Abstract
Classical galactosemia is an autosomal recessive disorder resulting from deficient galactose-1-phosphateuridyl transferase (GALT) activity. Verbal dyspraxia is an unusual outcome in galactosemia. Here we validated a simplified breath test of total body galactose oxidation against genotype and evaluated five potential biochemical risk indicators for verbal dyspraxia in galactosemia: cumulative percentage dose (CUMPCD) of 13CO2 in breath, mean erythrocyte galactose-1-phosphate, highest erythrocyte galactose-1-phosphate, mean urinary galactitol, and erythrocyte GALT activity. Thirteen controls and 42 patients with galactosemia took a 13C-galactose bolus, and the (CUMPCD) of 13CO2 in expired air was determined. Patients with <5% CUMPCD had mutant alleles that severely impaired human GALT enzyme catalysis. Patients with ≥5% CUMPCD had milder mutant human GALT alleles. Twenty-four patients consented to formal speech evaluation; 15 (63%) had verbal dyspraxia. Dyspraxic patients had significantly lower CUMPCD values (2.84 ± 5.76%versus 11.51 ± 7.67%;p < 0.008) and significantly higher mean erythrocyte galactose-1-phosphate (3.38 ± 0.922 mg/dL versus 1.92 ± 1.28 mg/dL;p = 0.019) and mean urinary galactitol concentrations (192.4 ± 75.8 mmol/mol creatinine versus 122.0 ± 56.4;p = 0.048) than patients with normal speech. CUMPCD values <5%, mean erythrocyte galactose-1-phosphate levels >2.7 mg/dL, and mean urinary galactitol levels >135 mmol/mol creatinine were associated with dyspraxic outcome with odds ratios of 21, 13, and 5, respectively. We conclude that total body oxidation of galactose to CO2 in expired air reflects genotype and that this breath test is a sensitive predictor of verbal dyspraxia in patients with galactosemia.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- hGALT:
-
human galactose-1-phosphate-uridyltransferase
- hUGP2:
-
human UDP-glucose pyrophosphorylase
- UDP-gal:
-
UDP-galactose
- UDP-glu:
-
UDP-glucose
- OR:
-
odds ratio
- CUMPCD:
-
cumulative percentage dose
References
Beutler E, Beluda ML, Sturgeon P, Day RW 1995 A new genetic abnormality resulting in galactose-1-phosphate deficiency. Lancet 1: 353–355
Holton JB, Walter JH, Tyfield LA 2001 Galactosemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York, 1553–1587.
Elsas LJ, Lai K 1998 The molecular biology of galactosemia. Genet Med 1: 40–48. Available at: http://www.pediatrics/medgen/research/db.html
Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas LJ, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD 1999 Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat 13: 417–430. Available at: http://www.ich.bris.ac.uk/galtda/mutations.html
Elsas LJ, Langley SD, Steele R, Eringer J, Fridovich-Keil JL, Brown A, Singh R, Fernhoff P, Hjelm LN, Dembure PP 1995 Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes. Am J Hum Gen 56: 630–639
Elsas LJ, Fernhoff P, Brown A 1983 Newborn screening for metabolic disorders in the state of Georgia. In: Naruse H, Irie M (eds) Neonatal Screening: Proceedings of the International Symposium on Neonatal Screening for Inborn Errors of Metabolism. Excerpta Medica, Tokyo, 117–118.
Waggoner DD, Buist NRM, Donnell GN 1990 Long-term prognosis in galactosemia: results of a survey of 350 cases. J Inherit Metab Dis 13: 802–818
Berry GT, Nissim I, Lin Z, Mazur A, Gibson JB, Segal S 1995 Endogenous synthesis of galactose in normal men and patients with hereditary galactosemia. Lancet 346: 1073–1074
Berry GT, Palmieri M, Gross KC, Acosta PB, Henstenberg JA, Mazur A, Reynolds R, Segal S 1993 The effects of dietary fruits and vegetables on urinary galactitol excretion in galactose-1-phosphate uridyltransferase deficiency. J Inherit Metab Dis 16: 91–100
Robertson A, Singh RH, Guerrero NV, Hundley M, Elsas LJ 2000 Outcomes analysis of verbal dyspraxia in classic galactosemia. Genet Med 2: 142–148
Schweitzer S, Shin Y, Jakobs C, Brodehl J 1993 Long term outcome in 134 patients with galactosemia. Eur J Pediatr 154: S45–S49
Hansen TWR, Henrichsen B, Rasmussen RK, Carling A, Andreassen AB, Skjeldal O 1996 Neuropsychological and linguistic follow-up studies of children with galactosaemia from an unscreened population. Acta Pediatr 85: 1197–1201
Kaufman FR, Reichardt JKV, Ng WG, Xu YK, Manis FR, McBride-Chang C, Wolff JA 1994 Correlation of cognitive, neurologic, and ovarian outcome with the Q188R mutation of the galactose-1-phosphate uridyltransferase gene. J Pediatr 125: 225–227
Nelson DC 1995 Verbal dyspraxia in children with galactosemia. Eur J Pediatr 154( S2): S6–S7
Nelson DC, Waggoner DD, Donnell GD, Tuerck JM, Buist NRM 1991 Verbal dyspraxia in treated galactosemia. Pediatrics 88: 346–350
Berry GT, Nissim I, Gibson JB, Mazur AT, Lin Z, Elsas LJ, Singh RH, Klein PD, Segal S 1997 Quantitative assessment of whole body galactose metabolism in galactosemic patients. Eur J Pediatr 156( S1): S43–S49
Berry GT, Singh RH, Mazur AT, Palmieri MJ, Guerrero NV, Kennedy MJ, Chen J, Reynolds R, Palmieri MJ, Klein PD, Segal S, Elsas LJE 2000 Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes. J Pediatr Res 48: 323–328
Lai K, Langley SD, Singh RS, Dembure PP, Hjelm LN, Elsas LJ 1996 A prevalent mutation for galactosemia among black Americans. J Pediatr 128: 89–95
Lai K, Elsas LJ 2001 Structure-function analysis of a common mutation in blacks with transferase-deficiency galactosemia. Mol Genet Metab 74: 264–272
Guerrero NV, Singh RH, Manatunga A, Berry GT, Steiner RD, Elsas LJ 2000 Risk factors for premature ovarian failure in females with galactosemia. J Pediatr 137: 833–841
Elsas LJ, Ellerine NP, Klein PD 1993 Practical methods to estimate whole body leucine oxidation in maple syrup urine disease. Pediatr Res 33: 445–451
de Weir JR 1949 New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 109: 1–9
Schofield WN 1985 Predicting basal metabolic rate, new standards and review of previous work. Hum Nutr Clin Nutr 39C: 5–41
Hickman LA 1997 The Apraxia Profile. A Descriptive Assessment Tool. Communication Skill Builders, a division of the Psychological Corporation, San Antonio, Texas
Bernmeyer H 1974 Galactose-1-P: determination as galactose after hydrolysis by alkaline phosphatase. In: Bermeyer H (ed) Methods of Enzymatic Analysis. pp 1291–1295. Verlag Chemie International, Deerfield Beach, FL
Rosner B 1994 Fundamentals of Biostatistics, 4th Ed. Wadsworth Publishing Co., New York
Lai K, Willis A, Elsas LJ 1999 The biochemical role of glutamine 188 in human galactose-1-phosphate uridyltransferase. J Biol Chem 274: 6559–6566
Hodge MN, Hancock HR 1994 Assessment of children with developmental apraxia of speech: a rationale. Clin Commun Disord 4: 91–101
Gitzelmann R 1995 Galactose-1-phosphate in the pathophysiology of galactosemia. Eur J Pediatr 154: S45–S49
Lai K, Elsas LJ 2000 Overexpression of human UDP-glucose pyrophosphorylase rescues galactose-1-phosphate uridyltransferase deficient yeast. Biochem Biophys Res Commun 271: 392–400
Stambolian D 1988 Galactose and cataract. Surv Ophthalmol 32: 333–349
Ai Y, Zheng Z, O'Brian-Jenkins A, Bernard DJ, Wynshaw-Boris T, Ning C, Reynolds R, Segal S, Huang K, Stambolian D 2000 A mouse model of galactose-induced cataracts. Hum Mol Genet 9: 1821–1827
Berry GT 1995 The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr 154: S53–S64
Jacobs C, Schweitzer S, Dorland B 1995 Galactitol in galactosemia. Eur J Pediatr 154: S45–S49
Green DA, Lang HJ, Stevens MJ, Obrosova IG 1999 Evaluation of aldose reductase inhibitor vs. sorbitol dehydrogenase inhibitor on diabetes-induced changes in retinal NAD(P)-redox status: support for the role of aldose reductase but not sorbitol dehydrogenase in diabetic retinopathy. Invest Ophthalmol Vis Sci 40: S370
Kashiwagi A, Asahani T, Ikebuchi M, Tanaka Y, Takagi Y, Nishio Y, Kikkawa R, Shigeta Y 1994 Abnormal glutathione metabolism and increased cytotoxicity of caused H2O2 in human umbilical vein endothelial cells cultured in high glucose medium. Diabetologia 37: 264–269
Qaun MR, Wells HJ, Wells WW, Sherman FE, Egan TJ 1966 Galactitol in the tissues of a galactosemic child. Am J Dis Child 112: 477–478
Berry GT, Hunter JV, Wang Z, Dreha S, Mazur A, Brooks DG, Ning C, Zimmerman RA, Segal S 2001 In vivo evidence of brain galactitol accumulation in an infant with galactosemia and encephalopathy. J Pediatr 138: 260–262
Wang ZJ, Berry GT, Dreha SF, Zhao H, Segal S, Zimmerman RA 2001 Proton magnetic resonance spectroscopy of brain metabolites in galactosemia. Ann Neurol 50: 266–269
Ornstein KS, McGuire J, Berry GT, Roth S, Segal S 1992 Abnormal galactosylation of complex carbohydrates in cultured fibroblasts from patients with galactose-1-phosphate uridyltransferase deficiency. Pediatr Res 31: 508–511
Prestoz LLC, Couto AS, Shin YS, Petry G 1997 Altered follicle stimulating hormone isoforms in female galactosaemia patients. Eur J Pediatr 156: 116–120
Charlewood J, Clayton P, Keir G, Mian N, Winchester B 1998 Defective galactosylation of serum transferrin in galactosemia. Glycobiology 8: 351–357
Petry K, Greinix HT, Nudelman E, Eisen H, Hakomori SI, Levy H, Reichardt JKV 1991 Characterization of a novel biochemical abnormality in galactosemia: deficiency of glycolipids containing galactose or N-acetylgalactosamine and accumulation of precursors in brain and lymphocytes. Biochem Med Metab Biol 46: 93–104
Hakomori S 1990 Bifunctional role of glycosphingolipids. J Biol Chem 265: 18713–18716
Ng WG, Xu YK, Kaufmann FR, Donnell GN 1989 Deficit of uridine diphosphate glucose and uridine diphosphate galactose in galactosemia. J Inherit Metab Dis 12: 257–266
Gibson JB, Reynolds RA, Palmieri MJ, Berry GT, Elsas LJ, Levy H, Segal S 1995 Comparison of erythrocyte uridine sugar nucleotide levels in normals, classic galactosemics, and patients with other metabolic disorders. Metabolism 44: 597–604
Acknowledgements
We thank Dr. Amita Manatunga, George Cotsonis, and Azhar Nizam for statistical guidance and advice. We thank the Emory Genetics Lab, Dr. Phillip Dembure, and Sharon Langley for biochemical phenotyping and molecular genotyping of analytes and GALT. We thank Dr. Stan Konopka of ABD, LLC, for quantifying 13CO2 in breath. We are also thankful for the participation of the patients and their referring physicians, without whom this research would not be possible. We thank Drs. Paul Fernhoff and R. Dwain Blackston for aiding in the management of the patients.
Author information
Authors and Affiliations
Corresponding author
Additional information
This research was supported in part by a grant from the Zoé Rochat Foundation for Research in Galactosemia, from Advanced Breath Diagnostics, LLC, and U.S. Public Health Services Grant MO1-RR00039 to the General Clinical Research Center of Emory University.
Rights and permissions
About this article
Cite this article
Webb, A., Singh, R., Kennedy, M. et al. Verbal Dyspraxia and Galactosemia. Pediatr Res 53, 396–402 (2003). https://doi.org/10.1203/01.PDR.0000049666.19532.1B
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000049666.19532.1B
This article is cited by
-
Biochemical changes and clinical outcomes in 34 patients with classic galactosemia
Journal of Inherited Metabolic Disease (2018)
-
Voice disorders in children with classic galactosemia
Journal of Inherited Metabolic Disease (2011)
-
Introduction to the Maastricht workshop: lessons from the past and new directions in galactosemia
Journal of Inherited Metabolic Disease (2011)
-
Cross‐sectional analysis of speech and cognitive performance in 32 patients with classic galactosemia
Journal of Inherited Metabolic Disease (2011)
-
Is prenatal myo‐inositol deficiency a mechanism of CNS injury in galactosemia?
Journal of Inherited Metabolic Disease (2011)
