In patients with mitochondrial disease, a particular group experiences paroxysmal neurological manifestations, presenting as 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. 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. 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. In addition, a detailed analysis of various lines of evidence underscores neuronal hyper-excitability as the core mechanism responsible for 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. No compelling evidence currently exists to confirm l-arginine's effectiveness in both acute and prophylactic settings. Progressive brain atrophy and dementia, consequences of recurring stroke-like episodes, are partly predictable based on the underlying genetic constitution.
Subacute necrotizing encephalomyelopathy, commonly referred to as Leigh syndrome, was recognized as a neurological entity in 1951. 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. Pan-ethnic Leigh syndrome typically presents in infancy or early childhood, but there are instances of delayed onset, even into adulthood. Over the past six decades, a complex neurodegenerative disorder has been revealed to encompass over a hundred distinct monogenic disorders, presenting significant clinical and biochemical diversity. selleck chemical The chapter investigates the clinical, biochemical, and neuropathological features of the condition, including its hypothesized pathomechanisms. Genetic defects, encompassing mutations in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes, are categorized as disorders of the five oxidative phosphorylation enzyme subunits and assembly factors, pyruvate metabolism disorders, vitamin and cofactor transport and metabolic issues, mtDNA maintenance defects, and problems with mitochondrial gene expression, protein quality control, lipid remodeling, dynamics, and toxicity. A strategy for diagnosis is described, accompanied by known manageable causes and a summation of current supportive care options and forthcoming therapeutic avenues.
Genetic disorders stemming from faulty oxidative phosphorylation (OxPhos) characterize the extreme heterogeneity of mitochondrial diseases. Despite the absence of a cure for these conditions, supportive interventions are implemented to alleviate the complications they cause. The genetic programming of mitochondria stems from the combined influence of mitochondrial DNA and nuclear DNA. In consequence, understandably, modifications in either genome can result in mitochondrial disease. Although traditionally associated with respiration and ATP production, mitochondria are essential players in a spectrum of biochemical, signaling, and execution pathways, each presenting a potential therapeutic target. Broad-based therapies for a range of mitochondrial conditions, or specialized therapies for individual mitochondrial diseases, such as gene therapy, cell therapy, and organ replacement, are the options. Clinical applications of mitochondrial medicine have seen a consistent growth, a reflection of the vibrant research activity in this field over the past several years. Preclinical research has yielded novel therapeutic strategies, which are reviewed alongside the current clinical applications in this chapter. We anticipate a new era where the treatment of the underlying cause of these conditions becomes a practical reality.
Mitochondrial disease encompasses a spectrum of disorders, characterized by a remarkable and unpredictable range of clinical presentations and tissue-specific symptoms. Patients' age and the nature of their dysfunction dictate the range of tissue-specific stress responses. In these responses, the secretion of metabolically active signal molecules contributes to systemic activity. Signals, in the form of metabolites or metabokines, can likewise be considered as biomarkers. Over the last decade, metabolite and metabokine biomarkers have been characterized for the diagnosis and monitoring of mitochondrial diseases, augmenting the traditional blood markers 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. The mitochondrial integrated stress response, through its messengers FGF21 and GDF15, provides greater specificity and sensitivity than conventional biomarkers for diagnosing mitochondrial diseases with muscle involvement. While the primary cause of some diseases initiates a cascade, a secondary consequence often includes metabolite or metabolomic imbalances (such as NAD+ deficiency). These imbalances are nonetheless significant as biomarkers and possible therapeutic targets. In the design of therapy trials, the appropriate biomarker panel should reflect the intricacies of the targeted disease. The diagnostic and monitoring value of blood samples in mitochondrial disease has been considerably boosted by the introduction of new biomarkers, allowing for personalized patient pathways and providing crucial insights into therapy effectiveness.
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). In 2000, the association of autosomal dominant optic atrophy (DOA) with mutations in the OPA1 gene located within the nuclear DNA became evident. Mitochondrial dysfunction underlies the selective neurodegeneration of retinal ganglion cells (RGCs) in 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. 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. DOA optic neuropathy, characterized by a slow and progressive course, commonly presents itself during early childhood. Antifouling biocides 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. Among the diverse presentations of mitochondrial optic neuropathies, including LHON and DOA, are both isolated optic atrophy and the more extensive multisystemic syndrome. Mitochondrial optic neuropathies are at the heart of multiple therapeutic programs, featuring gene therapy as a key element. Currently, idebenone is the sole approved medication for any mitochondrial disorder.
Inherited primary mitochondrial diseases represent some of the most prevalent and intricate inborn errors of metabolism. Finding effective disease-modifying therapies has been complicated by the substantial molecular and phenotypic diversity, resulting in lengthy delays for clinical trials due to multiple significant challenges. The intricate process of clinical trial design and execution has been constrained by an insufficient collection of natural history data, the obstacles to identifying definitive biomarkers, the lack of reliable outcome measurement tools, and the small number of patients. Promisingly, escalating attention towards treating mitochondrial dysfunction in common ailments, alongside regulatory incentives for developing therapies for rare conditions, has resulted in a notable surge of interest and dedicated endeavors in the pursuit of drugs for primary mitochondrial diseases. This review encompasses historical and contemporary clinical trials, as well as prospective approaches to drug development for primary mitochondrial diseases.
Mitochondrial disease management requires customized reproductive counseling, acknowledging the variations in potential recurrence and the spectrum of reproductive possibilities. Mutations in nuclear genes are the source of many mitochondrial diseases, displaying Mendelian patterns of inheritance. The availability of prenatal diagnosis (PND) and preimplantation genetic testing (PGT) aims to prevent the birth of another seriously affected child. bioanalytical accuracy and precision Mutations in mitochondrial DNA (mtDNA), occurring either independently (25%) or passed down through the mother, are implicated in a substantial proportion (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. Maternally inherited heteroplasmic mitochondrial DNA mutations frequently exhibit unpredictable recurrence risks, primarily because of 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. Preventing the inheritance of mitochondrial DNA disorders can be achieved through the application of Preimplantation Genetic Testing (PGT). Embryos with mutant loads that stay under the expression threshold are being transferred. Oocyte donation presents a secure alternative for couples opposing PGT, safeguarding future offspring from inherited mtDNA diseases. Mitochondrial replacement therapy (MRT) has recently become a clinically viable option to avert the transmission of heteroplasmic and homoplasmic mitochondrial DNA (mtDNA) mutations.