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August 2015; 1 (2) Clinical/Scientific NotesOpen Access

Posterior reversible encephalopathy syndrome is not associated with mutations in aquaporin-4

Marcelo Matiello, Rajanandini Muralidharan, David Sun, Alejandro A. Rabinstein, Brian G. Weinshenker
First published July 16, 2015, DOI: https://doi.org/10.1212/NXG.0000000000000013
Marcelo Matiello
From the Department of Neurology (M.M.), Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neuroscience (R.M.), Winthrop University Hospital, Mineola, NY; and Department of Neurology (D.S., A.A.R., B.G.W.), Mayo Clinic, Rochester, MN.
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Rajanandini Muralidharan
From the Department of Neurology (M.M.), Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neuroscience (R.M.), Winthrop University Hospital, Mineola, NY; and Department of Neurology (D.S., A.A.R., B.G.W.), Mayo Clinic, Rochester, MN.
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David Sun
From the Department of Neurology (M.M.), Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neuroscience (R.M.), Winthrop University Hospital, Mineola, NY; and Department of Neurology (D.S., A.A.R., B.G.W.), Mayo Clinic, Rochester, MN.
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Alejandro A. Rabinstein
From the Department of Neurology (M.M.), Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neuroscience (R.M.), Winthrop University Hospital, Mineola, NY; and Department of Neurology (D.S., A.A.R., B.G.W.), Mayo Clinic, Rochester, MN.
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Brian G. Weinshenker
From the Department of Neurology (M.M.), Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neuroscience (R.M.), Winthrop University Hospital, Mineola, NY; and Department of Neurology (D.S., A.A.R., B.G.W.), Mayo Clinic, Rochester, MN.
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Citation
Posterior reversible encephalopathy syndrome is not associated with mutations in aquaporin-4
Marcelo Matiello, Rajanandini Muralidharan, David Sun, Alejandro A. Rabinstein, Brian G. Weinshenker
Neurol Genet Aug 2015, 1 (2) e19; DOI: 10.1212/NXG.0000000000000013

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Posterior reversible encephalopathy syndrome (PRES) is characterized by acute reversible subcortical vasogenic edema that is typically bilateral and self-limiting. It preferentially affects posterior regions of the brain. Clinical manifestations include encephalopathy, seizures, headache, and cortical blindness. PRES may be precipitated by hypertensive crises such as eclampsia and by immunosuppressive agents. The pathophysiology of PRES is incompletely understood. Disordered cerebral autoregulation leading to protein and fluid extravasation is thought to be important.1 Other theories implicate endothelial dysfunction or vasospasm.2

Aquaporin-4 (AQP4) is the most abundant water channel in the CNS. AQP4-null mice are less susceptible to cytotoxic cerebral edema following brain insults and have improved neurologic outcome after focal cerebral ischemia and bacterial meningitis compared with wild-type mice. However, brain swelling and clinical outcome are worse in AQP4-null mice after insults producing vasogenic edema, probably due to impaired AQP4-dependent brain water clearance.3

Four AQP4 single nucleotide polymorphisms (SNPs) found in healthy humans have been linked with reduced water permeability.4 We have reported an association between PRES and neuromyelitis optica, a disease characterized by autoimmunity against AQP4 that ultimately results in reduced immunoreactivity for this channel protein and reduced water transport.5 Here we investigate whether mutations in AQP4 are present in patients who had PRES and did not have neuromyelitis optica.

Methods.

All patients had given written informed consent. Patients with a diagnosis of PRES were identified during admission to Saint Mary's Hospital, Mayo Clinic, Rochester, MN, from October 1, 2005, through April 30, 2009. Three criteria were required for inclusion: (1) clinical history of acute neurologic change, including headache, encephalopathy, seizure, visual disturbance, or focal deficit; (2) brain imaging findings of focal vasogenic edema; and (3) clinical or radiologic proof of reversibility. Patient records were assessed for demographic data, clinical presentation, comorbid and predisposing conditions, PRES recurrence, and family history. Patients with neuromyelitis optica who had similar comprehensive sequencing of AQP4 but did not have an episode of PRES served as controls, and they were matched to patients with PRES based on ethnicity.6

DNA was obtained from blood samples. The human AQP4 gene maps to 18q11.2—q12.1 and is encoded by 5 exons. We sequenced AQP4 in both downstream and upstream orientations after amplification of genomic DNA in 4 fragments that included 1,000 base pairs upstream of the exon 0, exons 0–4, 5′ and 3′ untranslated regions, and splice consensus sequences flanking the exons. Chromatograms were analyzed using mutation detection software (Mutation Surveyor V3.12, Softgenetics, State College, PA).

Results.

DNA was isolated from 23 patients, 14 of whom were women (60.9%). The median age at PRES onset was 52.5 years (range 25–78 years). Eight-seven percent (n = 20) of the patients were white, 1 was Asian, and 2 did not disclose their ethnicity. No patients had a family history of PRES.

One patient (4.3%) had recurrent PRES 15 months after her initial episode. Most patients (78.2%, n = 18) experienced the characteristic manifestations of PRES, including headache, mental status changes, seizure, cortical blindness, visual hallucinations, and focal motor, sensory, or coordination deficits in various combinations. Atypical presentations were status epilepticus in 2 cases, coma in 2, and isolated confusion in 1. Precipitating factors for PRES included hypertension (n = 11, 47.8%), renal failure (n = 5, 21.7%), cytotoxic medications (n = 4, 17.4%), and sepsis (n = 3, 13%).

We did not find any novel coding mutations in patients with PRES, nor did we identify variants previously reported to be associated with impairment of water transport. Sixteen previously reported SNPs (National Center for Biotechnology Information) were polymorphic in patients with PRES (table). The minor allele frequencies of these SNPs were similar to those detected in matched controls.

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Table

Minor allele frequencies of SNPs in patients with PRES and control subjects

Discussion.

In this comprehensive genomic sequencing study of AQP4 in a cohort of patients with PRES, we found no evidence for the association of genetic variation of AQP4 with susceptibility to PRES, allowing for the power of this study. We did not detect novel allelic mutations that could disrupt the water transport properties of AQP4.

Four rare coding SNPs (I128T, D184E, I205L, and M224T) were previously reported4 to alter water permeability by 26%–48% compared with the wild-type AQP4 in cellular assays. These variants had been detected in otherwise healthy individuals and were not found in the patients we studied. It is unclear whether they might be susceptibility factors for PRES.

Recently it was noted that a high percentage of patients with PRES have autoimmune disorders,7 and it was suggested that PRES may be associated with inflammatory endothelial dysfunction. We have previously tested 17 patients with PRES for anti-AQP4 antibodies; none was positive.5

Study limitations include small sample size and limited evaluation of nonwhite patients; we did not assess copy number variations. Based on our sample, AQP4 genomic variations affecting protein structure or expression are unlikely to be major contributors to the development of typical PRES.

Footnotes

  • Author contributions: Dr. Matiello participated in the analysis, interpretation, writing, and critical review of the manuscript for important intellectual content. Dr. Muralidharan participated in the analysis, interpretation, writing, and critical review of the manuscript. Dr. Sun participated in the analysis, interpretation, and critical review of the manuscript. Dr. Rabinstein participated in the analysis, interpretation, writing, and critical review of the manuscript for important intellectual content. Dr. Weinshenker participated in the analysis, interpretation, writing, and critical review of the manuscript for important intellectual content.

  • Study funding: Dr. Matiello was supported by a postdoctoral fellowship from the National Multiple Sclerosis Society. This study was supported by the Mayo Clinic Neurology Department and by the Guthy-Jackson Charitable Foundation.

  • Disclosure: Dr. Matiello was supported by a fellowship grant from the National MS Society and has received speaker honoraria from TerumoBCT. Dr. Muralidharan and Dr. Sun report no disclosures. Dr. Rabinstein has been a member of the external committee for adverse event adjudication for PREVAIL trial; has been an editorial board member for Neurocritical Care; has received royalties for publications Practical Neuroimaging in Stroke (Elsevier, 2009) and What to Do? Neurocritical Care (Oxford, 2011); and has received research support from an unrestricted research grant from DJO Global. Dr. Weinshenker has been a member of data safety monitoring boards for Novartis, Biogen Idec, and Mitsubishi; has been an adjudication panel member for MedImmune Pharmaceuticals; has been a consultant for Elan, GlaxoSmithKline, Ono, CHORD Therapeutics, and Chugai; has served on the editorial boards of Neurology, the Canadian Journal of Neurological Sciences, and the Turkish Journal of Neurology; has received research support from Guthy-Jackson Charitable Foundation; and has received royalties for a patent regarding AQP4-associated antibodies for diagnosis of neuromyelitis optica. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors.

  • Received March 29, 2015.
  • Accepted in final form June 8, 2015.
  • © 2015 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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