Brain & Development 29 (2007) 124–126 www.elsevier.com/locate/braindev
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 . Purine nucleoside phosphorylase (PNP) deﬁciency is a rare primary immunodeﬁciency presenting predominantly with a profound defect of cellular immunity and variable humoral immune abnormalities . Clinically, patients with PNP deﬁciency suﬀer from recurrent infections, failure to thrive, neurologic impairment, malignancies, and autoimmune phenomena . PNP is an enzyme in the purine salvage pathway that reversibly *
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converts inosine to hypoxanthine and guanosine to guanine . PNP deﬁciency leads to an intracellular accumulation of deoxyguanosine triphosphate (dGTP), which is toxic to T cells . 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
Uric acid (mg/dl) Inosin (lM/l)
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 . It occurs almost exclusively in immunocompromised individuals with AIDS, malignancies or in organ transplant patients on immunosuppressive therapy . HIV infection accounts for 85% of all PML cases . Several reports have described PML in primary immunodeﬁciencies, most often cellular defects (Table 2) . Patients with PML present with a sub-acute onset of neurological deﬁcits, corresponding to white matter lesions on brain MRI . 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 . 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 . 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 . Hypouricemia caused by defective transformation of inosine into hypoxanthine is suggestive of PNP deﬁciency . ADA and PNP deﬁciency are usually diagnosed by ﬁnding decreased enzyme activity in hemolysates or measuring ADA and PNP substrates in plasma or urine .
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 . 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  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.  Cohen A, Grunebaum E, Arpaia E, Roifman CM. Immunodeﬁciency caused by purine nucleotide phosphorylase deﬁciency. Immunol Allergy Clin North Am 2000;20:143–61.  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.  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.  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.  Koralnik IJ. New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004;17:365–70.  Markert ML. Purine nucleoside phosphorylase deﬁciency. Immunodeﬁc Rev 1991;3(1):45–81.  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.  Soutar RL, Day RE. Dysequilibrium/ataxic diplegia with immunodeﬁciency. Arch Dis Child 1991;66:982–3.  Tam Jr DA, Leshner RT. Stroke in purine nucleoside phosphorylase deﬁciency. Pediatr Neurol 1995;12:146–8.  Tyler K. The uninvented guest. JC virus infection in neurons in PML. Neurology 2003;61:734–5.