A specific subset of mitochondrial disease patients are affected by stroke-like episodes, a type of paroxysmal neurological manifestation. Episodes resembling strokes commonly exhibit focal-onset seizures, encephalopathy, and visual disturbances, often affecting the posterior cerebral cortex. Stroke-like episodes are most often caused by the m.3243A>G variant in the MT-TL1 gene, followed closely in frequency by recessive variations in 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. Not only that, but a consideration of several lines of evidence emphasizes the central role of neuronal hyper-excitability in stroke-like episodes. Aggressive seizure management is essential, along with the prompt and thorough treatment of concurrent complications, such as intestinal pseudo-obstruction, when managing stroke-like episodes. The purported benefits of l-arginine in both acute and preventative scenarios remain unsupported by robust evidence. Progressive brain atrophy and dementia are consequences of recurring stroke-like episodes, and the underlying genetic profile is, in part, indicative of the prognosis.
In 1951, the medical community formally recognized the neuropathological entity known as Leigh syndrome, or subacute necrotizing encephalomyelopathy. The microscopic presentation of bilateral symmetrical lesions, which typically originate in the basal ganglia and thalamus, progress through brainstem structures, and extend to the posterior columns of the spinal cord, consists of capillary proliferation, gliosis, extensive neuronal loss, and comparatively intact astrocytes. Infancy or early childhood is the common onset for Leigh syndrome, a condition observed across various ethnicities; however, late-onset manifestations, including in adulthood, do occur. This complex neurodegenerative disorder has, over the past six decades, been found to encompass more than a hundred separate monogenic disorders, revealing a considerable range of clinical and biochemical manifestations. Brassinosteroid biosynthesis Within this chapter, a thorough examination of the disorder's clinical, biochemical, and neuropathological attributes is undertaken, alongside the proposed pathomechanisms. Defects in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes manifest as disorders, encompassing disruptions in the subunits and assembly factors of the five oxidative phosphorylation enzymes, issues with pyruvate metabolism and vitamin/cofactor transport/metabolism, disruptions in mtDNA maintenance, and defects in mitochondrial gene expression, protein quality control, lipid remodeling, dynamics, and toxicity. Diagnostic procedures are presented, along with treatable causes, a summary of existing supportive care methods, and a look at forthcoming therapeutic advancements.
Mitochondrial diseases, a result of faulty oxidative phosphorylation (OxPhos), exhibit a significant and extreme genetic heterogeneity. These ailments currently lack a cure; only supportive interventions to ease complications are available. Mitochondria's genetic makeup is influenced by two sources: mtDNA and nuclear DNA. Subsequently, logically, changes to either DNA sequence can provoke mitochondrial disease. 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. Treatments for various mitochondrial conditions can be categorized as general therapies or as therapies specific to a single disease—gene therapy, cell therapy, and organ replacement being examples of personalized approaches. The field of mitochondrial medicine has experienced a surge in research activity, with a notable upswing in clinical application over recent years. A review of the most recent therapeutic strategies arising from preclinical investigations and the current state of clinical trials are presented in this chapter. We consider that a new era is underway where the causal treatment of these conditions is becoming a tangible prospect.
The clinical variability in the mitochondrial disease group extends to a remarkable diversity of symptoms in different tissues, across multiple disorders. The age and type of dysfunction in patients influence the variability of their tissue-specific stress responses. Systemic circulation receives secreted metabolically active signal molecules in these reactions. Such signals, being metabolites or metabokines, can also be employed as biomarkers. Ten years of research have yielded metabolite and metabokine biomarkers for assessing and tracking mitochondrial diseases, building upon the established blood markers 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. 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. To achieve optimal results in therapy trials, the biomarker set must be meticulously curated to align with the specific disease pathology. In the diagnosis and follow-up of mitochondrial disease, new biomarkers have significantly enhanced the value of blood samples, enabling customized diagnostic pathways for patients and playing a crucial role in assessing the impact of therapy.
Within the domain of mitochondrial medicine, mitochondrial optic neuropathies have assumed a key role starting in 1988 with the first reported mutation in mitochondrial DNA, tied to Leber's hereditary optic neuropathy (LHON). The year 2000 saw a correlation established between autosomal dominant optic atrophy (DOA) and mutations within the OPA1 gene located in the nuclear DNA. The selective neurodegeneration of retinal ganglion cells (RGCs) in LHON and DOA is directly attributable to mitochondrial dysfunction. The observed clinical variations are rooted in the combination of respiratory complex I impairment characteristic of LHON and defective mitochondrial dynamics within the context of OPA1-related DOA. Central vision loss, subacute, severe, and rapid, affecting both eyes within weeks or months, is a hallmark of LHON, typically in individuals between the ages of 15 and 35. DOA, a type of optic neuropathy, usually becomes evident in early childhood, characterized by its slower, progressive course. enzyme-based biosensor Marked incomplete penetrance and a clear male bias are hallmarks of LHON. 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. Optic atrophy, or a more intricate multisystemic syndrome, may be hallmarks of mitochondrial optic neuropathies, encompassing conditions like LHON and DOA. Within a multitude of therapeutic schemes, gene therapy is significantly employed for addressing mitochondrial optic neuropathies. Idebenone, however, stands as the only approved medication for any mitochondrial condition.
Complex inherited inborn errors of metabolism, like primary mitochondrial diseases, are quite common. Due to a wide array of molecular and phenotypic differences, the search for disease-modifying therapies has proven challenging, and clinical trial progressions have been significantly hindered. Designing and carrying out clinical trials has proven challenging due to the lack of substantial natural history data, the difficulty in discovering pertinent biomarkers, the absence of reliable outcome measures, and the constraints imposed by small patient populations. With encouraging signs, a burgeoning interest in addressing mitochondrial dysfunction in prevalent illnesses, coupled with regulatory support for therapies targeting rare conditions, has spurred significant investment and efforts in creating medications for primary mitochondrial diseases. Herein, we evaluate past and present clinical trials in primary mitochondrial diseases, while also exploring future strategies for drug development.
The differing recurrence risks and reproductive options for mitochondrial diseases necessitate a tailored approach to reproductive counseling. Mutations in nuclear genes account for the majority of mitochondrial diseases, and their inheritance pattern is Mendelian. Prenatal diagnosis (PND) and preimplantation genetic testing (PGT) serve to prevent the birth of an additional severely affected child. Tertiapin-Q 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. Concerning de novo mtDNA mutations, the likelihood of recurrence is slight, and pre-natal diagnosis (PND) can provide a sense of relief. Maternal inheritance of heteroplasmic mitochondrial DNA mutations presents a frequently unpredictable recurrence risk, 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. Preimplantation Genetic Testing (PGT) is an additional option for obstructing the transfer of mitochondrial DNA diseases. Embryos with mutant loads that stay under the expression threshold are being transferred. To circumvent PGT and prevent mtDNA disease transmission to their future child, couples can opt for oocyte donation, a safe procedure. A novel clinical application of mitochondrial replacement therapy (MRT) is now available to help in preventing the transmission of both heteroplasmic and homoplasmic mitochondrial DNA mutations.