A paroxysmal neurological manifestation, the stroke-like episode, specifically impacts patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are frequently observed in stroke-like episodes, particularly affecting the posterior cerebral cortex. The m.3243A>G variant in the MT-TL1 gene, and subsequent recessive POLG variants, are the most commonly encountered causes of stroke-like episodes. 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. When dealing with stroke-like episodes, prioritizing aggressive seizure management and treatment for co-occurring complications, including intestinal pseudo-obstruction, is vital. 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.
The neuropathological condition, subacute necrotizing encephalomyelopathy, better known as Leigh syndrome, was initially identified and categorized in 1951. Bilateral, symmetrical lesions, typically traversing from the basal ganglia and thalamus, through brainstem structures, to the posterior columns of the spinal cord, exhibit microscopic features including capillary proliferation, gliosis, substantial neuronal loss, and a relative preservation of astrocytes. Infancy or early childhood often mark the onset of Leigh syndrome, a condition affecting people of all ethnic backgrounds; however, delayed-onset forms, including those appearing in adulthood, are also observed. In the last six decades, the complexity of this neurodegenerative disorder has emerged, including over one hundred distinct monogenic disorders, leading to significant clinical and biochemical heterogeneity. Structured electronic medical system This chapter delves into the clinical, biochemical, and neuropathological facets of the disorder, along with proposed 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 diagnostic method is introduced, with a comprehensive look at treatable causes, a review of current supportive management, and an examination of the next generation of therapies.
Oxidative phosphorylation (OxPhos) malfunctions contribute to the extremely diverse and heterogeneous genetic nature of mitochondrial diseases. Currently, there is no known cure for these conditions, except for supportive measures designed to alleviate associated complications. Mitochondria operate under the dual genetic control of mitochondrial DNA (mtDNA) and the genetic material present within the nucleus. Consequently, unsurprisingly, alterations within either genome can induce mitochondrial ailments. Mitochondria, though primarily linked to respiration and ATP creation, are crucial components in a multitude of biochemical, signaling, and execution cascades, presenting opportunities for therapeutic intervention in each pathway. Treatments for mitochondrial disorders can be broadly categorized as general therapies, applicable to multiple conditions, or specific therapies focused on individual diseases, including, for example, gene therapy, cell therapy, and organ replacement. Recent years have marked a significant increase in clinical applications within mitochondrial medicine, a direct consequence of the substantial research activity in this field. Preclinical research has yielded novel therapeutic strategies, which are reviewed alongside the current clinical applications in this chapter. We consider that a new era is underway where the causal treatment of these conditions is becoming a tangible prospect.
Mitochondrial disease encompasses a spectrum of disorders, characterized by a remarkable and unpredictable range of clinical presentations and tissue-specific symptoms. Age and dysfunction type of patients are factors determining the degree of variability in their tissue-specific stress responses. These responses involve the systemic release of metabolically active signaling molecules. Biomarkers can also include such signals, which are metabolites or metabokines. 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. These new instruments encompass the metabokines FGF21 and GDF15; cofactors such as NAD-forms; curated sets of metabolites (multibiomarkers); and the full metabolome. The integrated stress response of mitochondria, as communicated by FGF21 and GDF15, offers greater specificity and sensitivity than conventional biomarkers in diagnosing muscle-presenting mitochondrial diseases. The primary cause of some diseases leads to a secondary consequence: metabolite or metabolomic imbalances (e.g., NAD+ deficiency). These imbalances are relevant as biomarkers and potential targets for therapies. To optimize therapy trials, the ideal biomarker profile must be meticulously selected to align with the specific disease being studied. New biomarkers have increased the utility of blood samples in both the diagnosis and ongoing monitoring of mitochondrial disease, facilitating a personalized approach to diagnostics and providing critical insights into the effectiveness of treatment.
The crucial role of mitochondrial optic neuropathies in the field of mitochondrial medicine dates back to 1988, when the very first mutation in mitochondrial DNA was found to be associated with Leber's hereditary optic neuropathy (LHON). The 2000 discovery established a link between autosomal dominant optic atrophy (DOA) and mutations within the OPA1 gene found in nuclear DNA. The selective neurodegeneration of retinal ganglion cells (RGCs), characteristic of LHON and DOA, is induced by mitochondrial dysfunction. Defective mitochondrial dynamics in OPA1-related DOA and respiratory complex I impairment in LHON contribute to the diversity of clinical presentations that are seen. 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. HCC hepatocellular carcinoma LHON is defined by its characteristically incomplete penetrance and a pronounced male prevalence. By implementing next-generation sequencing, scientists have substantially expanded our understanding of the genetic basis of various rare mitochondrial optic neuropathies, including those linked to recessive and X-linked inheritance patterns, underscoring the remarkable sensitivity of retinal ganglion cells to impaired mitochondrial function. LHON and DOA, as examples of mitochondrial optic neuropathies, are capable of presenting either as simple optic atrophy or a more complex, multisystemic ailment. 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.
Primary mitochondrial diseases, a subset of inherited metabolic disorders, are noted for their substantial prevalence and intricate characteristics. 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. 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. 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. We delve into past and present clinical trials, and prospective future strategies for pharmaceutical development in primary mitochondrial diseases.
For mitochondrial diseases, reproductive counseling strategies must be individualized, acknowledging diverse recurrence risks and reproductive choices. Mutations in nuclear genes are the source of many mitochondrial diseases, displaying Mendelian patterns of inheritance. Prenatal diagnosis (PND) and preimplantation genetic testing (PGT) provide avenues to prevent the birth of another gravely affected child. learn more In a substantial proportion, roughly 15% to 25%, of mitochondrial diseases, the underlying cause is mutations in mitochondrial DNA (mtDNA), potentially originating spontaneously (25%) or transmitted through the maternal line. New mitochondrial DNA mutations often have a low recurrence risk, allowing pre-natal diagnosis (PND) for peace of mind. For heteroplasmic mitochondrial DNA mutations passed down through maternal lines, the likelihood of recurrence is frequently uncertain, stemming from the mitochondrial bottleneck effect. 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. An alternative method to avert the spread of mitochondrial DNA diseases is Preimplantation Genetic Testing (PGT). Transferring embryos whose mutant load falls below the expression threshold. To circumvent PGT and prevent mtDNA disease transmission to their future child, couples can opt for oocyte donation, a safe procedure. Recently, mitochondrial replacement therapy (MRT) has been introduced as a clinical procedure, offering a method to prevent the inheritance of heteroplasmic and homoplasmic mtDNA mutations.