Abstract
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.
Competing interests: None declared
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References
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 29:309–312
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 12:479–482
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 24:69–71
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 128:373–376
Bzowska A, Kulikowska E, Shugar D (2000) Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol Ther 88:349–425
Carpenter PA, Ziegler JB, Vowels MR (1996) Late diagnosis and correction of purine nucleoside phosphorylase deficiency with allogeneic bone marrow transplantation. Bone Marrow Transplant 17:121–124
Chan K, Puck JM (2005) Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol 115:391–398
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 28:93–96
Cohen A, Grunebaum E, Arpaia E, Roifman CM (2000) Immunodeficiency caused by purine nucleoside phosphorylase deficiency. Immunol Allergy Clin North Am 20(1):143–159
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 11:799–803
Dror Y, Grunebaum E, Hitzler J et al (2004) Purine nucleoside phosphorylase deficiency associated with a dysplastic marrow morphology. Pediatr Res 55:472–477
ESID/EBMT (2011) EBMT/ESID guidelines for haematopoietic stem cell transplantation for primary immunodeficiencies
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 1:1010–1013
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 13:630–638
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 134:155–159
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 2011
Mansouri A, Min W, Cole CJ et al (2012) Cerebellar abnormalities in purine nucleoside phosphorylase deficient mice. Neurobiol Dis 47:201–209
Markert ML (1991) Purine nucleoside phosphorylase deficiency. Immunodefic Rev 3:45–81
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 145:710–712
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), e222
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 22:741–743
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 98:706–709
Parvaneh N, Ashrafi MR, Yeganeh M, Pouladi N, Sayarifar F, Parvaneh L (2007) Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency. Brain Dev 29:124–126
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 6:39–42
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 56:150–154
Tam DA Jr, Leshner RT (1995) Stroke in purine nucleoside phosphorylase deficiency. Pediatr Neurol 12:146–148
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 29:466–470
Walker PL, Corrigan A, Arenas M, Escuredo E, Fairbanks L, Marinaki A (2011) Purine nucleoside phosphorylase deficiency: a mutation update. Nucleosides Nucleotides Nucleic Acids 30:1243–1247
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Communicated by: Jerry Vockley, M.D., Ph.D.
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Synopsis
Hematopoietic stem cell transplant is an effective treatment immunodeficiency caused by purine nucleoside phosphorylase deficiency and ameliorates neurological symptoms of the disorder.
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Informed Consent
All procedures followed were in accordance with the ethical standards of the Helsinki Declaration of 1975, as revised in 2000.
Upon contact with the Regional Ethical Review Board in Lund, we were advised that signed consent from the patient’s parents is sufficient for publication of this case report and the consent was obtained.
Author Contributions
Nicholas Brodszki: conception, planning, collection and compiling of the clinical and laboratory data and writing the manuscript.
Maria Svensson: collection and compiling of the clinical and laboratory data and drafting the manuscript.
André B.P. van Kuilenburg: supervising enzymatic and genetic analysis, cowriting of the manuscript.
Judith Meijer: experimental analysis, cowriting of the manuscript.
Lida Zoetekouw: experimental analysis.
Lennart Truedsson and Jacek Toporski: interpretation of the results and supervising the writing of the manuscript.
All authors read and approved the final manuscript.
Conflict of Interest
Nicholas Brodszki, Maria Svensson, André B.P. van Kuilenburg, Judith Meijer, Lida Zoetekouw, Lennart Truedsson, and Jacek Toporski declare that they have no conflict of interest.
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Brodszki, N. et al. (2015). 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. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 24. JIMD Reports, vol 24. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_444
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DOI: https://doi.org/10.1007/8904_2015_444
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