Paroxysmal neurological manifestations, exemplified by stroke-like episodes, are seen in a specific cohort of individuals with mitochondrial disease. A key finding in stroke-like episodes is the presence of visual disturbances, focal-onset seizures, and encephalopathy, particularly within the posterior cerebral cortex. Among the most common causes of stroke-like symptoms are the m.3243A>G mutation in the MT-TL1 gene, followed by recessive POLG variants. In this chapter, the definition of a stroke-like episode will be revisited, and the chapter will delve into the clinical features, neuroimaging and EEG data often observed in patients exhibiting these events. The following lines of evidence underscore neuronal hyper-excitability as the key mechanism behind stroke-like episodes. Treatment protocols for stroke-like episodes must emphasize aggressive seizure management and address concomitant complications, including the specific case of intestinal pseudo-obstruction. For both acute and preventative purposes, l-arginine's effectiveness is not firmly established by reliable evidence. The sequelae of repeated stroke-like events are progressive brain atrophy and dementia, the prediction of which is partly dependent on the underlying genetic makeup.

The clinical entity of Leigh syndrome, or subacute necrotizing encephalomyelopathy, was first characterized as a neuropathological entity in the year 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. Pan-ethnic Leigh syndrome typically presents in infancy or early childhood, but there are instances of delayed onset, even into adulthood. Within the span of the last six decades, it has become clear that this intricate neurodegenerative disorder includes well over a hundred separate monogenic disorders, characterized by extensive clinical and biochemical discrepancies. selleck products Within this chapter, a thorough examination of the disorder's clinical, biochemical, and neuropathological attributes is undertaken, alongside the 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. The diagnostic process, including recognized treatable factors, is presented, along with a synopsis of existing supportive management and the emerging therapeutic landscape.

Mitochondrial diseases display extreme genetic heterogeneity stemming from failures within the oxidative phosphorylation (OxPhos) process. These conditions are, at present, incurable; only supportive measures are available to reduce the resulting complications. The genetic control of mitochondria is a two-pronged approach, managed by mitochondrial DNA (mtDNA) and nuclear DNA. Hence, not unexpectedly, variations in either genome can initiate mitochondrial diseases. While typically linked to respiration and ATP creation, mitochondria's involvement extends to a wide range of biochemical, signaling, and execution pathways, each holding potential for therapeutic strategies. General therapies, applicable to various mitochondrial conditions, contrast with personalized approaches, like gene therapy, cell therapy, and organ replacement, which target specific diseases. A marked intensification of research in mitochondrial medicine has resulted in an escalating number of clinical applications over the last several years. Emerging preclinical therapies and the status of their ongoing clinical implementation are detailed in this chapter. We envision a new era where the treatment targeting the root cause of these conditions is achievable.

Differing disorders within the mitochondrial disease group showcase unprecedented variability in clinical presentations, including distinctive tissue-specific symptoms. The age and type of dysfunction in patients influence the variability of their tissue-specific stress responses. These responses involve the systemic release of metabolically active signaling molecules. Biomarkers can also be these signals—metabolites, or metabokines—utilized. Mitochondrial disease diagnosis and management have been advanced by the identification of metabolite and metabokine biomarkers over the last ten years, expanding upon the established blood biomarkers of lactate, pyruvate, and alanine. Incorporating the metabokines FGF21 and GDF15, NAD-form cofactors, multibiomarker sets of metabolites, and the entire metabolome, these new instruments offer a comprehensive approach. Mitochondrial integrated stress response messengers FGF21 and GDF15 exhibit enhanced specificity and sensitivity over conventional biomarkers for the detection of muscle-manifestations of mitochondrial diseases. Some diseases manifest secondary metabolite or metabolomic imbalances (e.g., NAD+ deficiency) stemming from a primary cause. Nevertheless, these imbalances hold significance as biomarkers and potential therapeutic targets. For therapeutic trial success, the ideal biomarker profile must be precisely matched to the particular disease being evaluated. The diagnostic accuracy and longitudinal monitoring of mitochondrial disease patients have been significantly improved by the introduction of novel biomarkers, which facilitate the development of individualized diagnostic pathways and are essential for evaluating treatment response.

Since 1988, when the first mutation in mitochondrial DNA was linked to Leber's hereditary optic neuropathy (LHON), mitochondrial optic neuropathies have held a prominent position within mitochondrial medicine. Subsequent to 2000, mutations in the OPA1 gene, situated within nuclear DNA, were found to be connected to autosomal dominant optic atrophy (DOA). Mitochondrial dysfunction triggers selective neurodegeneration of retinal ganglion cells (RGCs) in both LHON and DOA. LHON's respiratory complex I impairment, combined with the mitochondrial dynamics defects associated with OPA1-related DOA, results in a range of distinct clinical presentations. Subacute, rapid, and severe central vision loss affecting both eyes, known as LHON, occurs within weeks or months, usually during the period between 15 and 35 years of age. Early childhood often reveals the slow, progressive nature of optic neuropathy, exemplified by DOA. host response biomarkers The presentation of LHON includes incomplete penetrance and a noticeable male bias. By implementing next-generation sequencing, scientists have substantially expanded our understanding of the genetic basis of various rare mitochondrial optic neuropathies, including those linked to recessive and X-linked inheritance patterns, underscoring the remarkable sensitivity of retinal ganglion cells to impaired mitochondrial function. Both pure optic atrophy and a more severe, multisystemic illness can result from various forms of mitochondrial optic neuropathies, including LHON and DOA. Mitochondrial optic neuropathies are currently the subject of numerous therapeutic programs, including the promising approach of gene therapy. In terms of medication, idebenone remains the only approved treatment for any mitochondrial disorder.

A significant portion of inherited inborn errors of metabolism involve mitochondria, and these are among the most common and complex. The multifaceted molecular and phenotypic variations have hampered the discovery of disease-altering therapies, and clinical trials have faced protracted delays due to substantial obstacles. A shortage of reliable natural history data, the struggle to pinpoint specific biomarkers, the absence of established outcome measures, and the small patient pool have all contributed to the complexity of clinical trial design and execution. Pleasingly, emerging interest in therapies for mitochondrial dysfunction in common diseases, combined with regulatory incentives for developing therapies for rare conditions, has led to substantial interest and ongoing research into drugs for primary mitochondrial diseases. A detailed analysis of past and present clinical trials, and future strategies for pharmaceutical development, is provided for primary mitochondrial diseases.

Customized reproductive counseling for patients with mitochondrial diseases is imperative to address the variable recurrence risks and available reproductive options. Mutations in nuclear genes, responsible for the majority of mitochondrial diseases, exhibit Mendelian patterns of inheritance. The option of prenatal diagnosis (PND) or preimplantation genetic testing (PGT) exists to preclude the birth of a severely affected child. Pathologic response 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. De novo mitochondrial DNA (mtDNA) mutations typically exhibit a low recurrence probability, and pre-natal diagnosis (PND) can provide comfort. Due to the mitochondrial bottleneck, the recurrence probability for heteroplasmic mtDNA mutations, transmitted maternally, is often unpredictable. PND for mtDNA mutations, while a conceivable approach, is often rendered unusable by the constraints imposed by the phenotypic prediction process. Preimplantation Genetic Testing (PGT) presents another avenue for mitigating the transmission of mitochondrial DNA diseases. Embryos exhibiting a mutant load below the expression threshold are being transferred. For couples declining PGT, oocyte donation stands as a secure method to prevent the transmission of mtDNA diseases to prospective children. Mitochondrial replacement therapy (MRT) has recently become a clinically viable option to avert the transmission of heteroplasmic and homoplasmic mitochondrial DNA (mtDNA) mutations.