What is Duarte galactosemia?

What is Duarte Galactosemia?

Duarte galactosemia (DG) is a mild biochemical variant of galactosemia characterized by approximately 25% residual GALT enzyme activity that is generally clinically benign and does not require lifelong dietary restriction, unlike classic galactosemia. 1

Genetic Basis

Duarte variant galactosemia results from compound heterozygosity for two specific alleles 1:

• One allele is a profound GALT pathogenic variant (G) causing classic galactosemia
• The second allele is Duarte 2 (D2), which reduces GALT activity by approximately 50%
• When present together in trans configuration, the net result is ~25% of normal GALT activity 1

The D2 allele encompasses a haplotype of four variants 1:

• Two intronic changes
• A 4-bp deletion in the promoter of the GALT gene (responsible for reduced enzyme activity)
• c.940A > G (p.N314D) variant

The D2 allele occurs in an estimated 11% of European American populations 1

Clinical Significance

Duarte galactosemia is fundamentally different from classic galactosemia in its clinical course and prognosis 2:

• Does NOT cause the life-threatening acute complications of classic galactosemia (liver failure, sepsis, death) 3
• Does NOT cause the long-term complications seen in classic galactosemia such as cerebellar ataxia and hypergonadotropic hypogonadism 2
• May be associated with transient mild developmental delays in early infancy that resolve over time 2, 4

Developmental Considerations

Research suggests subtle neurodevelopmental impacts 2, 4:

• Approximately 42% of children with DG participated in early intervention and/or special education 2
• 32% received speech therapy 2
• Cognitive/language and motor skills remain within normal limits, though language-related motor skills may show transient delays during early infancy 2
• School-age studies show some differences in socio-emotional development, delayed recall, and auditory processing speed compared to controls 4
• These developmental concerns are transient and resolve over time, with no evidence of progressive deterioration 2

Diagnosis

Testing for the 4-bp GALT promoter deletion is the most appropriate confirmatory test to distinguish between D1 and D2 variants when Duarte variant galactosemia is suspected 1:

• D2 contains the 4-bp promoter deletion and causes reduced GALT activity
• D1 (Los Angeles variant) shares the electrophoretic banding pattern but lacks the 4-bp promoter deletion and does NOT cause reduced GALT activity 1
• Integrating biochemical and molecular results improves diagnostic accuracy by differentiating pathogenic from non-pathogenic variants 1

Management

Dietary galactose restriction is NOT required for Duarte galactosemia 2, 5:

• Unlike classic galactosemia, individuals with DG do not require diet therapy 2
• History of diet treatment was not related to developmental outcomes or use of special services 2
• Recent clinical studies suggest dairy restriction could be reconsidered in these cases 5

Common Pitfalls

Do not confuse Duarte galactosemia with classic galactosemia - they are fundamentally different conditions 2, 6:

• DG is not a bona fide biochemical genetic disease requiring lifelong treatment 2
• The transient developmental delays in DG are hypothesized to result from elements in the genomic space that include the GALT gene, rather than from galactose toxicity 2
• Newborn screening practices vary among US states, with some choosing to identify DG and others not, reflecting ongoing uncertainty about clinical significance 4