Mitochondrial disease patients experience paroxysmal neurological manifestations, often taking the form of stroke-like episodes. Encephalopathy, visual disturbances, and focal-onset seizures are salient features of stroke-like episodes, showing a strong association with the posterior cerebral cortex. Recessive POLG variants, and the m.3243A>G mutation in the MT-TL1 gene, are the most common causes of transient ischemic attacks (TIAs). This chapter undertakes a review of the definition of a stroke-like episode, along with an exploration of the clinical presentation, neuroimaging, and EEG characteristics frequently observed in patients. A consideration of the following lines of evidence suggests neuronal hyper-excitability is the primary mechanism causing stroke-like episodes. To effectively manage stroke-like episodes, a prioritized approach should focus on aggressive seizure control and addressing concomitant complications like intestinal pseudo-obstruction. Conclusive proof of l-arginine's efficacy for both acute and prophylactic treatments remains elusive. In the wake of recurrent stroke-like episodes, progressive brain atrophy and dementia ensue, partly contingent on the underlying genetic makeup.

The year 1951 marked the initial identification of a neuropathological condition now known as Leigh syndrome, or subacute necrotizing encephalomyelopathy. Microscopically, bilateral symmetrical lesions, originating in the basal ganglia and thalamus, progress through the brainstem, reaching the posterior columns of the spinal cord, display capillary proliferation, gliosis, pronounced neuronal loss, and a relative preservation of astrocytes. Usually appearing during infancy or early childhood, Leigh syndrome, a condition prevalent across all ethnicities, can also manifest much later, including in adult life. 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. Pulmonary Cell Biology Within this chapter, a thorough examination of the disorder's clinical, biochemical, and neuropathological attributes is undertaken, alongside the proposed pathomechanisms. A variety of disorders are linked to known genetic causes, including defects in 16 mitochondrial DNA genes and nearly 100 nuclear genes, categorized as disruptions in the oxidative phosphorylation enzymes' subunits and assembly factors, issues in pyruvate metabolism and vitamin/cofactor transport and metabolism, mtDNA maintenance problems, and defects in mitochondrial gene expression, protein quality control, lipid remodeling, dynamics, and toxicity. An approach to diagnosis is presented, including its associated treatable etiologies and an overview of current supportive care strategies, alongside the burgeoning field of prospective therapies.

The varied and extremely heterogeneous genetic make-up of mitochondrial diseases is a consequence of faulty oxidative phosphorylation (OxPhos). Currently, there is no known cure for these conditions, except for supportive measures designed to alleviate associated complications. The genetic regulation of mitochondria is a collaborative effort between mitochondrial DNA (mtDNA) and nuclear DNA. Hence, not unexpectedly, variations in either genome can initiate mitochondrial diseases. 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. Broad-spectrum therapies for mitochondrial ailments, potentially applicable to many types, are distinct from treatments focused on individual disorders, such as gene therapy, cell therapy, or organ replacement procedures. Mitochondrial medicine has seen considerable activity in research, resulting in a steady augmentation of clinical applications over the recent years. The chapter presents a synthesis of recent preclinical therapeutic advancements and a summary of the currently active clinical trials. We envision a new era where the treatment targeting the root cause of these conditions is achievable.

A hallmark of mitochondrial disease is the significant variability in clinical presentations, where tissue-specific symptoms manifest across different disorders. Patients' age and the nature of their dysfunction dictate the range of tissue-specific stress responses. Systemic circulation receives secreted metabolically active signal molecules in these reactions. These signals—metabolites or metabokines—can also be leveraged as diagnostic markers. Metabolites and metabokines have been used as biomarkers for the diagnosis and follow-up of mitochondrial disease over the last ten years, serving to enhance existing blood tests including lactate, pyruvate, and alanine. Amongst these new tools are metabokines FGF21 and GDF15; NAD-form cofactors; comprehensive metabolite sets (multibiomarkers); and the complete metabolome. For diagnosing muscle-presenting mitochondrial diseases, the messenger proteins FGF21 and GDF15, part of the mitochondrial integrated stress response, surpass conventional biomarkers in terms of specificity and sensitivity. In certain diseases, a metabolite or metabolomic imbalance, such as a NAD+ deficiency, arises as a secondary effect of the primary cause, yet it remains significant as a biomarker and a possible target for therapeutic interventions. To ensure robust therapy trial outcomes, the selected biomarker set must be tailored to the characteristics of the disease being studied. Blood samples' value in mitochondrial disease diagnosis and follow-up has been enhanced by the introduction of new biomarkers, thus enabling a more targeted diagnostic pathway for patients and playing a critical role in monitoring treatment efficacy.

From 1988 onwards, the association of the first mitochondrial DNA mutation with Leber's hereditary optic neuropathy (LHON) has placed mitochondrial optic neuropathies at the forefront of mitochondrial medicine. The year 2000 saw a correlation established between autosomal dominant optic atrophy (DOA) and mutations within the OPA1 gene located in the nuclear DNA. Selective neurodegeneration of retinal ganglion cells (RGCs) is a hallmark of both LHON and DOA, arising from mitochondrial dysfunction. 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. LHON manifests as a swift, severe, subacute loss of central vision in both eyes, developing within weeks or months, typically presenting between the ages of 15 and 35. Early childhood often reveals the slow, progressive nature of optic neuropathy, exemplified by DOA. Berzosertib ATM inhibitor A clear male tendency and incomplete penetrance are distinguishing features of LHON. Next-generation sequencing's introduction has significantly broadened the genetic underpinnings of rare mitochondrial optic neuropathies, encompassing recessive and X-linked forms, highlighting the remarkable vulnerability of retinal ganglion cells to compromised mitochondrial function. Mitochondrial optic neuropathies, including specific conditions like LHON and DOA, can cause a variety of symptoms, ranging from pure optic atrophy to a more significant, multisystemic illness. Currently, a multitude of therapeutic programs, prominently featuring gene therapy, are targeting mitochondrial optic neuropathies. Idebenone stands as the sole approved medication for mitochondrial disorders.

Primary mitochondrial diseases, a class of inherited metabolic errors, are amongst the most frequent and intricate. The substantial molecular and phenotypic diversity within this group has made the identification of effective disease-modifying therapies challenging, significantly delaying clinical trial progress due to the numerous significant roadblocks. The intricate process of clinical trial design and implementation has been significantly impacted by the deficiency of robust natural history data, the difficulty in identifying precise biomarkers, the absence of validated outcome measures, and the limitation presented by a modest number of patients. Remarkably, renewed focus on treating mitochondrial dysfunction in widespread diseases, along with supportive regulatory frameworks for therapies for rare conditions, has spurred considerable enthusiasm and activity in developing medications for primary mitochondrial diseases. Past and present clinical trials, and future drug development strategies for primary mitochondrial diseases, are scrutinized in this review.

Reproductive counseling for mitochondrial diseases must be approached with customized strategies to account for the diversity in risks of recurrence and reproductive choices. A significant proportion of mitochondrial diseases arise from mutations within nuclear genes, following the principles of Mendelian inheritance. Prenatal diagnosis (PND) or preimplantation genetic testing (PGT) are offered as methods to prevent another severely affected child from being born. Colorimetric and fluorescent biosensor Mitochondrial DNA (mtDNA) mutations, arising either spontaneously (25%) or inherited from the mother, are responsible for a substantial portion, 15% to 25%, of mitochondrial diseases. In cases of de novo mtDNA mutations, the risk of recurrence is low, and pre-natal diagnosis (PND) can offer peace of mind. Unpredictable recurrence is a common feature of maternally transmitted heteroplasmic mtDNA mutations, a consequence of the mitochondrial bottleneck. Although mtDNA mutation analysis through PND is technically feasible, its clinical applicability is often restricted by the inability to precisely predict the resulting phenotypic expression. Mitochondrial DNA disease transmission can be potentially mitigated through the procedure known as Preimplantation Genetic Testing (PGT). Embryos exhibiting a mutant load below the expression threshold are being transferred. For couples rejecting PGT, oocyte donation provides a safe means of averting mtDNA disease transmission in a future child. In recent times, mitochondrial replacement therapy (MRT) has become clinically applicable as a means of preventing the transmission of both heteroplasmic and homoplasmic mitochondrial DNA mutations.