What is galactosemia?

What is Galactosemia

Galactosemia is a life-threatening inherited disorder of carbohydrate metabolism caused by deficiency in one of three enzymes in the Leloir pathway of galactose metabolism, requiring immediate dietary galactose restriction to prevent acute mortality from liver failure, sepsis, and death in untreated infants. 1, 2

Biochemical Basis

• The disorder prevents the body from converting galactose (a sugar found in milk) into glucose, the body's primary energy source 3
• Three distinct enzyme deficiencies can cause galactosemia, each affecting a different step in the Leloir pathway: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate (UDP)-galactose-4′-epimerase (GALE) 1
• The pathway is critical for both converting D-galactose to glucose-1-phosphate for entry into glycolysis and supplying UDP-galactose for galactosylation of carbohydrates and lipids 1

Types of Galactosemia

Classic Galactosemia (Type I)

• Classic galactosemia, caused by GALT deficiency, is the most frequent and most severe form of the three enzyme deficiencies 1, 2
• Prevalence is approximately 1 in 30,000 to 1 in 60,000 births 2
• Deficient GALT activity leads to elevated galactose-1-phosphate (Gal-1-P) and other galactose metabolites in blood and urine 1
• If untreated, causes failure to thrive with poor feeding and vomiting within days of milk ingestion, hepatic dysfunction progressing to liver failure with jaundice and coagulopathy, and E. coli sepsis particularly in the first week of life 2

Duarte Variant Galactosemia

• Characterized by approximately 25% of normal GALT activity and is clinically benign 1, 4
• Results from compound heterozygosity for a profound GALT pathogenic variant and the Duarte 2 allele 4
• Does not cause life-threatening acute complications such as liver failure, sepsis, or death, and dietary galactose restriction is not required 4
• The Duarte 2 allele occurs in an estimated 11% of European American populations 4

Galactokinase Deficiency (Type II)

• Caused by deficiency in the galactokinase enzyme encoded by the GALK1 gene on chromosome 17q25.1 2
• Primarily causes infantile cataracts without systemic toxicity, requiring ophthalmologic examination 2

UDP-Galactose-4′-Epimerase Deficiency (Type III)

• Clinically and biochemically distinct from classic galactosemia 1
• Screening for GALE deficiency is not universal across all states 1

Type IV Galactosemia

• Recently identified novel type caused by biallelic GALM mutations 5
• Estimated incidence is 1:228,411 in all populations, 1:10,388 in the African population, and 1:80,747 in the Japanese population 5

Diagnosis

Newborn Screening

• Galactosemia is included in all newborn screening programs in the United States, identifying the majority of cases before symptom onset with approximately 90% sensitivity 2
• Screening methods include GALT enzyme activity measurement in dried blood spots and/or elevated total galactose 2
• Critical pitfall: Screening may miss GALT deficiency in infants already on galactose-restricted formula 2
• States that include galactose sugars as part of screening also identify cases of GALK and GALE deficiencies, while those relying only on enzyme activity may miss these variants 1

Confirmatory Testing

• Diagnosis is established by demonstrating severely reduced or absent enzyme activity in red blood cells (RBCs) with approximately 95% diagnostic accuracy 2
• Molecular genetic testing of GALT, GALK1, or GALE genes identifies pathogenic variants 2
• Metabolite measurement shows elevated galactose-1-phosphate (Gal-1-P) and galactose in blood/urine supporting diagnosis 2
• Important caveat: Blood transfusions cause false-negative enzyme results by introducing donor RBCs with normal enzyme activity 2
• For Duarte variant, testing for the 4-bp GALT promoter deletion is the most appropriate confirmatory test to distinguish between D1 and D2 variants 4

Treatment and Management

Dietary Restriction

• The current standard of care is immediate and lifelong dietary restriction of galactose, which prevents or resolves acute sequelae including liver failure, sepsis, and death 2
• Dietary restriction should eliminate all foods containing galactose, including sucrose, lactose, and fructose, with a goal of reducing galactose intake to less than 10 mg per day 2
• Although diet reverses the neonatal clinical picture, it does not prevent the development of long-term complications 3

Monitoring

• RBC Gal-1-P levels should be monitored every 3-6 months to assess dietary compliance and therapeutic response, with a target range of 2-4 mg/dl 2

Long-Term Complications

• Despite dietary treatment, long-term complications are common, including cognitive and psychomotor impairment, hepatic, ophthalmological, and bone structural damage 6
• Metabolomic studies have identified 14 significantly perturbed pathways beyond the Leloir pathway, including multiple redox, amino acid, and mitochondrial pathways 7