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

Hannah Hayhurst,John P Grady,Robert Mcfarland,Helen J Bogle,Laurence A Bindoff,Doug M Turnbull,Robert W Taylor,Maria‐Eleni Anagnostou,Nichola Z Lax

doi:10.1111/bpa.12640

Abstract

Alpers’ 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 characterized by intractable epilepsy, developmental regression and liver failure which typically affects children aged 6 months–3 years. Although later onset variants are now recognized, 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.

Highlights

Alpers’ syndrome, more correctly described as AlpersHuttenlocher syndrome, is a severe early-onset neurodegenerative disorder characterized by a clinical triad of intractable epilepsy, psychomotor regression and liver failure [2]
Molecular genetic diagnosis was achieved for five patients and Sanger sequencing confirmed the presence of mutated POLG variants (Table 1)
Due to the fulminant epilepsy, this syndrome is associated with poor prognosis and a rapidly progressive disease course

Summary

Introduction

Alpers’ syndrome, more correctly described as AlpersHuttenlocher syndrome, is a severe early-onset neurodegenerative disorder characterized by a clinical triad of intractable epilepsy, psychomotor regression and liver failure [2]. Other symptoms include developmental delay, failure to thrive, hypotonia, spasticity and ataxia. The exact prevalence of Alpers’ syndrome is unknown due to high mortality and early death but it is estimated to affect 1:100,000 births [38]. A bimodal disease onset has been described with the first peak of onset affecting infants between the ages of 6 months and 3 years and a second peak, typified by an epileptic encephalopathy, during adolescence [16, 48]. The disorder is progressive, without cure and is invariably fatal caused by status epilepticus or hepatic failure.

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