AB154. Molecular characterization of Filipino patients with variant galactosemia

Background: Classical galactosemia is a disorder of carbohydrate metabolism caused by low to absent activity of the GALT (galactose-1-phosphate uridyltransferase) enzyme. The clinical manifestations occur early and are severe if untreated. In contrast, patients with variant galactosemia (VG) are apparently healthy and do not manifest elevated galactose levels in spite of low GALT activity. The question of whether to restrict dietary galactose in variant VG remains unanswered. The Philippine newborn screening program does not impose any dietary restriction on patients with VG but monitors their total blood galactose for 5 years. The objective of the study was to determine the molecular basis of VG in 13 clinically diagnosed patients.

Methods: The coding sequence of the GALT gene of 13 Filipino patients clinically diagnosed to have VG was examined. GALT exons were PCR-amplified using genomic DNA as template and subsequently sequenced in both forward and reverse directions.

Results: None of the patients had the D/G galactosemia variant genotype. Five patients were heterozygous for classic galactosemia allele/potential G allele (G/- genotype), while three patients were heterozygous for the Duarte allele, p.N314D in cis configuration with c.-119_-116delGTCA, (D/- genotype). Five patients did not have detectable mutations in the coding region of the GALT gene. Two mutations, p.R80Q and p.Y89C, are novel, but cursory in silico analysis predicts that these are deleterious mutations. Three of the five patients without detectable mutations by sequence analysis were each assessed to have one of the following: learning disability, attention deficit disorder and global delay. Another two patients were assessed to have an error of refraction.

Conclusions: Mutations not evident by direct sequence analysis may be present in the GALT gene of the five patients without detectable mutations. Therefore, additional molecular testing aside from direct sequence analysis (e.g., whole gene deletion detection) is needed to fully analyze the GALT gene in VG patients.

Keywords: Variant galactosemia (VG); molecular diagnosis; GALT gene