol within the lens leads to the imbibition of water to maintain osmotic equilibrium, which leads to lens fiber swelling, vacuole formation, and subsequent opacification. The process of sugar cataract formation in animals can be prevented by inhibiting aldose reductase. The development of galactose-induced cataract in galactosemic humans is thought to occur by the same mechanism as described for the rat.

Effects of Galactosemia in utero

There is direct evidence that in galactosemia due to GALT deficiency, galactose, galactose-1-P, and galactitol accumulate in the fetus by week 20 of gestation. However, the metabolic abnormality may develop earlier than this, since the key enzymes in galactose metabolism have been shown to be present in normal fetal liver from week 10 of gestation. There has been a report of increased galactitol in amniotic fluid obtained at week 10 of gestation, the outcome being that the baby is affected.

Cataract formation in the fetus is rare and is the only direct evidence that galactosemia may have harmful effects in utero. However, it has been concluded that the liver pathology seen in some infants who died in the neonatal period originated prenatally, and some studies have found that galactosemia is associated with reduced birth weight. Other observations, particularly those made from animal models, would suggest that ovarian dysfunction may have been caused in utero.

With regard to maternal galactose restriction, available biochemical evidence is insufficient to suggest any advantage to the fetus and galactitol accumulates in utero despite maternal galactose restriction.

Screening of Newborns

Methods for mass screening of newborns for galactosemia have been available since 1964. These are based mainly on measurements in blood of galactose, with or without galactose-1-P, and sometimes also including assay of GALT activity. Although galactosemia is rare, a number of countries (e.g., Germany, Switzerland, Canada, Norway, and some states in the United States) have included screening for galactosemia in their national screening programs, but many have not. Prenatal diagnosis for this disorder may be carried out by GALT assay in cultured amniotic fluid cells or in chorionic villus biopsies and by galactitol estimation in amniotic fluid supernatant.

One of the outcomes of screening programs has been the discovery of subjects with partial GALT deficiency who have mildly elevated blood galactose. These occur with a frequency about 10 times that of classical galactosemia (homozygotes with essentially total GALT deficiency) and are considered to be heterozygotes for classical galactosemia. Although there is no evidence of adverse effects of galactose consumption in these subjects, elimination of dietary galactose for at least the early months of life has been recommended as a prudent measure.


After the cloning and sequencing of the GALT gene, more than 160 mutations have been described that have been associated with GALT deficiency. Q188R is the most common mutation in north European populations and those predominantly of European descent. K285N is much rarer but in some countries of eastcentral Europe it is the second most common mutation. In some populations of northern Europe and the white population in North America, these two mutations account for 70–80% of mutant chromosomes. Both mutations appear to be associated with a complete loss of enzyme activity and thus, a more severe biochemical phenotype. S135L is found almost exclusively in galactosemic individuals of African origin. In North America, this accounts for 62% of the alleles causing galactosemia in the black population and is associated with good outcomes.

The Duarte galactosemia variant is caused by a single amino acid substitution, N314D, which is found on both Duarte 1 and Duarte 2 alleles. Additional base changes that are different on each distinguish D1 from D2 alleles. Homozygosity for N314D reduces GALT activity to 50%. When either E203K or L218L (a neutral polymorphism arising from the 1721C → T transition (Los Angeles variant)) is present in cis with N314D, GALT activity reverts to normal.

Galactokinase-Deficient Galactosemia

GALK-deficient galactosemia, which occurs with a frequency of about 1 in 40 000, is characterized by cataracts that occur in the first or second decade of life but the subject is otherwise normal. In such patients, ingested galactose remains unphosphorylated and may be converted into galactitol, which causes damage to the lens fibers of the eye. The marked differences between GALK-deficient galactosemia and classical galactosemia in the severity and diversity of the symptoms and in the timescales within which they occur demonstrate that galactose-1-P is much more toxic than galactitol.

GALK deficiency is readily treated with a galactose-free diet and if this is started early in life, the only complication, cataracts, is avoided.

Epimerase-Deficient Galactosemia

Impairment of GALE results in epimerase-deficient galactosemia, an inborn error of metabolism with variable biochemical presentation and clinical outcomes reported to range from benign to severe. Molecular studies of the GALE loci from patients with GALE deficiency reveal significant allelic heterogeneity, raising the possibility that variable genotypes may constitute at least one factor contributing to the biochemical and clinical heterogeneity observed.

Inherited deficiencies of GALE have been associated with two distinct phenotypes. The vast majority of North American patients are clinically asymptomatic, are identified through newborn screening programs for classical galactosemia, and are of African-American descent. However, a severe, generalized form of GALE-deficient galactosemia has been described in a small number of subjects. The initial presentation is similar to classical galactosemia, including cataract, sepsis, and liver, kidney, and brain abnormalities. Despite treatment with a galactose-restricted diet, all have shown poor growth and moderate learning difficulties.

A single substitution mutation, V94M, is present in the homozygous state in all patients genotyped with the severe, generalized form of GALE-deficient galactosemia. Studies on the enzyme in a yeast model system support the hypothesis that elevated levels of galactose-1-P may underlie the observed toxicity.


Significant advances have been made in recent years in understanding the genetics of galactosemia. However, clinical galactosemia is a complex trait and the phenotypic expression is often not predictable. Except for cataract, the pathophysiology of galactosemia is poorly understood. Despite the concept that there may be continuous endogenous production of galactose in affected individuals, the treatment remains a diet as devoid of galactose as possible, within the confines of adequate nutrition for normal growth and development. However, it is now recognized that this does not prevent long-term complications and there is a need for new approaches to treatment, in combination with diet therapy, that could improve the outcome of patients with galactosemia.

See also

LACTOSE AND OLIGOSACCHARIDES | Lactose: Galacto-Oligosaccharides; LACTOSE AND OLIGOSACCHARIDES | Lactose Intolerance.

Further Reading
  • P.B. Acosta; K.C. Gross Hidden sources of galactose in the environment European Journal of Pediatrics 154 supplement 2 1995 S87-S92.
  • G.T. Berry; I. Nissim; Z.P. Lin; A.T. Mazur; J.B. Gibson; S. Segal Endogenous synthesis of galactose in normal men and patients with hereditary galactosaemia Lancet 346 1995 1073-1074.
  • A.M. Bosch Classical galactosaemia revisited Journal of Inherited Metabolic Diseases 29 2006 516-525.
  • L.J. Elsas, II; K. Lai The molecular biology of galactosemia Genetic Medicine 1 1998 40-48.
  • T. Forges; P. Monnier-Barbarino; B. Leheup; P. Jouvet Pathophysiology of impaired ovarian function in galactosaemia Human Reproduction Update 12 2006 573-584.
  • J.B. Gibson Gonadal function in galactosemics and in galactose-intoxicated animals European Journal of Pediatrics 154 supplement 2 1995 S14-S20.
  • R. Gitzelmann Galactose-1-phosphate in the pathophysiology of galactosemia European Journal of Pediatrics 154 supplement 2 1995 S45-S49.
  • J.B. Holton Effects of galactosemia in utero European Journal of Pediatrics 154 supplement 2 1995 S77-S81.
  • G. Liu; G.E. Hale; C.L. Hughes Galactose metabolism and ovarian toxicity Reproductive Toxicology 14 2000 377-384.
  • G. Novelli; J.K. Reichardt Molecular basis of disorders of human galactose metabolism: Past, present and future Molecular Genetics and Metabolism 71 2000 62-65.
  • S. Schweitzer Newborn mass screening for galactosemia European Journal of Pediatrics 154 supplement 2 1995 S37-S39.
  • S. Segal; G.T. Berry Disorders of galactose metabolism C.H. Scriver; A.L. Beaudet; W.S. Sly; D. Valle 7th edn. The Metabolic and Molecular Bases of Inherited Diseases Vol. 1 1995 McGraw-Hill New York 967-1000.
  • L.A. Tyfield Galactosaemia and allelic variation at the galactose-1 phosphate uridyltransferase gene: A complex relationship between genotype and phenotype European Journal of Pediatrics 159 2000 S204-S207.
  • J.H. Walter; R.E.P. Roberts; G.T.N. Besley Generalized uridine diphosphate galactose-4-epimerase deficiency Archives of Disease in Childhood 80 1999 374-376.
  • A. Flynn
    University College, Cork, Ireland
    Copyright © 2011 Elsevier Ltd. All rights reserved

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