This blog is a way of sharing the information and resources that have helped me to recover my son Roo from an Autism Spectrum Disorder. What I have learned is to view our symptoms as the results of underlying biological cause, which can be identified and healed. I say "our symptoms" because I also have a neuro-immune disorder called Myalgic Encephalomyelitis.

And, of course, I am not a doctor (although I have been known to impersonate one while doing imaginative play with my son)- this is just our story and information that has been helpful or interesting to us. I hope it is helpful and interesting to you!

Sunday, November 9, 2014

Vertical Viral Transmission as Pathogenesis in Autism?

A study published in 2010 out of Rome, Italy has found evidence of vertical viral transmission in postmortem evaluations of the brains of people with autism.  The study was undertaken because there is evidence of heritability of autism, that is of it being passed along in families, that is stronger than the evidence that is being found for a genetic cause for this heritability.  So the question was asked, in what other ways could a disorder such as autism be passed from one generation to the next?  Infections are certainly one way that this can occur.  To quote from the study "Autism is a highly heritable behavioral disorder. Yet, two decades of genetic investigation have unveiled extremely few cases that can be solely explained on the basis of de novo mutations or cytogenetic abnormalities. Vertical viral transmission represents a non-genetic mechanism of disease compatible with high parent-to-offspring transmission and with low rates of disease-specific genetic abnormalities."

This study, Association of autism with polyomavirus infection in postmortem brains,
found that three viruses were significantly more prevalent in the brains of people with autism than in the controls "BKV, JCV, and SV40 combined are significantly more frequent among autistic patients compared to controls (67% versus 23%, respectively; P < .05). "  SV40 is Simian Virus 40, a monkey virus that was a contaminant in polio vaccines used between 1955 and 1963.  BK and JC viruses are closely related to each other, and are part of the family of polyomaviruses (which is a subgroup of papovaviruses). SV40 is also a papovavirus.

SV40 has long been suspected of causing cancer in humans, but evidence has been mixed and inconclusive.   The Immunization Safety Review Committee of the Institute of Medicine put out a report on this question that can be viewed here, which essentially says that the epidemiological evidence that has been used to deny a connection between SV40 and cancer is too flawed to rule out a possible connection, that the idea that SV40 could contribute to human cancers is plausible, and that ongoing investigation is required.

The paper "BK Virus: A Clinical Review" provides more information about BK virus:

-the etiologic agent of progressive multifocal leukoencephalopathy (PML).
-The kidney, lung, eye, liver, and brain are sites of BK virus-associated disease, both primary and reactivated.
-BK virus has also been detected in the tissue samples of a variety of neoplasms, which have predominantly been brain tumors of glial and neural origin, although there is controversy regrading associations between these neoplasms and BK virus.
-A few investigators have proposed various mechanisms whereby BK virus can induce neoplasia (cancer).
-There may even be an association between BK virus and autoimmune disease.
-Although rarely recognized, BK virus might cause both primary CNS disease and reactivation CNS disease as well.
-Additional disorders of the CNS associated with BK virus include encephalitis, Guillain-Barre Syndrome, and Meningoencephalitis.
-Many authors have reported that BK virus can exist in a latent phase in various organs [1227]. Much of the data are based on PCR experiments; exceptions are mentioned below. Similar in concept to the latent state of the herpesvirus [101], these authors propose that BK virus can remain within a cell in a nonreplicating or minimally replicating form. Within the cell, the latent viral genome may either remain episomal or it may be integrated in the host cell genome. In either state, few if any viral genes are transcribed, thereby keeping the virus out of reach of the immune system. Implicit in the definition of latency is the concept of virus reactivation in certain settings.
-Reactivation disease is observed in patients with relative or absolute immunodeficiency (generally cellular immunodeficiency rather than humoral immunodeficiency).
-researchers reported an increased prevalence and persistence of BK viruria in patients with systemic lupus erythematosus. In their study, the prevalence of BK viruria was 16% in patients with systemic lupus erythematosus and 0% in controls. Of the 20 patients who were tested, persistent or recurrent viruria was found in 60% of patients with systemic lupus erythematosus [90]. This same relationship is seen between BK virus and other autoimmune diseases, including rheumatoid arthritis and polymyositis [117]. Although whether there is causality has not been determined.
-Although it is not proof of causality, the strongest data, including demonstration of viral DNA integration into tumor cell genomes, and even the findings of some in situ studies, support a correlation between BK virus and many brain and urinary tract tumors [66, 70, 87].
-Other researchers that have observed the same phenomenon from a different perspective have examined the association of BK viral infection with an increased number of chromosomal aberrations. The induction of chromosomal aberrations via BK virus T antigen is observed in vitro in human fibroblast cell lines [85]. Also, one study reported that a group of patients with polyomavirus infection who were exposed to radiation experienced a greater number of chromosomal aberrations than did a similar group of persons without infection [86].
-Moens et al. [88, 89] demonstrated indirect interaction between the large T antigen of BK virus and native cell estrogen receptors that, via trans activation, enhances the promoter of BK virus. The researchers postulated that there was a hormone-mediated association with BK virus reactivation and even neoplasia.

More on JC Virus:

From Understanding the JC VIrus and the Risks for MS Patients:
-The JC Virus is the cause of Progressive Multifocal Leukoencephalopathy (PML), in which "it infects the white matter of the brain and attacks the cells responsible for making myelin, the protective coating that covers and protects nerve cells.".  
-This virus can be triggered to reactivate either because the immune system of the person with MS is compromised, or because the person is taking immune-suppressing medications.  

More information on JC infection can be found here:

-Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system (CNS), caused by the polyoma virus JC virus (JCV) and characterized by focal demyelination.
-PML manifests as focal neurological deficits, usually with insidious onset and steady progression. Because the demyelinating lesions can involve different brain regions, specific deficits vary from patient to patient. Any region of the CNS can be involved, although some areas seem to be more favored, including the occipital lobes (with hemianopsia), frontal and parietal lobes (aphasia, hemiparesis, and hemisensory deficits), and cerebellar peduncles and deep white matter (dysmetria and ataxia).
-Spinal cord involvement is rare.
-Although lesions can be multiple, one often is clinically predominant.
-Initial symptoms and signs often begin as partial deficits (e.g., weakness in one leg) that worsen over time and involve a larger territory (e.g., evolution to hemiparesis) as individual lesions expand concentrically or along white matter tracts. The focal or multifocal nature of the pathology is responsible for the consistency of clinical presentations with distinct focal symptoms and signs, rather than as a more diffuse encephalopathy, or isolated dementia or behavioral syndrome, all of which are uncommon without concomitant focal findings.

The article JC Virus Infection of the Brain has some more updated information:

-Since its initial description, there have been significant changes in the epidemiology, pathogenesis, and clinical and imaging manifestations of JCV infection of brain. The most common clinical manifestation is PML. Other recently described CNS manifestations are JCE (JCV encephalopathy), JCVGCN (JCV Granular Cell Neuronopathy), and JCM (JCV Meningitis).
-Although AIDS is the most common predisposing factor for JCV reactivation, there is increasing incidence of brain manifestations of JCV reactivation in non-HIV settings, including different rheumatologic, hematologic, and oncologic conditions; monoclonal antibody therapy; transplant recipients; primary immunodeficiency syndromes; and even in patients without any recognizable immune deficiency.
-It has become evident that PML has outgrown its name. JCV infection is no longer a 1-dimensional opportunistic infection, limited to HIV and lymphoproliferative disorders. Although HIV accounts for approximately 80% of the PML cases, there is increasing incidence of the disease in non-HIV settings.
-JCV is a ubiquitous human pathogen, and both inhalation and ingestion of contaminated water have been suggested as major modes of transmission of the virus.
-Usually, severe deficiency of T-cell immunity (cellular immunity) is necessary for reactivation of JCV.
-Calabrese et al18 recently reviewed 37 cases of PML in the setting of rheumatic diseases. All patients in this series were treated with some form of immunosuppressant before PML manifestation. Of all the rheumatologic conditions SLE was most commonly associated (65%) with PML. Other associated rheumatic diseases were rheumatoid arthritis, Wegener granulomatosis, dermatomyositis, polymyositis, and scleroderma. There are also reports of PML in patients with Sjogren syndrome19 and sarcoidosis20 with no prior immunomodulator therapy. In both of these cases, there was associated lymphocytopenia. It is unclear whether the rheumatologic condition or the lymphocytopenia was responsible for PML.
-PML has also been described in patients with primary immunodeficiency disorders, ICL being the most common condition to be associated with PML.2830 PML has also been described in patients with common variable immune deficiency.
-Until recently, severe depletion of cellular immunity was considered an absolute requirement for the development of PML. However, there are now case reports of PML with less overt immunodeficiency, such as cirrhosis, renal failure, psoriasis, dermatomyositis, and even pregnancy.6 Furthermore, there are multiple reports in the literature of PML without any documented immunodeficiency.6 It is very important that neuroradiologists be aware of this expanding demography of PML, JCE, JCVGCN, and JCM.
-The pathogenesis of PML is divided into 3 phases. The first phase is a primary clinically unapparent infection. In the second phase, the virus maintains a persistent latent peripheral infection in the urinary tract, bone marrow, and probably the spleen.35 The presence of JCV in the bone marrow and shedding of the virus in urine are well documented in asymptomatic immunocompetent carriers.36,37 The CNS has also been suggested as a potential site for JCV persistence. The third or final phase is that of reactivation and dissemination of the virus with presumed hematogenous spread to the CNS.
-The authors concluded that tests for BK virus and JCV should be included in the investigative program for patients with meningitis or encephalitis.
-PML may involve gray matter as well. The thalamus is the most common area, followed by the basal ganglia.49,88 Usually gray matter lesions are associated with white matter involvement in almost all cases. Vary rarely, PML lesions can be isolated to the gray matter.
-As briefly mentioned previously, PML can occur in MS patients treated with natalizumab. It is very difficult to differentiate a new PML lesion from an MS plaque in patients treated with natalizumab.

More interesting finds about BK virus, JC virus, and SV 40:

Hypothesis- "Rogue cell"-type chromosomal damage in lymphocytes is associated with infection with the JC human polyoma virus and has implications for oncopenesis

Abstract- "The hemagglutination inhibition antibody titers against the JC and BK polyoma viruses (JCV and BKV, respectively) are significantly elevated in individuals exhibiting "rogue" cells among their cultured lymphocytes. However, the elevation is so much greater with respect to JCV that the BKV elevation could readily be explained by cross reactivity to the capsid protein of these two closely related viruses. The JCV exhibits high sequence homology with the simian papovavirus, simian virus 40 (SV40), and inoculation of human fetal brain cells with JCV produces polyploidy and chromosomal damage very similar to that produced by SV40. We suggest, by analogy with the effects of SV40, that these changes are due to the action of the viral large tumor antigen, a pluripotent DNA binding protein that acts in both transcription and replication. The implications of these findings for oncogenesis are briefly discussed."