title: Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene.
abstract: Classical galactosemia is an autosomal recessive inborn error of metabolism due to mutations of the GALT gene leading to toxic accumulation of galactose and derived metabolites. With the benefit of early diagnosis by neonatal screening and early therapy, the acute presentation of classical galactosemia can be prevented. However, despite early diagnosis and treatment, the long term outcome for these patients is still unpredictable because they may go on to develop cognitive disability, speech problems, neurological and/or movement disorders and, in females, ovarian dysfunction. The objectives of the current study were to report our experience with a group of galactosemic patients identified through the neonatal screening programs in northeastern Italy during the last 30years. No neonatal deaths due to galactosemia complications occurred after the introduction of the neonatal screening program. However, despite the early diagnosis and dietary treatment, the patients with classical galactosemia showed one or more long-term complications. A total of 18 different variations in the GALT gene were found in the patient cohort: 12 missense, 2 frameshift, 1 nonsense, 1 deletion, 1 silent variation, and 1 intronic. Six (p.R33P, p.G83V, p.P244S, p.L267R, p.L267V, p.E271D) were new variations. The most common variation was p.Q188R (12 alleles, 31.5%), followed by p.K285N (6 alleles, 15.7%) and p.N314D (6 alleles, 15.7%). The other variations comprised 1 or 2 alleles. In the patients carrying a new mutation, the biochemical analysis of GALT activity in erythrocytes showed an activity of <1%. In silico analysis (SIFT, PolyPhen-2 and the computational analysis on the static protein structure) showed potentially damaging effects of the six new variations on the GALT protein, thus expanding the genetic spectrum of GALT variations in Italy. The study emphasizes the difficulty in establishing a genotype-phenotype correlation in classical galactosemia and underlines the importance of molecular diagnostic testing prior to making any treatment.
authors.affiliation: Division of Inborn Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Viggiano
authors.affiliation: Department of Chemistry and Biology, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Marabotti
authors.affiliation: Neurological Unit, St. Bassiano Hospital, Bassano del Grappa, Consultant in Neurometabolic Hereditary Diseases at the University Hospital of Padova, Italy.
authors.forename: A P
authors.initials: AP
authors.lastname: Burlina
authors.affiliation: Division of Inborn Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cazzorla
authors.affiliation: Department of Biomedicine and Prevention, School of Medicine, University of Rome "Tor Vergata" and Fondazione PTV "Policlinico Tor Vergata", Rome, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: D'Apice
authors.affiliation: Division of Inborn Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Giordano
authors.affiliation: Division of Inborn Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Fasan
authors.affiliation: Department of Biomedicine and Prevention, School of Medicine, University of Rome "Tor Vergata" and Fondazione PTV "Policlinico Tor Vergata", Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Novelli
authors.affiliation: National Research Council, Institute of Food Science, via Roma 64, 83100 Avellino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Facchiano
authors.affiliation: Division of Inborn Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Italy. Electronic address: alberto.burlina@unipd.it.
authors.forename: A B
authors.initials: AB
authors.lastname: Burlina
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005693:Galactosemias / Q000175:diagnosis / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D008297:Male; D020125:Mutation, Missense; D015997:Neonatal Screening; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase / Q000235:genetics*; D055815:Young Adult
chemical_list: D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase
keywords: Classic galactosemia; GALT variations; In silico analysis; Long-term outcome