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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

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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

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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

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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.

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Correspondence to C. Prasad .

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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.

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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).

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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.

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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

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

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