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Journal of Inherited Metabolic Disease

, Volume 32, Issue 3, pp 412–415 | Cite as

Negative screening tests in classical galactosaemia caused by S135L homozygosity

  • E. Crushell
  • J. Chukwu
  • P. Mayne
  • J. Blatny
  • E. P. Treacy
Original Article

Summary

Classical galactosaemia is relatively common in Ireland due to a high carrier rate of the Q188R GALT mutation. It is screened for using a bacterial inhibition assay (BIA) for free galactose. A Beutler assay on day one of life is performed only in high risk cases (infants of the Traveller community and relatives of known cases). A 16-month-old Irish-born boy of Nigerian origin was referred for investigation of developmental delay, and failure to thrive. He had oral aversion to solids and his diet consisted of cow’s milk and milk-based cereal mixes. He was found to have microcephaly, weight <2nd percentile, hepatomegaly and bilateral cataracts. Coagulation screen was normal and transaminases were slightly elevated. His original newborn screen was reviewed and confirmed to have been negative; urinary reducing substances on three separate occasions were negative. Beutler assay demonstrated “absent” red cell galactose-1-phosphate uridyltransferase (GALT) activity. GALT enzyme activity was <0.5 gsubs/h per gHb confirming classical galactosaemia. Gal-1-P was elevated at 1.88 μmol/gHb. Mutation analysis of the GALT gene revealed S135L homozygosity. S135L/S135L galactosaemia is associated with absent red cell GALT activity but with approximately 10% activity in other tissues such as the liver and intestines, probably explaining the negative screening tests and the somewhat milder phenotype associated with this genotype. The patient was commenced on galactose-restricted diet; on follow-up at 2 years of age, growth had normalized but there was global developmental delay. In conclusion, galactosaemia must be considered in children who present with poor growth, hepatomegaly, developmental delay and cataracts and GALT enzyme analysis should be a first line test in such cases. Non-enzymatic screening methods such as urinary reducing substances and BIA for free galactose are not reliable in S135L homozygous galactosaemia.

Keywords

Newborn Screen GALT Activity G6PD Enzyme Classical Galactosaemia High Carrier Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

BIA

bacterial inhibition assay

CDG

congenital disorders of glycosylation

G6PD

glucose-6-phosphate dehydrogenase

G6PDD

glucose-6-phosphate dehydrogenase deficiency

GALT

galactose-1-phosphate uridyltransferase

MCH

mean corpuscular haemoglobin

MCV

mean corpuscular volume

References

  1. Badawi N, Cahalane SF, McDonald M, (1996) Galactosaemia–a controversial disorder. Screening and outcome, Ireland 1972–1992. Irish Med J 89:16–17Google Scholar
  2. Berry GT, Singh RH, Mazur AT, (2000) Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes. Pediatr Res 48: 323–328 doi: 10.1203/00006450-200009000-00010 PubMedCrossRefGoogle Scholar
  3. Beutler E, Baluda MC (1966) A simple spot screening test for galactosaemia. J Lab Clin Med 68:137PubMedGoogle Scholar
  4. Henderson H, Liesegang F, Brown R, (2002) Clinical and molecular spectrum of galactosaemia in patients from the Cape Town region of South Africa. BMC Pediatr 2:7 doi: 10.1186/1471-2431-2-7 PubMedCrossRefGoogle Scholar
  5. Holton JB, Walter JH, Tyfield LA (2001) Galactosaemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 1553–1579Google Scholar
  6. Lai K, Elsas LJ (2001) Structure-function analyses of a common mutation in blacks with transferase-deficiency galactosaemia. Mol Genet Metab 74: 264–272 doi: 10.1006/mgme.2001.3230 PubMedCrossRefGoogle Scholar
  7. Lai K, Langley SD, Singh R, (1996) A prevalent mutation for galactosaemia among black Americans. J Pediatr 128:89–95 doi: 10.1016/S0022-3476(96)70432-8 PubMedCrossRefGoogle Scholar
  8. Landt M, Ritter D, Lai K, (1997) Black children deficient in galactose-1-phosphate uridyl-transferase: correlation of activity and immunoreactive protein in erythrocytes and leukocytes. J Pediatr 130:972–980 doi: 10.1016/S0022-3476(97)70286-5 PubMedCrossRefGoogle Scholar
  9. Murphy M, McHugh B, Tighe O, (1999) Genetic basis of transferase-deficient galactosaemia in Ireland and the population history of Irish Travellers. Eur J Hum Genet 7:549–554 doi: 10.1038/sj.ejhg.5200327 PubMedCrossRefGoogle Scholar
  10. Roche G, McGarrity J, O'Grady L, et al (2009) Development of an enhanced screening strategy for classical galactosaemia in the Republic of Ireland. 6th International Society of Neonatal Screening European Regional Meeting, Prague, April 2009Google Scholar
  11. Schweitzer S, Shin Y, Jakobs C, Brodehl J (1993) Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr 152(1):36–43 doi: 10.1007/BF02072514 PubMedCrossRefGoogle Scholar
  12. Segal S, Blair A, Roth H (1965) The metabolism of galactose by patients with classical galactosaemia. Am J Med 38:62 doi: 10.1016/0002-9343(65)90160-9 PubMedCrossRefGoogle Scholar
  13. Tyfield L, Reichardt J, Fridovich-Kiel J, (1999) Classical galactosaemia and mutations at the galactose-1-phosphate uridyl transferase gene. Hum Mutat 13:417–430 doi: 10.1002/(SICI)1098-1004(1999)13:6<417::AID-HUMU1>3.0.CO;2-0 PubMedCrossRefGoogle Scholar
  14. Waggoner DD, Buist NR, Donnell GN (1990) Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inherit Metab Dis 13(6):802–818 doi: 10.1007/BF01800204 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • E. Crushell
    • 1
  • J. Chukwu
    • 1
  • P. Mayne
    • 2
  • J. Blatny
    • 3
  • E. P. Treacy
    • 1
  1. 1.National Centre for Inherited Metabolic DisordersChildren’s University HospitalDublin 1Ireland
  2. 2.Department of Chemical PathologyChildren’s University HospitalDublin 1Ireland
  3. 3.Department of HaematologyChildren’s University HospitalDublin 1Ireland

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