An unconditioned bone marrow transplantation in a child with purine nucleoside phosphorylase deficiency and its unique complication

Aytekin, Caner; Yüksek, Mutlu; Doğu, Figen; Yağmurlu, Aydın; Yıldıran, Alişan; Fítöz, Suat; Koloğlu, Meltem Bingöl; Babacan, Emel; Hershfield, Michael S.; İkincioğulları, Aydan

doi:10.1111/j.1399-3046.2007.00890.x

Cited by 28 publications

(29 citation statements)

References 10 publications

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“…She died from disseminated M. tuberculosis infection despite intensive antimycobacterial treatment. To the best of our knowledge, this patient is the second report of mycobacterial disease in PNP deficiency [4].…”

Section: Discussionmentioning

confidence: 83%

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Purine nucleoside phosphorylase deficiency with fatal course in two sisters

et al. 2009

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Purine nucleoside phosphorylase (PNP) deficiency is a rare combined immunodeficiency disorder presenting with clinically recurrent infections, failure to thrive, various neurological disorders, malignancies, and autoimmune diseases. Here, we report two sisters with a fatal course of PNP deficiency due to delay in diagnosis. The first patient developed a liver abscess by Aspergillus fumigatus and the second patient developed Mycobacterium tuberculosis complex lymphadenitis and probable pulmonary tuberculosis due to disseminated BCG infection. The patients also suffered from sclerosing cholangitis. Mutation analysis of the PNP gene from both sisters revealed a homozygous mutation for a G>A at nucleotide 349 (349 G>A transition), which changes alanine 117 to theronine in exon 4 (A117T). An increased awareness of early signs, symptoms, and abnormal laboratory findings of PNP deficiency will establish the early prognosis and treatment.

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Section: Discussionmentioning

confidence: 83%

“…Clinically, PNP-deficient patients suffer from recurrent bacterial, viral, and fungal infections, failure to thrive, various neurological disorders, malignancies, and autoimmune diseases [17]. The only curative treatment is hematopoietic stem cell transplantation (HSCT) [4].…”

Section: Introductionmentioning

confidence: 99%

Purine nucleoside phosphorylase deficiency with fatal course in two sisters

et al. 2009

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“…This typically follows a period of conditioning with chemotherapy, before infusion from a matched donor. A previous report of an unconditioned infusion from an HLA-matched non-sibling family member in a patient with PNP deficiency reported donor T-lymphocyte engraftment with no B-lymphocyte (and presumably no stem cell) engraftment (17). Failure of stem cell engraftment may have been due to the inflammatory mileau caused by pre-existing BCG infection.…”

Section: Discussionmentioning

confidence: 99%

Infusion of Sibling Marrow in a Patient with Purine Nucleoside Phosphorylase Deficiency Leads to Split Mixed Donor Chimerism and Normal Immunity

2017

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Purine nucleoside phosphorylase (PNP) deficiency, a rare autosomal recessive metabolic disease causes combined immunodeficiency and developmental delay, hypotonia, and spasticity. Patients present with recurrent infections associated with T-lymphocytopenia, characteristically presenting later than patients with classical severe combined immunodeficiency (SCID). PNP, with adenosine deaminase (ADA), is part of the purine salvage pathway. The only curative therapy is hematopoietic stem cell transplantation. Myeloablative conditioning is recommended to prevent rejection caused by residual immune function. However, HLA-identical sibling stem cell infusions in ADA-SCID result in some donor stem cell engraftment and long-term thymopoiesis. We report a patient with PNP deficiency, who received HLA-identical sibling marrow without chemotherapy because of disseminated cytomegalovirus (CMV) infection. The patient presented at 14 months of age following recurrent infections, from early infancy, with persistent irritability, developmental delay, and hypotonia. She had neutropenia, pan-lymphocytopenia, and hypogammaglobulinemia with low plasma urate and erythrocyte PNP activity. Diagnosis was confirmed with a homozygous mutation in PNP. The patient was viremic with CMV detected in blood and CSF by PCR. Dual antiviral therapy improved the clinical condition and reduced the viral load. In view of the disseminated CMV infection, the decision was made to infuse stem cells without any pre-conditioning chemotherapy. She received a matched sibling donor unconditioned stem cell infusion at 16 months of age. The post-transplant course was uneventful. Blood PCR became negative for CMV. Global hypotonia persisted, although with significant improvement in irritability. At 4 years of age and 29 months post-transplant, the patient demonstrated normal T-lymphocyte and natural killer cell numbers. Recent thymic emigrants represented 12% of the total T-lymphocyte population. Lymphocyte proliferative responses to phytohemagglutinin were normal. Memory and class-switched B-lymphocytes were present. Immunoglobulin replacement had been discontinued, and there were normal IgG responses to tetanus vaccine, Haemophilus influenzae type B and pneumococcal conjugate vaccine antigens. There was 93% donor T-lymphocytes, 20% donor B-lymphocytes, and 5% donor myeloid cells, indicative of some donor stem cell engraftment. There was no significant infection history despite regular nursery attendance. Height and weight were following the 50th centile. Split mixed donor chimerism has corrected the immunological defect.

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“…We found ten articles describing 14 cases of HSCT-treated PNP deficiency (Markert 1991;Broome et al 1996;Carpenter et al 1996;Pannicke et al 1996;Classen et al 2001;Baguette et al 2002;Myers et al 2004;Delicou et al 2007;Aytekin et al 2008;Singh 2012). Of these, two articles describing six cases had no description of the neurological outcome (Markert 1991;Broome et al 1996).…”

Section: Literature Reviewmentioning

confidence: 96%

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

et al. 2015

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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.

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An unconditioned bone marrow transplantation in a child with purine nucleoside phosphorylase deficiency and its unique complication

Cited by 28 publications

References 10 publications

Purine nucleoside phosphorylase deficiency with fatal course in two sisters

Purine nucleoside phosphorylase deficiency with fatal course in two sisters

Infusion of Sibling Marrow in a Patient with Purine Nucleoside Phosphorylase Deficiency Leads to Split Mixed Donor Chimerism and Normal Immunity

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

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