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Dissecting the neuronal vulnerability underpinning Alpers' syndrome: A clinical and neuropathological study

Lookup NU author(s): Dr Hannah Hayhurst, Maria Anagnostou, Helen Bogle, Dr John Grady, Professor Robert Taylor, Professor Bobby McFarland, Professor Doug Turnbull, Dr Nichola Lax

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

AbstractAlpers’ syndrome is an early‐onset neurodegenerative disorder often caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase‐gamma (POLG) which is essential for mitochondrial DNA (mtDNA) replication. Alpers’ syndrome is characterised by intractable epilepsy, developmental regression and liver failure which typically affects children aged 6 months ‐ 3 years. Although later onset variants are now recognised, they differ in that they are primarily an epileptic encephalopathy with ataxia. The disorder is progressive, without cure and inevitably leads to death from drug‐resistant status epilepticus, often with concomitant liver failure. Since our understanding of the mechanisms contributing the neurological features in Alpers’ syndrome is rudimentary, we performed a detailed and quantitative neuropathological study on 13 patients with clinically and histologically‐defined Alpers’ syndrome with ages ranging from 2 months to 18 years. Quantitative immunofluorescence showed severe respiratory chain deficiencies involving mitochondrial respiratory chain subunits of complex I and, to a lesser extent, complex IV in inhibitory interneurons and pyramidal neurons in the occipital cortex and in Purkinje cells of the cerebellum. Diminished densities of these neuronal populations were also observed. This study represents the largest cohort of post‐mortem brains from patients with clinically‐defined Alpers’ syndrome where we provide quantitative evidence of extensive complex I defects affecting interneurons and Purkinje cells for the first time. We believe interneuron and Purkinje cell pathology underpins the clinical development of seizures and ataxia seen in Alpers’ syndrome. This study also further highlights the extensive involvement of GABAergic neurons in mitochondrial disease.


Publication metadata

Author(s): Hayhurst H, Anagnostou ME, Bogle HJ, Grady JP, Taylor RW, Bindoff LA, McFarland R, Turnbull DM, Lax NZ

Publication type: Article

Publication status: Published

Journal: Brain Pathology

Year: 2018

Issue: ePub ahead of Print

Online publication date: 18/07/2018

Acceptance date: 18/07/2018

ISSN (print): 1015-6305

ISSN (electronic): 1750-3639

Publisher: Wiley-Blackwell Publishing, Inc.

URL: https://doi.org/10.1111/bpa.12640

DOI: 10.1111/bpa.12640


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