A specific subset of mitochondrial disease patients are affected by stroke-like episodes, a type of paroxysmal neurological manifestation. A key finding in stroke-like episodes is the presence of visual disturbances, focal-onset seizures, and encephalopathy, particularly within the posterior cerebral cortex. Among the most common causes of stroke-like symptoms are the m.3243A>G mutation in the MT-TL1 gene, followed by recessive POLG variants. This chapter will comprehensively review the definition of a stroke-like episode, outlining the diverse clinical presentations, neuroimaging findings, and associated EEG patterns characteristic of patients experiencing them. Moreover, the supporting evidence for neuronal hyper-excitability as the key mechanism behind stroke-like episodes is explored. Aggressive seizure management and the treatment of concomitant complications, such as intestinal pseudo-obstruction, should be the primary focus of stroke-like episode management. For both acute and preventative purposes, l-arginine's effectiveness is not firmly established by reliable evidence. The repeated occurrence of stroke-like episodes is a cause for progressive brain atrophy and dementia, the course of which is partially determined by the underlying genetic type.
In 1951, the neuropathological condition known as Leigh syndrome, or subacute necrotizing encephalomyelopathy, was first identified. Bilateral symmetrical lesions, typically extending from the basal ganglia and thalamus to the posterior columns of the spinal cord via brainstem structures, display microscopic features of capillary proliferation, gliosis, severe neuronal loss, and relative astrocyte preservation. Characterized by a pan-ethnic prevalence, Leigh syndrome frequently begins in infancy or early childhood; nevertheless, later occurrences, extending into adult life, do exist. The intricate neurodegenerative disorder, in the last six decades, has been recognized to involve over a hundred different monogenic conditions, manifesting in substantial clinical and biochemical disparity. https://www.selleck.co.jp/products/mi-773-sar405838.html The disorder's clinical, biochemical, and neuropathological characteristics, and the hypothesized pathomechanisms, are discussed in this chapter. 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. This presentation outlines a diagnostic strategy, alongside remediable causes, and provides a synopsis of current supportive care protocols and upcoming therapeutic developments.
The varied and extremely heterogeneous genetic make-up of mitochondrial diseases is a consequence of faulty oxidative phosphorylation (OxPhos). Currently, there is no known cure for these conditions, except for supportive measures designed to alleviate associated complications. Mitochondrial DNA (mtDNA) and nuclear DNA both participate in the genetic control that governs mitochondria's function. Accordingly, as anticipated, mutations in either genetic makeup can lead to mitochondrial illnesses. Mitochondria, while frequently linked to respiratory function and ATP generation, play fundamental roles in diverse biochemical, signaling, and execution pathways, opening avenues for targeted therapeutic interventions. These therapies can be categorized as broadly applicable treatments for mitochondrial conditions, or as specialized treatments for specific diseases, encompassing personalized approaches like gene therapy, cell therapy, and organ replacement. The last few years have witnessed a substantial expansion in the clinical utilization of mitochondrial medicine, a direct outcome of the highly active research efforts. The chapter presents a synthesis of recent preclinical therapeutic advancements and a summary of the currently active clinical trials. We hold the view that a new era is beginning, in which the treatment of the causes of these conditions is becoming a realistic possibility.
The diverse group of mitochondrial diseases presents a wide array of clinical manifestations and tissue-specific symptoms, exhibiting unprecedented variability. Patient age and the nature of the dysfunction correlate to the different tissue-specific stress responses observed. Systemic circulation is engaged in the delivery of metabolically active signaling molecules from these responses. Biomarkers can also be these signals—metabolites, or metabokines—utilized. 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. FGF21 and GDF15 metabokines, NAD-form cofactors, multibiomarker metabolite sets, and the full scope of the metabolome are all encompassed within these novel instruments. In terms of specificity and sensitivity for muscle-manifesting mitochondrial diseases, FGF21 and GDF15, messengers of the mitochondrial integrated stress response, significantly outperform traditional 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. For successful therapy trials, the most effective biomarker panel needs to be tailored to the particular disease type. 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.
Since 1988, when the first mutation in mitochondrial DNA was linked to Leber's hereditary optic neuropathy (LHON), mitochondrial optic neuropathies have held a prominent position within mitochondrial medicine. The year 2000 saw a correlation established between autosomal dominant optic atrophy (DOA) and mutations within the OPA1 gene located in the nuclear DNA. Due to mitochondrial dysfunction, LHON and DOA are characterized by the selective neurodegeneration of retinal ganglion cells (RGCs). 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. 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. A slower, progressive optic neuropathy, DOA, is commonly apparent in young children. Stereotactic biopsy LHON's presentation is typified by incomplete penetrance and a prominent predisposition for males. 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. Both pure optic atrophy and a more severe, multisystemic illness can result from various forms of mitochondrial optic neuropathies, including LHON and DOA. Mitochondrial optic neuropathies are now central to several ongoing therapeutic initiatives, encompassing gene therapy, while idebenone remains the only approved pharmaceutical for mitochondrial conditions.
Amongst inherited metabolic disorders, primary mitochondrial diseases stand out as some of the most prevalent and complex. 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. Clinical trials have faced major hurdles in design and execution due to a dearth of strong natural history data, the difficulty in identifying relevant biomarkers, the absence of properly validated outcome measures, and the small size of the patient groups. 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.
Personalized reproductive counseling strategies are essential for mitochondrial diseases, taking into account individual variations in recurrence risk and available reproductive choices. Mutations in nuclear genes account for the majority of mitochondrial diseases, and their inheritance pattern is Mendelian. Prenatal diagnosis (PND) or preimplantation genetic testing (PGT) are offered as methods to prevent another severely affected child from being born. medicare current beneficiaries survey 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. For newly arising mitochondrial DNA mutations, the chance of a repeat occurrence is small, and pre-natal diagnosis (PND) can offer reassurance. The recurrence risk for maternally inherited heteroplasmic mitochondrial DNA mutations is frequently unpredictable, owing to the variance introduced by the mitochondrial bottleneck. Technically, PND can be applied to mitochondrial DNA (mtDNA) mutations, but it's often unviable due to limitations in the prediction of the resulting traits. An alternative method to avert the spread of mitochondrial DNA diseases is Preimplantation Genetic Testing (PGT). Embryos carrying a mutant load that remains below the expression threshold are being transferred. Oocyte donation is a secure avenue for couples who eschew PGT to avoid the transmission of mtDNA diseases to their future child. As a recent clinical advancement, mitochondrial replacement therapy (MRT) now offers a means to preclude the transmission of heteroplasmic and homoplasmic mitochondrial DNA mutations.