Novel Genetic Mutations in the First Swedish Patient with Purine Nucleoside Phosphorylase Deficiency and Clinical Outcome After Hematopoietic Stem Cell Transplantation with HLA-Matched Unrelated Donor

  • Nicholas BrodszkiEmail author
  • Maria Svensson
  • André B. P. van Kuilenburg
  • Judith Meijer
  • Lida Zoetekouw
  • Lennart Truedsson
  • Jacek Toporski
Research Report
Part of the JIMD Reports book series (JIMD, volume 24)


Purine nucleoside phosphorylase (PNP) is an enzyme active in the purine salvage pathway. PNP deficiency caused by autosomal recessive mutations in the PNP gene leads to severe combined immunodeficiency (SCID) and in two thirds of cases also to neurological effects such as developmental delay, ataxia, and motor impairment.

PNP deficiency has a poor outcome, and the only curative treatment is allogenic hematopoietic stem cell transplantation (HSCT). We present the first Swedish patient with PNP deficiency with novel mutations in the PNP gene and the immunological results of the HSCT and evaluate the impact of HSCT on the neurological symptoms. The patient presented early in life with neurological symptoms and suffered later from repeated serious respiratory tract infections. Biochemical tests showed severe reduction in PNP activity (1% residual activity). Genetic testing revealed two new mutations in the PNP gene: c.729C>G (p.Asn243Lys) and c.746A>C (p.Tyr249Cys). HSCT was performed with an unrelated donor, resulting in prompt and sustained engraftment and complete donor chimerism. There was no further aggravation of the patient’s neurological symptoms at 21 months post HSCT, and appropriate developmental milestones were achieved. HSCT is curative for the immunological defect caused by PNP deficiency, and our case strengthens earlier reports that HSCT is effective as a treatment even for neurological symptoms in PNP deficiency.


Developmental delay Hematopoietic stem cell transplantation Immunodeficiency Lymphocytes Matched unrelated donor Pediatric Purine nucleoside phosphorylase 


  1. Alangari A, Al-Harbi A, Al-Ghonaium A, Santisteban I, Hershfield M (2009) Purine nucleoside phosphorylase deficiency in two unrelated Saudi patients. Ann Saudi Med 29:309–312PubMedCentralCrossRefPubMedGoogle Scholar
  2. Aytekin C, Yuksek M, Dogu F et al (2008) An unconditioned bone marrow transplantation in a child with purine nucleoside phosphorylase deficiency and its unique complication. Pediatr Transplant 12:479–482CrossRefPubMedGoogle Scholar
  3. Baguette C, Vermylen C, Brichard B et al (2002) Persistent developmental delay despite successful bone marrow transplantation for purine nucleoside phosphorylase deficiency. J Pediatr Hematol Oncol 24:69–71CrossRefPubMedGoogle Scholar
  4. Broome CB, Graham ML, Saulsbury FT, Hershfield MS, Buckley RH (1996) Correction of purine nucleoside phosphorylase deficiency by transplantation of allogeneic bone marrow from a sibling. J Pediatr 128:373–376CrossRefPubMedGoogle Scholar
  5. Bzowska A, Kulikowska E, Shugar D (2000) Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol Ther 88:349–425CrossRefPubMedGoogle Scholar
  6. Carpenter PA, Ziegler JB, Vowels MR (1996) Late diagnosis and correction of purine nucleoside phosphorylase deficiency with allogeneic bone marrow transplantation. Bone Marrow Transplant 17:121–124PubMedGoogle Scholar
  7. Chan K, Puck JM (2005) Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol 115:391–398CrossRefPubMedGoogle Scholar
  8. Classen CF, Schulz AS, Sigl-Kraetzig M et al (2001) Successful HLA-identical bone marrow transplantation in a patient with PNP deficiency using busulfan and fludarabine for conditioning. Bone Marrow Transplant 28:93–96CrossRefPubMedGoogle Scholar
  9. Cohen A, Grunebaum E, Arpaia E, Roifman CM (2000) Immunodeficiency caused by purine nucleoside phosphorylase deficiency. Immunol Allergy Clin North Am 20(1):143–159CrossRefGoogle Scholar
  10. Delicou S, Kitra-Roussou V, Peristeri J et al (2007) Successful HLA-identical hematopoietic stem cell transplantation in a patient with purine nucleoside phosphorylase deficiency. Pediatr Transplant 11:799–803CrossRefPubMedGoogle Scholar
  11. Dror Y, Grunebaum E, Hitzler J et al (2004) Purine nucleoside phosphorylase deficiency associated with a dysplastic marrow morphology. Pediatr Res 55:472–477CrossRefPubMedGoogle Scholar
  12. ESID/EBMT (2011) EBMT/ESID guidelines for haematopoietic stem cell transplantation for primary immunodeficienciesGoogle Scholar
  13. Giblett ER, Ammann AJ, Wara DW, Sandman R, Diamond LK (1975) Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet 1:1010–1013CrossRefPubMedGoogle Scholar
  14. Grunebaum E, Cohen A, Roifman CM (2013) Recent advances in understanding and managing adenosine deaminase and purine nucleoside phosphorylase deficiencies. Curr Opin Allergy Clin Immunol 13:630–638CrossRefPubMedGoogle Scholar
  15. la Marca G, Canessa C, Giocaliere E et al (2014) Diagnosis of immunodeficiency caused by a purine nucleoside phosphorylase defect by using tandem mass spectrometry on dried blood spots. J Allergy Clin Immunol 134:155–159CrossRefPubMedGoogle Scholar
  16. Madkaikar MR, Kulkarni S, Utage P et al (2011) Purine nucleoside phosphorylase deficiency with a novel PNP gene mutation: a first case report from India. BMJ Case Rep 2011Google Scholar
  17. Mansouri A, Min W, Cole CJ et al (2012) Cerebellar abnormalities in purine nucleoside phosphorylase deficient mice. Neurobiol Dis 47:201–209CrossRefPubMedGoogle Scholar
  18. Markert ML (1991) Purine nucleoside phosphorylase deficiency. Immunodefic Rev 3:45–81PubMedGoogle Scholar
  19. Myers LA, Hershfield MS, Neale WT, Escolar M, Kurtzberg J (2004) Purine nucleoside phosphorylase deficiency (PNP-def) presenting with lymphopenia and developmental delay: successful correction with umbilical cord blood transplantation. J Pediatr 145:710–712CrossRefPubMedGoogle Scholar
  20. Nakagawa N, Imai K, Kanegane H et al (2011) Quantification of kappa-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects. J Allergy Clin Immunol 128(223–225), e222Google Scholar
  21. Ozkinay F, Pehlivan S, Onay H et al (2007) Purine nucleoside phosphorylase deficiency in a patient with spastic paraplegia and recurrent infections. J Child Neurol 22:741–743CrossRefPubMedGoogle Scholar
  22. Pannicke U, Tuchschmid P, Friedrich W, Bartram CR, Schwarz K (1996) Two novel missense and frameshift mutations in exons 5 and 6 of the purine nucleoside phosphorylase (PNP) gene in a severe combined immunodeficiency (SCID) patient. Hum Genet 98:706–709CrossRefPubMedGoogle Scholar
  23. Parvaneh N, Ashrafi MR, Yeganeh M, Pouladi N, Sayarifar F, Parvaneh L (2007) Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency. Brain Dev 29:124–126CrossRefPubMedGoogle Scholar
  24. Singh V (2012) Cross correction following haemopoietic stem cell transplant for purine nucleoside phosphorylase deficiency: engrafted donor-derived white blood cells provide enzyme to residual enzyme-deficient recipient cells. JIMD Rep 6:39–42PubMedCentralCrossRefPubMedGoogle Scholar
  25. Somech R, Lev A, Grisaru-Soen G, Shiran SI, Simon AJ, Grunebaum E (2013) Purine nucleoside phosphorylase deficiency presenting as severe combined immune deficiency. Immunol Res 56:150–154CrossRefPubMedGoogle Scholar
  26. Tam DA Jr, Leshner RT (1995) Stroke in purine nucleoside phosphorylase deficiency. Pediatr Neurol 12:146–148CrossRefPubMedGoogle Scholar
  27. van Kuilenburg AB, Zoetekouw L, Meijer J, Kuijpers TW (2010) Identification of purine nucleoside phosphorylase deficiency in dried blood spots by a non-radiochemical assay using reversed-phase high-performance liquid chromatography. Nucleosides Nucleotides Nucleic Acids 29:466–470CrossRefPubMedGoogle Scholar
  28. Walker PL, Corrigan A, Arenas M, Escuredo E, Fairbanks L, Marinaki A (2011) Purine nucleoside phosphorylase deficiency: a mutation update. Nucleosides Nucleotides Nucleic Acids 30:1243–1247CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Nicholas Brodszki
    • 1
    Email author
  • Maria Svensson
    • 2
  • André B. P. van Kuilenburg
    • 3
  • Judith Meijer
    • 3
  • Lida Zoetekouw
    • 3
  • Lennart Truedsson
    • 4
  • Jacek Toporski
    • 1
  1. 1.Childrens Hospital, Skåne University HospitalLundSweden
  2. 2.Lund UniversityLundSweden
  3. 3.Academic Medical Center Lab. Genetic Metabolic DiseasesUniversity of AmsterdamAmsterdamThe Netherlands
  4. 4.Department of Laboratory Medicine, Section of Microbiology, Immunology and GlycobiologyLund UniversityLundSweden

Personalised recommendations