A paroxysmal neurological manifestation, the stroke-like episode, specifically impacts patients with mitochondrial disease. Episodes resembling strokes commonly exhibit focal-onset seizures, encephalopathy, and visual disturbances, often affecting the posterior cerebral cortex. The prevailing cause of stroke-mimicking episodes is the m.3243A>G variation in the MT-TL1 gene, coupled with recessive alterations to the POLG gene. The current chapter seeks to examine the meaning of a stroke-like episode, and systematically analyze the associated clinical features, neurological imaging, and electroencephalographic data for afflicted individuals. Furthermore, a discussion of several lines of evidence illuminates neuronal hyper-excitability as the primary mechanism driving 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. No compelling evidence currently exists to confirm l-arginine's effectiveness in both acute and prophylactic settings. Due to recurring stroke-like episodes, progressive brain atrophy and dementia manifest, with the underlying genotype partially influencing the prognosis.
In 1951, the neuropathological condition known as Leigh syndrome, or subacute necrotizing encephalomyelopathy, was first identified. Characterized microscopically by capillary proliferation, gliosis, substantial neuronal loss, and a comparative sparing of astrocytes, bilateral symmetrical lesions commonly extend from the basal ganglia and thalamus through brainstem structures to the posterior spinal columns. Leigh syndrome, a disorder present across diverse ethnicities, commonly manifests during infancy or early childhood, but it can also emerge later in life, even into adulthood. For the last six decades, this multifaceted neurodegenerative disorder has manifested as more than a hundred unique monogenic conditions, displaying substantial clinical and biochemical variation. CWI1-2 chemical structure From a clinical, biochemical, and neuropathological standpoint, this chapter investigates the disorder and its postulated pathomechanisms. Mitochondrial dysfunction, stemming from known genetic causes, includes defects in 16 mtDNA genes and nearly 100 nuclear genes, affecting the five 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. We present a method for diagnosis, coupled with recognized treatable factors, and a review of contemporary supportive therapies, as well as future treatment directions.
Oxidative phosphorylation (OxPhos) malfunctions contribute to the extremely diverse and heterogeneous genetic nature of mitochondrial diseases. These conditions are, at present, incurable; only supportive measures are available to reduce the resulting complications. Mitochondria's genetic blueprint is dual, comprising both mitochondrial DNA and nuclear DNA. So, not unexpectedly, alterations to either genome can create mitochondrial disease. Despite their primary association with respiration and ATP synthesis, mitochondria are integral to a vast array of biochemical, signaling, and execution processes, making each a possible therapeutic focus. General mitochondrial therapies, applicable across numerous conditions, stand in contrast to personalized therapies—gene therapy, cell therapy, and organ replacement—tailored to specific diseases. Mitochondrial medicine has seen considerable activity in research, resulting in a steady augmentation of clinical applications over the recent years. Emerging preclinical therapies and the status of their ongoing clinical implementation are detailed in this chapter. In our estimation, a new era is underway, where the treatment targeting the cause of these conditions becomes a real and attainable goal.
Unprecedented variability is a defining feature of the clinical manifestations and tissue-specific symptoms seen across the range of mitochondrial diseases. Variations in patients' tissue-specific stress responses are contingent upon their age and the kind of dysfunction they experience. These reactions result in the release of metabolically active signaling molecules into the systemic circulation. As biomarkers, such signaling molecules—metabolites or metabokines—can also be used. 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. The novel tools under consideration incorporate FGF21 and GDF15 metabokines; NAD-form cofactors; a collection of metabolites (multibiomarkers); and the entirety of the 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. 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. 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. Autosomal dominant optic atrophy (DOA) was subsequently found to have a connection to mutations in the OPA1 gene present in the nuclear DNA, starting in 2000. Retinal ganglion cells (RGCs) in LHON and DOA experience selective neurodegeneration, a consequence of mitochondrial dysfunction. A key determinant of the varied clinical pictures is the interplay between respiratory complex I impairment in LHON and dysfunctional mitochondrial dynamics in OPA1-related DOA. A subacute, swift, and severe loss of central vision in both eyes defines LHON, usually developing within weeks or months of onset, and affecting individuals between the ages of 15 and 35. DOA optic neuropathy, characterized by a slow and progressive course, commonly presents itself during early childhood. Properdin-mediated immune ring A conspicuous male predisposition and incomplete penetrance define LHON. The introduction of next-generation sequencing has led to a dramatic expansion in the genetic understanding of various rare mitochondrial optic neuropathies, including recessive and X-linked forms, further emphasizing the exceptional sensitivity 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. Several therapeutic programs, notably those involving gene therapy, are presently addressing mitochondrial optic neuropathies. Idebenone is the only formally authorized medication for mitochondrial disorders.
Inborn errors of metabolism, particularly those affecting mitochondria, are frequently encountered and are often quite complex. The extensive array of molecular and phenotypic variations has led to roadblocks in the quest for disease-altering therapies, with clinical trial progression significantly affected by multifaceted challenges. 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. In an encouraging development, a surge of interest in treating mitochondrial dysfunction in common illnesses, coupled with supportive regulatory frameworks for rare conditions, has fueled significant interest and effort to develop drugs for primary mitochondrial diseases. Current and previous clinical trials, and future directions in drug development for primary mitochondrial ailments are discussed here.
The differing recurrence risks and reproductive options for mitochondrial diseases necessitate a tailored approach to reproductive counseling. Mutations in nuclear genes, responsible for the majority of mitochondrial diseases, exhibit Mendelian patterns of inheritance. Preventing the birth of another severely affected child is possible through prenatal diagnosis (PND) or preimplantation genetic testing (PGT). immunotherapeutic target 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. The recurrence risk associated with de novo mtDNA mutations is low, and pre-natal diagnosis (PND) can be used for reassurance. The recurrence risk associated with heteroplasmic mtDNA mutations, inherited maternally, is often unpredictable, due to the inherent variability of the mitochondrial bottleneck. Despite the theoretical possibility of using PND to detect mtDNA mutations, it is often inapplicable because of the difficulties in predicting the clinical presentation of the mutations. Preventing the inheritance of mitochondrial DNA disorders can be achieved through the application of Preimplantation Genetic Testing (PGT). The transfer procedure includes embryos where the mutant load is below the expression threshold. Oocyte donation is a secure avenue for couples who eschew PGT to avoid the transmission of mtDNA diseases to their future child. Recently, the clinical use of mitochondrial replacement therapy (MRT) has become accessible as a strategy to prevent the passage of heteroplasmic and homoplasmic mtDNA mutations.