What is the management and treatment of galactosemia, an inborn error of metabolism?

Inborn Errors of Metabolism: Galactosemia

Overview of Galactosemia

Galactosemia is a life-threatening inherited disorder of carbohydrate metabolism requiring immediate dietary galactose restriction to prevent acute mortality from liver failure, sepsis, and death in untreated infants. 1

Galactosemia encompasses three distinct enzymatic deficiencies in the Leloir pathway of galactose metabolism, which converts dietary galactose (primarily from lactose in milk) to glucose-1-phosphate for energy production and provides UDP-galactose for cellular processes. 1

Types of Galactosemia

Type I: Classic Galactosemia (GALT Deficiency)

• Most frequent and most severe form caused by deficient galactose-1-phosphate uridyltransferase (GALT) activity (MIM 230400). 1
• Results in elevated galactose-1-phosphate (Gal-1-P) and other galactose metabolites in blood and urine. 1
• Without treatment, characterized by failure to thrive, liver failure, susceptibility to sepsis, and death. 1

Type II: Galactokinase (GALK) Deficiency

• Caused by deficiency in galactokinase enzyme (MIM 230200), encoded by GALK1 gene on chromosome 17q25.1. 1
• The most common variant in European descent is c.563A > G (p.Q188R), accounting for 64% of pathogenic variants. 1
• Generally presents with milder phenotype than classic galactosemia. 2

Type III: UDP-Galactose-4'-Epimerase (GALE) Deficiency

• Third enzyme of Leloir pathway (MIM 230350), encoded by GALE gene on chromosome 1p36.11. 1
• Catalyzes reversible conversion of UDP-galactose to UDP-glucose. 1
• Clinical severity varies depending on extent of enzyme deficiency. 2

Duarte Variant (DG) Galactosemia

• Characterized by approximately 25% of normal GALT activity and may be clinically benign. 1
• Results from compound heterozygosity for a profound GALT pathogenic variant and Duarte 2 allele. 1

Diagnosis

Newborn Screening

• Galactosemia is included in all newborn screening programs in the United States, identifying the majority of cases. 1
• Screening identifies patients with decreased GALT activity in dried blood spots (DBS) and, in some states, elevated galactose sugars. 1
• States including galactose sugars identify GALK and GALE deficiencies, while those relying only on enzyme activity may miss GALT deficiency in patients already on galactose-limited diet. 1

Confirmatory Testing

• Diagnosis is based on demonstration of severely reduced or absent enzyme activity in red blood cells (RBCs). 1
• Full gene sequencing of G6PC (GSD Ia) and SLC37A4 (GSD Ib) genes should confirm diagnosis. 1
• DNA analysis of GALT, GALK1, or GALE genes is often performed as part of diagnostic evaluation. 1
• Reduced GALT activity of ≤3% of normal is diagnostic for classic galactosemia. 1

Metabolite Testing

• Untreated patients have markedly elevated RBC Gal-1-P concentrations that decrease rapidly upon galactose elimination. 1
• Gal-1-P is routinely used to monitor therapy response and dietary compliance, with therapeutic range of 2-4 mg/dl. 1
• Takes 2-3 months for Gal-1-P to fall within therapeutic range after dietary restriction. 1

Treatment and Management

Dietary Intervention: The Cornerstone of Treatment

Immediate and lifelong dietary restriction of galactose is the current standard of care and only available treatment for galactosemia. 3, 4

Acute Management

• All foods containing galactose must be eliminated from the diet immediately upon suspicion of galactosemia. 5
• Dietary restriction prevents or resolves acute sequelae including liver failure, sepsis, and death. 6
• Infants require soy-based, sugar-free formula or formula free of sucrose, fructose, and lactose fed every 2-3 hours. 1

Dietary Composition

• Sucrose (fructose and glucose) and lactose (galactose and glucose) are often limited or avoided, as fructose and galactose cannot be metabolized to glucose-6-phosphate. 1
• Limiting these sugars reduces or eliminates sugar, fruit, juice, dairy, and foods containing these products. 1
• Careful assessment and supplementation of micronutrients is required to avoid nutrient deficiencies. 1

Monitoring

• RBC Gal-1-P levels should be monitored to assess dietary compliance and therapeutic response. 1
• Therapeutic target is Gal-1-P concentration of 2-4 mg/dl. 1

Long-Term Complications and Prognosis

Critical Limitation of Current Treatment

Although dietary galactose restriction is efficient in resolving acute complications, it does not prevent long-term complications affecting the brain and female gonads, the two main target organs of damage. 2

• Long-term developmental complications are experienced by most patients later in childhood despite early treatment. 4
• Common complications include cognitive impairment, speech difficulties, motor dysfunction, and primary ovarian insufficiency in females. 3

Metabolic Perturbations Beyond the Leloir Pathway

• Untargeted metabolomic studies identified 252 differentially abundant features in plasma of treated patients compared to controls. 6
• 14 significantly perturbed pathways were identified, including multiple redox, amino acid, and mitochondrial pathways. 6
• These findings suggest pathophysiology extends substantially beyond the primary enzyme deficiency. 6

Novel Therapeutic Approaches Under Investigation

Experimental Interventions

• Small molecule inhibitors or effectors, chaperones, and DNA or RNA-based gene therapy are being explored. 4
• Bone marrow transplantation (BMT) has been tested in GALT-null rat models but showed limited efficacy, with GALT activity normalized only in red blood cells but not in liver or brain tissues. 4
• Novel therapies may be beneficial if access issues to affected tissues are circumvented and optimum use of therapeutic window is achieved. 2

Clinical Pitfalls and Caveats

Screening Limitations

• Infants exhibiting symptoms suggestive of galactosemia should undergo in-depth testing even when newborn screening shows normal results. 5
• Patients on galactose-limited diet may have false-negative screening results if only galactose sugars are measured. 1

Variant Forms

• Molecular testing distinguishes between classic galactosemia (G/g), Duarte variant homozygotes (D2/D2), and LA variant galactosemia (D1/G), all showing approximately 50% normal enzyme activity. 1
• The D1 variant is not associated with decreased GALT activity and should be reported as benign when detected. 1

Duarte Variant Considerations

• Patients with DG galactosemia often show elevated Gal-1-P (up to 30-40 mg/dl) in first weeks of life, which normalizes without dietary intervention. 1