Galactosemia

Douglas J Lanska MD MS MSPH

Neurogenetic Disorders

Updated 05.14.2024
Released 02.01.1995
Expires For CME 05.14.2027

Galactosemia

Author: Douglas J Lanska MD MS MSPH

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Galactosemia

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Introduction

Overview

Hereditary galactosemia due to galactose-1-phosphate uridyltransferase (GALT) deficiency is one of the inborn errors of carbohydrate metabolism and can be a life-threatening illness during the newborn period. First described in the United States literature in a variant patient in 1935 by Mason and Turner, galactose-1-phosphate uridyltransferase (GALT) deficiency is the most common enzyme deficiency that causes clinically relevant hypergalactosemia. Removing lactose by stopping breast milk or proprietary formula feedings largely eliminates the toxicity associated with newborn disease, but long-term complications almost always occur in the severe form of GALT deficiency, as reported by Komrower and Lee in 1970, Fishler and colleagues in 1980, and, most convincingly, in the 1990 retrospective survey by Waggoner and colleagues. In this article, the author reviews the clinical, laboratory, and imaging features of this enigmatic disease, including putative biochemical toxicities that center around galactose-1-phosphate and galactitol metabolism.

Key points

	• Galactosemia is a medical emergency in the newborn period.
	• Dietary lactose restriction usually rescues affected newborn infants, preventing multiorgan toxicity syndrome and eliminating E coli sepsis.
	• Prospective dietary therapy does not prevent long-term CNS complications nor does it prevent primary ovarian insufficiency in affected women.

Historical note and terminology

Lactose and galactose. It took several centuries from the first crude isolation of lactose to a fairly complete understanding of its components and their structures.

In 1633, Italian physician Fabrizio Bartoletti (1576–1630) was the first to isolate lactose, although his isolation was somewhat crude (04). In 1700, the Venetian pharmacist Lodovico Testi (1640–1707) advocated milk sugar (Saccharum lactis) for the relief of multiple ailments (136). In 1715, Testi's procedure for making milk sugar was published (137). Lactose was identified as a sugar in 1780 by Swedish-German pharmaceutical chemist Carl Wilhelm Scheele (1742–1786) (123).

Swedish-German pharmaceutical chemist Carl Wilhelm Scheele (1742-1786)

Carl Vilhelm Scheele, statue by Johan Börjeson, in Humlegarden in Stockholm, unveiled on December 9, 1892. This picture was found in "Words and Pictures" in 1892. (Courtesy of Wikimedia Commons. Public domain. Image restored an...

In 1812, Heinrich Vogel (1778–1867) recognized that glucose was a product of hydrolyzing lactose (145; 146). Lactose was named by the French chemist Jean-Baptiste André Dumas (1800–1884) in 1843 (37). In 1856, French chemist and microbiologist Louis Pasteur (1812–1895) crystallized the other component of lactose, galactose, but called it “lactose.” In 1860, French chemist Marcellin Berthelot (1827–1907) renamed it "galactose," and transferred the name "lactose" to the disaccharide "milk sugar" (19).

French chemist Jean-Baptiste André Dumas (1800-1884)

(Courtesy of Wikimedia Commons. Public domain. Image restored and edited by Dr. Douglas J Lanska.)
Studio portrait of French chemist and microbiologist Louis Pasteur (1812-1895) by French photographer Paul Tournachon Nadar (1856-1939)

(Courtesy of Wikimedia Commons. Public domain.)
Portrait of French chemist Marcellin Berthelot (1827-1907)

(Courtesy of Wikimedia Commons. Public domain.)

By 1894, German chemist (and later Nobel Laureate) Emil Fischer (1852–1919) had established the configurations of the component sugars, glucose in 1891 and, with Robert Selby Morrell (1867–1946), galactose in 1894 (Fischer 1891a; Fischer 1891b; 42).

German chemist (and later Nobel Laureate) Emil Fischer (1852-1919), c 1897

(Courtesy of the Academy of Sciences of Turin and Wikimedia Commons. Public domain. Image restored and edited by Dr. Douglas J Lanska.)
Emil Fischer's proposed structure for d-galactose in 1894

(Source: Fischer E, Morrell RS. Ueber die Configuration der Rhamnose und Galactose [On the configuration of rhamnose and galactose]. Berichte der Deutschen chemischen Gesellschaft zu Berlin 1894;27:382-94. Public domain.)

Galactosemia. The first report of galactosemia was by Austrian pediatrician August von Reuss (1879–1954) in 1908; it concerned an infant on breastmilk with failure to thrive, hepatosplenomegaly, and galactosuria (147; 148). The galactosuria resolved after stopping dietary milk products, but the infant ultimately died. Autopsy showed hepatic cirrhosis. In 1917, German pediatrician Friedrich Göppert (1870–1927) reported an infant with poor growth, lactose exposure, and hypergalactosuria (53).

In 1935, American pediatrician Howard Harris Mason MD and Mary E Turner PhD at the College of Physicians and Surgeons, Columbia University, provided the first comprehensive description of the clinical variant form of hereditary galactosemia (97). It was also the first report of a patient with any form of galactosemia due to galactose-1-phosphate uridyltransferase (GALT) deficiency in the American literature. This African-American infant had not been placed on a lactose-restricted diet until 10 months of age. The diet treatment reversed the complications of poor growth, developmental delay, liver disease, and anemia relatively quickly. More infants with classic galactosemia had not been described until 1935 because most untreated babies die of E coli sepsis in the newborn period (10).

This review focuses primarily on hereditary galactosemia due to severe GALT deficiency.

Clinical manifestations

Presentation and course

As over 300 mutations or polymorphisms in the GALT gene have been identified, different forms of the deficiency exist (39; 141; 24; 43).

Classic galactosemia

Infants with complete or near-complete deficiency of the enzyme (classic galactosemia) have normal weight at birth but, as they start ingesting lactose-containing breast milk or formula, lose more weight than their healthy peers and fail to regain birth weight (124; 08; 49; 17). Almost all infants on a lactose-containing diet manifest poor weight gain. Symptoms appear in the second half of the first week and include refusal to feed, vomiting, jaundice, and lethargy. Parents often report various feeding difficulties with their newborn, most notably, vomiting. Hepatomegaly, edema, and ascites may follow. Ascites may be detected in early infancy. In some patients, ascites are detected as early as the first few days of life. Death from sepsis, usually due to E coli, may occur in most infants with classic disease not detected by newborn screening. Symptoms are milder and the course is less precipitous when milk is temporarily withdrawn and replaced by intravenous nutrition. Nuclear cataracts appear within days or weeks and become irreversible within weeks of their appearance. Congenital cataracts and vitreous hemorrhages may also be present (85; 133). In an infant or child with cataracts, galactosemia must be excluded. An ophthalmologist needs to be consulted because some cataracts, especially congenital cataracts, are visible only with a slit lamp. Vitreous hemorrhage is a known complication of galactosemia, although its prevalence is unknown (85; 133).

Acute clinical manifestations

	• Untreated infants with severely deficient galactose-1-phosphate uridyltransferase (GALT) activity typically present with the following variable findings:
		- Poor growth within the first few weeks of life - Jaundice - Bleeding from coagulopathy - Liver dysfunction or hepatomegaly - Cataracts (sometimes as early as the first few days of life) - Lethargy - Hypotonia - Brain edema (bulging anterior fontanel) - Sepsis (E coli) - Death

Long-term or chronic clinical manifestations

	• Learning problems and speech and language deficits are common; language acquisition may be delayed (150; 98; 71; 154; 106; 105; 129; 138; 107; 88; 87; 139). Cognitive impairment is present in most patients (36; 121; 62).
	• Almost all females with classic disease manifest hypergonadotropic hypogonadism or primary ovarian insufficiency presenting as primary or secondary amenorrhea (69; 48; 118; 115; 47; 55); some women were able to become pregnant, including African Americans who probably had variant disease (09; 56; 54).
	• Short stature or poor growth occurs in a minority of patients (104).
	• Neurologic abnormalities (eg, tremor, ataxia, dystonia) occur in a minority of patients (34; 59; 67; 159; 20; 75; 112; 32; 114).
	• Decreased bone mineral density (70; 116; 05).
	• Anxiety, depression, and reduced quality of life (57; 135; 61; 151).

In many countries, newborns with galactosemia are discovered through newborn screening by quantifying blood galactose, the GALT enzyme, or both; this screening is performed using dried blood spots, usually collected on the second day of life in the United States (10; 109; 110). At the time of discovery, the first symptoms may already have appeared, and the infant may already have been admitted to a hospital, usually for jaundice. Where newborns are not screened for galactosemia or when the results of screening are not yet available, diagnosis rests on clinical awareness. It is crucial that milk feeding be stopped as soon as galactosemia is considered and resumed only when a galactose disorder has been excluded. The presence of a reducing substance in a routine urine specimen may be the first diagnostic clue. Galactosuria will be present provided that last milk feed does not date back more than a few hours and vomiting has not been excessive. However, owing to the early development of a proximal renal tubular syndrome, the acutely ill galactosemic infant may also excrete some glucose, together with an excess of amino acids. However, glucosuria may be recognized, and the galactosuria missed. On withholding milk, galactosuria ceases, but amino acids in excess continue to be excreted for a few days. However, galactitol and galactonate continue to be excreted in large amounts. Albuminuria may also be an early finding that disappears with dietary lactose restriction.

As an autosomal recessive disorder, galactosemia equally affects males and females.

Clinical variant galactosemia

Clinical variant galactosemia, as exemplified by the disease that occurs in African Americans and native Africans in South Africa (125; 127; 03; 126; 113; 124; 10) can result in life-threatening complications in untreated infants, including feeding problems, failure to thrive, hepatocellular damage including cirrhosis, and bleeding. Affected individuals may have approximately 10% of enzyme activity in liver and intestinal epithelium but no activity in erythrocytes.

The S135L mutation in the GALT gene is a prevalent cause of galactosemia among black patients, accounting for almost half of the GALT alleles in galactosemia patients of African-American descent (79; 80; 156; 94; 08; 60). African Americans with clinical variant galactosemia who receive adequate early treatment are apparently not at risk for long-term complications. If a lactose-restricted diet is provided during the first 10 days of life, the severe acute neonatal complications are usually prevented. Unfortunately, the ability of an individual with the variant gene defect to tolerate ingestion of some milk may hinder diagnosis in locales without newborn screening. Even in areas with newborn screening, the clinical variant form of galactosemia due to homozygosity for the S135L GALT gene mutation can be missed when newborn screening depends on an elevated total galactose level (35; 10).

Benign variant galactosemia (Duarte variant galactosemia)

Benign variant galactosemia, the most common of which is Duarte variant galactosemia, is associated with partial deficiency in erythrocyte GALT enzyme activity but is typically not associated with clinical disease (28; 46). It is most often discovered by newborn screening because of moderately elevated blood galactose (free or total) or low GALT activity. Dietary therapy is often not recommended and may not necessary (27), although some suggest that dairy restriction should be reconsidered in these cases (134).

During infancy, but less so in childhood, these individuals may have elevated galactose metabolite levels (40). Whether dietary galactose restriction is necessary or beneficial for patients with Duarte variant galactosemia was long unknown and a matter of intense debate (108; 02; 46; 93). An important study by Carlock and colleagues directly assessed speech–language outcomes in 350 children (250 with Duarte galactosemia and 144 controls) (27; 45). Duarte galactosemia was not associated with adverse developmental outcomes in children aged 6 to 12 years compared to children without Duarte galactosemia. Milk exposure during infancy was not associated with adverse developmental outcomes in children with Duarte galactosemia.

Prognosis and complications

Most patients with classic galactosemia who are detected via newborn screening between 4 to 7 days and placed on a lactose-restricted diet will not develop severe multiorgan disease and E coli sepsis. However, if these steps are not taken, affected infants are likely to die of E coli sepsis or go on to develop cirrhosis and/or severe white matter lesions (102). Even patients treated on day 1 of life may manifest CNS disease associated with language delay, speech defects, cognitive impairment, learning problems, and, less commonly, tremors, ataxia, and dystonia, plus, at least in females, hypergonadotropic hypogonadism or primary ovarian insufficiency. Therefore, all patients with classic disease require multiple evaluations at different points in time and appropriate treatment. Complications that can vary in severity for each individual independent of erythrocyte galactose-1-phosphate and urine galactitol levels collected over many years on diet therapy. The variation in developmental, cognitive, and neurologic complications may be striking for one individual compared to another, but this is less so for primary ovarian insufficiency in females, as almost all show biochemical evidence of hypergonadotropic hypogonadism.

Clinical vignette

On day 6 of life, a male infant was lethargic, feeding poorly, and had temperature instability. A workup for sepsis was negative. On day 8, urine-reducing substances were 4+, and results of newborn screening on a sample obtained on day two were positive for galactosemia with a total blood galactose plus galactose-1-phosphate level higher than 9 mg/dL (normal, less than 7.2). Galactose-restricted feeding was initiated with Isomil (Ross Laboratories, Columbus, Ohio). Because his condition continued to deteriorate, he was transferred to the neonatal intensive care unit on day 10. On physical examination, the infant was quiet but arousable. Skin perfusion was poor. Spontaneous deep hyperventilation was occasionally noted. Jaundice and hepatomegaly were present. Major laboratory abnormalities consisted of hyperchloremic metabolic acidosis, mild hypertransaminasemia, hypofibrinogenemia, prolonged prothrombin and partial thromboplastin times, hyperbilirubinemia, and thrombocytopenia. The erythrocyte galactose-1-phosphate level was 33.9 mg/dL (normal, less than 1 mg/dL). The plasma galactitol concentration was 407 μmol/L (normal, less than 1 μmol/L), and urinary galactitol excretion was 4754 μmol/mmol creatinine (normal, 2 to 78 μmol/mmol creatinine for infants younger than 1 year old). Erythrocyte GALT activity was absent, and the patient was homozygous for Q188R, the most common severe GALT mutation. Brain magnetic resonance imaging and 1H-MRS studies were performed with a Siemens Magnetom Vision 1.5 T whole-body MRI scanner. Brain MRI on day 10 revealed cytotoxic edema in the white matter. On the midline sagittal T1-weighted image, there was diffuse low signal in the supratentorial white matter. On the T2-weighted images, signal intensities were increased in the white matter in a patchy distribution. The most prominent abnormalities were in the periventricular white matter, in the middle cerebellar peduncles, and around the dentate nuclei. The apparent diffusion coefficient in the white matter was consistently lower than that of a healthy control subject of the same age. Using in vivo proton magnetic resonance spectroscopy, approximately 8 mmol galactitol per kilogram of brain tissue was detected.

Biological basis

Etiology and pathogenesis

Carbohydrates are involved in many cellular processes, including the following: (1) energy production, storage, and transport; (2) regulation of glycemia (insulin/glucagon cycle); (3) fermentation processes; (4) regulation of cholesterol and triglyceride; and (5) glycan synthesis and glycosylation. Glycans are needed for the following: (1) lipid modulation and glycolipid synthesis; (2) glycocalyx formation (ie, a gel-like layer covering the luminal surface of vascular endothelial cells); (3) cell-extracellular matrix adhesion; (4) cell-cell interaction and communication; (5) immune response modulation; (6) protein modulation and glycoprotein synthesis; (7) enzyme activity control; (8) hormonal activity; and (9) receptor activity and intracellular signaling. In addition, glycoconjugates are involved in the pathogenesis of a wide array of pathological conditions, including inflammation, cancer, degenerative neuromuscular disorders, and diabetes.

Summary of the main biological functions of carbohydrates

The green boxes indicate the main biochemical functions of carbohydrates in eukaryotic cells, specifically human cells. The blue boxes indicate the main biological roles of glycans and glycoconjugates. The box labeled "pathogen...

Lactose. Lactose is a disaccharide composed of two monosaccharides: galactose and glucose.

Lactose in Haworth projection

(Illustration prepared by NEUROtiker on May 2, 2007. Public domain.)

The enzyme lactase is essential to the complete digestion of whole milk, splitting the disaccharide lactose into its component monosaccharides. Lactase is located in the brush border of the small intestine of humans and other mammals.

Chemical reaction catalyzed by the lactase enzyme, converting the disaccharide lactose to the monosaccharides galactose and glucose

(Illustration prepared by Boghog2. Public domain.)
Enzymatic hydrolysis of lactose to D-galactose and D-glucose in Haworth projections

(Illustration prepared by Ed [Edgar181] on October 31, 2011. Public domain.)

With congenital lactase deficiency (congenital alactasia), infants cannot break down lactose in breast milk or formula. If affected infants are not given a lactose-free infant formula, they develop severe diarrhea with resulting severe dehydration and weight loss.

Adult lactose intolerance is typically caused by reduced production of lactase after infancy (lactase nonpersistence). When such individuals consume lactose-containing dairy products, they develop abdominal cramps, pain, bloating, flatulence, nausea, and diarrhea beginning 30 minutes to 2 hours later. Treatment focuses on avoidance of dairy products, use of lactose-free products, or the use of lactase supplements.

Most people with lactase nonpersistence retain some lactase activity and can consume some lactose without experiencing symptoms. Affected individuals typically have difficulty digesting fresh milk but can eat modest amounts of dairy products (eg, cheese or yogurt) without discomfort because these foods are made with fermentation processes that break down much of the lactose.

D-galactose. Galactose (sometimes abbreviated Gal) is a monosaccharide sugar that is about as sweet as glucose and about two thirds as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose.

Galactose exists in both open-chain and cyclic forms. The open-chain form has a carbonyl at the end of the chain. Four isomers are cyclic: two with a pyranose (6-membered) ring and two with a furanose (5-membered) ring. The open-chain and cyclic forms can interconvert.

Cyclic and linear configurations of the enantiomeric pairs of galactose

The hydroxy group on the hemiacetal carbon (C-1) is indicated in blue in the alpha (α) anomer and in yellow in the beta (β) anomer. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glyc...
Structural formulae of D- and L-galactose

(Illustration prepared by NEUROtiker on February 25, 2007. Public domain.)
Haworth projections of some of the enantiomers of D-galactose

(Illustration prepared by NEUROtiker on March 16, 2007. Public domain.)
D-galactose in alpha and beta chair conformations

(Illustration prepared by Naturwiki on October 5, 2020. Public domain.)
Interconversion of alpha- and beta-D-galactose (furanose forms)

(Illustration prepared by Jü on November 8, 2012. Public domain.)
Interconversion of alpha- and beta-D-galactose (pyranose forms)

(Illustration prepared by Jü on November 7, 2012. Public domain.)
Equilibrium of galactose in aqueous solution at 20°C

(Illustration prepared by NadirSH on June 31, 2021. Public domain.)

The metabolism of dietary disaccharides (lactose and sucrose). The principal dietary disaccharides are lactose, sucrose, and maltose (Table 1). Disturbed metabolism of the disaccharides is by far the most serious with the galactose component of lactose, resulting in forms of galactosemia. Dietary lactose is converted to its component monosaccharides in the small intestine (brush border), and these then enter the blood. From there, they are distributed to the liver, brain, and other organs. Under normal circumstances, the galactose is metabolized to glucose-1-phosphate, which can then be used in glycogenesis or metabolized to pyruvate through the glycolysis metabolic pathway.

Overview of fructose and galactose metabolism

(Illustration prepared by Luigi Albert Maria on October 21, 2019. Creative Commons Attribution-Share Alike 4.0 International License, https://creativecommons.org/licenses/by-sa/4.0/deed.en.)
Diagram of galactose metabolic pathways

(Illustration prepared by Gracelaidlaw on May 17, 2010. Public domain.)

Table 1. The Principal Dietary Disaccharides

Disaccharide	Component monosaccharides	Dietary source
Lactose	Galactose + glucose	Milk and dairy products
Sucrose	Glucose + fructose	Fruits, vegetables, nuts (commercial "table sugar" from sugar cane and sugar beets)
Maltose	Glucose + glucose	Cereals, certain fruits, and sweet potatoes

Catabolism of d-galactose (the Leloir pathway). The Leloir pathway is a metabolic pathway for the catabolism of D-galactose. It is named after Argentine physician and biochemist Luis Federico Leloir (1906–1987) (140; 25; 26; 83; 81; 82; 100; 44; 63; 132).

Biochemist Luis Federico Leloir

(Courtesy of Wikimedia Commons. Public domain.)
Luis Leloir and Carlos Eugenio Cardini at the Instituto Campomar (1960)

Luis Leloir (seated) and Carlos Eugenio Cardini at the Instituto Campomar (Campomar Institute) in 1960. (Source: Instituto Leloir via Wikimedia Commons. Public domain.)

Catabolism of d-galactose through the Leloir pathway proceeds in four enzymatic steps: (1) the enzyme galactose mutarotase catalyzes the conversion of β-D-galactose to alpha-D-galactose; (2) alpha-D-galactose is phosphorylated by galactokinase (GALK) to galactose-1-phosphate; (3) D-galactose-1-phosphate uridylyltransferase (GALT) converts galactose-1-phosphate to UDP-galactose using UDP-glucose as the uridine diphosphate source; (4) UDP-galactose 4-epimerase (GALE) recycles the UDP-galactose to UDP-glucose for the transferase reaction. In addition, phosphoglucomutase converts the D-glucose 1-phosphate to D-glucose 6-phosphate.

Leloir pathway of galactose metabolism

The enzymes catalyzing the different steps are Scheme 1. Leloir pathway of galactose metabolism. The enzymes catalyzing the different steps are galactose mutarotase (GALM), galactokinase 1 (GALK), galactose-1-phosphate uridylyl...
Leloir pathway

The four steps of the Leloir pathway are shown in order of activity, and they are mediated by (1) GALM, (2) GALK, (3) GALT, and (4) GALE. Legend: the anomeric carbon 1 (C-1) of galactose is indicated by a red dot; the UMP part ...
The galactose mutarotase enzyme

(Illustration prepared by Emw on December 15, 2009. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)
Leloir pathway, step 1

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)
Human galactokinase 1 monomer in complex with galactose and an analog of adenosine triphosphate

Cartoon diagram of a human galactokinase 1 monomer in complex with galactose (red) and an analog of adenosine triphosphate (orange). A magnesium ion is visible as a green sphere. (Illustration prepared by Fvasconcellos on Augus...
Leloir pathway, step 2

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)
A dimer of Escherichia coli galactose-1-phosphate uridylyltransferase in complex with UDP-galactose

Cartoon diagram of a dimer of Escherichia coli galactose-1-phosphate uridylyltransferase (GALT) in complex with UDP-galactose (stick models). Potassium, zinc, and iron ions are visible as purple, gray, and bronze-color...
Leloir pathway, step 3

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)
Uridine diphosphate galactose

(Illustration prepared by Fvasconcellos on May 4, 2007. Public domain.)
Leloir pathway, step 4

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)
Schematic representation of the Leloir pathway and associated reactions

Several forms of galactosemia can be caused by deficiency of GALM, GALT, GALK1, or GALE. (Source: Succoio M, Sacchettini R, Rossi A, Parenti G, Ruoppolo M. Galactosemia: biochemistry, molecular genetics, newborn screening, and ...

In 1970, Leloir was awarded the Nobel Prize in Chemistry for this work.

Dr. Luis Federico Leloir celebrating the Nobel Prize in Chemistry (1970)

Dr. Luis Federico Leloir (left) on December 10, 1970, drinking champagne from a test tube celebrating the Nobel Prize in Chemistry. (Source: Instituto Leloir via Wikimedia Commons. Public domain.)

Catabolism of d-galactose (the alternate pathway). In addition to the Leloir pathway, there is an alternate pathway to the pentose phosphate pathway via galactonate (30).

Alternative route for metabolism of galactose to the pentose phosphate pathway via galactonate

The names of the human enzymes that catalyze each reaction are reported in blue color. The name of the synthesized compound is reported in grey color. The colored blocks indicate the chemical groups modified in each reaction. T...

A combined scheme of galactose catabolism. A scheme of galactose metabolism includes the Leloir and alternate pathways of galactose catabolism as well as the linkages with glycosylation, glycogen synthesis, glycolysis and the tricarboxylic cycle, and the pentose phosphate pathway. In addition, some galactitol is formed by the action of aldose reductase on galactose; under normal circumstances, this is excreted in the urine.

Diagram of galactose metabolic pathways

(Illustration prepared by Gracelaidlaw on May 17, 2010. Public domain.)
Scheme of galactose metabolism

Abbreviations: CO2, carbon dioxide; GALE, UDP-alpha-D-galactose 4-epimerase; GALK, galactokinase; GALT, galactose 1-phosphate uridylyltransferase; HK, hexokinase; PGM1, phosphoglucomutase isoform I; UGP, UDP-alpha-D-glucose pyr...
Structural formula of galactitol

(Illustration prepared by Fvasconcellos on August 8, 2008. Public domain.)

Glycosylation pathways involving galactose. Galactose is metabolized into UDP-Gal, which is used as a precursor for glycosylation of different macromolecules. Galactose is a component of both N-glycan structures and the four types of human mucin O-glycans.

UDP-galactose synthesis and function in glycosylation

Solid line arrows indicate direct enzymatic reactions, whereas dashed line arrows indicate a series of sequential reactions. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylati...
Schematic representation of the glycosylation pathways involving galactose

Galactose is metabolized into UDP-Gal, which is used as a precursor for the glycosylation of different macromolecules. UDP-Gal can be used as a building block for synthesis of N-glycans and O-glycans. Moreover, UDP-Gal can be u...
Examples of N-glycan structures and the four types of human mucin O-glycans

Examples of N-glycan structures and the four types of human mucin O-glycans, namely: [core 1] Galβ1–3GalNAcαSer/Thr; [core 2] GlcNAcβ1–6(Galβ1–3) GalNAcαSer/Thr; [core 3] GlcNAcβ1–3GalNAcαSer/Thr; [core 4] GlcNAcβ1–6(GlcNAcβ1–3...

Galactosemia. Individuals with a profound deficiency of GALT can phosphorylate ingested galactose but fail to metabolize galactose-1-phosphate (66). As a consequence, galactose-1-phosphate and galactose accumulate, and the alternate pathway metabolites, galactitol and galactonate, are formed. Cataract formation can be explained by galactitol accumulation. The pathogenesis of the hepatic, renal, and cerebral disturbances is less clear but is probably related to the accumulation of galactose-1-phosphate; galactitol may play a role as well, especially in brain edema (11). However, the mechanisms of the disease are far from clear (29; 33; 157; 95).

Galactose metabolic pathway showing the enzyme block responsible for classic galactosemia and the buildup of precursors in the pathway

Diagram of the galactose metabolic pathway shows the enzyme block responsible for classic galactosemia (galactose 1-phosphate uridyltransferase [GALT]) and the buildup of precursors in the pathway. (Illustration prepared by Can...
Mutations in galactosemia result in metabolic errors from the inability to process dietary galactose

(Source: The University of Arizona Health Sciences: https://disorders.eyes.arizona.edu/disorders/galactosemia. Creative Commons Attribution-Share Alike 4.0 International License, https://creativecommons.org/licenses/by-sa/4.0/d...

Hypergalactosemia may be associated with deficiencies of the following three enzymes, all of which are from the Leloir pathway.

• Galactokinase (GALK) converts galactose to galactose-1-phosphate.
• Galactose-1-phosphate uridyltransferase (GALT) catalyzes conversion of galactose-1-phosphate and UDP-glucose to UDP-galactose and glucose-1-phosphate.
• Uridine diphosphate (UDP) galactose-4-epimerase (GALE) epimerizes UDP galactose to UDPglucose.

GALT is primarily responsible for classic hereditary galactosemia. Individuals with GALT deficiency manifest abnormal galactose tolerance.

Galactose-1-phosphate uridyltransferase (GALT) deficiency. Reichardt and Berg cloned the first cDNA encoding human GALT in 1988 (111). Over 300 mutations or polymorphisms of the GALT gene have now been reported (84; 39; 141; 24). Classic galactosemia is caused by a severe deficiency in GALT that is transmitted as an autosomal recessive trait. The GALT gene is located on chromosome 9p13. The gene for GALT is located on chromosome 9p13. It has 11 exons and contains approximately 4.3 kb of genomic DNA. Almost 90% of mutant alleles in classic galactosemia are due to the following four severe mutations.

Amino acid alteration	Genomic DNA/nucleotide mutation	Region	Comments
Q188R	c. 563 A→ G	Exon 6	Severe: 60% to 70% of mutant alleles
K285N	c. 855 G→T	Exon 9	Severe: 8% of European alleles
L195P	c. 584 T→C	Exon 7	Severe
Δ5.2 kb del	5.2 kb del	Almost all exons	Severe: 1 in 127 individuals of Ashkenazi Jewish descent in Israel are carriers (52)
S135L	C. 404 C→T	Exon 5	Clinical variant: 50% of mutant alleles in African Americans
N314D + c.-116-119 del GTCA (D2 with 5´ 4-bp deletion in cis)	c. 940 A→G	Exon 10	Benign (biochemical) variant: allele frequency of 0.133 in populations of European ancestry

Galactokinase (GALK) deficiency. The human GALK1 gene is located on chromosome 17q24. The enzyme catalyzes the first step in galactose metabolism, and its deficiency, although rare, results in cataracts in infancy.

Uridine diphosphate galactose-4´-epimerase (GALE) deficiency. GALE deficiency galactosemia is also known as epimerase deficiency galactosemia. The human GALE gene is located on chromosome 1p36.

Differential diagnosis

Confusing conditions

The clinical presentation of galactosemia overlaps with that of other galactose-related congenital disorders of glycosylation and galactose-related lysosomal storage disorders (30).

Summary of the details and clinical presentation of galactosemia and other galactose-related congenital disorders of glycosylation

Red color, reported symptom; grey color, absent symptom; the symbol “?” indicates symptoms unclearly correlated with the disease. Abbreviations: chr, chromosome; Gal, galactose; Glc, glucose; GalNAc, N-acetyl-α-D-galactosamine;...
Summary of the details and clinical presentation of galactose-related lysosomal storage disorders

Legend: red color, reported symptom; pink color, more rare or suspected symptoms; grey color, absent symptom. Numbers of patients in red color indicate numbers calculated using references from OMIM and available literature. Abb...

The differential diagnosis for galactosemia includes:

• Severe UDP-galactose-4´-epimerase (GALE) deficiency
• Galactokinase (GALK) deficiency
• Fructose 1-phosphate aldolase deficiency (hereditary fructose intolerance)
• Neonatal hemochromatosis
• Fanconi-Bickel syndrome
• Tyrosinemia type 1
• Respiratory chain disorders (usually associated with hyperlacticacidemia)
• Citrullinemia type 2
• Alpha1-antitrypsin deficiency
• Sepsis

Galactokinase deficiency

Clinical presentation. Cataracts are the only consistent manifestation of the untreated disorder, though pseudotumor cerebri has been described (50; 22; 49). Liver, kidney, and brain damage, as seen in transferase deficiency, are not features of untreated galactokinase deficiency, and hypergalactosemia and increased galactose and galactitol excretion are the only chemical signs.

Metabolic derangement. Persons with GALK deficiency cannot phosphorylate galactose. Consequently, nearly all of the ingested galactose is excreted, either as such or as its reduced metabolite, galactitol, formed by aldose reductase. As in GALT deficiency, cataracts result from the accumulation of galactitol in the lens, causing osmotic swelling of lens fibers and denaturation of proteins.

Genetics. The mode of inheritance is autosomal recessive. In most parts of Europe, in the United States, and in Japan, birth incidence is in the order of 1 in 150,000 to 1 million. It is higher in the Balkan countries, the former Yugoslavia, Romania, and Bulgaria, where it favors the Romani population, in whom the birth incidence was calculated as 1 in 2500.

The gene GK1, which encodes galactokinase, is located on chromosome 17q24. Many GK1 mutations have now been described. The GK1 P28T mutation was identified as the founder mutation responsible for galactokinase deficiency in the Romani from eastern European regions and in immigrants from Bosnia in Berlin (64). Different mutations have been documented (99).

Diagnostic tests. Provided they have been fed breastmilk or a lactose-containing formula before the test, newborns with the defect are discovered by newborn screening methods for detecting elevated blood galactose. If they have been fed glucose-containing fluid, the screening test could be false-negative. Every person with nuclear cataracts ought to be examined for GALK deficiency. Final diagnosis is made by assaying GALK activity in red blood cell lysates (90).

Treatment and prognosis. Treatment may be limited to the elimination of milk and dairy products from the diet. Minor sources of galactose, such as fruit, vegetables, and legumes, can probably be disregarded. When diagnosis is made rapidly and treatment begun promptly (during the first 2 to 3 weeks of life), cataracts can clear. When treatment is late and the cataracts are too dense, they will not clear completely (or at all) and must be removed surgically.

As in carriers with GALT deficiency, the speculation that heterozygosity for GALK deficiency predisposes to the formation of presenile cataracts remains unproven. It has been suggested that heterozygotes restrict their milk intake, though scientific proof of the merits of this measure is lacking.

Uridine diphosphate-galactose-4'-epimerase deficiency

Clinical presentation. This disorder exists in at least two forms (153; 49), both of which are discovered through newborn screening using suitable tests sensitive to both galactose and galactose-1-phosphate in dried blood spots. However, there are patients with intermediate levels of residual GALE activity, and it is unclear whether these subjects have disease-causing mutations (101). In five patients from three families with the severe form of the disorder, the enzyme defect was subtotal (153). The newborns presented with vomiting, jaundice, and hepatomegaly reminiscent of untreated classical galactosemia. All had galactosuria and hyperaminoaciduria, one had cataracts, and one had sepsis. In some, there was evidence for sensorineural deafness or dysmorphic features, but it is unclear whether this is related to solely to GALE deficiency because there was a high degree of consanguinity in the families of Pakistani/Asian ancestry with homozygosity for the V94M GALE gene mutation. An additional patient from India was reported (120).

Infants with the mild form appear healthy. The enzyme defect is incomplete. Lactose-fed newborns with the mild form detected in newborn screening are healthy and have neither hypergalactosemia nor galactosuria or hyperaminoaciduria.

Metabolic derangement. The GALE enzyme deficiency provokes an accumulation of UDP-galactose after milk feeding. This build-up also results in the accumulation of galactose-1-phosphate.

Genetics. Epimerase deficiency is inherited as an autosomal recessive trait. The epimerase gene resides on chromosome 1. Several mutations have been identified and characterized, including the V94M mutation that was present in a homozygous form in all of the patients tested with a severe phenotype (158). It is also well established that this enzyme catalyzes the conversion of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. A compound heterozygous patient (L183P/N34S) of mixed Pakistani/Caucasian ancestry with a mild form and mental retardation, which may or may not be related to the underlying GALE deficiency, has been reported. As in GALT deficiency, abnormal glycosylation of proteins that appears to be dependent, at least in part, on lactose consumption has been reported in severe GALE deficiency and is thought to be a secondary biochemical complication, not primarily related to the genetic defect.

Diagnostic tests. The deficiency should be suspected when red cell galactose-1-phosphate is measurable while GALT is normal. Diagnosis is confirmed by the assay of epimerase in erythrocytes. Diagnosis of the severe form is based on the clinical symptoms, chemical signs, and more marked deficiency of epimerase in red cells. The utility of studying the enzyme deficiency in whole white cell pellets, isolated lymphocytes, and EBV-transformed lymphoblasts in potentially clinically relevant variant cases is under scrutiny.

Treatment and prognosis. The child with the severe form of epimerase deficiency is unable to synthesize galactose from glucose and is, therefore, galactose dependent. Dietary galactose in excess of actual biosynthetic needs will cause accumulation of UDP-galactose and galactose-1-phosphate, the latter being one presumptive toxic metabolite. When the amount of ingested galactose does not meet biosynthetic needs, synthesis of galactosylated compounds, such as galactoproteins and galactolipids, is impaired. As there is no easily available chemical parameter on which to base the daily galactose allowance (such as blood phenylalanine in phenylketonuria), treatment is extremely difficult. Children known to suffer from the disorder have impaired psychomotor development.

Infants with the mild form of epimerase deficiency described thus far have not required treatment, but it is advisable to examine one or two urine specimens to reduce substances and aminoaciduria within a couple of weeks after diagnosis, while the infant is still being fed milk.

Fanconi-Bickel syndrome

This is a recessively inherited disorder of glucose and galactose transport due to GLUT2 deficiency and is extremely rare (119). Several cases have been discovered during newborn screening for galactose in blood.

Portosystemic venous shunting and hepatic arteriovenous malformation

Portosystemic bypass of splanchnic blood via ductus venosus Arantii or intrahepatic shunts cause alimentary hypergalactosemia, which may be discovered during metabolic newborn screening (51; 07; 72).

Diagnostic workup

Consultation with a clinical biochemical geneticist or metabolic disease specialist is advisable for diagnostic laboratory evaluation, monitoring, and clinical care of patients with galactosemia.

Galactosemia is most often diagnosed in infancy by newborn screening because all states in the U.S. include galactosemia as part of their newborn screening; however, methods are not uniform (10; 110). Variant forms of galactosemia can present later.

A positive (abnormal) result on the newborn screen must be followed by a quantitative erythrocyte galactose-1-phosphate uridyltransferase (GALT) analysis by a laboratory that routinely performs biochemical genetic testing and consultation (89; 90). In the pre-molecular diagnostic era, a GALT isoelectric-focusing electrophoresis test helped distinguish variant forms such as the Duarte defect (38; 91).

GALT genotyping usually provides a specific molecular diagnosis. The most common GALT allele in Caucasians is the Q188R mutation (approximately 65% of mutant alleles). The patients with a Q188R/Q188R genotype may have no residual GALT enzyme activity in erythrocytes (89). The S135L mutation is common in African Americans (79). The K285N mutation is common in Eastern Europe (92).

A urine-reducing substances test may be helpful. The results of this test are almost always abnormal (positive) in infants with galactosemia who are ingesting lactose. This is a tube test rather than a dipstick test and must be differentiated from the routine urine dipstick test for glucose.

Patients with galactosemia may exhibit white matter abnormalities on MRI of the brain (71); uncommonly, cerebellar atrophy may also be present. Pseudotumor cerebri and lethal cerebral edema have been detected in the newborn period (65; 06; 96). In sick neonates, white matter edema may be associated with brain galactitol accumulation (12).

Infants with galactosemia can become jaundiced. Hyperbilirubinemia is often unconjugated but can become conjugated later.

Urine examination reveals evidence of albuminuria and, later, a generalized aminoaciduria. Eliminating lactose-containing formula from the diet quickly resolves the albuminuria.

Fatty infiltration and inflammatory changes initially may occur in the liver. Portal hypertension and pseudoacinar formation occur in later stages. Cirrhosis occurs in the final stage and is indistinguishable from other causes.

Leptin levels may be altered in galactosemia (73).

Leptin is a hormone predominantly made by adipose cells and enterocytes in the small intestine. It helps to regulate energy balance by inhibiting hunger, which, in turn, diminishes fat storage in adipocytes.

Management

A more uniform and evidence-based medical approach to dietary therapy and disease management after infancy is needed (21; 78; 68; 155). Treatment is generally focused on dietary therapy and management of complications. Drug therapy is not part of the standard of care for this condition.

Postnatal care. The mainstay of medical care in the postnatal period is to immediately discontinue breastfeeding and ingestion of lactose-containing formula. This ameliorates the acute toxicity in the neonatal period but does not prevent all long-term complications.

Clotting abnormalities may be cryptic and require fresh frozen plasma treatments.

Galactosemia should be high on the differential diagnosis of term infants with E coli sepsis. Workup for sepsis and use of antibiotics must be employed as indicated.

Chronic dietary therapy. A lactose-restricted diet must be provided for infants with galactosemia. Most metabolic specialists support a lifelong diet therapy, although older patients may tolerate lactose better than infants. Rare reports of patients with severe galactosemia off dietary therapy since childhood have raised questions about whether lactose restriction needs to be maintained after infancy (23; 103). Liberalizing galactose intake in older patients has been reported to improve the glycan structures in circulating IgG molecules (31; 74; 131).

Because dietary therapy is generally necessary, patients need to be followed by a dietitian who has experience with metabolic disorders. Dietary therapy requires both parental and patient education. Children should be involved in their dietary management as soon as appropriate.

Totally eliminating galactose is difficult because it is present in a wide variety of foods (infant foods, fruits, vegetables), especially in the macromolecular form (01). It does not appear to be reasonable to restrict fruits and vegetables, only cow’s milk and dairy products (142). The restriction of milk intake throughout life is controversial.

Complications may be related to endogenous production of galactose as galactose-1-phosphate and galactitol levels remain elevated despite strict adherence to a lactose-restricted diet (14; 13; 122). Not surprisingly, as patients maintain steady-state levels of galactose metabolites in blood and urine, even patients with absent GALT activity are capable of oxidizing galactose to CO2 (15; 08; 16).

Because many patients develop abnormalities of bone mineral density with abnormal fragility, calcium and vitamin D intake should be monitored (151; 144).

Management of complications. During the initial hospitalization of a child with symptomatic, severe classic galactosemia, the major concerns are sepsis, bleeding, liver dysfunction, and brain swelling. These conditions are to be treated as they would be in patients who do not have galactosemia. Immediate and total removal of lactose from the diet is the only specific treatment for a patient with galactosemia that differs from treatments for patients with sepsis or liver dysfunction from other causes.

Chronic disease management requires time-dependent testing and consultations (152). The etiology of long-term complications is unknown (11).

Infants should be screened for speech and language deficits between 7 to 12 months of age; additional screening should then be performed at 2, 3, and 5 years of age (107; 86). Affected infants and children should then be referred to appropriate speech and language centers (138; 88); optimal individualized treatment is necessary to help address learning problems.

Adolescent females should be referred to an adolescent medicine specialist or endocrinologist and women to a reproductive gynecologist for appropriate treatment for primary ovarian insufficiency (130). Fertility preservation requires careful consideration as ethical concerns exist (143). Males do not appear to manifest severe primary gonadal disease (Rubio-Gonzalbo 2010; 58).

No standardized treatment for short stature has been established, and the etiology is unknown in most instances.

Gastrointestinal tract dysfunction may be more common during the lifetime of the patient (128).

Outcomes

If untreated, classic galactosemia is a life-threatening disorder. Infants with classic galactosemia who are severely ill (eg, those with sepsis, coagulopathy, or liver dysfunction) before dietary treatment for galactosemia is initiated may develop permanent liver, brain, or eye damage (although cataracts may be completely reversible). Most patients with severe galactosemia who do not receive treatment probably do not survive the newborn period.

Fortunately, most developed countries screen for galactosemia in the newborn period, and infants affected with classic galactosemia are treated before they become very ill. Following the institution of a galactose-restricted diet, most patients appear to reach adulthood. Even with appropriate dietary therapy, most patients with classic disease have long-term complications, including delayed language acquisition, speech defects, learning problems, decreased bone mineral density, and hypergonadotropic hypogonadism. Less common are short stature, poor growth, tremors, ataxia, and dystonia (151).

Patients with clinical variant galactosemia with higher residual GALT enzyme activities may not develop these long-term complications (10; 117).

Duarte variant galactosemia has a benign course. Duarte galactosemia is not associated with adverse developmental outcomes in children aged 6 to 12 years compared to children without Duarte galactosemia, and milk exposure during infancy is not associated with adverse developmental outcomes in children with Duarte galactosemia (27; 45). Therefore, dietary therapy is often not recommended (and likely not necessary) for this variant (27).

Media

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile

Former Authors

Louis J Elsas II MD
Silvia T Remolina MD
Maria T Acosta MD
Phillip L Pearl MD
Gerard T Berry MD
Tyler Reimschisel MD

Patient Profile

Age range of presentation: 0 to 23 months
Sex preponderance: male=female

Ovarian dysfunction observed in females, but no reproductive dysfunction observed in males so far.
Heredity: heredity may be a factor

heredity typical

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Galactosemia: E74.2
ICD-11: Disorders of galactose metabolism, unspecified: 5C51.4Z

Galactose-1-phosphate uridyltransferase deficiency: 5C51.40
OMIM: Galactosemia: #230400

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Galactosemia

Differential Diagnosis

prolonged neonatal jaundice
cataracts
failure to thrive
liver disease
pseudotumor cerebri syndrome
- positive Clinitest reaction
- cognitive and developmental delays
- ataxia
- dyspraxic speech
- primary amenorrhea
- early menopause
- intellectual disability
- citrullinemia type 2
- galactokinase deficiency
- epimerase deficiency

Galactosemia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Classic galactosemia

Acute clinical manifestations

Long-term or chronic clinical manifestations

Clinical variant galactosemia

Benign variant galactosemia (Duarte variant galactosemia)

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. The Principal Dietary Disaccharides

Epidemiology

Differential diagnosis

Confusing conditions

Galactokinase deficiency

Uridine diphosphate-galactose-4'-epimerase deficiency

Fanconi-Bickel syndrome

Portosystemic venous shunting and hepatic arteriovenous malformation

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

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