International Journal of Molecular Sciences · 16 authors, 4 centres
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A two-week-old female with classic galactosemia was found to be a compound heterozygote for the known pathogenic variant p.K285N and a novel GALT missense variant p.A303D, which in silico analyses predicted to be structurally damaging. A literature review of 54 patients with p.K285N in compound heterozygosity showed that most developed classic galactosemia, with acute liver failure in 61.9% during the first weeks of life.
This study reports on a two-week-old female newborn diagnosed with classic galactosemia who was found to be a compound heterozygote for the known pathogenic variant p.K285N, inherited from her father, and a novel missense variant p.A303D, inherited from her mother. In silico prediction analyses consistently indicated that the A303D substitution negatively impacts GALT structural stability. The mother also carried two additional GALT variants (p.N314D and p.L218L) in cis (D1 Duarte variant), which may have compensated for the deleterious effect of p.A303D. A literature review identified 16 pathogenic GALT missense variants in 54 patients in compound heterozygosity with p.K285N. Of these patients, 63% carried variants affecting residues near the Glc-1-P binding sites, and most developed classic galactosemia. Acute liver failure was reported in 61.9% of these patients during the first weeks of life. These findings expand the mutational spectrum of classic galactosemia.
