ArticleBrain pathology (Zurich, Switzerland)2019
Dissecting the neuronal vulnerability underpinning Alpers' syndrome: a clinical and neuropathological study.
Article in Brain pathology (Zurich, Switzerland), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 31 citations in OpenAlex.
- Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.Acta neuropathologica · 2025Article
- Rhythmic high-amplitude delta with superimposed spikes (RHADS): a treatment dilemma.Oxford medical case reports · 2024Article
- Differentiating rhythmic high-amplitude delta with superimposed (poly) spikes from extreme delta brushes: limitations of standardized nomenclature and implications for patient management.World journal of pediatrics : WJP · 2024Review
- Hallmark Molecular and Pathological Features of POLG Disease are Recapitulated in Cerebral Organoids.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.Biochemical Society transactions · 2024Review
- Article
- The NADInternational journal of biological sciences · 2024Article
- Applications of near-infrared spectroscopy in epilepsy, with a focus on mitochondrial disorders.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- A novel mouse model of mitochondrial disease exhibits juvenile-onset severe neurological impairment due to parvalbumin cell mitochondrial dysfunction.Communications biology · 2023Article
- Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology.International journal of molecular sciences · 2023Review
- Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases.IBRO neuroscience reports · 2023Article
- Astrocytic pathology in Alpers' syndrome.Acta neuropathologica communications · 2023Article
- Delineating selective vulnerability of inhibitory interneurons in Alpers' syndrome.Neuropathology and applied neurobiology · 2022Article
- Mitochondrial Ataxias: Molecular Classification and Clinical Heterogeneity.Neurology international · 2022Review
- A perspective on human cell models for POLG-spectrum disorders: advantages and disadvantages of CRISPR-Cas-based vs. patient-derived iPSC models.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2021Article
- Imaging mass cytometry reveals generalised deficiency in OXPHOS complexes in Parkinson's disease.NPJ Parkinson's disease · 2021Article
- Clinical Attributes and Electroencephalogram Analysis of Patients With Varying Alpers' Syndrome Genotypes.Frontiers in pharmacology · 2021Article
- Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy.PloS one · 2019Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
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.
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