In patients with mitochondrial disease, a particular group experiences paroxysmal neurological manifestations, presenting as stroke-like episodes. Episodes resembling strokes commonly exhibit focal-onset seizures, encephalopathy, and visual disturbances, often affecting the posterior cerebral cortex. Following the m.3243A>G variant in the MT-TL1 gene, recessive POLG gene variants represent a significant contributor to the incidence of stroke-like episodes. This chapter's purpose is to examine the characteristics of a stroke-like episode, analyzing the various clinical manifestations, neuroimaging studies, and electroencephalographic data often present in these cases. Several lines of evidence are presented in support of neuronal hyper-excitability as the principal mechanism implicated in 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. The purported benefits of l-arginine in both acute and preventative scenarios remain unsupported by robust evidence. Recurring stroke-like episodes result in progressive brain atrophy and dementia, with the underlying genetic code partially influencing the eventual outcome.
Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, was first identified as a distinct neurological condition 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. Leigh syndrome, a pan-ethnic disorder, typically presents during infancy or early childhood, though late-onset cases, encompassing those in adulthood, also exist. 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 Within this chapter, a thorough examination of the disorder's clinical, biochemical, and neuropathological attributes is undertaken, alongside the proposed pathomechanisms. Genetic predispositions, encompassing defects in 16 mitochondrial DNA genes and nearly 100 nuclear genes, manifest as disorders that can disrupt the five oxidative phosphorylation enzyme subunits and assembly factors, impact pyruvate metabolism and vitamin/cofactor transport and metabolism, affect mtDNA maintenance, and lead to defects in 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.
The extremely heterogeneous genetic makeup of mitochondrial diseases arises from malfunctions in oxidative phosphorylation (OxPhos). No remedy presently exists for these medical issues, apart from supportive treatments focusing on alleviating complications. Mitochondria's genetic makeup is influenced by two sources: mtDNA and nuclear DNA. Thus, as might be expected, mutations in either genetic composition can cause mitochondrial disease. Mitochondria, while primarily recognized for their roles in respiration and ATP production, exert fundamental influence over diverse biochemical, signaling, and execution pathways, potentially offering therapeutic interventions in each. 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. 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 are confident that a new era is emerging, in which addressing the root causes of these conditions becomes a realistic approach.
Differing disorders within the mitochondrial disease group showcase unprecedented variability in clinical presentations, including distinctive tissue-specific symptoms. Depending on the patients' age and the type of dysfunction, their tissue-specific stress responses demonstrate variations. Secreted metabolically active signal molecules are part of the systemic response. Biomarkers can also include such signals, which are metabolites or metabokines. During the last ten years, research has yielded metabolite and metabokine biomarkers as a way to diagnose and track mitochondrial disease progression, adding to the range of existing blood markers such as lactate, pyruvate, and alanine. Amongst these new tools are metabokines FGF21 and GDF15; NAD-form cofactors; comprehensive metabolite sets (multibiomarkers); and the complete metabolome. Mitochondrial diseases manifesting in muscle tissue find their diagnosis enhanced by the superior specificity and sensitivity of FGF21 and GDF15, messengers of the integrated stress response, compared to conventional biomarkers. The primary driver of certain diseases leads to secondary metabolite or metabolomic imbalances (e.g., NAD+ deficiency). These imbalances, however, serve as valuable biomarkers and potential therapeutic targets. To optimize therapy trials, the ideal biomarker profile must be meticulously selected to align with the specific disease being studied. The use of new biomarkers has augmented the value of blood samples in the diagnosis and monitoring of mitochondrial disease, allowing for more effective patient stratification and having a pivotal role in evaluating treatment efficacy.
In the field of mitochondrial medicine, mitochondrial optic neuropathies have played a defining role since 1988, when the first mitochondrial DNA mutation was discovered in conjunction with Leber's hereditary optic neuropathy (LHON). Mutations affecting the OPA1 gene, situated within nuclear DNA, were discovered in 2000 to be related to autosomal dominant optic atrophy (DOA). LHON and DOA share a common thread: selective neurodegeneration of retinal ganglion cells (RGCs), stemming from mitochondrial issues. The core of the clinical distinctions observed arises from the interplay between respiratory complex I impairment in LHON and the defective mitochondrial dynamics seen in OPA1-related DOA. 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, a condition that develops progressively, is usually detected during early childhood. the new traditional Chinese medicine LHON is defined by its characteristically incomplete penetrance and a pronounced male prevalence. Next-generation sequencing's impact on the understanding of genetic causes for rare forms of mitochondrial optic neuropathies, including those displaying recessive or X-linked inheritance, has been profound, further demonstrating the remarkable sensitivity of retinal ganglion cells to mitochondrial dysfunction. A spectrum of presentations, from isolated optic atrophy to a more severe, multisystemic illness, can be observed in mitochondrial optic neuropathies, including LHON and DOA. Several therapeutic programs, notably those involving gene therapy, are presently addressing mitochondrial optic neuropathies. Idebenone is the only formally authorized medication for mitochondrial disorders.
A significant portion of inherited inborn errors of metabolism involve mitochondria, and these are among the most common and complex. 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. Significant obstacles to clinical trial design and execution are the absence of strong natural history data, the difficulty in pinpointing relevant biomarkers, the lack of rigorously validated outcome measures, and the limitations presented by a small patient population. Significantly, renewed interest in addressing mitochondrial dysfunction in common diseases, combined with encouraging regulatory incentives for therapies of rare conditions, has resulted in notable enthusiasm and concerted activity in the production of 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.
To effectively manage mitochondrial diseases, reproductive counseling needs to be personalized, considering the unique aspects of recurrence risk and reproductive options. Mendelian inheritance characterizes the majority of mitochondrial diseases, which are frequently linked to mutations in nuclear genes. The availability of prenatal diagnosis (PND) and preimplantation genetic testing (PGT) aims to prevent the birth of another seriously affected child. Multiple markers of viral infections A significant fraction, ranging from 15% to 25% of cases, of mitochondrial diseases stem from mutations in mitochondrial DNA (mtDNA). These mutations can emerge spontaneously (25%) or be inherited from the maternal lineage. 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 face an unpredictable risk of recurrence, a direct result of the mitochondrial bottleneck phenomenon. The potential of employing PND in the analysis of mtDNA mutations is theoretically viable, however, its practical utility is typically hampered by the limitations inherent in predicting the resulting phenotype. To impede the transmission of mitochondrial DNA illnesses, Preimplantation Genetic Testing (PGT) is a viable option. Embryos with mutant loads that stay under the expression threshold are being transferred. In lieu of PGT, a secure method for preventing the transmission of mtDNA diseases to future children is oocyte donation for couples who decline the option. 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.