The neurological manifestation, paroxysmal and akin to a stroke, frequently affects a targeted group of patients possessing mitochondrial disease. Encephalopathy, visual disturbances, and focal-onset seizures are salient features of stroke-like episodes, showing a strong association with the posterior cerebral cortex. The m.3243A>G variant in the MT-TL1 gene, followed by recessive POLG variants, is the most frequent cause of stroke-like episodes. This chapter will comprehensively review the definition of a stroke-like episode, outlining the diverse clinical presentations, neuroimaging findings, and associated EEG patterns characteristic of patients experiencing them. Moreover, the supporting evidence for neuronal hyper-excitability as the key mechanism behind stroke-like episodes is explored. In stroke-like episode management, a key focus should be on aggressively addressing seizures while also handling accompanying conditions, like intestinal pseudo-obstruction. The efficacy of l-arginine for both acute and prophylactic use is not backed by substantial and trustworthy evidence. Due to recurring stroke-like episodes, progressive brain atrophy and dementia manifest, with the underlying genotype partially influencing the prognosis.

Subacute necrotizing encephalomyelopathy, commonly referred to as Leigh syndrome, was recognized as a neurological entity in 1951. Symmetrically situated lesions, bilaterally, generally extending from the basal ganglia and thalamus, traversing brainstem structures, and reaching the posterior spinal columns, are microscopically defined by capillary proliferation, gliosis, significant neuronal loss, and the comparative sparing of astrocytes. Characterized by a pan-ethnic prevalence, Leigh syndrome frequently begins in infancy or early childhood; nevertheless, later occurrences, extending into adult life, do exist. Through the last six decades, it has been determined that this intricate neurodegenerative disorder is composed of more than a hundred individual monogenic disorders, showcasing remarkable clinical and biochemical diversity. Selleck GSK-3008348 This chapter comprehensively explores the disorder's clinical, biochemical, and neuropathological dimensions, while also considering proposed pathomechanisms. Disorders with known genetic origins, encompassing defects in 16 mitochondrial DNA genes and nearly 100 nuclear genes, are characterized by impairments in oxidative phosphorylation enzyme subunits and assembly factors, pyruvate metabolism, vitamin/cofactor transport/metabolism, mtDNA maintenance, and mitochondrial gene expression, protein quality control, lipid remodeling, dynamics, and toxicity. This presentation outlines a diagnostic strategy, alongside remediable causes, and provides a synopsis of current supportive care protocols and upcoming therapeutic developments.

Mitochondrial diseases, a result of faulty oxidative phosphorylation (OxPhos), exhibit a significant and extreme genetic heterogeneity. No remedy presently exists for these medical issues, apart from supportive treatments focusing on alleviating complications. The genetic control of mitochondria is a two-pronged approach, managed by mitochondrial DNA (mtDNA) and nuclear DNA. Therefore, predictably, modifications to either genetic code can trigger mitochondrial disorders. While commonly recognized for their role in respiration and ATP production, mitochondria are pivotal in numerous other biochemical, signaling, and effector pathways, each potentially serving as a therapeutic target. General therapies, applicable to various mitochondrial conditions, contrast with personalized approaches, like gene therapy, cell therapy, and organ replacement, which target specific diseases. A considerable increase in clinical applications of mitochondrial medicine has characterized the field's recent evolution, demonstrating the robust nature of the research. This chapter examines cutting-edge preclinical therapeutic developments and provides an update on the presently active clinical applications. We hold the view that a new era is beginning, in which the treatment of the causes of these conditions is becoming a realistic possibility.

Differing disorders within the mitochondrial disease group showcase unprecedented variability in clinical presentations, including distinctive tissue-specific symptoms. Tissue-specific stress responses exhibit variability correlating with patient age and the type of dysfunction present. Systemic circulation receives secreted metabolically active signal molecules in these reactions. Biomarkers can also be these signals—metabolites, or metabokines—utilized. In the past decade, metabolite and metabokine biomarkers have been documented for the diagnosis and longitudinal evaluation of mitochondrial disease, improving upon the standard blood biomarkers of lactate, pyruvate, and alanine. Key components of these newly developed instruments include metabokines FGF21 and GDF15; cofactors, including NAD-forms; detailed metabolite collections (multibiomarkers); and the entire metabolome. Mitochondrial diseases manifesting in muscle tissue find their diagnosis enhanced by the superior specificity and sensitivity of FGF21 and GDF15, messengers of the integrated stress response, compared to conventional biomarkers. A secondary effect of some diseases' primary cause is a metabolite or metabolomic imbalance (e.g., NAD+ deficiency). This imbalance, however, proves important as a biomarker and a potential target for therapy. For effective therapy trials, the optimal selection of biomarkers needs to be adapted to precisely target the disease's characteristics. New biomarkers have elevated the clinical significance of blood samples in diagnosing and managing mitochondrial disease, enabling the stratification of patients into specialized diagnostic tracks and providing essential feedback on treatment effectiveness.

Mitochondrial optic neuropathies have been crucial to mitochondrial medicine ever since 1988, when the first mitochondrial DNA mutation connected to Leber's hereditary optic neuropathy (LHON) was established. Mutations affecting the OPA1 gene, situated within nuclear DNA, were discovered in 2000 to be related to autosomal dominant optic atrophy (DOA). Selective neurodegeneration of retinal ganglion cells (RGCs) is a hallmark of both LHON and DOA, arising from mitochondrial dysfunction. The different clinical expressions observed result from the intricate link between respiratory complex I impairment in LHON and the mitochondrial dynamics defects present in OPA1-related DOA. Within weeks or months, a subacute, severe, and rapid loss of central vision in both eyes characterizes LHON, typically appearing in individuals aged 15 to 35. DOA, a type of optic neuropathy, usually becomes evident in early childhood, characterized by its slower, progressive course. Hepatoid carcinoma The presentation of LHON includes incomplete penetrance and a noticeable male bias. The advent of next-generation sequencing has dramatically increased the catalog of genetic causes for other rare mitochondrial optic neuropathies, including those inherited recessively and through the X chromosome, further illustrating the exquisite sensitivity of retinal ganglion cells to disruptions in mitochondrial function. Mitochondrial optic neuropathies, including LHON and DOA, may exhibit a spectrum of manifestations, ranging from singular optic atrophy to a more broadly affecting multisystemic syndrome. Therapeutic strategies, including gene therapy, are currently being applied to mitochondrial optic neuropathies. Idebenone, however, continues to be the only approved drug for any mitochondrial disorder.

Inherited inborn errors of metabolism, with a focus on primary mitochondrial diseases, are recognized for their prevalence and complexity. The complexities inherent in molecular and phenotypic diversity have impeded the development of disease-modifying therapies, and clinical trials have been significantly delayed due to a multitude of significant obstacles. Obstacles to effective clinical trial design and execution include insufficient robust natural history data, the complexities in pinpointing specific biomarkers, the absence of thoroughly vetted outcome measures, and the restriction imposed by a small number of participating patients. Positively, heightened attention to the treatment of mitochondrial dysfunction in common diseases, alongside favorable regulatory frameworks for rare disease therapies, has generated significant interest and dedicated efforts in drug development for primary mitochondrial diseases. Current and previous clinical trials, and future directions in drug development for primary mitochondrial ailments are discussed here.

To effectively manage mitochondrial diseases, reproductive counseling needs to be personalized, considering the unique aspects of recurrence risk and reproductive options. Nuclear gene mutations are the causative agents in a considerable number of mitochondrial diseases, manifesting as Mendelian inheritance. Preventing the birth of another severely affected child is possible through prenatal diagnosis (PND) or preimplantation genetic testing (PGT). Comparative biology Cases of mitochondrial diseases, approximately 15% to 25% of the total, are influenced by mutations in mitochondrial DNA (mtDNA), which can emerge spontaneously (25%) or be inherited from the mother. The recurrence risk associated with de novo mtDNA mutations is low, and pre-natal diagnosis (PND) can be used for reassurance. The recurrence risk for maternally inherited heteroplasmic mitochondrial DNA mutations is frequently unpredictable, owing to the variance introduced by the mitochondrial bottleneck. While mitochondrial DNA (mtDNA) mutations can theoretically be predicted using PND, practical application is frequently hindered by the challenges of accurately forecasting the resultant phenotype. Another approach to curtail the transmission of mtDNA diseases is to employ Preimplantation Genetic Testing (PGT). Currently, embryos with a mutant load level below the expression threshold are being transferred. In lieu of PGT, a secure method for preventing the transmission of mtDNA diseases to future children is oocyte donation for couples who decline the option. The recent availability of mitochondrial replacement therapy (MRT) as a clinical option aims to prevent the hereditary transmission of heteroplasmic and homoplasmic mtDNA mutations.