Vitamin B12 deficiency – another challenge to expand newborn laboratory screening?

Česká verzia

Authors: Stanovský Samuel ¹; Bártl Josef ¹; Barvíková Kristýna ¹; Chrastina Petr ¹; Krijt Jakub ¹; Sokolová Jitka ¹; Berková Klára ²; Straňák Zbyněk ²; Tichá Katarína ³; Janota Jan ³; Eliášová Mária ⁴; Plavka Richard ⁴; Zach Jiří ⁵; Kožich Viktor ¹; Honzík Tomáš ¹
Authors place of work: Klinika pediatrie a dědičných, poruch metabolismu, 1. lékařská fakulta, Univerzita Karlova, a Všeobecná fakultní, nemocnice, Praha ¹; Ústav pro péči o matku a dítě, Praha ²; Novorozenecké oddělení, Fakultní nemocnice Motol, Praha ³; Klinika gynekologie, porodnictví a neonatologie, 1. lékařská fakulta, Univerzita, Karlova a Všeobecná fakultní, nemocnice, Praha ⁴; Novorozenecké oddělení, Fakultní Thomayerova, nemocnice, Praha ⁵
Published in the journal: Čes-slov Pediat 2024; 79 (3): 145-149.
Category: Original Papers
doi: https://doi.org/10.55095/CSPediatrie2024/024

Summary

Introduction: Cobalamin (Cbl, B₁₂) deficiency manifests in infancy as failure to thrive, macrocytic anemia, hypotonia, developmental delay/regression, microcephaly, and epilepsy. One of the causes of B₁₂ deficiency in newborns is in-utero acquired deficiency caused by maternal deficiency. Following the example of other EU countries, we present interim data from a pilot project of newborn laboratory screening (NLS) for Cbl deficiency, which has been conducted at cooperating Prague hospitals.

Methods: At least one abnormal primary marker is required for suspected B₁₂ deficiency: propionylcarnitine > 3.8 μmol/l, propionylcarnitine/acetylcarnitine ratio > 0.3, methionine < 7 μmol/l, propionylcarnitine/methionine ratio > 0.5 (determined by tandem mass spectrometry). Secondary markers include methylmalonic acid (MMA) > 2.5 μmol/l and total homocysteine (tHcy) > 12 μmol/l. In the case of NLS positivity, both the newborn and the mother undergo a Cbl absorption test. We determine total B₁₂ (measured by electrochemiluminescence immunoassay), holoTC (measured by chemiluminescence immunoassay), folates (measured by electrochemiluminescence immunoassay), serum MMA

Keywords:

vitamin B12 – : newborn screening – cobalamin – B12 deficiency

Zdroje

Korespondenční adresa:

prof. MUDr. Tomáš Honzík, Ph.D.
Klinika pediatrie a dědičných poruch metabolismu 1. LF UK a VFN
Ke Karlovu 455/2
128 08 Praha 2
e-mail: tomas.honzik@vfn.cz

1. Gille D, Schmid A. Vitamin B12 in meat and dairy products. Nutr Rev 2015; 73(2): 106–115.

2. Murphy MM, et al. Longitudinal study of the effect of pregnancy on maternal and fetal cobalamin status in healthy women and their offspring. J Nutr 2007; 137(8): 1863–1867.

3. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academies Press 1998.

4. Stubbe J. Binding site revealed of nature’s most beautiful cofactor. Science 1994; 266(5191): 1663–1664.

5. Mascarenhas R, Gouda H, Ruetz M, Banerjee R. Human B12-dependent enzymes: Methionine synthase and methylmalonyl-CoA mutase. 2022: 309–326. doi: 10.1016/bs.mie.2021.12.012

6. Froese DS, Gravel RA. Genetic disorders of vitamin B 12 metabolism: eight complementation groups – eight genes. Expert Rev Mol Med 2010; 12: e37.

7. Bassila C, et al. Methionine synthase and methionine synthase reductase interact with MMACHC and with MMADHC. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 2017; 1863(1): 103–112.

8. Huemer M, Baumgartner MR. The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways. J Inherit Metab Dis 2019; 42(4): 686–705.

9. Fedosov SN. Physiological and molecular aspects of cobalamin transport. 2012: 347–367. doi: 10.1007/978-94-007-2199-9_18

10. Herrmann W, Obeid R. Cobalamin deficiency. 2012: 301–322. doi: 10.1007/978-94-007-2199-9_16

11. Hannibal L, et al. Biomarkers and algorithms for the diagnosis of vitamin B12 deficiency. Front Mol Biosci 2016; 3.

12. Hvas AM, Nexo E. Holotranscobalamin as a predictor of vitamin B12 status. Clin Chem Lab Med 2003; 41(11). doi: 10.1515/CCLM.2003.228

13. Nexo E, Hoffmann-Lücke E. Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility. Am J Clin Nutr 2011; 94(1): 359S–365S.

14. Bjørke Monsen AL, Ueland PM. Homocysteine and methylmalonic acid in diagnosis and risk assessment from infancy to adolescence. Am J Clin Nutr 2003; 78(1): 7–21.

15. Bailey RL, et al. Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12. Am J Clin Nutr 2011; 94(2): 552–561.

16. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994; 96(3): 239–246.

17. Hay G, Johnston C, Whitelaw A, et al. Folate and cobalamin status in relation to breastfeeding and weaning in healthy infants. Am J Clin Nutr 2008; 88(1): 105–114.

18. E. Greibe, et al. Cobalamin and haptocorrin in human milk and cobalamin-related variables in mother and child: a 9-mo longitudinal study. Am J Clin Nutr 2013; 98(2): 389–395.

19. Herrmann W, Obeid R. Utility and limitations of biochemical markers of vitamin B12 deficiency. Eur J Clin Invest 2013; 43(3): 231–237.

20. Kim J, Kim H, Roh H, Kwon Y. Causes of hyperhomocysteinemia and its pathological signifikance. Arch Pharm Res 2018; 41(4): 372–383.

21. Honzik T, Adamovicova M, Smolka V, et al. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency – What have we learned? Eur J Paediatric Neurol 2010; 14(6): 488–495.

22. Wirthensohn M, Wehrli S, Ljungblad UW, Huemer M. Biochemical, nutritional, and clinical parameters of vitamin B12 deficiency in infants: a systematic review and analysis of 292 cases published between 1962 and 2022. Nutrients 2023; 15(23): 4960.

23. Depuis Z, et al. Pancytopenia due to vitamin B12 and folic acid deficiency —a case report. Pediatr Rep 2022; 14(1): 106–114.

24. Simşek OP, Gönç N, Gümrük F, Cetin M. A child with vitamin B12 deficiency presenting with pancytopenia and hyperpigmentation. J Pediatr Hematol Oncol 2004; 26(12): 834–6.

25. Ho CH, Thomas M, McGuire E, Yano S. 2-year-old girl with pancytopenia due to vitamin B12 (cobalamin) deficiency. J Paediatr Child Health 2014; 50(11): 926–928.

26. Monsen ALB, et al. Determinants of cobalamin status in newborns. Pediatrics 2001; 108(3): 624–630.

27. Hussein L, Abdel Aziz S, Tapouzada S. Serum vitamin B 12 concentrations among mothers and newborns and follow-up study to assess implication on the growth velocity and the urinary methylmalonic acid excretion. Int J Vitamin Nutr Res 2009; 79(56): 297–307.

28. Jawaid I, Beales I, Brown, M, et al. Vitamin B12 deficiency in over 16s: diagnosis and management. Dostupné na: https://www.nice.org.uk/guidance/ng239

29. Levtova A, et al. Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort. J Inherit Metab Dis 2019; 42(1): 107–116.

30. Gramer G, et al. Newborn screening for vitamin B12 deficiency in Germany—strategies, results, and public health implications. J Pediatr 2020; 216: 165–172.e4.

31. Scolamiero E, et al. Maternal vitamin B12 deficiency detected in expanded newborn screening. Clin Biochem 2014; 47(18): 312–317.

32. Reinson K, Künnapas K, Kriisa A, et al. High incidence of low vitamin B12 levels in Estonian newborns. Mol Genet Metab Rep 2018; 15: 1–5.