Fatal Human Herpesvirus 6–Associated Encephalitis in Two Boys With Underlying POLG Mitochondrial Disorders

Al-Zubeidi, Duha; Thangarajh, Mathula; Pathak, Sheel; Cai, Chunyu; Schlaggar, Bradley L.; Storch, Gregory A.; Grange, Dorothy K.; Watson, Michael

doi:10.1016/j.pediatrneurol.2014.04.006

Cited by 20 publications

(27 citation statements)

References 20 publications

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“…Genetic polymorphisms in POLG also explain the variation in mitochondrial toxicity in HIV-infected patients (61,62). Other viruses, such as human herpesvirus 6, caused encephalitis in two patients with mutations in POLG and exacerbated the Alpers phenotype, contributing to a more rapid clinical deterioration (63). Although not tied to specific POLG mutations, mitochondria are susceptible to environmental toxicants, such as heavy metals and pesticides (64,65), which leads to questioning whether exposure to environmental contaminants could contribute to altering the age of onset and severity of POLG diseases.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations

DeBalsi

Longley

Hoff

et al. 2017

Journal of Biological Chemistry

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Human mitochondrial DNA (mtDNA) polymerase γ (Pol γ) is the only polymerase known to replicate the mitochondrial genome. The Pol γ holoenzyme consists of the p140 catalytic subunit (POLG) and the p55 homodimeric accessory subunit (POLG2), which enhances binding of Pol γ to DNA and promotes processivity of the holoenzyme. Mutations within impede maintenance of mtDNA and cause mitochondrial diseases. Two common mutations usually found in patients primarily with progressive external ophthalmoplegia generate T251I and P587L amino acid substitutions. To determine whether T251I or P587L is the primary pathogenic allele or whether both substitutions are required to cause disease, we overproduced and purified WT, T251I, P587L, and T251I + P587L double variant forms of recombinant Pol γ. Biochemical characterization of these variants revealed impaired DNA binding affinity, reduced thermostability, diminished exonuclease activity, defective catalytic activity, and compromised DNA processivity, even in the presence of the p55 accessory subunit. However, physical association with p55 was unperturbed, suggesting intersubunit affinities similar to WT. Notably, although the single mutants were similarly impaired, a dramatic synergistic effect was found for the double mutant across all parameters. In conclusion, our analyses suggest that individually both T251I and P587L substitutions functionally impair Pol γ, with greater pathogenicity predicted for the single P587L variant. Combining T251I and P587L induces extreme thermal lability and leads to synergistic nucleotide and DNA binding defects, which severely impair catalytic activity and correlate with presentation of disease in patients.

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Section: Discussionmentioning

confidence: 99%

Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations

DeBalsi

Longley

Hoff

et al. 2017

Journal of Biological Chemistry

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“…following acute HHV-6 infection were recently reported for two children with underlying genetic mitochondrial disorders (158). As in benign forms of CNS involvement, the recognition of a concomitant active infection permits the etiological diagnosis and is founded on a combination of virological parameters which include the finding of HHV-6 DNA in blood, saliva, and CSF, as well as specific seroconversion and IgM detection (3,136).…”

Section: Clinical Impacts Of Hhv-6 Infections Primary Infectionsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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“…294,301,309 However, even among immunocompetent subjects, rare cases of hepatitis, infectious mononucleosislike syndrome, gastroenteritis, colitis, and neurological complications (seizures, encephalitis, chronic psychiatric disorders) may occur. 294,314,315 Further, several studies suggest a link between chronic HHV-6 infection and multiple sclerosis. [316][317][318] Fatal myocarditis, although rare, has been described.…”

Section: Primary Hhv-6 Infectionmentioning

confidence: 99%

Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes

Reid

Lynch

Weigt

et al. 2016

Semin Respir Crit Care Med

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Among immunocompromised individuals, members of the human Herpesviridae family are frequently encountered pathogens. Cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and human herpesvirus-6, -7, and -8 all establish latency after infection and can reactivate during periods of immunosuppression, leading to both direct and indirect adverse effects on the host including severe organ dysfunction as well as allograft rejection and loss after transplantation. While not all herpesviruses are primary respiratory pathogens, many of their manifestations include involvement of the respiratory tract. This article discusses the individual viruses, their epidemiology, and clinical manifestations as well as recommended treatment and preventive strategies.

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Fatal Human Herpesvirus 6–Associated Encephalitis in Two Boys With Underlying POLG Mitochondrial Disorders

Cited by 20 publications

References 20 publications

Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations

Synergistic Effects of the in cis T251I and P587L Mitochondrial DNA Polymerase γ Disease Mutations

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes

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