Progressive multifocal leukoencephalopathy in purine

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Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the cen- tral nervous system. Although ...

Brain & Development 29 (2007) 124–126

Case report

Progressive multifocal leukoencephalopathy in purine nucleoside phosphorylase deficiency Nima Parvaneh a b


, Mahmoud-Reza Ashrafi a, Mehdi Yeganeh b, Nima Pouladi b, Fatemeh Sayarifar a, Leila Parvaneh c

Children’s Hospital Center, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran c Department of Clinical Biochemistry, Tarbiat Modares University, Tehran, Iran Received 16 May 2006; received in revised form 12 July 2006; accepted 17 July 2006

Abstract Progressive multifocal leukoencephalopathy is a demyelinating disease caused by JC virus, an opportunistic infection of the central nervous system. Although the majority of cases are infected with the human immunodeficiency virus (HIV), other immunocompromised patients are also at risk. Purine nucleoside phosphorylase is an enzyme in the purine salvage pathway that reversibly converts inosine to hypoxanthine and guanosine to guanine. Purine nucleoside phosphorylase deficiency is a combined immunodeficiency with a profound cellular defect. Neurologic abnormalities are salient features of this syndrome. We describe for the first time a patient with this rare disorder presented with progressive multifocal leukoencephalopathy. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Immunodeficiency; JC virus; Progressive multifocal leukoencephalopathy; Purine nucleoside phosphorylase

1. Background Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease due to infection with polyoma virus JC and occurs almost exclusively in immunocompromised individuals, most notably acquired immunodeficiency syndrome (AIDS) patients [6]. Purine nucleoside phosphorylase (PNP) deficiency is a rare primary immunodeficiency presenting predominantly with a profound defect of cellular immunity and variable humoral immune abnormalities [2]. Clinically, patients with PNP deficiency suffer from recurrent infections, failure to thrive, neurologic impairment, malignancies, and autoimmune phenomena [7]. PNP is an enzyme in the purine salvage pathway that reversibly *

Corresponding author. Tel.: +98 21 6693 5855; fax: +98 21 6642 8995. E-mail address: [email protected] (N. Parvaneh). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.07.008

converts inosine to hypoxanthine and guanosine to guanine [2]. PNP deficiency leads to an intracellular accumulation of deoxyguanosine triphosphate (dGTP), which is toxic to T cells [3]. Neurologic abnormalities have been reported in more than half of PNP deficient children including mental retardation, hyper/hypotonia, cerebral palsy, and ataxia [7–9]. Herein, we report a 9year-old patient presented with PML. Immunologic studies revealed PNP deficiency as his underlying immunodeficiency. To our knowledge this case is the first report of PML in PNP deficiency.

2. Case report A 9-year-old Iranian boy was admitted to the intensive care unit of Children’s Hospital in Tehran for progressive encephalopathy of 3 weeks. The patient gradually developed cognitive deficits and slowing in

N. Parvaneh et al. / Brain & Development 29 (2007) 124–126

mentation over this period. During the week before admission he had 3 episodes of generalized tonic–clonic seizures. In the past history, he was born by vaginal delivery to consanguineous parents. Development was normal in infancy and early childhood. Medical concerns for this patient began at 7 years of age when he developed sinopulmonary infections, requiring antibiotic therapy. Six months later, he had right knee arthritis, for which no organism was cultured from synovial fluid. Daily activities became restricted due to progressive spastic paraparesis at 8 years. On admission the patient was comatose with irregular respirations necessitating assisted ventilation. Painful stimuli resulted in decorticate (abnormal flexor) posture. Pupils were midsize and reactive. Reflex eye movements were intact. No signs of meningeal irritation were detected. Lower limbs were spastic, tendon reflexes were brisk and extensor plantar responses were symmetrically positive. On general examination, he had no fever. He was at the 5th percentiles for weight and height, and 50th percentile for head circumference. His tonsils were absent and lymph nodes were not palpable. Brain CT scan showed bilateral hypodencities in the subcortical white matter with no mass effect. Brain magnetic resonance imaging (MRI) revealed T2-hyperintense lesions in the white matter of both hemispheres which particularly affecting the parietal regions (Fig. 1).The lesions were not surrounded by edema and not enhanced by gadolinium. Cerebrospinal fluid (CSF) composition was normal, with 0 red blood cells/ll, 0 white blood cells/ll, protein level of 25 mg/dl, and glucose level of 75 mg/dl. CSF polymerase chain reaction (PCR) was negative for HSV, EBV, and enteroviruses. EEG showed high voltage discharges with diffuse slowing.


The clinical suspicion of PML was confirmed by detection of JC virus DNA in CSF. Laboratory evaluation was notable for, marked lymphopenia, thrombocytopenia and mild Coombs-positive hemolytic anemia (Table 1). RT-PCR for HIV genome was negative. Plasma uric acid was low and inosine was elevated. Based on marked lymphopenia, history of autoimmunity and biochemical profile, PNP deficiency was the most likely diagnosis. However, analysis of PNP enzyme activity and genetic study were not performed. Intravenous immunoglobulin replacement, Terimethoprim-Sulfamethoxazole (TMP-SMZ) and exchange transfusion were introduced as medical treatments. His neurological status progressively worsened and he no

Table 1 Laboratory data Test



WBC (cells/ll) Hb (mg/dl) Platelets (cells/ll)

5,000 9.2 110,000

4,400–9,500 11–16 >150,000

ALC (cells/ll) CD3 (cells/ll) CD4 (cells/ll) CD8 (cells/ll) CD19 (cells/ll) CD16 (cells/ll)

410 220 137 64 55 120

1,900–3,700 1,200–2,600 650–1,500 370–1,100 270–860 100–480

IgG (mg/dl) IgM (mg/dl) IgA (mg/dl)

500 undetectable undetectable

608–1,572 52–242 33–236

DTH to PPD antigen DTH to DT antigen

negative negative

Uric acid (mg/dl) Inosin (lM/l)

1 10

2–6 undetectable

ALC, absolute lymphocytes count; DTH, delayed type hypersensitivity reaction; PPD, purified protein derivative; DT, diphteria/tetanus toxoid.

Fig. 1. T2-weighted MRI of brain showing hyperintense lesions in the subcortical white matter in bilateral hemispheres.


N. Parvaneh et al. / Brain & Development 29 (2007) 124–126

Table 2 Primary immunodeficiencies in which PML has been reported Isolated CD4 deficiency Hyper IgE syndrome Hyper IgM syndrome ICF syndrome Adenosine deaminase deficiency Wiscott-aldrich syndrome X-linked agammaglobulinemia Common variable immunodeficiency Purine nucleoside phosphorylase deficiency

longer responded to deep stimuli. He passed away three days after admission due to cardiac arrest. 3. Discussion PML is a fatal demyelinating disease of the CNS caused by JC polyoma virus [6]. It occurs almost exclusively in immunocompromised individuals with AIDS, malignancies or in organ transplant patients on immunosuppressive therapy [6]. HIV infection accounts for 85% of all PML cases [11]. Several reports have described PML in primary immunodeficiencies, most often cellular defects (Table 2) [4]. Patients with PML present with a sub-acute onset of neurological deficits, corresponding to white matter lesions on brain MRI [6]. Clinical evidence of PML is conclusively supported by the CSF detection of JC virus DNA by PCR. There is no specific treatment for JC virus. Irisolidone, an isoflavone metabolite, may provide therapeutic potential for PML [5]. We reported a patient with late onset of primary immunodeficiency and major neurologic problems. The late onset of immunodeficiency with prominent neurologic manifestations makes the probable diagnosis of a defect in purine salvage pathway. Adenosine deaminase (ADA) and PNP are the key enzymes in this pathway, important in the removal of toxic metabolites of DNA breakdown [2]. ADA deficiency, typically leads to severe combined immunodeficiency that can lead to the death of affected individuals early in life. Late onset of immune defect in ADA deficiency is reported infrequently. Moreover, affected children have skeletal abnormalities [1,2]. PNP deficiency is a combined immunodeficiency characterized by recurrent infections, autoimmune phenomena and neurologic abnormalities. There is a considerable heterogeneity both in age of presentation and severity of symptoms [2]. Hypouricemia caused by defective transformation of inosine into hypoxanthine is suggestive of PNP deficiency [7]. ADA and PNP deficiency are usually diagnosed by finding decreased enzyme activity in hemolysates or measuring ADA and PNP substrates in plasma or urine [2].

In the presented case, late onset of immunodeficiency, absence of skeletal abnormalities, hypouricemia and increased plasma level of inosine are highly suggestive of PNP deficiency. However, definitive diagnosis necessitates PNP enzyme assay and mutation analysis. Progressive encephalopathy, brain MRI findings and presence of JC virus genome in CSF made the diagnosis of PML. Neurologic abnormalities are common in PNP deficiency, mostly related to the motor system dysfunction, such as nonprogressive cerebral palsy, or spastic paresis [2]. Other neurologic findings include disequilibrium/spastic diplegia, tremor, behavioral problems, and mental retardation [7,9,10]. Although, pathogenesis of neurologic abnormality is unclear, depletion of dGTP, and recurrent brain infarcts have been proposed to correlate with neurologic deficits in PNP deficient patients [8,10]. This is the first report of PML accompanying PNP deficiency. To our knowledge there is no published data describing neurological imaging in patients with this syndrome. The study of possible role of PML in development of neurologic problems in PNP deficiency sounds noteworthy. This also adds a new etiology to the list of underlying immunodeficiencies predisposing to PML.

References [1] Cederbaum SD, Kaitila I, Rimoin DL, Stiehm ER. The chondroosseous dysplasia of adenosine deaminase deficiency with severe combined immunodeficiency. J Pediatr 1976;89:737–42. [2] Cohen A, Grunebaum E, Arpaia E, Roifman CM. Immunodeficiency caused by purine nucleotide phosphorylase deficiency. Immunol Allergy Clin North Am 2000;20:143–61. [3] Cohen A, Gudas LJ, Ammann AJ, Staal GE, Martin Jr DW. Deoxyguanosine triphosphate as a possible toxic metabolite in the immunodeficiency associated with purine nucleoside phosphorylase deficiency. J Clin Invest 1978;61:1405–9. [4] Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J. Progressive multifocal leukoencephalopathy and idiopathic CD4+lymphocytopenia: a case report and review of reported cases. Clin Infect Dis 2000;31:E20–2. [5] Kim SY, Kim DH, Hyun JW, Henson JW, Kim HS. Irisolidone, an isoflavone metabolite, represses JC virus gene expression via inhibition of Sp1 binding in human glial cells. Biochem Biophys Res Commun 2006;344:3–8. [6] Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004;17:365–70. [7] Markert ML. Purine nucleoside phosphorylase deficiency. Immunodefic Rev 1991;3(1):45–81. [8] Simmonds HA, Fairbanks LD, Morris GS, Morgan G, Watson AR, Timms P, Singh B. Central nervous system dysfunction and erythrocyte guanosine triphosphate depletion in purine nucleoside phosphorylase deficiency. Arch Dis Child 1987;62:385–91. [9] Soutar RL, Day RE. Dysequilibrium/ataxic diplegia with immunodeficiency. Arch Dis Child 1991;66:982–3. [10] Tam Jr DA, Leshner RT. Stroke in purine nucleoside phosphorylase deficiency. Pediatr Neurol 1995;12:146–8. [11] Tyler K. The uninvented guest. JC virus infection in neurons in PML. Neurology 2003;61:734–5.

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