• Alpers’ syndrome
• MELAS
• MERRF
• Oxidative phosphorylation (OXPHOS)
• POLG
• mtDNA

• Alpers–Huttenlocher syndrome
• Autoimmune encephalitis
• Extreme delta brush
• Neurological disorder
• Polyspike
• Rhythmic delta activity
• Rhythmic high-amplitude delta activity
• Seizure

• Humans
• Electroencephalography
• Terminology as Topic
• Diagnosis, Differential
• Delta Rhythm
• Child
• Infant
• Adolescent

• DNA damage
• DNA replication and recombination
• mitochondrial dysfunction
• mtDNA

• Humans
• DNA, Mitochondrial/genetics
• DNA, Mitochondrial/metabolism
• DNA Replication
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/metabolism
• Mitochondrial Diseases/pathology
• Sequence Deletion
• Genome, Mitochondrial
• Mitochondria/genetics
• Mitochondria/metabolism
• DNA Repair

• Saccharomyces cerevisiae
• drug drop test
• drug repurposing
• mitochondrial diseases
• yeast model

• cerebellar ataxia
• inhibitory neurons
• neurodegeneration

• 203105 Wellcome Trust

• Alpers’ syndrome
• Aquaporin 4 (AQP4)
• GFAP
• Glutamine synthetase (GS)
• Kir4.1
• Mitochondrial Epilepsy
• POLG
• Reactive astrogliosis

• Humans
• Child
• Astrocytes/metabolism
• Diffuse Cerebral Sclerosis of Schilder/genetics
• Diffuse Cerebral Sclerosis of Schilder/metabolism
• Sudden Unexpected Death in Epilepsy
• Seizures/genetics
• DNA, Mitochondrial/genetics
• Epilepsy/metabolism
• Glial Fibrillary Acidic Protein/metabolism

• Department of Health
• G0800674 Medical Research Council
• MR/S005021/1 Medical Research Council
• G0400074 Medical Research Council
• 203105/Z/16/Z Wellcome Trust
• Wellcome Centre for Mitochondrial Research
• Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease
• Mitochondrial Disease Patient Cohort (UK)
• UK NIHR Biomedical Research Centre for Ageing and Age-related disease
• The Ryan Stanford Appeal (UK)
• Alzheimer’s Research UK Senior Fellowship

Ketogenic diet is recommended as a treatment to reduce seizure frequency in patients with intractable epilepsy. The evidence and safety results are sparse for diet interventions in patients with pathogenic polymerase gamma (POLG) variants and intractable epilepsy. The aim of this systematic review is to summarize the efficacy of diet treatment on seizure frequency, clinical symptoms, and potential deleterious effect of liver involvement in patients with mitochondrial diseases caused by pathogenic POLG variants. Literature was searched in PubMed, Embase; and Cochrane in April 2022; no filter restrictions were imposed. The reference lists of retrieved studies were checked for additional literature. Eligibility criteria included verified pathogenic POLG variant and diet treatment. Overall, 880 studies were identified, providing eight case-reports representing nine patients eligible for inclusion. In eight of nine cases, clinical symptoms were improved; six out of nine cases reported improvements in seizure frequency. However, increasing levels of liver enzymes after initiating ketogenic diet were found in four of the nine cases, with one case revealing decreased levels of liver enzymes after initiating long-chain triglyceride restriction. Viewed together, the studies imply that ketogenic diet can have a positive impact on seizure frequency, but may induce progression of liver impairment in patients with pathogenic POLG variants.

• DNA Polymerase gamma/genetics
• Drug Resistant Epilepsy
• Epilepsy/genetics
• Epilepsy/pathology
• Humans
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/therapy
• Nucleotidyltransferases
• Prospective Studies
• Seizures
• Treatment Outcome
• Triglycerides

• Alpers
• Leigh
• mitochondrial disease
• mtDNA depletion
• ophthalmoplegia

Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA found in mitochondria themselves, and are termed mitochondrial DNA (mtDNA). Mutations striking either genome can lead to mitochondrial impairment, determining infantile, childhood or adult neurodegeneration. Mitochondrial disorders are complex neurological syndromes, and are often part of a multisystem disorder. In this paper, we divide the diseases into those caused by mtDNA defects and those that are due to mutations involving nuclear genes; from a clinical point of view, we discuss pediatric disorders in comparison to juvenile or adult-onset conditions. The complementary genetic contributions controlling organellar function and the complexity of the biochemical pathways present in the mitochondria justify the extreme genetic and phenotypic heterogeneity of this new area of inborn errors of metabolism known as ‘mitochondrial medicine’.

Mitochondria, the powerhouse of a cell, are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond. Evolution supports a prokaryotic descent, and, unsurprisingly, the organelle is worthy of being labeled an organism in itself. Since highly metabolically active organs require a continuous feed of energy, any dysfunction in the structure and function of mitochondria can have variable impact, with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition. Though categorized a hepatopathy, mitochondrial respiratory chain defects are not limited to the liver in time and space. The liver involvement is also variable in clinical presentation as well as in age of onset, from acute liver failure, cholestasis, or chronic liver disease. Other organs like eye, muscle, central and peripheral nervous system, gastrointestinal tract, hematological, endocrine, and renal systems are also variably involved. Diagnosis hinges on recognition of subtle clinical clues, screening metabolic investigations, evaluation of the extra-hepatic involvement, and role of genetics and tissue diagnosis. Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation. This review lists and discusses the burden of mitochondrial respiratory chain defects, including various settings when to suspect, their evolution with time, including certain specific disorders, their tiered evaluation with diagnostic algorithms, management dilemmas, role of liver transplantation, and the future research tools.

• Mitochondrial hepatopathy
• Respiratory chain defects
• Maternal inheritance
• Neonatal liver failure
• DNA depletion syndrome
• Pearson syndrome

Mitochondrial DNA (mtDNA) maintenance is critical for oxidative phosphorylation (OXPHOS) since some subunits of the respiratory chain complexes are mitochondrially encoded. Pathological mutations in nuclear genes involved in the mtDNA metabolism may result in a quantitative decrease in mtDNA levels, referred to as mtDNA depletion, or in qualitative defects in mtDNA, especially in multiple deletions. Since, in the last decade, most of the novel mutations have been identified through whole-exome sequencing, it is crucial to confirm the pathogenicity by functional analysis in the appropriate model systems. Among these, the yeast Saccharomyces cerevisiae has proved to be a good model for studying mutations associated with mtDNA instability. This review focuses on the use of yeast for evaluating the pathogenicity of mutations in six genes, MPV17/SYM1, MRM2/MRM2, OPA1/MGM1, POLG/MIP1, RRM2B/RNR2, and SLC25A4/AAC2, all associated with mtDNA depletion or multiple deletions. We highlight the techniques used to construct a specific model and to measure the mtDNA instability as well as the main results obtained. We then report the contribution that yeast has given in understanding the pathogenic mechanisms of the mutant variants, in finding the genetic suppressors of the mitochondrial defects and in the discovery of molecules able to improve the mtDNA stability.

• MPV17/SYM1
• MRM2/MRM2
• OPA1/MGM1
• POLG/MIP1
• RRM2B/RNR2
• SLC25A4 (ANT1)/AAC2
• diseases associated with mtDNA deletions
• drug repurposing
• mtDNA depletion syndromes
• yeast model

• R01 CA234245 NCI NIH HHS
• R01 DK080425 NIDDK NIH HHS
• R35 CA220538 NCI NIH HHS
• U54 CA132379 NCI NIH HHS
• F32 DK126418 NIDDK NIH HHS
• P30 CA014195 NCI NIH HHS
• National Institutes of Health

• CRISPR-Cas9
• disease modelling
• hESC
• hPSC
• iPSC
• mitochondrial disease
• mtDNA
• stem cell

• Animals
• Cell Differentiation/genetics
• Cell Differentiation/physiology
• DNA, Mitochondrial/genetics
• Humans
• Mitochondria/genetics
• Mitochondria/pathology
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/pathology
• Phenotype
• Pluripotent Stem Cells/pathology

Background: To evaluate the use of the ketogenic diet (KD) for treatment of super-refractory status epilepticus (SRSE) at a pediatric intensive care unit (PICU).

Design: A retrospective analysis of all pediatric patients treated for SRSE with the KD at our center was performed using patient data from our prospective longitudinal KD database.

Setting: SRSE is defined as refractory SE that continues or recurs 24 h or more after initiation of anesthetic drugs. We describe the clinical and electroencephalographic (EEG) findings of all children treated with KD at our PICU. The KD was administered as add-on after failure of standard treatment. Response was defined as EEG seizure resolution (absence of seizures and suppression–burst ratio ≥50%).

Patients: Eight consecutive SRSE patients (four females) treated with KD were included. Median age at onset of SRSE was 13.6 months (IQR 0.9–105), and median age at KD initiation was 13.7 months (IQR 1.9 months to 8.9 years). Etiology was known in 6/8 (75%): genetic in 4 (50%), structural in 1 (12.5%), and autoimmune/inflammatory in 1 (12.5%).

Main Results: Time from onset of SRSE to initiation of KD was median 6 days (IQR 1.3–9). Time until clinically relevant ketosis (beta-hydroxybutyrate (BHB) >2 mmol/L in serum) was median 68.0 h (IQR 27.3–220.5). Higher ketosis was achieved when a higher proportion of enteral feeds was possible. Four (50%) patients responded to KD treatment within 7 days. During follow-up (median 4.2 months, IQR 1.6–12.3), 5/8 patients—three of them responders—died within 3–12 months after SRSE.

Conclusions: In eight patients with SRSE due to severe etiologies including Alpers syndrome, we report an initial 50% response to KD. KD was used early in SRSE and sufficient levels of ketosis were reached early in most patients. Higher ketosis was achieved with combined enteral and parenteral feedings.

• beta-hydroxybutyrate
• ketogenic diet
• parenteral diet
• pediatric
• status epilepticus

• Alpers syndrome
• POLG
• epilepsy
• mitochondrial disease
• stroke-like episodes

• Adolescent
• Adult
• Age of Onset
• Aged
• Aged, 80 and over
• Child
• Child, Preschool
• DNA Polymerase gamma/genetics
• Europe
• Female
• Genetic Predisposition to Disease/genetics
• Humans
• Infant
• Male
• Middle Aged
• Mitochondrial Diseases/classification
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/mortality
• Mutation
• Retrospective Studies
• Survival Analysis
• Young Adult

• Department of Health

• Electroretinography
• Light signal transduction
• POLG
• POLG1
• Polymerase gamma
• Retinal bipolar cells

• Anticonvulsants/adverse effects
• Anticonvulsants/therapeutic use
• Epilepsy/complications
• Epilepsy/drug therapy
• Humans
• Mitochondrial Diseases/complications
• Mitochondrial Diseases/drug therapy

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.

• alpers’ syndrome
• mitochondrial DNA
• neurodegeneration
• polymerase gamma
• respiratory chain deficiency

• Alpers-Huttenlocher syndrome
• Liver failure

Epilepsy is common in polymerase gamma (POLG) related disease and is associated with high morbidity and mortality. Epileptiform discharges typically affect the occipital regions initially and focal seizures, commonly evolving to bilateral convulsive seizures which are the most common seizure types in both adults and children. Our work has shown that mtDNA depletion—i.e., the quantitative loss of mtDNA—in neurones is the earliest and most important factor of the subsequent development of cellular dysfunction. Loss of mtDNA leads to loss of mitochondrial respiratory chain (MRC) components that, in turn, progressively disables energy metabolism. This critically balanced neuronal energy metabolism leads to both a chronic and continuous attrition (i.e., neurodegeneration) and it leaves the neurone unable to cope with increased demand that can trigger a potentially catastrophic cycle that results in acute focal necrosis. We believe that it is the onset of epilepsy that triggers the cascade of damage. These events can be identified in the stepwise evolution that characterizes the clinical, Electroencephalography (EEG), neuro-imaging, and neuropathology findings. Early recognition with prompt and aggressive seizure management is vital and may play a role in modifying the epileptogenic process and improving survival.

• POLG
• epilepsy
• mechanism
• mitochondria
• mtDNA
• occipital lobe epilepsy
• status epilepticus
• stroke-like episodes

• Animals
• Cerebral Cortex/pathology
• DNA Polymerase gamma/genetics
• DNA Polymerase gamma/metabolism
• Disease Susceptibility
• Electroencephalography
• Epilepsy/diagnosis
• Epilepsy/etiology
• Epilepsy/metabolism
• Epilepsy/therapy
• Humans
• Magnetic Resonance Imaging/methods
• Neurons/metabolism

• DNA Polymerase gamma
• DNA-Directed DNA Polymerase/genetics
• Diffuse Cerebral Sclerosis of Schilder/diagnosis
• Diffuse Cerebral Sclerosis of Schilder/drug therapy
• Diffuse Cerebral Sclerosis of Schilder/etiology
• Diffuse Cerebral Sclerosis of Schilder/genetics
• Heterozygote
• Humans
• Infant
• Male
• Mutation

• FARS2
• mitochondrial tRNA synthetase
• progressive myoclonus epilepsy

Alpers–Huttenlocher syndrome (AHS) is a mitochondrial DNA-depletion syndrome. Age of onset is bimodal: early onset at 2–4 years and later adolescent onset at 17–24 years of age. Early development is usually normal, with epilepsy heralding the disorder in ~50% of patients. The onset of seizures is coupled with progressive cognitive decline. Hepatopathy is variable, and when present is a progressive dysfunction leading to liver failure in many cases. These features of seizures, cognitive degeneration, and hepatopathy represent the “classic triad” of AHS. However, most patients develop other system involvement. Therefore, although AHS is ultimately a lethal disorder, medical care is required for sustained quality of life. Frequently, additional organ systems – gastrointestinal, respiratory, nutritional, and psychiatric – abnormalities appear and need treatment. Rarely, cardiovascular dysfunction and even pregnancy complicate medical treatment. Optimal care requires a team of physicians and caretakers to make sure quality of life is optimized. The care team, together with the family and palliative care specialists, need to be in communication as the disease progresses and medical changes occur. Although the unpredictable losses of function challenge medical care, the team approach can foster the individual quality-of-life care needed for the patient and family.

• Mitochondrial depletion syndrome
• clinical care
• mitochondria
• polymerase gamma 1

To identify the molecular genetic basis of a syndrome characterized by rapidly progressing cerebral atrophy, intractable seizures, and intellectual disability.

We performed exome sequencing in the proband and whole-genome single nucleotide polymorphism genotyping (copy number variant analysis) in the proband-parent trio. We used heterologous expression systems to study the functional consequences of identified mutations.

The search for potentially deleterious recessive or de novo variants yielded compound heterozygous missense (c.1202G>A, p.Cys401Tyr) and frameshift deletion (c.2396delG, p.Ser799IlefsTer96) mutations in ADAM22, which encodes a postsynaptic receptor for LGI1. The deleterious effect of the mutations was observed in cell surface binding and immunoprecipitation assays, which revealed that both mutant proteins failed to bind to LGI1. Furthermore, immunoprecipitation assays showed that the frameshift mutant ADAM22 also did not bind to the postsynaptic scaffolding protein PSD-95.

The mutations identified abolish the LGI1-ADAM22 ligand-receptor complex and are thus a likely primary cause of the proband's epilepsy syndrome, which is characterized by unusually rapidly progressing cortical atrophy starting at 3–4 months of age. These findings are in line with the implicated role of the LGI1-ADAM22 complex as a key player in nervous system development, specifically in functional maturation of postnatal synapses. Because the frameshift mutation affects an alternatively spliced exon with highest expression in postnatal brain, the combined effect of the mutations is likely to be hypomorphic rather than complete loss of function. This is compatible with the longer survival of the patient compared to Lgi1^−/− and Adam22^−/− mice, which develop lethal seizures during the first postnatal weeks.

• Alpers syndrome
• CARS2
• aminoacyl-tRNA synthetases
• exome sequencing
• mitochondrial translation

• Animals
• Brain Diseases, Metabolic, Inborn/genetics
• Brain Diseases, Metabolic, Inborn/metabolism
• Brain Diseases, Metabolic, Inborn/pathology
• DNA, Mitochondrial/genetics
• Gastrointestinal Diseases/genetics
• Gastrointestinal Diseases/metabolism
• Gastrointestinal Diseases/pathology
• Humans
• Liver Diseases/genetics
• Liver Diseases/metabolism
• Liver Diseases/pathology
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/metabolism
• Mitochondrial Diseases/pathology
• Mitochondrial Encephalomyopathies/genetics
• Mitochondrial Encephalomyopathies/metabolism
• Mitochondrial Encephalomyopathies/pathology
• Purpura/genetics
• Purpura/metabolism
• Purpura/pathology

• Medical Research Council
• Wellcome Trust

• brain injury
• diffusion tensor imaging (dti)
• functional mri (fmri)
• inborn error of metabolism
• metabolism
• magnetic resonance imaging (mri)
• magnetic resonance spectroscopy (mrs)
• mitochondrial disorder.

• Diffusion Magnetic Resonance Imaging
• Humans
• Image Processing, Computer-Assisted
• Magnetic Resonance Imaging
• Mitochondrial Diseases/diagnosis
• Nervous System Diseases/diagnosis
• Neuroimaging/methods

• alpers-huttenlocher syndrome
• alpers syndrome
• dna polymerase gamma
• mitochondrial disease
• mitochondrial dna depletion
• cerebrohepatopathy

• Electroencephalography
• Energy Metabolism/physiology
• Epilepsy/etiology
• Humans
• Metabolic Diseases/complications
• Neurodegenerative Diseases/etiology
• Neurotransmitter Agents/metabolism
• Skin/pathology
• Skin/ultrastructure
• Sleep/physiology

• Brain/physiopathology
• Channelopathies/complications
• Channelopathies/genetics
• Diagnosis, Differential
• Energy Metabolism/physiology
• Humans
• Infant
• Infant, Newborn
• Neurogenesis/genetics
• Neurotransmitter Agents/metabolism
• Seizures/diagnosis
• Seizures/etiology
• Seizures/genetics
• Seizures/metabolism