Lookup NU author(s): Dr Hannah Hayhurst,
Dr John Grady,
Professor Robert Taylor,
Professor Bobby McFarland,
Emeritus Professor Doug Turnbull,
Dr Nichola Lax
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
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
Print publication date: 01/01/2019
Online publication date: 18/07/2018
Acceptance date: 18/07/2018
Date deposited: 11/09/2018
ISSN (print): 1015-6305
ISSN (electronic): 1750-3639
Publisher: Wiley-Blackwell Publishing, Inc.
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