Fatal HHV-6 encephalitis in children with POLG mitochondrial disorders

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Does HHV-6 encephalitis trigger mitochondrial disease in children with POLG mitochondrial disorders? Two cases of fatal Alpers-Huttenlocher syndrome

A team of clinicians and researchers from the University of Michigan Medical School and Washington University in St. Louis has detailed two cases of fatal HHV-6 encephalitis in children with underlying polymerase gamma (POLG) mitochondrial disorders. In the report, published this month in the journal Pediatric Neurology, the group describes a marked disease progression in two previously healthy young boys with HHV-6-associated encephalitis that developed into a progressive, and ultimately fatal, encephalopathy with refractory movement disorder concurrent with acquisition of acute HHV-6 infection.

A post-mortem examination revealed that both children had mutations in the mitochondrial polymerase γ gene, POLG. Mutations in this gene are associated with Alpers-Huttenlocher syndrome, a condition characterized by intractable seizures, developmental regression and, ultimately, death due to liver and renal failure.

While no prior studies have examined the role of acute HHV-6 infection in Alpers-Huttenlocher patients presenting with severe neurologic disease, several groups have found significant associations between HHV-6B and seizure/epileptic disorders, including Febrile Status Epilepticus (FEBSTAT studies), Symptomatic Generalized Epilepsy (Howell, Raspall Chaure) and Mesial Temporal Lobe Epilepsy (Li, Niehusmann).

The authors propose that the POLG mutation phenotype may have been unmasked and/or exacerbated by HHV-6 infection in these two patients, potentially contributing to a more rapid clinical deterioration. An unanswered question is whether or not prompt antiviral treatment of the HHV-6 encephalitis might have made a difference. Both children were treated with ganciclovir, but not immediately. Studies of HHV-6 encephalitis in cord blood transplant patients suggest that due to the rapid and persistent progression of this condition, it is difficult to treat HHV-6 encephalitis once it has progressed and that prophylactive therapy is therefore preferable in patients at risk for developing HHV-6 encephalitis (Ishiyama 2012).

Of interest, a previous study (Yeo 2008) found that the U95 “intermediate early” gene of HHV-6B interacts with GRIM-19 (a gene that is an essential component of the oxidative phosphorylation system) to damage the mitochondria. The authors found that by silencing the HHV-6B U95 gene, there was no longer an interaction with GRIM-19 or a loss of mitochondrial function.

Although HHV-6B primary and reactivated infection has been identified as the likely cause of one-third of children who develop febrile status epilepticus, patients with FSE are not routinely tested for HHV-6 and are not offered antiviral therapy. Furthermore, if viral testing is conducted in such cases, it is usually for CMV (HHV-5) and herpes simplex (HSV-1), rather than HHV-6A/B. Of note, infants with symptomatic congenital CMV infection are typically administered 6 weeks of ganciclovir antiviral therapy, a protocol that has been shown to stop the progression of the infection and prevent subsequent CNS dysfunction, hearing loss and seizures.

For more information, read the full paper, and visit the HHV-6 Foundation webpage on HHV-6 & Epilepsy. A summary of abstracts on HHV-6 & seizures/epilepsy can be downloaded here.

NOTE TO PATIENT FAMILIES: HHV-6 PCR DNA testing is available at most commercial laboratories in the US (Viracor, Quest, Labcorp) but testing in other countries is difficult to arrange. A few specialty labs in Europe such as RedLabs offer testing for HHV-6. Healthy individuals are not positive for HHV-6 except (a) briefly during the initial infection that occurs between 3 months and 3 years of age, or (b) if they have inherited or chromosomally integrated HHV-6, a condition that affects less than 1% of the population.