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Galactosemia: Clinical features and diagnosis

Galactosemia: Clinical features and diagnosis
Author:
V Reid Sutton, MD
Section Editors:
Sihoun Hahn, MD, PhD
Elizabeth B Rand, MD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Jun 2022. | This topic last updated: Mar 01, 2022.

INTRODUCTION — Altered metabolism of galactose caused by deficient activity of one of three enzymes results in elevated blood galactose concentration (galactosemia). Classic galactosemia, caused by complete deficiency of galactose-1-phosphate uridyl transferase (GALT), is the most common and severe type. The early signs and symptoms, such as liver dysfunction, susceptibility to infections, failure to thrive, and cataracts, can be prevented or improved by early diagnosis and treatment, but patients can still have chronic and progressive neuropsychiatric impairments. Diagnosis requires measurement of enzyme activity in red blood cells (RBCs) and genetic testing.

The clinical features and diagnosis of galactosemia caused by genetic defects are reviewed here. The management of galactosemia is discussed separately. (See "Galactosemia: Management and complications".)

EPIDEMIOLOGY — Classic galactosemia occurs in approximately 1 of 60,000 livebirths. However, the reported incidence of galactosemia varies geographically from 1 in 30,000 to 40,000 in Europe [1] to one in one million in Japan [2]. The estimated incidence in the United States is 1 in 53,000 [3].

PATHOGENESIS — Galactose is a sugar found primarily in human and bovine milk and milk products as part of the disaccharide lactose. Lactose is hydrolyzed to glucose and galactose by the intestinal enzyme lactase. The galactose then is converted to glucose for use as an energy source (figure 1). Free galactose also is present in some fruits and vegetables, such as tomatoes, brussels sprouts, bananas, and apples. Altered metabolism of galactose caused by deficient enzyme activity or impaired liver function results in elevated blood galactose concentration and the condition known as galactosemia. Impaired galactose metabolism appears to alter gene expression through epigenetic mechanisms, which may contribute to cognitive and other problems [4].

Galactosemia can result from deficiencies of three different enzymes (figure 1), each with a distinct phenotype:

Galactose-1-phosphate uridyl transferase (GALT) deficiency – The most common and severe form of galactosemia is caused by deficiency of GALT, the enzyme that converts galactose-1-phosphate (galactose-1-P) to uridine diphosphate galactose (UDPgalactose) (figure 1).

Complete deficiency of GALT activity is known as classic galactosemia, often referred to by the isolated term, "galactosemia." Untreated patients typically have failure to thrive, liver and kidney dysfunction, and sepsis. Both treated and untreated patients may have cataracts, abnormal neurodevelopment, and premature ovarian failure. The pathogenic mechanisms underlying these complications are unclear.

Partial GALT activity occurs in numerous variants. The most common of these is the Duarte variant, in which patients have one Duarte allele and one classic allele (D/G), resulting in GALT activity that is approximately 5 to 25 percent of normal [5]. Patients with two Duarte alleles (D/D) have approximately 25 percent normal GALT activity [5,6]. Patients with GALT activity ≥50 percent of normal appear to have little to no evidence of neonatal or long-term morbidity if untreated [7-9]. (See 'Clinical features' below.)

Galactokinase (GALK) deficiency – GALK is the first enzyme in the pathway of galactose metabolism, converting galactose to galactose-1-P (figure 1). The only consequence of GALK deficiency is the development of cataracts. The pathogenic mechanisms underlying this localized defect are unclear.

Uridine diphosphate (UDP) galactose 4-epimerase (GALE) deficiency – UDP GALE converts UDPgalactose to UDPglucose (figure 1). In most patients with GALE (or epimerase) deficiency, the defect is localized to red blood cells (RBCs). The pathogenic mechanisms underlying this limited defect are unclear. These individuals typically have normal growth and development, whereas patients with generalized GALE deficiency in both RBCs and all other tissues present with symptoms similar to classic galactosemia.

GENETICS — Galactosemia is an autosomal-recessive disorder. More than 150 disease-causing mutations have been characterized for the galactose-1-phosphate uridyl transferase (GALT) gene, located on chromosome 9p13 [10], although a few are common. Fewer than 10 percent of mutations occur in multiple ethnic groups or geographic areas.

The most common alleles occurring in the North American population are the following (table 1):

Q188R – Glutamine to arginine missense mutation at amino acid position 188. It is the most common classic galactosemia allele in White and Hispanic Americans.

K285N – Lysine to asparagine missense mutation at amino acid position 285. It is a classic galactosemia allele that is a frequent occurrence in Eastern European persons.

S135L – Serine to leucine missense mutation at amino acid position 135. It is the most common allele in African American persons with classic galactosemia.

N314D – Asparagine to aspartate missense mutation at amino acid position 314 (Duarte variant allele). This allele is thought to be more prevalent in White populations than Black or Asian populations, but actual detection rates vary significantly depending upon the screening approach used [6].

Individuals with classic galactosemia have two classic alleles (G/G). Individuals with the Duarte variant are compound heterozygotes, with one Duarte allele and one classic allele (D/G).

Genotype-phenotype correlation — Phenotype does not appear to correlate with genotype in classic galactosemia, although data are conflicting. In one study, intelligence quotient (IQ) scores were lower in children homozygous for the Q188R mutation than in those heterozygous for Q188R with other mutations (73.6 versus 94.8), independent of sociodemographic characteristics and metabolic control (galactose-1-P levels) [11]. However, in other reports, deficits in cognitive function, neurologic signs, and ovarian failure did not correlate with genotype [12,13]. Thus, mutation analysis is not useful for prognosis or therapy in an individual with classic galactosemia.

African Americans may have a milder form of galactosemia, probably because the S135L allele is more common in that population. However, the milder disease also may be caused by other epigenetic (not heritable) factors.

CLINICAL FEATURES

Classic galactosemia — Classic galactosemia caused by complete deficiency of galactose-1-phosphate uridyl transferase (GALT) is the most common and severe type. Early diagnosis and treatment usually prevent or resolve the early signs and symptoms, such as liver dysfunction, susceptibility to infections, failure to thrive, and cataracts. However, despite dietary management, neuropsychiatric and ovarian problems occur in most adolescents and adults with this disorder [14,15].

All states in the United States and several other countries include galactosemia in their newborn screening (NBS) programs. However, affected infants may become symptomatic before the screening results become available (approximately 10 to 14 days after sample collection) [16]. Thus, clinicians must consider the diagnosis in infants with the signs and symptoms noted below.

Early manifestations — Infants with classic galactosemia usually present in the first few days after birth and initiation of feedings that contain galactose (eg, breast milk or cow's milk-based formula), often before the results of NBS are available. The use of galactose-limited or galactose-free formulas (such as the soy protein-based Enfamil ProSobee, which has demonstrated safety in infants with galactosemia) may mask the initial presentation.

Specific signs and symptoms occur with different frequencies. The most common findings are [15]:

Jaundice (74 percent)

Vomiting (47 percent)

Hepatomegaly (43 percent)

Failure to thrive (29 percent)

Poor feeding (23 percent)

Lethargy (16 percent)

Diarrhea (12 percent)

Sepsis (10 percent)

Among infants with sepsis, the most common organism is Escherichia coli sepsis (76 percent). Less frequent findings are coagulopathy, ascites, and seizures.

On physical examination, infants typically appear jaundiced, with hepatomegaly, lethargy, and hypotonia. They may have edema and ascites, a full fontanelle, encephalopathy, and excessive bruising or bleeding.

Cataracts may be present at birth but generally appear after two weeks as a result of galactitol deposition in the lens. In untreated classic galactosemia and galactokinase deficiency, typically there is initial clouding of the embryonic nucleus in the central lens followed by spreading to the cortex. Occasionally, children who are not caught early develop a nuclear cataract as they grow, similar to nucleus pulverulentus (derived from the Latin "pulver" = dust) where the nucleus of the lens looks like a cloud of dust. (See "Cataract in children".)

Late manifestations — Monitoring for and management of the later problems that develop in patients with galactosemia, including neurodevelopmental impairment, cataracts, growth delay, and premature ovarian failure, are discussed in detail separately. (See "Galactosemia: Management and complications", section on 'Monitoring' and "Galactosemia: Management and complications", section on 'Complications and prognosis'.)

Laboratory findings — Laboratory findings of classic galactosemia include the following [17]:

Abnormal carbohydrate metabolism – Increased plasma galactose and red blood cell (RBC) galactose-1-P concentration, increased blood and urine galactitol levels. Hypoglycemia is not a primary manifestation of classic galactosemia, since the inability to convert galactose to glucose does not cause hypoglycemia. However, as discussed above (see 'Early manifestations' above), lethargy, poor feeding, and liver dysfunction can result in hypoglycemia, as it could in any infant with these problems.

Liver dysfunction – Conjugated and/or unconjugated hyperbilirubinemia, abnormal liver function tests (elevated transaminases), coagulopathy, increased levels of plasma amino acids (especially phenylalanine, tyrosine, and methionine).

Renal tubular dysfunction – Metabolic acidosis, galactosuria (which may be indicated by the presence of reducing substances in the urine), glycosuria, aminoaciduria, albuminuria.

Hemolytic anemia.

Classic galactosemia case study — A four-day-old breastfed male was taken to the pediatrician for poor feeding. On exam, he was hypothermic with low muscle tone and, therefore, was referred to the emergency department. Laboratory testing was notable for alanine transaminase (ALT) 230 units/L (reference range 12 to 45), aspartate aminotransferase (AST) 721 units/L (reference range 35 to 140), prothrombin time (PT) 51.3 seconds (reference range 10.5 to 15.7), and international normalized ratio (INR) 5.5 (reference range 0.8 to 1.2). Complete blood count (CBC; including absolute neutrophil count), cerebrospinal fluid (CSF) cell count, and urine analysis were all normal. He was treated empirically with intravenous (IV) antibiotics and fresh frozen plasma with little change in status, and liver transplantation was discussed with the parents.

On day-of-life 6, his NBS was reported as having low GALT activity, concerning for galactosemia. He was placed on a galactose-restricted diet, and RBC enzyme testing for GALT and DNA testing were sent (and ultimately confirmed classic galactosemia, homozygous for the common p.Q188R allele). The antibiotic regimen was altered to provide antimicrobial coverage for E. coli. His blood ammonia level, which was initially normal, peaked at 167 micromol/L (reference range 47 to 80) on day-of-life 8 and then declined. Blood, urine, and CSF cultures all had no growth, and herpes simplex virus (HSV) polymerase chain reaction (PCR) testing was normal. Other laboratory abnormalities normalized approximately 10 days after starting the galactose-restricted diet. The diet was consistently followed and, at two years of age, he was growing and developing normally with no concerns.

Galactokinase (GALK) deficiency — The consistent phenotypic feature of GALK deficiency is lenticular cataracts, identical to those seen in classic galactosemia [18]. The cataracts usually are bilateral and resolve with dietary therapy. (See "Cataract in children".)

A rare presentation of GALK deficiency is pseudotumor cerebri [19]. The mechanism is thought to be increased CSF oncotic pressure resulting from elevated CSF galactitol concentration. Clinical features of classic galactosemia such as liver, kidney, and brain damages typically are not present in GALK deficiency. Hypergalactosemia is the only abnormal biochemical laboratory finding. There are no other laboratory findings of note for GALK deficiency on routine laboratory testing.

Uridine diphosphate galactose 4-epimerase (GALE) deficiency — Deficiency of GALE is classically thought to be confined to erythrocytes. Affected individuals typically are asymptomatic, although erythrocyte levels of galactose-1-P are elevated. Generalized deficiency of this enzyme is rarely described.

In one report, five children from two families with generalized epimerase deficiency had dysmorphic facial features, sensorineural deafness, poor growth, and global developmental delay but not ovarian failure [20]. However, another review of 10 patients found a spectrum of GALE activity ranging from 15 to 64 percent of control levels, suggesting that the metabolic defect is a continuum from mild (ie, red cell) to severe (ie, both red cells and lymphoblasts) impairment of galactose metabolism in vitro [21]. Patients with GALE deficiency may be detected by NBS when states screen by measuring total galactose. (See 'Bacterial inhibition assay to measure total galactose' below.)

DIAGNOSIS

GALT deficiency — Classic galactosemia should be considered in any newborn who presents with the findings noted above (jaundice, vomiting, hepatomegaly, poor feeding, failure to thrive, lethargy, diarrhea, or sepsis) and/or any infant with a positive newborn screening (NBS) test. Affected infants may become symptomatic before NBS results are available [16]. (See 'Newborn screening' below.)

Red blood cell GALT activity — The demonstration of nearly complete absence of galactose-1-phosphate uridyl transferase (GALT) activity in red blood cells (RBCs) is the gold standard for diagnosis [14]. Quantitative assay of RBC GALT activity (using a fluoroimmunoassay or radioimmunoassay) is necessary to confirm the diagnosis. This assay also identifies variants with partial enzyme activity [17]. (See 'Fluorometric assay of GALT enzyme activity' below.)

Quantitative assay of RBC GALT activity may be affected for as long as three months by the transfusion of RBCs from a normal donor. In such cases, DNA testing is necessary. Other tests that may be helpful in transfused infants include measurement of GALT activity in the RBCs of both parents to determine whether they are carriers and measurement of RBC galactose-1-P in the infant [17].

Other tests — Increased RBC galactose-1-phosphate concentration is a characteristic finding of classic galactosemia. The RBC galactose-1-P concentrations should not be significantly affected by RBC transfusion [17]. RBC galactose-1-P levels cannot accurately distinguish between partial and complete GALT deficiency [14].

Enzyme isoelectric focusing can be a helpful adjunctive test in cases of intermediate enzyme activity levels, where ranges for Duarte galactosemia and other carrier states may overlap.

The presence of reducing substances in the urine is neither sensitive nor specific for galactosemia [17]. However, in a symptomatic infant, it may raise the clinical suspicion enough to trigger further evaluation and empiric treatment [14]. (See "Galactosemia: Management and complications".)

DNA analysis is available for select common mutations, and full gene sequencing is also available. In the majority of cases, enzyme analysis along with RBC galactose-1-phosphate and analysis of common mutations is sufficient to establish a diagnosis. Full gene sequencing alone (ie, without enzyme or other biochemical testing) may not be able to confirm a diagnosis, because of the large number of GALT mutations and difficulty in assessing pathogenicity of rare mutations [14].

Prenatal diagnosis — Prenatal counseling should be provided before conception to parents with a family history of galactosemia or a previously affected child. Prenatal diagnosis can be made by GALT assay in fibroblasts cultured from amniotic fluid or chorionic villus biopsy or mutation analysis of DNA extracted from chorionic villus biopsy if the genotype of the index case is known [22]. When two mutations are found in a proband with classic galactosemia, carrier screening for GALT mutations is highly effective in determining risk [14]. Clinicians and families should also be aware that this method of testing can uncover mistaken or misassigned paternity.

GALK deficiency — Galactokinase (GALK) deficiency should be considered in infants with lenticular cataracts. In addition, GALK deficiency should be considered in neonates who have positive bacterial inhibition on NBS because this screen detects elevated blood galactose without distinguishing between the three potentially causative enzymes. GALK deficiency is confirmed by assay of GALK activity in RBC and genetic testing. The results of the enzyme assay may be affected by the transfusion of RBC from a normal donor. (See 'Bacterial inhibition assay to measure total galactose' below.)

GALE deficiency — Galactose-4-epimerase (GALE) deficiency should be considered in neonates who have positive bacterial inhibition on NBS because this screen detects elevated blood galactose without distinguishing between the three potentially causative enzymes. GALE deficiency is confirmed by assay of GALE activity in RBCs and/or lymphoblasts and genetic testing. The results of the enzyme assay may be affected by the transfusion of RBC from a normal donor. (See 'Bacterial inhibition assay to measure total galactose' below.)

DIFFERENTIAL DIAGNOSIS — Galactose often is mildly elevated in normal newborns (6 to 10 mg/dL), resulting in false-positive results. Glucose-6-phosphate dehydrogenase (G6PD) deficiency can also result in a false positive on newborn screening (NBS). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Other causes of elevated galactose include liver dysfunction from conditions that include portosystemic vascular shunts, biliary atresia, and Fanconi-Bickel syndrome (glucose transporter 2 [GLUT2] deficiency) [23-25]. (See "Biliary atresia" and "Other disorders of glycogen metabolism: GLUT2 deficiency and aldolase A deficiency", section on 'GLUT2 deficiency'.)

NEWBORN SCREENING — The newborn screening (NBS) programs of all states in the United States test for galactosemia [26]. Most programs screen with a fluorometric assay of galactose-1-phosphate uridyl transferase (GALT) enzyme activity in red blood cells (RBCs), while some use a bacterial inhibition assay. A newborn with a positive screening test for galactosemia should be changed immediately to a soy-based infant formula (does not contain galactose), and the screening test should be repeated. If the second screen is positive, further testing is performed. A quantitative assay of RBC GALT confirms the diagnosis and measures the specific level of enzyme activity. (See 'Diagnosis' above.)

Fluorometric assay of GALT enzyme activity — The fluorometric assay does not depend upon the infant having been fed but may yield false-negative results if performed within three months of a blood transfusion or false-positive results if the filter paper sample is heated inadvertently (the GALT enzyme may be inactivated by heating).

This fluorometric method may miss compound heterozygotes for Duarte/classic alleles and will not detect galactokinase (GALK) or epimerase (GALE) deficiency. A false-positive result may occur with glucose-6-phosphate dehydrogenase (G6PD) deficiency [17].

If the fluorometric method is positive or the diagnosis is suspected despite a negative test, GALT activity should be measured from a new blood sample in a regular laboratory (not a NBS laboratory) and GALT electrophoresis/isoelectric focusing performed. GALT electrophoresis/isoelectric focusing distinguishes among normal (N), classic (G), and Duarte (D) alleles. If the quantitative test for GALT activity is negative, further testing is typically not performed. The most common causes of false positives on NBS are high levels of galactose in normal newborns or G6PD deficiency. Most do not test for G6PD deficiency unless there is evidence of hemolytic anemia. (See 'Genetics' above and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Bacterial inhibition assay to measure total galactose — NBS programs in some states use a bacterial inhibition assay that detects blood galactose. In this test, elevated galactose levels inhibit bacterial growth around the filter paper blood spot after incubation in a special medium. False-negative results may occur in infants who fed poorly before the blood sample was obtained, were fed soy formula initially, or received antibiotics. If galactose levels are elevated, further testing should include an assay for GALT activity and electrophoretic mobility, and measurement of epimerase (GALE) and kinase (GALK) activity in RBCs. (See 'Diagnosis' above.)

Other causes of elevated galactose are discussed above. (See 'Differential diagnosis' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Galactosemia".)

SUMMARY AND RECOMMENDATIONS

Galactosemia can result from deficiencies of three different enzymes (figure 1), each with a distinct phenotype. (See 'Pathogenesis' above.)

Classic galactosemia is caused by complete deficiency of galactose-1-phosphate uridyl transferase (GALT). It is an autosomal-recessive disorder and occurs in approximately 1 in 60,000 livebirths. Infants with classic galactosemia usually present in the first few days after initiation of galactose-containing human breast milk or cow's milk-based feedings. Signs and symptoms include jaundice, vomiting, hepatomegaly, failure to thrive, poor feeding, lethargy, diarrhea, and sepsis (particularly due to Escherichia coli). (See 'Classic galactosemia' above.)

Quantitative assay of red blood cell (RBC) GALT activity is necessary to confirm the diagnosis of classic galactosemia. The results of this assay may be affected by the transfusion of RBCs from a normal donor, in which case genetic testing is required for diagnosis. (See 'GALT deficiency' above.)

The most common feature of galactokinase (GALK) deficiency is lenticular cataracts. Quantitative assay of RBC GALK activity and genetic testing are necessary to confirm the diagnosis. (See 'Galactokinase (GALK) deficiency' above and 'GALK deficiency' above.)

Newborn screening (NBS) for galactosemia is performed in all states in the United States. Newborns with a positive screening test for galactosemia should be changed immediately to a soy-based infant formula pending confirmation of the diagnosis. (See 'Newborn screening' above and "Galactosemia: Management and complications".)

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