Amongst those with mitochondrial disease, a distinct patient group experiences paroxysmal neurological events, including stroke-like episodes. Stroke-like episodes frequently manifest with focal-onset seizures, encephalopathy, and visual disturbances, predominantly in the posterior cerebral cortex. The m.3243A>G variant in the MT-TL1 gene, followed by recessive POLG variants, is the most frequent cause 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. In addition, a detailed analysis of various lines of evidence underscores neuronal hyper-excitability as the core mechanism responsible for stroke-like episodes. Managing stroke-like episodes requires a multifaceted strategy that prioritizes aggressive seizure management alongside treatment for concomitant issues, including intestinal pseudo-obstruction. No compelling evidence currently exists to confirm l-arginine's effectiveness in both acute and prophylactic settings. The pattern of recurrent stroke-like episodes leads to the unfortunate sequelae of progressive brain atrophy and dementia, and the underlying genotype plays a part in predicting the 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. For the last six decades, this multifaceted neurodegenerative disorder has manifested as more than a hundred unique monogenic conditions, displaying substantial clinical and biochemical variation. acquired antibiotic resistance The disorder's clinical, biochemical, and neuropathological characteristics, and the hypothesized pathomechanisms, are discussed in this chapter. Genetic defects, including those affecting 16 mitochondrial DNA genes and nearly 100 nuclear genes, lead to disorders that affect the subunits and assembly factors of the five oxidative phosphorylation enzymes, pyruvate metabolism, vitamin and cofactor transport and metabolism, mtDNA maintenance, and mitochondrial gene expression, protein quality control, lipid remodeling, dynamics, and toxicity. This approach to diagnosis is explored, together with established treatable origins, a synopsis of current supportive care, and an examination of evolving therapies.

Faulty oxidative phosphorylation (OxPhos) is the root cause of the extremely heterogeneous genetic nature of mitochondrial diseases. For these conditions, no cure is currently available; supportive measures are utilized to lessen their 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. Though commonly identified with respiration and ATP production, mitochondria are crucial for a multitude of other biochemical, signaling, and execution pathways, thereby creating diverse therapeutic targets. 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. 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. A review of the most recent therapeutic strategies arising from preclinical investigations and the current state of clinical trials are presented in this chapter. In our estimation, a new era is underway, where the treatment targeting the cause of these conditions becomes a real and attainable goal.

Mitochondrial disease, a group of disorders, is marked by an unprecedented degree of variability in clinical symptoms, specifically affecting tissues in distinctive ways. Age and dysfunction type of patients are factors determining the degree of variability in their tissue-specific stress responses. The systemic circulation is the target for metabolically active signaling molecules in these reactions. These signals—metabolites or metabokines—can also be leveraged as diagnostic markers. 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. Key components of these newly developed instruments include metabokines FGF21 and GDF15; cofactors, including NAD-forms; detailed metabolite collections (multibiomarkers); and the entire metabolome. FGF21 and GDF15, acting as messengers of the mitochondrial integrated stress response, demonstrate superior specificity and sensitivity compared to conventional biomarkers in identifying muscle-related mitochondrial diseases. While a primary cause drives disease progression, metabolite or metabolomic imbalances (like NAD+ deficiency) emerge as secondary consequences. However, these imbalances are vital as biomarkers and prospective therapeutic targets. To achieve optimal results in therapy trials, the biomarker set must be meticulously curated to align with the specific disease pathology. 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.

Mitochondrial optic neuropathies have been a significant focus in mitochondrial medicine, particularly since the discovery in 1988 of the first mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy (LHON). Autosomal dominant optic atrophy (DOA) was subsequently found to have a connection to mutations in the OPA1 gene present in the nuclear DNA, starting in 2000. Mitochondrial dysfunction underlies the selective neurodegeneration of retinal ganglion cells (RGCs) in LHON and DOA. Defective mitochondrial dynamics in OPA1-related DOA and respiratory complex I impairment in LHON contribute to the diversity of clinical presentations that are seen. Subacute, rapid, and severe central vision loss affecting both eyes, known as LHON, occurs within weeks or months, usually during the period between 15 and 35 years of age. Usually noticeable during early childhood, DOA optic neuropathy is characterized by a more slowly progressive form of optic nerve dysfunction. Picropodophyllin concentration LHON exhibits a notable lack of complete manifestation, especially in males. The introduction of next-generation sequencing technologies has considerably augmented the genetic explanations for other rare mitochondrial optic neuropathies, encompassing recessive and X-linked forms, thus further emphasizing the impressive susceptibility of retinal ganglion cells to compromised mitochondrial function. 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. 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. Obstacles to effective clinical trial design and execution include insufficient robust natural history data, the complexities in pinpointing specific biomarkers, the absence of thoroughly vetted outcome measures, and the restriction imposed by a small number of participating patients. Encouragingly, there's a growing interest in tackling mitochondrial dysfunction in prevalent medical conditions, and the supportive regulatory environment for therapies in rare conditions has prompted substantial interest and investment in the development of drugs for primary mitochondrial diseases. Current and previous clinical trials, and future directions in drug development for primary mitochondrial ailments are discussed here.

Reproductive counseling for mitochondrial diseases must be approached with customized strategies to account for the diversity in risks of recurrence and reproductive choices. Mendelian inheritance characterizes the majority of mitochondrial diseases, which are frequently linked to mutations in nuclear genes. To avert the birth of a severely affected child, prenatal diagnosis (PND) or preimplantation genetic testing (PGT) are viable options. immune effect Mitochondrial DNA (mtDNA) mutations, which account for 15% to 25% of mitochondrial diseases, can arise spontaneously in a quarter of cases (25%) or be maternally inherited. De novo mutations in mitochondrial DNA carry a low risk of recurrence, allowing for pre-natal diagnosis (PND) for reassurance. The recurrence risk for maternally inherited heteroplasmic mitochondrial DNA mutations is frequently unpredictable, owing to the variance introduced by the mitochondrial bottleneck. Although possible, using PND to analyze mtDNA mutations is frequently impractical because of the inherent difficulty in predicting the associated clinical manifestations. Preventing the inheritance of mitochondrial DNA disorders can be achieved through the application of Preimplantation Genetic Testing (PGT). Embryos are being transferred which have a mutant load below the defined expression threshold. For couples rejecting PGT, oocyte donation provides a safe means of averting mtDNA disease transmission in a future child. Mitochondrial replacement therapy (MRT) has been made clinically available as a preventative measure against the transmission of heteroplasmic and homoplasmic mtDNA mutations.