Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Matched unrelated donor transplantation in glycogen storage disease type 1b patient corrects severe neutropenia and recurrent infections

Bone Marrow Transplantation volume 53, pages 1076–1078 (2018)Cite this article

Subjects

Glycogen storage disease type 1b (GSD-1b) (OMIM 232220) is an autosomal recessive disorder that was first distinguished as a separate entity in 1978 [1]. GSD-1b is caused by a mutation in the glucose-6-phosphate transporter 1 gene (G6PT1) located on chromosome 11q23 [2, 3]. This transporter is important in translocating the glucose-6-phosphate (G6P) from the cytoplasm across the endoplasmic reticulum (ER) where distinctive enzymes, depending on the cell type, hydrolyze this compound [4]. Glucose-6-phosphatase-α (G6Pase-α) that is strictly expressed and embedded in the ER of the liver, kidney, and intestines hydrolyzes G6P to glucose, an essential component of glucose homeostasis between meals [4]. Its deficiency leads to GSD type 1a [5]. Glucose-6-phosphatase-β (G6Pase-β) is another enzyme that is expressed ubiquitously in cells with increased glucose demands including neutrophils [6, 7]. Failure to meet these demands results in stressed ER and ultimately apoptosis of neutrophils [8]. Therefore, G6PT1 mutation results in defective translocation of G6P in all of the above-mentioned cell types and in addition to the GSD-1a phenotype, the majority of patients with GSD-1b develop neutropenia, neutrophil dysfunction, recurrent infections, and inflammatory bowel disease (IBD) [9, 10]. Dietary modifications, granulocytes colony-stimulating factor (G-CSF), and liver transplant are the main management strategies [11]. While G-CSF has been used successfully to improve neutrophil counts and decrease recurrent infections, it has not been shown to decrease apoptosis or improve chemotaxis [8, 12]. Besides, G-CSF has its own risks including splenomegaly with hypersplenism, osteoporosis/osteopenia, and leukemic transformation [13, 14]. Liver transplant can restore glucose homeostasis for GSD-1a but cannot resolve the neutropenia component in GSD-1b. Hematopoietic cell transplant (HCT) from a matched related donor has been reported in one patient for extremely poor quality of life despite maximal therapy as evidenced by frequent hospital stays and life-threatening complications caused by impaired bone marrow function [15]. Post-transplant course in that patient was notable for improved neutrophil counts, decreased infections, improved metabolic control, and the original plan for liver transplant was postponed indefinitely [15].

Our patient is a 5-year-old Hispanic male born to consanguineous parents, who presented at 4 months of age with abdominal distension and vomiting. He had hepatosplenomegaly, mild neutropenia >1 × 109/L, blood glucose of 20 mg/dL, transaminitis, lactic acidosis, and hypertriglyceridemia. Gastrostomy tube (G-tube) was placed and continuous feeds were initiated after initial unsuccessful attempts at daytime bolus feeding. Liver biopsy showed glycogenosis with micro and macro-vesicular steatosis. GSD in the liver was significant for low G6P activity (Table 1). Analysis of the G6PT1 gene, SLC37A4 sequence, revealed a novel homozygous mutation at c.170C>A (p.S57X) predicted to result in a stop codon and thus, a deleterious mutation, consistent with GSD-1b. His neutropenia gradually worsened and he eventually developed severe neutropenia.

Table 1 Liver screening test results for glycogen storage disorder
Full size table

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Igarashi Y, Otomo H, Narisawa K, Tada K. A new variant of glycogen storage disease type 1: probably due to a defect in the glucose-6-phosphate transport system. J Inherit Metab Dis. 1980;2:45–9. (e-pub ahead of print 1 Jan 1980).

    Article  CAS  Google Scholar 

  2. Gerin I, Veiga-da-Cunha M, Achouri Y, Collet JF, Van Schaftingen E. Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib. FEBS Lett. 1997;419:235–8. (e-pub ahead of print 15 Jan 1998).

    Article  CAS  Google Scholar 

  3. Annabi B, Hiraiwa H, Mansfield BC, Lei KJ, Ubagai T, Polymeropoulos MH, et al. The gene for glycogen-storage disease type 1b maps to chromosome 11q23. Am J Hum Genet. 1998;62:400–5. https://doi.org/10.1086/301727. (e-pub ahead of print 16 Apr 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pan CJ, Lei KJ, Chen H, Ward JM, Chou JY. Ontogeny of the murine glucose-6-phosphatase system. Arch Biochem Biophys. 1998;358:17–24. https://doi.org/10.1006/abbi.1998.0849. (e-pub ahead of print 29 Sept 1998).

    Article  CAS  Google Scholar 

  5. Lei KJ, Shelly LL, Pan CJ, Sidbury JB, Chou JY. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a. Science. 1993;262:580–3. (e-pub ahead of print 22 Oct 1993).

    Article  CAS  Google Scholar 

  6. Ueno N, Tomita M, Ariga T, Ohkawa M, Nagano S, Takahashi Y, et al. Impaired monocyte function in glycogen storage disease type Ib. Eur J Pediatr. 1986;145:312–4. (e-pub ahead of print 1 Sept 1986).

    Article  CAS  Google Scholar 

  7. Lin B, Annabi B, Hiraiwa H, Pan CJ, Chou JY. Cloning and characterization of cDNAs encoding a candidate glycogen storage disease type 1b protein in rodents. J Biol Chem. 1998;273:31656–60. https://doi.org/10.1074/jbc.273.48.31656

    Article  CAS  PubMed  Google Scholar 

  8. Kuijpers TW, Maianski NA, Tool ATJ, Smit GPA, Rake JP, Roos D, et al. Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b). Blood. 2003;101:5021–4. https://doi.org/10.1182/blood-2002-10-3128

    Article  CAS  PubMed  Google Scholar 

  9. Beaudet AL, Anderson DC, Michels VV, Arion WJ, Lange AJ. Neutropenia and impaired neutrophil migration in type IB glycogen storage disease. J Pediatr. 1980;97:906–10. https://doi.org/10.1016/S0022-3476(80)80418-5

    Article  CAS  PubMed  Google Scholar 

  10. Visser G, Rake JP, Fernandes J, Labrune P, Leonard JV, Moses S, et al. Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on Glycogen Storage Disease type I. J Pediatr. 2000;137:187–91. https://doi.org/10.1067/mpd.2000.105232. (e-pub ahead of print 10 Aug 2000).

    Article  CAS  PubMed  Google Scholar 

  11. Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med: Off J Am Coll Med Genet. 2014;16:e1 https://doi.org/10.1038/gim.2014.128. (e-pub ahead of print 31 Oct 2014).

    Article  CAS  Google Scholar 

  12. Schroten H, Roesler J, Breidenbach T, Wendel U, Elsner J, Schweitzer S, et al. Granulocyte and granulocyte-macrophage colony-stimulating factors for treatment of neutropenia in glycogen storage disease type Ib. J Pediatr. 1991;119:748–54. (e-pub ahead of print 1 Nov 1991).

    Article  CAS  Google Scholar 

  13. Pinsk M, Burzynski J, Yhap M, Fraser RB, Cummings B, Ste-Marie M. Acute myelogenous leukemia and glycogen storage disease 1b. J Pediatr Hematol/Oncol. 2002;24:756–8. (e-pub ahead of print 7 Dec 2002).

    Article  Google Scholar 

  14. Cottle TE, Fier CJ, Donadieu J, Kinsey SE. Risk and benefit of treatment of severe chronic neutropenia with granulocyte colony-stimulating factor. Semin Hematol. 2002;39:134–40. (e-pub ahead of print 17 Apr 2002).

    Article  CAS  Google Scholar 

  15. Pierre G, Chakupurakal G, McKiernan P, Hendriksz C, Lawson S, Chakrapani A. Bone marrow transplantation in glycogen storage disease type 1b. J Pediatr. 2008;152:286–8. https://doi.org/10.1016/j.jpeds.2007.09.031. (e-pub ahead of print 22 Jan 2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Nationwide Children’s Hospital, Columbus, OH, USA

    Lubna S. Mehyar, Rolla Abu-Arja, Hemalatha G. Rangarajan, Vinita Pai, Melissa J. Rose & Rajinder P. S. Bajwa

  2. Department of Pediatrics, The Ohio State University, Columbus, OH, USA

    Lubna S. Mehyar, Rolla Abu-Arja, Hemalatha G. Rangarajan, Dennis W. Bartholomew, Melissa J. Rose & Rajinder P. S. Bajwa

  3. Department of Pharmacy, Nationwide Children’s Hospital, Columbus, OH, USA

    Vinita Pai

  4. Division of Molecular and Human Genetics, Nationwide Children’s Hospital, Columbus, OH, USA

    Dennis W. Bartholomew

Authors
  1. Lubna S. Mehyar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rolla Abu-Arja
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hemalatha G. Rangarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vinita Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dennis W. Bartholomew
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Melissa J. Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rajinder P. S. Bajwa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lubna S. Mehyar.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehyar, L.S., Abu-Arja, R., Rangarajan, H.G. et al. Matched unrelated donor transplantation in glycogen storage disease type 1b patient corrects severe neutropenia and recurrent infections. Bone Marrow Transplant 53, 1076–1078 (2018). https://doi.org/10.1038/s41409-018-0147-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0147-z

Search

Advanced search

Quick links