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Routine use of next-generation sequencing has shown that most common phenotypes are genetically heterogeneous and that in many cases, mutations in the same gene may cause markedly different phenotypes. Furthermore, complex clinical presentations are often due to multiple coexisting genetic defects. Here, we describe a patient with a complex clinical phenotype: a childhood-onset neurodevelopmental disorder with progressive intellectual disability, and supraventricular tachyarrhythmias that led to cardiac arrest in early teens. The complex phenotype is paralleled by a complex genotype. The neurological manifestations were likely due to biallelic POLG variants. POLG encodes the catalytic subunit of mitochondrial polymerase gamma. Pathogenic POLG variants cause both autosomal and recessive diseases, with a wide variety of clinical presentations. This heterogeneity makes validating novel substitutions challenging. One of the patient’s variants, p.(W113R), was novel, and to assess its pathogenicity, we employed a functional yeast-based assay. The cardiac phenotype was likely due to a de novo pathogenic variant in the RYR2 gene, which encodes a calcium release channel that plays an essential role in heart excitation-contraction coupling. The yeast assay was essential to establish the pathogenicity of the novel POLG variant and to correctly characterize this complex genotype.

Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.

Background: Focal-onset seizures and encephalopathy are prominent features of a stroke-like episode, which is a severe neurological manifestation associated with subtypes of mitochondrial disease. Despite more than 30 years of research, the acute treatment of stroke-like episodes remains controversial. Methods: We used the modified Delphi process to harness the clinical expertise of a group of mitochondrial disease specialists from five European countries to produce consensus guidance for the acute management of stroke-like episodes and commonly associated complications. Results: Consensus on a new definition of mitochondrial stroke-like episodes was achieved and enabled the group to develop diagnostic criteria based on clinical features, neuroimaging and/or electroencephalogram findings. Guidelines for the management of strokelike episodes were agreed with aggressive seizure management strongly recommended at the outset of stroke-like episodes. Conclusions: Our consensus statement defines stroke-like episodes in terms of an epileptic encephalopathy and we have used this to revise both diagnostic criteria and guidelines for management. A prospective, multi-centre, randomised controlled trial is required for evaluating the efficacy of any compound on modifying the trajectory of stroke-like episodes.

Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology that can readily detect and discriminate between these two types of events is lacking. Here we establish a computational method, MitoSAlt, for accurate identification, quantification and visualization of mtDNA deletions and duplications from genomic sequencing data. Our method was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy.

Background: Cerebellar ataxia is one of the most common movement disorders in mitochondrial disease, with POLG mutations being a frequent cause. This scoping review aimed to summarize current knowledge regarding cerebellar ataxia due to POLG mutations, focusing on epidemiological, clinical, radiological features and genotype-phenotype correlations. Methods: We searched PubMed and Web of Science databases for all articles published in English till September 2025 describing cases of POLG-related cerebellar ataxia. Results: In homozygous or compound heterozygous POLG mutation carriers, cerebellar ataxia seems to be progressive, and can initiate from either the bulbar muscles, trunk, or limbs. Age at onset varies greatly, ranging from birth to the early 70s. The most common variants in POLG-related cerebellar ataxia are W748S and A476T, localized in the linker region of POLG gene. Cerebellar ataxia due to POLG mutations can present in combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy (including status epilepticus), headache, other hyperkinetic movement disorders such as myoclonus and tremor, cognitive or affective disorders. Brain imaging commonly reveals atrophy of the vermis or cerebellar hemispheres, cortical atrophy, and/or bilateral T2/FLAIR lesions in both white matter and deep brain nuclei, including inferior olivary nuclei. Conclusion: POLG-related ataxia should be included in the differential diagnosis of slowly progressive cerebellar ataxias. POLG-related disease comprises a continuum of clinical features; the combination with progressive external ophthalmoplegia, sensory neuropathy, epilepsy, hyperkinetic movement disorders, as well as characteristic imaging findings, can aid the diagnosis of this underdiagnosed entity. These findings contribute to a better characterization of the phenotype-genotype relationship in the extended pool of POLG-related mitochondrial diseases. Highlights This review summarizes current knowledge regarding cerebellar ataxia due to POLG mutations. A slowly progressive cerebellar ataxia in combination with sensory neuropathy, progressive external ophthalmoplegia, epilepsy, myoclonus, and characteristic imaging findings, including cerebellar atrophy, bilateral lesions in deep brain nuclei (thalami, olivary nuclei) should raise suspicion for POLG-related disease.

Mitochondrial dysfunction and impaired neurogenesis are central to mitochondrial DNA polymerase (POLG)‐related disorders, yet therapeutic options remain limited. Here, patient‐derived induced pluripotent stem cell (iPSC)‐based cortical organoids are used to model POLG‐associated neurodegeneration and assess the therapeutic potential of metformin. Single‐cell RNA‐seq reveals distinct vulnerabilities in dopaminergic, glutamatergic, and GABAergic neuronal subtypes, with dopaminergic neurons exhibiting the most severe loss and mitochondrial transcriptomic deficits. Metformin treatment (250 µm, 2 months) significantly restores neuronal identity, subtype‐specific gene expression, and mitochondrial function. Functional assays demonstrate improved mitochondrial membrane potential (TMRE), increased mitochondrial mass (MTG, MTDR), and reduced oxidative stress (MitoSOX, BAX/cleaved caspase 3). Notably, mitochondrial DNA (mtDNA) copy number and the expression of mitochondrial replisome proteins (POLG, POLG2) are upregulated, indicating enhanced mitochondrial genome maintenance. Calcium measurement confirms improved neuronal excitability. Untargeted metabolomics further reveals metformin‐induced metabolic reprogramming, including enrichment of the tricarboxylic acid (TCA) cycle, amino acid metabolism, and redox‐related pathways. Together, these findings demonstrate that metformin enhances mitochondrial integrity and neural function across multiple neuronal subtypes and offer mechanistic insights into its potential as a treatment for POLG‐related disorders. Patient‐derived POLG‐mutant cortical organoids reveal neuronal subtype‐specific mitochondrial and synaptic defects, with dopaminergic neurons most affected. Metformin treatment restores neuronal identity, mitochondrial function, and excitability, increased mtDNA maintenance, and reprogrammed metabolism via TCA and redox pathways. These results highlight metformin's potential to treat POLG‐related neurodegeneration through mitochondrial repair and functional restoration.

Mutations in POLG disrupt mtDNA replication and cause devastating diseases often with neurological phenotypes. Defining disease mechanisms has been hampered by limited access to human tissues, particularly neurons. Using patient cells carrying POLG mutations, we generated iPSCs and then neural stem cells. These neural precursors manifested a phenotype that faithfully replicated the molecular and biochemical changes found in patient post‐mortem brain tissue. We confirmed the same loss of mtDNA and complex I in dopaminergic neurons generated from the same stem cells. POLG‐driven mitochondrial dysfunction led to neuronal ROS overproduction and increased cellular senescence. Loss of complex I was associated with disturbed NAD + metabolism with increased UCP2 expression and reduced phosphorylated SirT1. In cells with compound heterozygous POLG mutations, we also found activated mitophagy via the BNIP3 pathway. Our studies are the first that show it is possible to recapitulate the neuronal molecular and biochemical defects associated with POLG mutation in a human stem cell model. Further, our data provide insight into how mitochondrial dysfunction and mtDNA alterations influence cellular fate determining processes. Synopsis Mutations in the POLG gene cause mitochondrial disease with devastating phenotypes in patients. Neural stem cells generated from patient iPSCs showed mitochondrial dysfunction and mtDNA depletion, leading to loss of complex I with concomitant ROS overproduction and disturbed NAD + metabolism. Human iPSCs carrying POLG mutations can be differentiated into high‐yield neural stem cells (NSCs). NSCs with disease caused by POLG mutations showed energy failure and mtDNA depletion, similar to findings in iPSC‐derived dopaminergic neurons. POLG NSCs recapitulated the disease phenotypes observed in POLG patient post‐mortem tissues. POLG NSCs showed loss of mitochondrial complex I and abnormal UCP2/SirT1 mediated NAD + homeostasis associated with overproduction of intercellular and mitochondrial reactive oxygen species (ROS). Elevated ROS triggered cell senescence and BNIP3‐mediated mitophagy, which contributes to pathological mechanisms in mitochondrial diseases. Graphical Abstract Mutations in the POLG gene cause mitochondrial disease with devastating phenotypes in patients. Neural stem cells generated from patient iPSCs showed mitochondrial dysfunction and mtDNA depletion, leading to loss of complex I with concomitant ROS overproduction and disturbed NAD + metabolism.

We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P  ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE.

Background Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan. Results We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 ( n  = 13), DGUOK ( n  = 3), POLG (n = 1), and MICOS13 ( n  = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive ( n  = 13, 56.5%). The most frequent liver symptom was cholestasis ( n  = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T. Conclusions MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17  mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort ( n  = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5–39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.