Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia) 

Updated: Nov 12, 2018
Author: Gerard T Berry, MD; Chief Editor: Maria Descartes, MD 

Overview

Background

Hereditary galactosemia is among the most common carbohydrate metabolism disorders and can be a life-threatening illness during the newborn period.[1, 2, 3, 4, 5, 6] In the American literature, it was first described in a variant patient in 1935 by Mason and Turner,[7] while, in Europe, the toxicity associated with breast milk consumption was first noted in 1908 by Von Reuss.[8] Both patients probably had galactose-1-phosphate uridyltransferase (GALT) deficiency, which is the most common enzyme deficiency that causes hypergalactosemia.[7] Removing lactose largely eliminates the toxicity associated with newborn disease, but long-term complications routinely occur, as reported by Komrower and Lee in 1970[9] and then delineated in a 1990 retrospective survey by Waggoner and associates[10] and Waisbren et al in 2012.[11]

Pathophysiology

Hypergalactosemia is associated with the following 3 enzyme deficiencies:[1]

  • Galactokinase converts galactose to galactose-1-phosphate and is not a common deficiency.
  • Uridine diphosphate (UDP) galactose-4-epimerase epimerizes UDP galactose to UDP glucose and is also uncommon. [12]
  • GALT is responsible for hereditary galactosemia and is the most common deficiency. This enzyme catalyzes conversion of galactose-1-phosphate and UDP glucose to UDP galactose and glucose-1-phosphate. Individuals with GALT deficiency manifest abnormal galactose tolerance.

Epidemiology

Frequency

United States

The incidence of galactosemia is approximately 1 case per 40,000-60,000 persons.[2]

International

Incidence widely varies (ie, 1 case in 70,000 people in the UK but 1 case in 16,476 people in Ireland[2, 3] ). The disorder is believed to be much less common in Asian persons.

Mortality/Morbidity

Aside from the high mortality rate in newborns with Escherichia colisepsis, life expectancy has never been studied in patients with galactosemia. Most patients appear to reach adulthood following institution of a galactose-restricted diet.[1, 5, 13]

Race

Galactosemia occurs in all races; however, galactosemia variants are based on the exact gene defect.

Variants are most notable among individuals of African ethnicity. African-Americans with galactosemia may have approximately 10% of enzyme activity in the liver but little or no activity in erythrocytes.[3, 4] The ability of an individual with the variant gene defect to tolerate ingestion of some milk may hinder diagnosis in states without newborn screening.

A likely benign variety is recognized, known as the Duarte D-2 variant, which is characterized by the simultaneous mutations c.940 A>G (p.Asn314Asp) and the tetranucleotide deletion GTCA in the promoter region of the gene.[14] Neonates with this variant may or may not have positive (ie, abnormal) newborn screening test results, and most can tolerate normal diets. During infancy, but less so in childhood, these individuals may have elevated galactose metabolite levels.

A different variant, the Los Angeles D-1 variant, has the same c.940 A>G (p.Asn314Asp) mutation as the Duarte variant but without the promoter region tetranucleotide GTCA deletion.[14] However, the Los Angeles variant has a different neutral polymorphism, delineated Leu218Leu.[15] This variant results in increased GALT activity and does not cause hypergalactosemia.

Dietary galactose restriction does not appear to be necessary or beneficial in patients with Duarte D-2 variant galactosemia. Many metabolic disease specialists take a conservative approach and recommend galactose restriction in the first year of life when milk intake is highest, but this restriction is based primarily on theoretical concerns of galactose toxicity in infants with the Duarte D-2 variant.[16, 17]

Sex

Galactosemia equally affects males and females.

Age

Galactosemia is most often diagnosed in infancy via newborn screening, because all states include galactosemia as part of their newborn screen.[5] Variant forms of galactosemia can present later.

Prognosis

Untreated severe classic galactosemia is a life-threatening disorder.[5] Fortunately, most states and developed countries screen for galactosemia in the newborn period, and affected infants are treated before they become very ill.[18]

Infants with galactosemia who are severely ill (eg, those with sepsis, coagulopathy, liver dysfunction) before treatment for galactosemia is initiated may develop permanent liver, brain, and/or eye damage (although cataracts are often completely reversible).

Most patients with severe galactosemia who do not receive treatment often do not survive the newborn period.

Even with appropriate dietary therapy, most patients have at least 1-2 long-term complications.

Almost all females with classic galactosemia present with hypergonadotropic hypogonadism/primary ovarian insufficiency (POI).[19]

Some patients with galactosemia may have cryptic gastrointestinal tract dysfunction.[20]

Patient Education

Dietary therapy requires both parental and patient education. Involve children in their dietary management as soon as appropriate.

 

Presentation

History

In all states, galactosemia is detected with a positive (ie, abnormal) newborn screening test result.[5]

Parents of newborns with galactosemia often complain to physicians about various feeding difficulties with their newborn, most notably vomiting.[1]

Almost all infants with galactosemia on a lactose-containing diet manifest poor weight gain.[1]

Physical

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 and/or hepatomegaly
  • Cataracts (sometimes as early as the first few days of life)
  • Lethargy
  • Hypotonia
  • Sepsis ( E coli)
  • Seizures
  • Brain edema

Surprisingly, ascites may also be detected during early infancy. In some patients, ascites are detected as early as the first few days of life.

In an infant or child with cataracts, galactosemia must be excluded. If unsure, consult an ophthalmologist because some cataracts, especially congenital cataracts, are visible only by using a slitlamp.

Vitreous hemorrhage is a known complication of galactosemia, although its prevalence is unknown.[21] An enigmatic linkage of E coli sepsis with galactosemia is noted. Galactosemia should be high on the differential diagnoses in term infants with sepsis caused by infection with this pathogen.

Learning problems and speech and language deficits are common; language acquisition may be delayed.[22, 23, 24, 25, 26, 27, 28, 29]

The most common findings in adults include hypergonadotropic hypogonadism or primary ovarian insufficiency (POI) in women, although some women have become pregnant,[30] most notably black women, who probably have variant disease, but also white women with classic galactosemia.[1, 31, 32, 33, 34, 35, 36, 37, 38] Short stature and neurologic abnormalities (eg, tremor, ataxia, dystonia) also occur in a minority of patients.[1, 11, 39]

Rare reports of patients with severe galactosemia off of diet therapy since childhood have raised concerns about whether lactose restriction needs to be maintained after infancy.[40, 41]

Causes

Classic galactosemia is caused by a severe deficiency in GALT.

The deficiency is an autosomal recessive genetic condition.

The gene for GALT is located on chromosome 9p13.[2, 42, 43]

Complications

An international database is under construction.[44]

 

DDx

 

Workup

Laboratory Studies

All states perform newborn screening for galactosemia.[3]

A positive (ie, abnormal) indication 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.

Usually, GALT genotyping provides a specific molecular diagnosis. The most common GALT allele in whites is the Q188R mutation. The S135L mutation is common in native South Africans and in African Americans.[2, 42, 45] The K285N mutation is common in Eastern Europe.[46, 47]

A urine-reducing substances test may help. This test's results are almost always abnormal (ie, 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.

Imaging Studies

Patients with galactosemia may exhibit white-matter abnormalities on brain MRI.[3, 48, 49]

Pseudotumor cerebri and lethal brain edema have been detected in the newborn period.[50]

Patients may exhibit cerebral atrophy.

A minority of patients manifest cerebellar atrophy.

Other Tests

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.

Histologic Findings

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.

 

Treatment

Medical Care

International treatment guidelines for galactosemia were published in 2017.[16]

The mainstay of medical care in the postnatal period is to immediately discontinue ingestion of lactose-containing formula.[16, 51, 52] This ameliorates the acute toxicity associated with the neonatal period but does not prevent all long-term complications.[53, 54]

Clotting abnormalities may be cryptic and require fresh frozen plasma treatments.[16]

Consultations

Refer children to appropriate language and speech centers to optimize treatment for learning problems.

Neuropsychological testing should be performed, as developmental delay and learning problems are common.[55]

Refer adolescent females to a pediatric endocrinologist and older adolescents and women to a reproductive gynecologist for appropriate treatment of hypergonadotropic hypogonadism and POI.[16]

No standardized treatment for short stature has been established, and the etiology is unknown in many instances.[56]

Because dietary therapy is necessary, refer patients to a dietitian who has experience with metabolic disorders.[57]

Decreased bone mineral density has been detected in a fraction of patients with galactosemia.[58]

Consultation with a biochemical geneticist (ie, metabolic disease specialist) is advisable for diagnostic laboratory evaluation, monitoring, and clinical care for patients with galactosemia.[59]

Diet

Prescribe a galactose-restricted diet for infants who are galactosemic. Older patients may tolerate lactose better than infants. The restriction of milk intake throughout life is controversial.[6, 40, 41, 60, 61] However, most metabolic specialists support life-long diet therapy.[13, 16]

Totally eliminating galactose is difficult because it is present in a wide variety of foods (eg, infant foods, fruits, vegetables), especially in the macromolecular form.[62]

The authors of this article do not recommend restriction of fruits and vegetables.[62]

Dietary restrictions during pregnancy, as well as prospectively during postnatal life, may have no effect on long-term complications of an affected fetus.

Further Inpatient Care

During the initial hospitalization for a child with symptomatic severe classic galactosemia, the major concerns are sepsis, bleeding, liver dysfunction, and brain swelling. Treat these conditions as they would be treated in patients who do not have galactosemia.

Immediate and total removal of galactose 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.

 

Guidelines

Guidelines Summary

International treatment guidelines for galactosemia were published in 2017.[16]

 

Medication

Medication Summary

Drug therapy currently is not a component of the standard of care for this condition. See Treatment.