Autosomal recessive inheritence
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Niemann-Pick Disease

Niemann-Pick disease is an inherited condition involving lipid metabolism (the breakdown and use of fats and cholesterol in the body) in which harmful amounts of lipids accumulate in the spleen, liver, lungs, bone marrow, and brain. more...

Necrotizing fasciitis
Neisseria meningitidis
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Niemann-Pick Disease
Nijmegen Breakage Syndrome
Non-Hodgkin lymphoma
Noonan syndrome
Norrie disease

There are four variants of Nieman-Pick disease based on the genetic cause and the symptoms exhibited by the patient. All variants are inherited in a autosomal recessive pattern.

Mutations in the NPC1, NPC2, and SMPD1 genes cause Niemann-Pick disease.

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann-Pick.


Types A and B

Type A Niemann-Pick disease begins during infancy and is characterized by an enlarged liver and spleen (hepatosplenomegaly), failure to thrive, and progressive deterioration of the nervous system. Children affected by this condition generally do not survive past early childhood. Niemann-Pick disease, type A occurs more frequently among individuals of Ashkenazi (eastern and central European) Jewish descent than in the general population. The incidence within the Ashkenazi population is approximately 1 in 40,000 people. The incidence for other populations is unknown.

Type B disease may include signs of hepatosplenomegaly, growth retardation, and problems with lung function including frequent lung infections. Other signs include blood abnormalities such as abnormal cholesterol and lipid levels, and low numbers of blood cells involved in clotting (platelets). People affected by this type of Niemann-Pick disease usually survive into adulthood. Niemann-Pick disease, type B occurs in all populations.

Mutations in the SMPD1 gene cause Niemann-Pick disease, types A and B. This gene carries instructions for cells to produce an enzyme called acid sphingomyelinase. This enzyme is found in the lysosomes (compartments that digest and recycle materials in the cell), where it processes lipids such as sphingomyelin. Mutations in this gene lead to a deficiency of acid sphingomyelinase and the accumulation of sphingomyelin, cholesterol, and other kinds of lipids within the cells and tissues of affected individuals.

Types C1 and C2

Niemann-Pick disease, type C is further subdivided into types C1 and C2, each caused by a different gene mutation. Both types C1 and C2 Niemann-Pick disease are most commonly characterized by onset in childhood, although infant and adult onsets are possible. Other signs include severe liver disease, breathing difficulties, developmental delay, seizures, increased muscle tone (dystonia), lack of coordination, problems with feeding, and an inability to move the eyes vertically. People with this disorder can survive into adulthood. The incidence of Niemann-Pick disease, type C is estimated to be 1 in 150,000 people. The disease occurs more frequently in people of French-Acadian descent in Nova Scotia.


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Kidney and Urinary Tract Polyomavirus Infection and Distribution: Molecular Biology Investigation of 10 Consecutive Autopsies
From Archives of Pathology & Laboratory Medicine, 1/1/05 by Boldorini, Renzo

Context.-Distinct human polyomavirus genotypes cause different diseases in patients with renal transplants: BK virus (BKV) causes tubulointerstitial nephritis and ureteral stenosis, whereas both JC virus (JCV) and BKV are responsible for hemorrhagic cystitis. These findings could result from a selective infection of kidney and urinary tract segments by JCV or BKV.

Objective.-To verify this hypothesis, 10 complete, unselected, consecutive autopsies from 9 immunocompetent patients and 1 patient affected by acquired immunodeficiency syndrome were investigated.

Design.-Samples from kidneys (n = 80), renal pelvis (n = 20), ureter (n = 40), and urinary bladder (n = 30) obtained from 10 consecutive autopsies were investigated by means of multiplex nested polymerase chain reaction to detect polyomavirus DNA and to distinguish different species of the Polyomavirus genus. In situ hybridization and immunohistochemistry were also carried out to define the viral status of the infected tissues.

Results.-Polyomavirus DNA was detected in all of the subjects (positive samples ranging from 2 to 7 samples), for a total of 43 of 170 samples (25.3%), distributed as follows: urinary bladder (10/30, 33%), renal pelvis (6/20, 30%), ureter (10/40, 25%), and kidney tissue (17/80, 21%). We found that JCV was most frequently detected overall (23/43 samples, 53.5%) and was also detected most frequently within the kidney (8/17 positive samples, 47%), the renal pelvis (5/6 positive samples, 70%), and the ureter (7/10 positive samples, 70%), whereas BKV was found in 14 samples (32.5%), and it was the prevailing genotype in urinary bladder (6/10 positive samples, 60%). Coinfection of BKV-JCV was found in 6 samples (14%). lmmunohistochemistry and in situ hybridization returned negative results.

Conclusions.-The viruses JCV and BKV latently persist randomly in kidney and urinary tract. Distinct diseases induced by them could be related more closely to molecular viral rearrangements than to the topographic distribution of latent viruses.

(Arch Pathol Lab Med. 2005;129:69-73)

BK virus (BKV) and JC virus (JCV) are human polyomaviruses (PVs), which infect most people throughout the world, as shown by the presence of antibodies against viral proteins in about 80% of the human population.1

Although a large number of studies have been carried out, the mode of transmission, mechanisms of PV infection, and the distinct organs and cell types targeted by the viruses in different phases of infection have not yet been completely clarified. This is particularly true for the target organs, where the viruses persist indefinitely in a latent state.2 Indeed, searches for the sites of viral latency have led to discordant results: DNA sequences of JCV, BKV, or both have been detected in almost all the organs (kidney, brain, lung, bone, spleen, placenta) by a few authors,3-5 but these results have not been confirmed by other researchers, who identified the kidney as the selective site of JCV and BKV latency and the brain as a site of JCV latency.*"8

Immune impairments are involved in the reactivation of PVs,9 leading to a wide spectrum of clinicopathologic consequences: in particular, progressive multifocal leukoencephalopathy (PML), a JCV-induced disease, has been frequently found in acquired immunodeficiency syndrome (AIDS) patients,10 and some diseases involving kidney and urinary tract, such as polyomavirus nephropathy (PVN),11 hemorrhagic cystitis, and ureteral stenosis, have been reported in kidney transplant patients12 and only rarely in AIDS patients.13

In the case of the latter group of diseases, BKV has been considered the only etiologic agent of renal damage14 and ureteral stenosis,15 whereas hemorrhagic cystitis has been attributed from time to time to both JCV and BKV.lh·17 This could suggest that not only various organs, but also different segments of the same apparatus or cell types, may be selectively infected by different types of PVs, and that the reactivation induced by immune impairment can cause organ-specific damage.

In an attempt to clarify this last hypothesis, kidney tissue and samples from various segments of the urinary tract (renal pelvis, ureter, and urinary bladder) obtained during 10 consecutive autopsies were investigated by means of molecular biology in order to detect the presence and distribution of the PV genome; moreover, in situ hybridization and immunohistochemistry were also carried out to define the viral status of the infected tissues.


The study involved complete autopsies of 10 unselected subjects consecutively performed between January and March 2003; the demographic and main pathologic data are shown in Table 1. It is worth stressing that, as shown by their clinical histories, all the subjects were immunocompetent except for patient 5, who was affected by AIDS.

Histologic, Immunohistochemical, and In Situ Hybridization Analysis

Seventeen samples for each case (N = 170) were taken from macroscopically undamaged areas of the kidney and urinary tract as follows: 2 cortical and 2 medullary samples of each kidney (n = 80 samples), 1 sample of each renal pelvis (n = 20 samples), 2 samples of each ureter (n = 40 samples), and 3 samples of the urinary bladder (n = 30 samples). All of the samples were fixed in 10% buffered formalin, embedded in paraffin, and routinely processed for histology. Four-micrometer-thick sections were stained with hematoxylin-eosin and examined by means of light microscopy in order to evaluate the integrity of the tissue before proceeding to molecular analysis, to identify possible pathologic changes, and in particular to search for the presence of morphologic equivalents of cellular PV infection (intranuclear viral inclusions of various types, as described by Nickeleit et al18).

The samples were stained with immunoperoxidase in order to identify the presence and (latent or replicative) status of PVs using a monoclonal antibody against simian virus 40 (SV40) T antigen (clone pAb416, Oncogene Science, Boston, Mass; dilution 1: 60) and a polyclonal antibody against capsid proteins SV40 (Lee Biomolecular Research Labs, San Diego, Calif; dilution 1:20000), both of which cross-react with human BKV and JCV.19 The reactions were detected by means of the streptavidin-biotin method and were revealed using diaminobenzidine as a chromogen. Brain sections with histologically proven PML from case 5 were used as a positive control.

In situ hybridization was performed to localize the nucleic acid sequences of BKV and JCV at the subcellular level using commercially available biotinylated DNA probes (Enzo Diagnostics, New York, NY). The reactions were detected by means of the streptavidin-biotin method and were revealed using diaminobenzidine as a chromogen. Brain sections of case 5 with PML and kidney sections of histologically proven BKV nephropathy were used as positive controls.

DNA Extraction and Polymerase Chain Reaction Amplification

Four-micrometer-thick sections from paraffin-embedded tissues were cut and placed into 1.5-mL Eppendorf tubes. To avoid cross-contamination of samples, the microtome blade was cleaned with xylene between each block.20 DNA was extracted using EDTA-SDS/proteinase K treatment followed by phenolchloroform, as previously described." DNA was resuspended with 50 µL of diethyl pyrocarbonate-treated and autoclaved pyrogen- and ribonuclease-free water, and 10 µL of extracted DNA was added to polymerase chain reaction (PCR) mixtures. To avoid false-negative results, nested PCR of the human androgenreceptor gene was performed in all cases as a positive control of DNA extraction.21

To identify the presence of PV sequences, the DNA was subjected to multiplex nested PCR in order to amplify the large T antigen (LT) regions using the following primers: (1) PM1+ and PM1 - as outer primers; and (2) PM2- (common to all PVs), JC+, BK+, and SV40+ as inner primers to distinguish different members of the Polyomavirus genus22 (Table 2). The amplification was performed on DNA extracted in a total volume of 50 µL with BioTaq DNA polymerase (Bioline, London, England) in the presence of 1:10 Bioline NH4 buffer, 2 mM MgCL (1 mM for the inner PCR), 10 pmol/µL of each primer (Roche Diagnostics, Milan, Italy), and 0.2 mM of dNTP, using a Progene Techno PCR System (Duotech, Milan, Italy). The samples were amplified by denaturation at 95°C for 5 minutes, followed by 40 cycles of denaturation at 95°C for 40 seconds, annealing at 61°C (55°C for the inner PCR) for 40 seconds, and extension at 72°C for 40 seconds. The cycles were terminated by means of a final extension at 72°C for 5 minutes. Diethyl pyrocarbonate-treated and ribonuclease-free water (Biotecx Laboratories, Houston, Tex) was used as negative control; the positive controls were DNA extracted from the brain tissue of subject 5 with PML (for JCV), the renal tissue of a subject with histologically proven BKV nephropathy (for BKV), and SVG cell lines (for SV40).


Histology, Immunohistochemistry, and In Situ Hybridization

Histologic examinations of the kidney and urinary tract samples (see Table 1) revealed ischemic changes and nephroangiosclerosis in 8 cases (cases 2 through 5 and 7 through 10), acute tubular necrosis and kidney localization of Niemann-Pick disease in 1 (case 1), and renal bacterial abscess in 1 case (case 6). No changes were found in the renal pelvis, ureter, and urinary bladder samples. No morphologic equivalents of PV infection were identified in the specimens stained with hematoxylin and eosin.

Immunohistochemistry using antibodies against capsid proteins and LT antigens of PVs was always negative, as was in situ hybridization with probes recognizing JCV and BKV genomes.

Molecular Analysis

DNA was obtained from all the examined samples, regardless of the time between death and autopsy.

On the whole, PV DNA was found in 43 (25.3%) of 170 samples from all patients. The frequency of PV detection in kidney and urinary tract segments is shown in Figure 1: urinary bladder (10/30 samples, 33%) and renal pelvis (6/20, 30%) were the main sites of PV DNA detection, whereas ureter and kidney tissue samples disclosed presence of PV DNA in 10 (25%) of 40 and 17 (21%) of 80 samples, respectively. Table 3 shows viral distribution and genotypes within kidney and urinary tract for each patient. Interestingly, PV DNA was detected in all of the subjects, with the number of positive samples ranging from 2 (cases 1 and 4) to 7 (case 6). As shown in Table 3, PV DNA was detected in only 1 case (case 3) in kidney and all segments of urinary tract; interestingly, PV was not detected more frequently in the patient with AIDS (case 5).

As shown in Figure 2, JCV was the genotype most frequently detected overall (23/43 positive samples, 53.5%) and within kidney (8/17 positive samples, 47%), renal pelvis (5/6 positive samples, 83%), and ureter (7/10 positive samples, 70%), whereas BKV was found in 14 samples (32.5%) and was the most frequent genotype found in the urinary bladder (6/10 positive samples, 60%). Coinfection by BKV-JCV was found on the whole in 6 samples (14%).


On the basis of the results of molecular studies of autopsy samples, the kidney is considered to be the main site of both JCV and BKV latency6,7; however, precise data concerning the distribution of PV infection in the kidney and the entire urinary tract are still lacking. Further evidence of the uropoietic system as the main site of PV latency is supplied by the frequency of hemorrhagic cystitis due to PV infection in patients with bone marrow transplants23,24 and the frequency of ureteral stenosis and PVN in patients with kidney transplants.12,14,15,25 It is not yet clear why PVN and ureteral stenosis are caused only by BKV infection18,25 and hemorrhagic cystitis by JCV or BKV damage to the urothelial cells of the urinary bladder,16,17 but one possible reason is a difference in cellular tropism for JCV and BKV; that is, the viruses may latently infect different segments of the uropoietic apparatus.

Although we studied only a small number of cases, the kidneys and urinary tracts were extensively sampled, and all samples underwent DNA extraction and amplification of the PV LT regions. Furthermore, the positive samples also underwent immunohistochemical examination and in situ hybridization. Our autopsy subjects were consecutive and unselected, and except for patient 5, who was affected by AIDS, all the others had no specific problems with immunosuppression; therefore, the subjects could be considered as representative of the general population.

Our results indicate that the kidney and the urinary tract are important sites of PV latency, because PV DNA was detected at these sites in all of our cases (with 2-7 positive samples for each autopsy). The urinary tract (renal pelvis, ureter, and urinary bladder) was the main site of viral detection, whereas PV DNA was found more rarely in the kidney (21% of cases). The latter finding confirms the Southern blot studies of Chesters et al,7 which revealed PV DNA in about 20% of cases; as far as we know, there are no published data concerning the distribution of PV in the urinary tract.

It is worth emphasizing that, in all of our cases (including the subject with AIDS), PV was present in a latent state, as indicated by the negative immunohistochemistry results. This analysis was performed using 1 antibody that recognizes viral capsid proteins (VP1-3) expressed only after virus assembly and an anti-LT antigen, which, although produced early after virus entry into the target cell, becomes detectable only during viral replication.2 The negative in situ hybridization results may have resulted from the fact that the number of copies in the cells was below the detection limit. False-negative results were avoided by the use of positive controls, including brain samples from the subject with PML (for JCV) and a kidney sample affected by BKV nephropathy.

JC virus was the main genotype identified overall and in kidney, renal pelvis, and ureter, whereas BKV prevailed in urinary bladder tissue. Because PVN and ureteral stenosis are caused by BKV reactivation and hemorrhagic cystitis by JCV and BKV, these results, although obtained in a small number of the cases, seem to indicate that both PVs persist randomly in the kidney and urinary tract and do not definitely explain the reasons for the different pathologic changes induced by JCV and BKV in the kidney and urinary tract.

However, some hypotheses can be tentatively proposed.

First of all, the sites of viral latency may be different from those in which PVs cause clinically relevant viral diseases: Nickeleit et al18 have suggested that in cases of PVN, viral particles produced after the lysis of infected cells in the renal pelvis or ureter could enter the capillary vessels and infect the tubular cells of the kidney, or that PVs may follow an ascending route of infection from transitional cells to kidney tubular cells.

Second, the susceptibility of transitional cells of the urinary tract and the tubular cells of the kidney to BKV or JCV infection may be different. For example, in patients with kidney transplants, JCV could damage the transitional cells of the urinary bladder but not the tubular cells of the kidney, where the virus seems to persist only in a latent state and does not cause renal disease.26

Third, type and severity of immune impairment could be responsible for different diseases induced by PVs in the kidney and urinary tract. Indeed, we have demonstrated in a recent paper21 that, unlike patients who have undergone renal transplantation, in AIDS subjects JCV is able to replicate actively into the kidney epithelial tubular cells.

Finally, PV diseases in the kidney and urinary tract may be caused by genomic rearrangements in the regulatory region of viruses that latently infect the kidney and urinary tract. Because this region controls viral replication and infectiousness,27 different conditions of immunosuppression or changes in the tissue microenvironment (such as those occurring during renal transplantation) represent a possible mechanism of genomic instability, as proposed by Agostini et al.28 On the basis of this last hypothesis, the critical mechanisms may be more closely related to molecular viral damage than to the topographic distribution of latent virus within the kidney and urinary tract.

Further studies of larger case series, sequence analyses of isolated viral strains, or cloning and investigations on the distribution of PV in histologically normal-appearing tissues of patients affected by active PV diseases are needed to verify these hypotheses.


1. Walker DL, Padgett BL The epidemiology of human polyomaviruses. In: Sever JL, Madden D, eds. Polyomaviruses and Human Neurological Disease. New York, NY: Alan R Liss; 1983:99-106.

2. Shah KV. Polyomaviruses. In: Fields BN, Kinipe DM, Howley PM, eds. Fields Virology. 3rd ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1996:2027-2043.

3. Barbanti-Brodano G, Martini F, De Mattei M, Lazzarin L, Corallini A,Tognon M. BK and JC human polyomaviruses and simian virus 40: natural history of infection in humans, experimental oncogenicity, and association with human tumors. Adv Virus Res. 1998:50:69-99.

4. Newman JT, Frisque RJ. Identification of JC virus variants in multiple tissues of pediatric and adult PML patients. I Med Virol. 1999;58:79-86.

5. Dorries K. Latent and persistent polyomavirus infection. In: Khalili K, Stoner GL, eds. Human Polyomaviruses: Molecular and Clinical Perspectives. New York, NY: Wiley and Sons lnc; 2001:197-235.

6. Heritage J, Chesters PM, McCane DJ. The persistence of papovavirus BK DNA sequences in normal human renal tissue. \ Med Virol. 1981:8:143-150.

7. Chesters PM, Heritage J, McCane DJ. Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis. 1983;147:676-684.

8. Ferrante P Caldarelli-Stefano R, Omodeo-Zorini E, Vago L, Boldorini R, Costanzi G. PCR detection of JC virus DNA in brain tissue from patients with and without progressive multifocal leukoencephalopathy. J Med Virol. 1995:47:219-225.

9. Dorries K. Molecular biology and pathogenesis of human polyomavirus infections. Dev Biol Stand. 1998:94:71-79.

10. Berger JR, Pall R, Lanska D, Whiteman M. Progressive multifocal leukencephalopathy in patients with HIV infection. J Neurovirol. 1998;4:59-68.

11. Binet I, Nickeleit V, Hirsch HH, et al. Polyomavirus disease under new immunosuppressive drugs. Transplantation. 1999;67:918-922.

12. Boubenider S, Hiesse C, Marchand S, Hafi A, Kriaa F, Charpentier B. Posttransplantation polyomavirus infections. J Nephrol. 1999:12:24-29.

13. Smith RD, CaIIa JH, Skahan K, et al. Tubulointerstitial nephritis due to a mutant polyomavirus BK virus strain, BK (Cin), causing end-stage renal disease. J Clin Microbiol. 1998;36:1660-1665.

14. Nickeleit V, Hirsch HH, Binet IF, et al. Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease. I Am Soc Nephrol. 1999;10:1080-1089.

15. Coleman DV, Mackenzie EFD, Gardner SD, Poulding ]M, Amer B, Russel WJ. Human polyomavirus (BK) infection and ureteric stenosis in renal allograft recipients. J din Pathol. 1978;31:338-347.

16. Boldorini R, Omodeo-Zorini E, Vigano P, Nebuloni M, Mena M, Monga G. Cytologie and biomolecular analysis of polyomavirus infection in urine specimens of HIV-positive patients. Acta Cytol. 2000;2:205-210.

17. Arthur RR, Shah K. The occurrence and significance of papovaviruses JC and BK in urine. Prog Mod UiVo/. 1989:36:42-61.

18. Nickeleit V, Hirsch HH, Zeiler M, et al. BK-virus nephropathy in rénal transplants: tubular necrosis, MHC-class II expression and rejection in a puzzling game. Nephrol Dial Transplant. 2000:15:324-332.

19. Shinohara T, Matsuda M, Cheng SH, Marshall J, Fujita M, Nagashima SHK. BK virus infection of the human urinary tract. J Med Virol. 1993:41:301-305.

20. Wright DK, Manos MM. Sample preparation from paraffin-embedded tissues. In: Innis MA, Gelfand DH, Svinskyy JJ, White TJ, eds. PCR Protocols. San Diego, Calif: Academic Press; 1990:153-158.

21. Boldorini R, Omodeo-Zorini E, Nebuloni M, et al. Lytic JC virus infection in the kidneys of AIDS subjects. Mod Pathol. 2003;16:35-42.

22. Fedele CG, Ciardi M, Delia S, et al. Multiplex polymerase chain reaction for the simultaneous detection and typing of polyomavirus JC, BK and SV40 DNA in clinical samples. I Virol Methods. 1999;82:137-144.

23. Peinemann F, de Villers EM, Dorries K, et al. Clinical course and treatment of haemorrhagic cystitis associated with BK type of human polyomavirus in nine paediatric recipents of allogenic bone marrow transplants. Eur 1 Pediatr. 2000: 159:182-188.

24. Azzi A, Cesaro S, Laszlo D, et al. Human polyomavirus BK (BKV) load and haemorrhagic cystitis in bone marrow transplantation patients. 1 CUn Virol. 1999; 14:79-86.

25. Reploeg MD, Storch GA, Clifford DB. BK virus: a clinical review. 1 Infect Dis. 2001;33:191-202.

26. Boldorini R, Omodeo-Zorini E, Suno A, et al. Molecular characterization and sequence analysis of polyomavirus strains isolated from needle biopsy specimens of kidney allograft recipients. Am I Clin Pathol. 2001 ;116:489-494.

27. Vaz B, Cinque P, Pickhardt M, et al. Analysis of the transcriptional control region in progressive multifocal leukoencephalopathy. J Neurovirol. 2000;6:398-409.

28. Agostini HT, Ryschkewitsch CF, Stoner GL. Rearrangements of archetypal regulatory regions in JC virus genomes from urine. Res Virol. 1998:149:163-170.

Renzo Boldorini, MD; Claudia Veggiani, BSc; Diana Barco, BSc; Guido Monga, MD

Accepted for publication September 10, 2004.

From the Department of Medical Science, University School of Medicine "Amedeo Avogadro" of Eastern Piedmont, Novara, Italy; and the Unit of Pathology, Ospedale Maggiore della Carita, Novara, Italy.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Renzo Boldorini, MD, Dipartimento di Scienze Mediche, Facolta di Medicina e Chirurgia, Universita del Piemonte Orientale "Amedeo Avogadro," Via Solaroli 17, 28100 Novara, Italy (e-mail:

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