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Biochemical changes and clinical outcomes in 34 patients with classic galactosemia

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Impaired activity of galactose-1-phosphate uridyltransferase (GALT) causes galactosemia, an autosomal recessive disorder of galactose metabolism. Early initiation of a galactose-restricted diet can prevent or resolve neonatal complications. Despite therapy, patients often experience long-term complications including speech impairment, learning disabilities, and premature ovarian insufficiency in females. This study evaluates clinical outcomes in 34 galactosemia patients with markedly reduced GALT activity and compares outcomes between patients with different levels of mean galactose-1-phosphate in red blood cells (GAL1P) using logistic regression: group 1 (n = 13) GAL1P ≤1.7 mg/dL vs. group 2 (n = 21) GAL1P ≥ 2 mg/dL. Acute symptoms at birth were comparable between groups (p = 0.30) with approximately 50% of patients presenting with jaundice, liver failure, and failure-to-thrive. However, group 2 patients had significantly higher prevalence of negative long-term outcomes compared to group 1 patients (p = 0.01). Only one of 11 patients >3 yo in group 1 developed neurological and severe behavioral problems of unclear etiology. In contrast, 17 of 20 patients >3 yo in group 2 presented with one or more long-term complications associated with galactosemia. The majority of females ≥15 yo in this group also had impaired ovarian function with markedly reduced levels of anti-Müllerian hormone. These findings suggest that galactosemia patients with higher GAL1P levels are more likely to have negative long-term outcome. Therefore, evaluation of GAL1P levels on a galactose-restricted diet might be helpful in providing a prognosis for galactosemia patients with rare or novel genotypes whose clinical presentations are not well known.

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References

  • Balakrishnan B, Chen W, Tang M et al (2016) Galactose-1 phosphate uridylyltransferase (GalT) gene: a novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts. Biochem Biophys Res Commun 470:205–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bandyopadhyay S, Chakrabarti J, Banerjee S et al (2003) Prenatal exposure to high galactose adversely affects initial gonadal pool of germ cells in rats. Hum Reprod 18:276–282

    Article  CAS  PubMed  Google Scholar 

  • Batey LA, Welt CK, Rohr F et al (2013) Skeletal health in adult patients with classic galactosemia. Osteoporo Int : J Estab Result Coop Between Europe Found Osteoporo Natl Osteoporo Found USA 24:501–509

    Article  CAS  Google Scholar 

  • Berry GT (2014) Classic Galactosemia and clinical variant Galactosemia. In: Pagon RA, Adam MP, Ardinger HH et al (eds). GeneReviews, Seattle

  • Berry GT, Elsas LJ (2011) Introduction to the Maastricht workshop: lessons from the past and new directions in galactosemia. J Inherit Metab Dis 34:249–255

    Article  PubMed  Google Scholar 

  • Calderon FR, Nelson L, Dobrowolski P et al (2007) Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene. J Inherit Metab Dis 30:818

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Yager C, Reynolds R, Palmieri M, Segal S (2002) Erythrocyte galactose 1-phosphate quantified by isotope-dilution gas chromatography-mass spectrometry. Clin Chem 48:604–612

    CAS  PubMed  Google Scholar 

  • Chen YT, Mattison DR, Feigenbaum L, Fukui H, Schulman JD (1981) Reduction in oocyte number following prenatal exposure to a diet high in galactose. Science 214:1145–1147

    Article  CAS  PubMed  Google Scholar 

  • Coelho AI, Rubio-Gozalbo ME, Vicente JB, Rivera I (2017) Sweet and sour: an update on classic galactosemia. J Inherit Metab Dis 40:325–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coffee B, Hjelm LN, DeLorenzo A, Courtney EM, Yu C, Muralidharan K (2006) Characterization of an unusual deletion of the galactose-1-phosphate uridyl transferase (GALT) gene. Genet Med 8:635–640

  • Committee on Gynecologic Practice (2015) Committee opinion no. 618: ovarian reserve testing. Obstet Gynecol 125:268–273

    Article  Google Scholar 

  • Coss KP, Hawkes CP, Adamczyk B et al (2014a) N-glycan abnormalities in children with galactosemia. J Proteome Res 13:385–394

    Article  CAS  PubMed  Google Scholar 

  • Coss KP, Treacy EP, Cotter EJ et al (2014b) Systemic gene dysregulation in classical Galactosaemia: is there a central mechanism? Mol Genet Metab 113:177–187

    Article  CAS  PubMed  Google Scholar 

  • Elsas LJ 2nd, Lai K (1998) The molecular biology of galactosemia. Genet Med : Off J Am College Med Genet 1:40–48

    Article  CAS  Google Scholar 

  • Frederick AB, Cutler DJ, Fridovich-Keil JL (2017) Rigor of non-dairy galactose restriction in early childhood, measured by retrospective survey, does not associate with severity of five long-term outcomes quantified in 231 children and adults with classic galactosemia. J Inherit Metab Dis 40:813-821

  • Fridovich-Keil JL, Gubbels CS, Spencer JB, Sanders RD, Land JA, Rubio-Gozalbo E (2011) Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 34:357–366

    Article  CAS  PubMed  Google Scholar 

  • Gitzelmann R, Steinmann B (1984) Galactosemia: how does long-term treatment change the outcome? Enzyme 32:37–46

    Article  CAS  PubMed  Google Scholar 

  • Goldstein N, Cohen Y, Pode-Shakked B et al (2011) The GALT rush: high carrier frequency of an unusual deletion mutation of the GALT gene in the Ashkenazi population. Mol Genet Metab 102:157–160

    Article  CAS  PubMed  Google Scholar 

  • Guerrero NV, Singh RH, Manatunga A, Berry GT, Steiner RD, Elsas LJ 2nd (2000) Risk factors for premature ovarian failure in females with galactosemia. J Pediatr 137:833–841

    Article  CAS  PubMed  Google Scholar 

  • Holden HM, Rayment I, Thoden JB (2003) Structure and function of enzymes of the Leloir pathway for galactose metabolism. J Biol Chem 278:43885–43888

    Article  CAS  PubMed  Google Scholar 

  • Hughes J, Ryan S, Lambert D et al (2009) Outcomes of siblings with classical galactosemia. J Pediatr 154:721–726

    Article  PubMed  Google Scholar 

  • Hutchesson AC, Murdoch-Davis C, Green A et al (1999) Biochemical monitoring of treatment for galactosaemia: biological variability in metabolite concentrations. J Inherit Metab Dis 22:139–148

    Article  CAS  PubMed  Google Scholar 

  • Hyman SL, Stewart PA, Schmidt B et al (2012) Nutrient intake from food in children with autism. Pediatrics 130(Suppl 2):S145–S153

    Article  PubMed  PubMed Central  Google Scholar 

  • Institute CaLS (2010) Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - 3rd Edition (C28-A3)

  • Jama M, Nelson L, Pont-Kingdon G, Mao R, Lyon E (2007) Simultaneous amplification, detection, and analysis of common mutations in the galactose-1-phosphate uridyl transferase gene. J Molec Diagnos 9:618–623

  • Jumbo-Lucioni PP, Garber K, Kiel J et al (2012) Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes. J Inherit Metab Dis 35:1037–1049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jumbo-Lucioni PP, Hopson ML, Hang D, Liang Y, Jones DP, Fridovich-Keil JL (2013) Oxidative stress contributes to outcome severity in a Drosophila Melanogaster model of classic galactosemia. Dis Model Mech 6:84–94

    Article  CAS  PubMed  Google Scholar 

  • Lai K, Elsas LJ (2001) Structure-function analyses of a common mutation in blacks with transferase-deficiency galactosemia. Mol Genet Metab 74(1–2):264–272

  • Lai K, Elsas LJ, Wierenga KJ (2009) Galactose toxicity in animals. IUBMB Life 61:1063–1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai K, Langley SD, Singh RH, Dembure PP, Hjelm LN, Elsas LJ 2nd (1996) A prevalent mutation for galactosemia among black Americans. J Pediatr 128:89–95

    Article  CAS  PubMed  Google Scholar 

  • Lebea PJ, Pretorius PJ (2005) The molecular relationship between deficient UDP-galactose uridyl transferase (GALT) and ceramide galactosyltransferase (CGT) enzyme function: a possible cause for poor long-term prognosis in classic galactosemia. Med Hypotheses 65:1051–1057

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Ptolemy AS, Harmonay L, Kellogg M, Berry GT (2010) Quantification of galactose-1-phosphate uridyltransferase enzyme activity by liquid chromatography-tandem mass spectrometry. Clin Chem 56:772–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Ptolemy AS, Harmonay L, Kellogg M, Berry GT (2011) Ultra fast and sensitive liquid chromatography tandem mass spectrometry based assay for galactose-1-phosphate uridylyltransferase and galactokinase deficiencies. Mol Genet Metab 102:33–40

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Xia B, Gleason TJ et al (2012) N- and O-linked glycosylation of total plasma glycoproteins in galactosemia. Mol Genet Metab 106:442–454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacDonald A, Gokmen-Ozel H, van Rijn M, Burgard P (2010) The reality of dietary compliance in the management of phenylketonuria. J Inherit Metab Dis 33:665–670

    Article  PubMed  Google Scholar 

  • Mari-Bauset S, Llopis-Gonzalez A, Zazpe I, Mari-Sanchis A, Morales Suarez-Varela M (2017) Comparison of nutritional status between children with autism spectrum disorder and typically developing children in the Mediterranean region (Valencia, Spain). Autism 21:310–322

  • Palmieri M, Mazur A, Berry GT et al (1999) Urine and plasma galactitol in patients with galactose-1-phosphate uridyltransferase deficiency galactosemia. Metab Clin Exp 48:1294–1302

    Article  CAS  PubMed  Google Scholar 

  • Panis B, Gerver WJ, Rubio-Gozalbo ME (2007) Growth in treated classical galactosemia patients. Eur J Pediatr 166:443–446

    Article  PubMed  Google Scholar 

  • Phillips KL, Schieve LA, Visser S et al (2014) Prevalence and impact of unhealthy weight in a national sample of US adolescents with autism and other learning and behavioral disabilities. Matern Child Health J 18:1964–1975

    Article  PubMed  PubMed Central  Google Scholar 

  • Riehman K, Crews C, Fridovich-Keil JL (2001) Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem 276:10634–10640

    Article  CAS  PubMed  Google Scholar 

  • Robertson A, Singh RH, Guerrero NV, Hundley M, Elsas LJ (2000) Outcomes analysis of verbal dyspraxia in classic galactosemia. Genet Med 2:142–148

  • Ryan EL, Lynch ME, Taddeo E, Gleason TJ, Epstein MP, Fridovich-Keil JL (2013) Cryptic residual GALT activity is a potential modifier of scholastic outcome in school age children with classic galactosemia. J Inherit Metab Dis 36:1049–1061

    Article  PubMed  Google Scholar 

  • Sanders RD, Spencer JB, Epstein MP et al (2009) Biomarkers of ovarian function in girls and women with classic galactosemia. Fertil Steril 92:344–351

    Article  CAS  PubMed  Google Scholar 

  • Schweitzer-Krantz S (2003) Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia. Eur J Pediatr 162(Suppl 1):S50–S53

    Article  CAS  PubMed  Google Scholar 

  • Schweitzer S, Shin Y, Jakobs C, Brodehl J (1993) Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr 152:36–43

    Article  CAS  PubMed  Google Scholar 

  • Shield JP, Wadsworth EJ, MacDonald A et al (2000) The relationship of genotype to cognitive outcome in galactosaemia. Arch Dis Child 83:248–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shih LY, Suslak L, Rosin I, Searle BM, Desposito F (1984) Gene dosage studies supporting localization of the structural gene for galactose-1-phosphate uridyl transferase (GALT) to band p13 of chromosome 9. Am J Med Genet 19:539–543

    Article  CAS  PubMed  Google Scholar 

  • Shulman S, Fisch RO, Zempel CE, Gadish O, Chang PN (1991) Children with phenylketonuria: the interface of family and child functioning. J Dev Behav Pediatr : JDBP 12:315–321

    Article  CAS  PubMed  Google Scholar 

  • Spencer JB, Badik JR, Ryan EL et al (2013) Modifiers of ovarian function in girls and women with classic galactosemia. J Clin Endocrinol Metab 98:E1257–E1265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stockler S, Moeslinger D, Herle M, Wimmer B, Ipsiroglu OS (2012) Cultural aspects in the management of inborn errors of metabolism. J Inherit Metab Dis 35:1147–1152

    Article  CAS  PubMed  Google Scholar 

  • Tang M, Facchiano A, Rachamadugu R et al (2012) Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose-1-phosphate uridylyltransferase gene. Hum Mutat 33:1107–1115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang M, Siddiqi A, Witt B et al (2014) Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model. Europe J Human Genet 22:1172–1179

  • Tietz NW (1995) Clinical guide to laboratory tests, 3rd edn. Saunders, Philadelphia, pp 268–273

  • Tyfield L, Reichardt J, Fridovich-Keil J et al (1999) Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat 13:417–430

    Article  CAS  PubMed  Google Scholar 

  • Tyfield LA (2000) Galactosaemia and allelic variation at the galactose-1-phosphate uridyltransferase gene: a complex relationship between genotype and phenotype. Eur J Pediatr 159(Suppl 3):S204–S207

    Article  CAS  PubMed  Google Scholar 

  • Van Calcar SC, Bernstein LE, Rohr FJ, Scaman CH, Yannicelli S, Berry GT (2014) A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab 112:191–197

    Article  PubMed  Google Scholar 

  • van Erven B, Welling L, van Calcar SC et al (2017) Bone health in classic Galactosemia: systematic review and meta-analysis. JIMD Rep 35:87–96

    Article  PubMed  Google Scholar 

  • Viggiano E, Marabotti A, Burlina AP et al (2015) 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. Gene 559:112–118

    Article  CAS  PubMed  Google Scholar 

  • Viggiano E, Marabotti A, Politano L, Burlina A (2017) Galactose-1-phosphate Uridyltransferase deficiency: a literature review of the putative mechanisms of short and long-term complications and allelic variants. Clin Genet. doi: 10.1111/cge.13030

  • Waggoner DD, Buist NR, Donnell GN (1990) Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inherit Metab Dis 13:802–818

    Article  CAS  PubMed  Google Scholar 

  • Waisbren SE, Potter NL, Gordon CM et al (2012) The adult galactosemic phenotype. J Inherit Metab Dis 35:279–286

    Article  PubMed  Google Scholar 

  • Walter JH, Collins JE, Leonard JV (1999) Recommendations for the management of galactosaemia. UK Galactosaemia Steering Group. Arch Disease Childhood 80:93–96

    Article  CAS  Google Scholar 

  • Webb AL, Singh RH, Kennedy MJ, Elsas LJ (2003) Verbal dyspraxia and galactosemia. Pediatr Res 53:396–402

    Article  CAS  PubMed  Google Scholar 

  • Welling L, Bernstein LE, Berry GT et al (2017) International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. J Inherit Metab Dis 40:171–176

    Article  PubMed  Google Scholar 

  • Yang YP, Corley N, Garcia-Heras J (2002) Molecular analysis in newborns from Texas affected with galactosemia. Hum Mutat 19:82–83

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the ARUP Institute for Clinical and Experimental Pathology®. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

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Authors and Affiliations

  1. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Tatiana Yuzyuk, Marzia Pasquali & Nicola Longo

  2. ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT, 84108, USA

    Tatiana Yuzyuk, Marzia Pasquali & Nicola Longo

  3. Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, UT, USA

    Krista Viau, Ashley Andrews & Nicola Longo

  4. Boston Children’s Hospital, Boston, MA, USA

    Krista Viau

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  1. Tatiana Yuzyuk
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  2. Krista Viau
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Correspondence to Tatiana Yuzyuk.

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Communicated by: William Ross Wilcox

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Yuzyuk, T., Viau, K., Andrews, A. et al. Biochemical changes and clinical outcomes in 34 patients with classic galactosemia. J Inherit Metab Dis 41, 197–208 (2018). https://doi.org/10.1007/s10545-018-0136-9

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  • DOI: https://doi.org/10.1007/s10545-018-0136-9

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