GALT – Classic Galactosemia

Classic galactosemia is a rare autosomal recessive metabolic disorder caused by pathogenic loss-of-function variants in the GALT gene, encoding galactose-1-phosphate uridylyltransferase (GALT). Affected neonates present with feeding intolerance, jaundice, hepatomegaly, and E. coli sepsis, and survivors develop cataracts and long-term neurodevelopmental deficits (PMID:2011574).

Extensive case series have established autosomal recessive inheritance, with biallelic GALT variants in over 123 unrelated patients by 2005 (PMID:15841485). Segregation studies demonstrate obligate carrier status in parents and affected siblings in multiple families, confirming full penetrance when enzyme activity is absent.

The spectrum of pathogenic alleles includes missense, nonsense, splice, and frameshift variants. The recurrent stop mutation c.1018G>T (p.Glu340Ter) was identified in multiple unrelated families and correlates with severe early-onset hepatopathy (PMID:8522334). Common missense alleles such as c.563A>G (p.Gln188Arg) and c.855G>T (p.Lys285Asn) account for >60% of alleles in Caucasian cohorts.

Functional assays in yeast, mammalian cells, and cell-free translation systems consistently show that classic alleles severely impair GALT activity and protein stability. The Q188R variant exhibits <10% residual activity in vitro and fails to complement yeast gal7∆ growth on galactose (PMID:8421669); cell-free expression confirmed absent activity for several novel missense variants (PMID:31392114). These data support a loss-of-function mechanism underlying classic galactosemia.

By contrast, certain noncoding or Duarte alleles (e.g., c.377+17C>T) show normal galactose-1-phosphate levels and no long-term clinical sequelae, underscoring the need for functional follow-up of novel variants (PMID:25920691).

In summary, biallelic pathogenic GALT variants cause classic galactosemia through a consistent loss-of-function mechanism. Newborn screening and rapid molecular diagnosis are critical for early dietary intervention and prevention of life-threatening neonatal complications.

References

• American Journal of Human Genetics • 1995 • Characterization of two stop codon mutations in the galactose-1-phosphate uridyltransferase gene of three male galactosemic patients with severe clinical manifestation. PMID:8522334
• Human Mutation • 2005 • Identification of novel mutations in classical galactosemia. PMID:15841485
• Proceedings of the National Academy of Sciences of the United States of America • 1991 • Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase. PMID:2011574
• Proceedings of the National Academy of Sciences of the United States of America • 1993 • A yeast expression system for human galactose-1-phosphate uridylyltransferase. PMID:8421669
• JIMD Reports • 2019 • Functional analysis of GALT variants found in classic galactosemia patients using a novel cell-free translation method. PMID:31392114
• Clinica Chimica Acta • 2015 • Genetic and functional studies reveal a novel noncoding variant in GALT associated with a false positive newborn screening result for galactosemia. PMID:25920691

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