Skip to main content
SpringerLink
Log in

Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario

  • Research Report
  • Chapter
  • First Online:
JIMD Reports, Volume 18

Part of the book series: JIMD Reports ((JIMD,volume 18))

Abstract

Intrinsic factor deficiency (OMIM #261000, IFD) is a rare inherited disorder of vitamin B12 metabolism due to mutations in the gastric intrinsic factor (GIF) gene.

We report three individuals from an Old Order Mennonite community who presented with B12 deficiency. Two cases are siblings born to consanguineous parents and the third case is not known to be closely related. The older male sib presented at 4 years with gastrointestinal symptoms, listlessness, and pallor. He had pancytopenia with megaloblastic anemia. Serum B12 was 61 (198–615 pmol/L). Methylmalonic aciduria was present. C3 was elevated on acylcarnitine profile. Homocysteine was high at 16.7 (5.0–12.0 umol/L). His asymptomatic female sibling was also found to have B12 deficiency. Genetic testing for methylmalonic aciduria (MMAA), transcobalamin deficiency (TCN2), and Imerslund-Gräsbeck syndrome (AMN) showed no mutation in both siblings. The third patient, a 34-year-old woman, had presented in infancy with a diagnosis of pernicious anemia. Mutation analysis of GIF revealed compound heterozygosity for a c.79+1G>A substitution and a c.973delG deletion in all three individuals. Oral or parenteral vitamin B12 has led to complete recovery of clinical parameters and vitamin B12 levels. Newborn screening samples on the siblings revealed normal methylcitrate, C3, and C3/C2 ratios thus indicating no disruption of propionic or methylmalonic acid metabolism.

A high index of suspicion should be maintained if children present with megaloblastic anemia since GIF deficiency is a treatable disorder and newborn screening may not be able to detect this condition.

Competing interests: None declared

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AMN :

Amnionless gene

B12 :

Vitamin B12 (cobalamin)

CUBN :

Cubilin gene

GIF:

Gastric intrinsic factor

GIF :

Gastric intrinsic factor gene

IFD:

Intrinsic factor deficiency

IGS:

Imerslund-Gräsbeck syndrome

MCEE :

Methylmalonic CoA epimerase gene

MMA:

Methylmalonic aciduria

MMAA :

Methylmalonic acidemia CblA type gene

MMAB :

Methylmalonic acidemia CblB type gene

MMADHC :

Methylmalonic acidemia CblD type gene

MUT :

Methylmalonic CoA mutase gene

TC:

Transcobalamin deficiency

TCN2 :

Transcobalamin II gene

References

  • Ament AE, Li Z, Sturm AC et al (2009) Juvenile cobalamin deficiency in individuals of African ancestry is caused by a founder mutation in the intrinsic factor gene GIF. Br J Haematol 144(4):622–624

    Article  PubMed Central  PubMed  Google Scholar 

  • Boina Abdallah A, Ogier de Baulny H, Kozyraki R et al (2012) How can cobalamin injections be spaced in long-term therapy for inborn errors of vitamin B(12) absorption? Mol Genet Metab 107(1–2):66–71

    Article  CAS  PubMed  Google Scholar 

  • Carmel R, Green R, Rosenblatt DS, Watkins D (2003) Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program 62–81

    Google Scholar 

  • Chery C, Hehn A, Mrabet N et al (2013) Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant. Biochimie 95(5):995–1001

    Article  CAS  PubMed  Google Scholar 

  • Garcia Jimenez MC, Baldellou Vazquez A, Calvo Martin MT, Perez-Lungmus G, Lopez Pison J (2008) Hereditary juvenile cobalamin deficiency due to mutations in GIF gene. Anales de Pediatria (Barcelona, Spain: 2003) 69(1):56–58

    Article  CAS  Google Scholar 

  • Gordon MM, Brada N, Remacha A et al (2004) A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency. Hum Mutat 23(1):85–91

    Article  CAS  PubMed  Google Scholar 

  • Grasbeck R (2006) Imerslund-Grasbeck syndrome (selective vitamin B(12) malabsorption with proteinuria). Orphanet J Rare Dis 1:17

    Article  PubMed Central  PubMed  Google Scholar 

  • Grasbeck R, Tanner SM (2011) Juvenile selective vitamin B(1)(2) malabsorption: 50 years after its description-10 years of genetic testing. Pediatr Res 70(3):222–228

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hewitt JE, Gordon MM, Taggart RT, Mohandas TK, Alpers DH (1991) Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11. Genomics 10(2):432–440

    Article  CAS  PubMed  Google Scholar 

  • Kozyraki R, Cases O (2013) Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders. Biochimie 95(5):1002–1007

    Article  CAS  PubMed  Google Scholar 

  • Overgaard UM, Tanner SM, Birgens HS (2010) Vitamin B12 deficiency in a 15-year old boy due to mutations in the intrinsic factor gene, GIF. Br J Haematol 150(3):369–371

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Prasad C, Rosenblatt DS, Corley K, Cairney AE, Rupar CA (2008) Transcobalamin (TC) deficiency–potential cause of bone marrow failure in childhood. J Inherit Metab Dis 31(Suppl 2):S287–S292

    Article  PubMed  Google Scholar 

  • Prasad C, Cairney AE, Rosenblatt DS, Rupar CA (2012) Transcobalamin (TC) deficiency and newborn screening. J Inherit Metab Dis 35(4):727

    Article  PubMed  Google Scholar 

  • Strauss KA, Puffenberger EG (2009) Genetics, medicine, and the plain people. Annu Rev Genomics Hum Genet 10:513–536

    Article  CAS  PubMed  Google Scholar 

  • Sturm AC, Baack EC, Armstrong MB et al (2013) Hereditary intrinsic factor deficiency in chaldeans. JIMD Rep 7:13–18

    Article  PubMed Central  PubMed  Google Scholar 

  • Tanner SM, Li Z, Perko JD et al (2005) Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci U S A 102(11):4130–4133

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tanner SM, Sturm AC, Baack EC, Liyanarachchi S, de la Chapelle A (2012) Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis 7:56

    Article  PubMed Central  PubMed  Google Scholar 

  • Trakadis YJ, Alfares A, Bodamer OA et al (2013) Update on transcobalamin deficiency: clinical presentation, treatment and outcome. J Inherit Metab Dis 37(3):461–473

    Article  PubMed  Google Scholar 

  • Watkins D, Rosenblatt DS (2011) Inborn errors of cobalamin absorption and metabolism. Am J Med Genet C Semin Med Genet 157C(1):33–44

    Article  PubMed  Google Scholar 

  • Yassin F, Rothenberg SP, Rao S, Gordon MM, Alpers DH, Quadros EV (2004) Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency. Blood 103(4):1515–1517

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patients and their families to allow us to share their information and Roger Dewar for DNA sequence analyses. This paper was presented as a poster in the Garrod Association meeting, May 2013, and as a poster at the Pediatric Research Day at London Health Sciences Centre, May 2014. A travel grant was received from the Garrod Association.

Author information

Authors and Affiliations

  1. Department of Paediatrics, London Health Sciences Centre, Western University, London, ON, Canada

    A. Ferrand, V. M. Siu, M. P. Napier & C. Prasad

  2. Medical Genetics Program of Southwestern Ontario, Children’s Health Research Institute, 800 Commissioners Road East, London, ON, Canada, N6C 2V5

    A. Ferrand, V. M. Siu & C. Prasad

  3. Departments of Pathology and Laboratory Medicine, Biochemistry and Paediatrics, Western University, Children’s Health Research Institute, Children’s Hospital of Western Ontario, London, ON, Canada

    C. A. Rupar

  4. Newborn Screening Ontario, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada

    O. Y. Al-Dirbashi & P. Chakraborty

Authors
  1. A. Ferrand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. M. Siu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. A. Rupar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. P. Napier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O. Y. Al-Dirbashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. Chakraborty
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Prasad .

Editor information

Editors and Affiliations

  1. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria

    Johannes Zschocke

  2. Division for Metabolic Diseases, University Children´s Hospital, Zürich, Switzerland

    Matthias Baumgartner

  3. Department of Pediatrics IGMD, Tulane University Medical School Hayward Genetics Center, New Orleans, Louisiana, USA

    Eva Morava

  4. Division of Child and Adolescent Neurolo, Mayo Clinic, Rochester, USA

    Marc Patterson

  5. Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, United Kingdom

    Shamima Rahman

  6. Heidelberg University Hospital Centre for Child & Adolescent Med, Heidelberg, Germany

    Verena Peters

Additional information

Communicated by: Verena Peters

Appendices

References to Electronic Databases

GeneReviews®: http://www.ncbi.nlm.nih.gov/books/NBK1116/

Human Genome Mutational Database HGMD®: http://www.hgmd.org

Online Mendelian Inheritance in Man: http://omim.org

Pubmed: http://www.ncbi.nlm.nih.gov/pubmed

Synopsis

A case report and literature review of inherited GIF deficiency mutation, a severe but treatable disorder of B12 metabolism whose presentation can mimic many disorders.

Compliance with Ethics Guidelines

Conflict of Interest

Amaryllis Cloelia Ferrand, Victoria Mok Siu, Melanie P Napier, Osama Al-Dirbashi, Pranesh Chakraborty, Chitra Prasad, and C Anthony Rupar declare no conflicts of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).

Declaration

The paper is being submitted as an original article.

This paper has not been previously submitted nor is under consideration for publication in any other journal.

Author Contribution

The paper’s submission for publication has been approved by all of the authors.

Amaryllis C. Ferrand: Conception, design and drafting. First Author.

Victoria M. Siu: Conception, design and critical revision.

C Anthony Rupar: Analysis and interpretation of data, critical revision.

Melanie P. Napier: Conception, design and critical revision.

Osama Y. Aldirbashi: Analysis and interpretation of data, critical revision.

Pranesh Chakraborty: Analysis and interpretation of data, critical revision.

Chitra Prasad: Conception, design and drafting. Guarantor.

Rights and permissions

Reprints and permissions

Copyright information

© 2014 SSIEM and Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Ferrand, A. et al. (2014). Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor (GIF) Deficiency: A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 18. JIMD Reports, vol 18. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_351

Download citation

  • DOI: https://doi.org/10.1007/8904_2014_351

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-44862-5

  • Online ISBN: 978-3-662-44863-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation