Abstract
Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a ‘best practice’ for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches.
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References
Anasti J, Kalantaridou S, Kimzey L, Defensor R, Nelson L (1998) Bone loss in young women with karyotypically normal spontaneous premature ovarian failure. Obstet Gynecol 91:12–15
Antshel K, Epstein I, Waisbren S (2004) Cognitive strengths and weaknesses in children and adolescents homozygous for the galactosemia Q188R mutation: a descriptive study. Neuropsychology 18:658–664
Berry G (2011) Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia? J Inherit Metab Dis 34:345–355
Berry GT, Nissim I, Lin Z, Mazur AT, Gibson JB, Segal S (1995) Endogenous synthesis of galactose in normal men and patients with hereditary galactosemia. Lancet 346:1073–1074
Berry GT, Reynolds RA, Yager CT, Segal S (2004) Extended [13C]galactose oxidation studies in patients with galactosemia. Mol Genet Metab 82:130–136
Bhat M, Haase C, Lee P (2005) Social outcome in treated individuals with inherited metabolic disorders: UK study. J Inherit Metab Dis 28:825–830
Bosch AM (2006) Classical galactosaemia revisited. J Inherit Metab Dis 29:516–525
Bosch A (2011) Classic galactosemia: dietary dilemmas. J Inherit Metab Dis 34:257–260
Bosch AM, Bakker HD, Wenniger-Prick LJ, Wanders RJ, Wijburg FA (2004a) High tolerance for oral galactose in classical galactosaemia: dietary implications. Arch Dis Child 89:1034–1036
Bosch AM, Grootenhuis MA, Bakker HD, Heijmans HS, Wijburg FA, Last BF (2004b) Living with classical galactosemia: health-related quality of life consequences. Pediatrics 113:e423–e428
Bosch A, Maurice-Stam H, Wijburg F, Grootenhuis M (2009) Remarkable differences: the course of life of young adults with galactosaemia and PKU. J Inherit Metab Dis 32:706–712
Carney A, Sanders R, Garza K et al (2009) Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Hum Mol Genet 18:1624–1632
Doyle C, Channon S, Orlowska D, Lee P (2010) The neuropsychological profile of galactosaemia. J Inherit Metab Dis 33:603–609
Ficicioglu C, Yager C, Segal S (2005) Galactitol and galactonate in red blood cells of children with the Duarte/galactosemia genotype. Mol Genet Metab 84:152–159
Ficicioglu C, Thomas N, Yager C et al (2008) Duarte (DG) galactosemia: a pilot study of biochemical and neurodevelopmental assessment in children detected by newborn screening. Mol Genet Metab 95:206–212
Fridovich-Keil JL, Walter JH (2008) Galactosemia. In: Valle D, Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A (eds) The online metabolic & molecular bases of inherited disease. McGraw-Hill, http://www.ommbid.com/
Fridovich-Keil J, Gubbels C, Spencer J, Sanders R, Land J, Rubio-Gozalbo E (2011) Ovarian function in girls and women with GALT-deficiency galactosemia. J Inherit Metab Dis 34:357–366
Gibson J (1995) Gonadal function in galactosemics and in galactose-intoxicated animals. Eur J Pediatr 154:S14–S20
Gubbels C, Kuppens S, Bakker J et al (2009) Pregnancy in classic galactosemia despite undetectable anti-Müllerian hormone. Fertility and Sterility. Fertil Steril 91(1293):e13–e16
Gubbels C, Maurice-Stam H, Berry G et al (2011) Psychosocial developmental milestones in men with classic galactosemia. J Inherit Metab Dis 34:415–419
Henderson M, Shapiro L, McCowan C (1988) Galactosemia detection from phenylketonuria screening. Clin Chem 34:188–189
Henderson H, Leisegang F, Brown R, Eley B (2002) The clinical and molecular spectrum of galactosemia in patients from the Cape Town region of South Africa. BMC Pediatr 2:7
Hoefnagel D, Wurster-Hill D, Child E (1979) Ovarian failure in Galactosaemia. Lancet 314:1197
Holton JB, Leonard JV (1994) Clouds still gathering over galactosaemia. Lancet 344:1242–1243
Honeyman M, Green A, Holton J, Leonard J (1993) Galactosaemia: results of the British Paediatric Surveillance Unit Study, 1988-90. Arch Dis Child 69:339–341
Hughes J, Ryan S, Lambert D et al (2009) Outcomes of siblings with classical galactosemia. J Pediatr 154:721–726
Huidekoper H, Bosch A, van der Crabben S, Sauerwein H, Ackermans M, Wijburg F (2005) Short-term exogenous galactose supplementation does not influence rate of appearance of galactose in patients with classical galactosemia. Mol Genet Metab 84:265–272
Kalantaridou S, Naka K, Papanikolaou E et al (2004) Impaired endothelial function in young women with premature ovarian failure: normalization with hormone therapy. J Clin Endocrinol Metab 89:3907–3913
Kaufman F, Kogut M, Donnell G, Koch H, Goebelsmann U (1979) Ovarian failure in galactosaemia. Lancet 2:737–738
Kaufman FR, Loro ML, Azen C, Wenz E, Gilsanz V (1993) Effect of hypogonadism and deficient calcium intake on bone density in patients with galactosemia. J Pediatr 123:365–370
Kaufman FR, Reichardt JK, Ng WG et al (1994) Correlation of cognitive, neurologic, and ovarian outcome with the Q188R mutation of the galactose-1-phosphate uridyltransferase gene. J Pediatr 125:225–227
Kaufman FR, McBride-Chang C, Manis FR, Wolff JA, Nelson MD (1995) Cognitive functioning, neurologic status and brain imaging in classical galactosemia. Eur J Pediatr 154:S2–S5
Kelly S, Katz S, Burns J, Boylan J (1970) Screening for galactosemia in New York State. Public Health Rep 85:575–578
Kiess W, Conway G, Ritzen M et al (2002) Induction of puberty in the hypogonadal girl–practices and attitudes of pediatric endocrinologists in Europe. Horm Res 57:66–71
Komrower G (1982) Galactosaemia - Thirty years on. The experience of a generation. F.P. Hudson Memorial Lecture. J Inherit Metab Dis 5:96–104
Krabbi K, Uudelepp M, Joost K, Zordania R, Õunap K (2011) Long-term complications in Estonian galactosemia patients with a less strict lactose-free diet and metabolic control. Mol Genet Metab 103:249–253
Lee PJ, Lilburn M, Wendel U, Schadewaldt P (2003) A woman with untreated galactosaemia. Lancet 362:446
Lee B, Cheon C, Kim J et al (2011) Low prevalence of classical galactosemia in Korean population. J Hum Genet 56:94–96
Leslie ND, Yager KL, McNamara PD, Segal S (1996) A mouse model of galactose-1-phosphate uridyl transferase deficiency. Biochem Mol Med 59:7–12
Manis F, Cohn L, McBride-Chang C, Wolff J, Kaufman F (1997) A longitudinal study of cognitive functioning in patients with classical galactosaemia, including a cohort treated with oral uridine. J Inherit Metab Dis 20:549–555
Mason HH, Turner ME (1935) Chronic galactosemia. Am J Dis Child 50:359–376
Murphy M, McHugh B, Tighe O et al (1999) Genetic basis of transferase-deficient galactosaemia in Ireland and the population history of the Irish Travellers. Eur J Hum Genet 7:549–554
Ning C, Reynolds R, Chen J et al (2000) Galactose metabolism by the mouse with galactose-1-phosphate uridyltransferase deficiency. Pediatr Res 48:211–217
Panis B, Forget PP, van Kroonenburgh MJPG et al (2004) Bone metabolism in galactosemia. Bone 35:982–987
Panis B, Bakker JA, Sels J-PJE, Spaapen LJM, van Loon LJC, Rubio-Gozalbo ME (2006a) Untreated classical galactosemia patient with mild phenotype. Mol Genet Metab 89:277–279
Panis B, Vermeer C, van Kroonenburgh MJPG et al (2006b) Effect of calcium, vitamins K1 and D3 on bone in galactosemia. Bone 39:1123–1129
Pesce M, Bodourian S (1982) Clinical significance of plasma galactose and erythrocyte galactose-1-phosphate measurements in transferase-deficient galactosemia and in individuals with below-normal transferase activity. Clin Chem 28:301–305
Robinson A (1963) The assay of galactokinase and galactose-1-phosphate uridyl transferase activity in human erythrocytes. A presumed test for heterozygous carriers of the galactosemic defect. J Exp Med 118:359–370
Rubio-Gozalbo M, Hamming S, van Kroonenburgh M, Bakker J, Vermeer C, Forget P (2002) Bone mineral density in patients with classic galactosaemia. Arch Dis Child 87:57–60
Rubio-Gozalbo M, Gubbels C, Bakker J, Menheere P, Wodzig W, Land J (2010) Gonadal function in male and female patients with classic galactosemia. Hum Reprod Update 16:177–188
Sanders R, Spencer J, Epstein M et al (2009) Biomarkers of ovarian function in girls and women with classic galactosemia. Fertil Steril 92:344–351
Schadewaldt P, Hoffmann B, Hammen H, Kamp G, Schweitzer-Krantz S, Wendel U (2010) Longitudinal assessment of intellectual achievement in patients with classical galactosemia. Pediatrics 125:e374–e381
Schweitzer S (1995) Newborn mass screening for galactosemia. Eur J Pediatr 154:S37–S39
Schweitzer S, Shin Y, Jakobs C, Brodehl J (1993) Long-term outcome in 134 patients with galactosemia. Eur J Pediatr 152:36–43
Schweitzer-Krantz S (2003) Early diagnosis of inherited metabolic disorders towards improving outcome: the controversial issue of galactosaemia. Eur J Pediatr 162:S50–S53
Segal S (1995) Galactosemia unsolved. Eur J Pediatr 154:S97–S102
Shield JP, Wadsworth EJ, MacDonald A et al (2000) The relationship of genotype to cognitive outcome in galactosaemia. Arch Dis Child 83:248–250
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
Waisbren S, Potter N, Gordon C et al (2011) The adult galactosemic phenotype. J Inherit Metab Dis 35:279–286
Walter JH, Collins JE, Leonard JV, Chiswick M, Marcovitch H (1999) Recommendations for the management of galactosaemia • Commentary. Arch Dis Child 80:93–96
Zlatunich C, Packman S (2005) Galactosaemia: early treatment with an elemental formula. J Inherit Metab Dis 28:163–168
Acknowledgments
We thank all of the health care professionals and their staff who helped to collect the data reported in this manuscript. This work is dedicated with admiration to all galactosemia patients and their families.
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This work was supported by the National Institutes of Health grant R01 DK059904 (to JLFK).
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Communicated by: Jean-Marie Saudubray
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Jumbo-Lucioni, P.P., Garber, K., Kiel, J. et al. Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes. J Inherit Metab Dis 35, 1037–1049 (2012). https://doi.org/10.1007/s10545-012-9477-y
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DOI: https://doi.org/10.1007/s10545-012-9477-y