Handbook of Clinical Neurology

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Mitochondria are essential for the health and viability of both motor and sensory neurons and their axons. Processes that disrupt their normal distribution and transport along axons will likely cause peripheral neuropathies. Similarly, mutations in mtDNA or nuclear encoded genes result in neuropathies that either stand alone or are part of multisystem disorders. This chapter focuses on the more common genetic forms and characteristic clinical phenotypes of "mitochondrial" peripheral neuropathies. We also explain how these various mitochondrial abnormalities cause peripheral neuropathy...

Progressive external ophthalmoplegia (PEO), characterized by ptosis and impaired eye movements, is a clinical syndrome with an expanding number of etiologically distinct subtypes. Advances in molecular genetics have revealed numerous pathogenic causes of PEO, originally heralded in 1988 by the detection of single large-scale deletions of mitochondrial DNA (mtDNA) in skeletal muscle of people with PEO and Kearns-Sayre syndrome. Since then, multiple point variants of mtDNA and nuclear genes have been identified to cause mitochondrial PEO and PEO-plus syndromes, including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and sensory ataxic neuropathy dysarthria ophthalmoplegia (SANDO)...

Degenerative ataxias and hereditary spastic paraplegias (HSPs) form a continuous, often overlapping disease spectrum sharing not only phenotypic features and underlying genes, but also cellular pathways and disease mechanisms. Mitochondrial metabolism presents a major molecular theme underlying both multiple ataxias and HSPs, thus indicating a heightened vulnerability of Purkinje cells, spinocerebellar tracts, and motor neurons to mitochondrial dysfunction, which is of particular interest for translational approaches...

Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are prominent findings associated with stroke-like episodes, with a predilection for the posterior cerebral cortex. The most common cause of stroke-like episodes is the m.3243A>G variant in MT-TL1 gene followed by recessive POLG variants. This chapter aims to review the definition of stroke-like episode and delineate the clinical phenomenology, neuroimaging and EEG findings typically seen in patients...

Leigh syndrome, or subacute necrotizing encephalomyelopathy, was initially recognized as a neuropathological entity in 1951. Bilateral symmetrical lesions, typically extending from the basal ganglia and thalamus through brainstem structures to the posterior columns of the spinal cord, are characterized microscopically by capillary proliferation, gliosis, severe neuronal loss, and relative preservation of astrocytes. Leigh syndrome is a pan-ethnic disorder usually with onset in infancy or early childhood, but late-onset forms occur, including in adult life...

This chapter provides a overview of this volume of the Handbook of Clinical Neurology, placing recent advances in our understanding of mitochondrial disorders in a historical context, and speculates about the future.

Mitochondrial diseases are extremely heterogeneous genetic disorders due to faulty oxidative phosphorylation (OxPhos). No cure is currently available for these conditions, beside supportive interventions aimed at relieving complications. Mitochondria are under a double genetic control carried out by the mitochondrial DNA (mtDNA) and by nuclear DNA. Thus, not surprisingly, mutations in either genome can cause mitochondrial disease. Although mitochondria are usually associated with respiration and ATP synthesis, they play fundamental roles in a large number of other biochemical, signaling, and execution pathways, each being a potential target for therapeutic interventions...

The mitochondrial disease group consists of different disorders with unprecedented variability of clinical manifestations and tissue-specific symptoms. Their tissue-specific stress responses vary depending on the patients' age and type of dysfunction. These responses include secretion of metabolically active signal molecules to systemic circulation. Such signals-metabolites or metabokines-can be also utilized as biomarkers. During the past 10 years, metabolite and metabokine biomarkers have been described for mitochondrial disease diagnosis and follow-up, to complement the conventional blood biomarkers lactate, pyruvate and alanine...

Mitochondrial optic neuropathies have a leading role in the field of mitochondrial medicine ever since 1988, when the first mutation in mitochondrial DNA was associated with Leber's hereditary optic neuropathy (LHON). Autosomal dominant optic atrophy (DOA) was subsequently associated in 2000 with mutations in the nuclear DNA affecting the OPA1 gene. LHON and DOA are both characterized by selective neurodegeneration of retinal ganglion cells (RGCs) triggered by mitochondrial dysfunction. This is centered on respiratory complex I impairment in LHON and defective mitochondrial dynamics in OPA1-related DOA, leading to distinct clinical phenotypes...

Primary mitochondrial diseases are some of the most common and complex inherited inborn errors of metabolism. Their molecular and phenotypic diversity has led to difficulties in finding disease-modifying therapies and clinical trial efforts have been slow due to multiple significant challenges. Lack of robust natural history data, difficulties in finding specific biomarkers, absence of well-validated outcome measures, and small patient numbers have made clinical trial design and conduct difficult. Encouragingly, new interest in treating mitochondrial dysfunction in common diseases and regulatory incentives to develop therapies for rare conditions have led to significant interest and efforts to develop drugs for primary mitochondrial diseases...

Mitochondrial diseases require customized approaches for reproductive counseling, addressing differences in recurrence risks and reproductive options. The majority of mitochondrial diseases is caused by mutations in nuclear genes and segregate in a Mendelian way. Prenatal diagnosis (PND) or preimplantation genetic testing (PGT) are available to prevent the birth of another severely affected child. In at least 15%-25% of cases, mitochondrial diseases are caused by mitochondrial DNA (mtDNA) mutations, which can occur de novo (25%) or be maternally inherited...

Mitochondrial diseases are a heterogeneous group of multisystem disorders caused by impaired mitochondrial function. These disorders occur at any age and involve any tissue, typically affecting organs highly dependent on aerobic metabolism. Diagnosis and management are extremely difficult due to various underlying genetic defects and a wide range of clinical symptoms. Preventive care and active surveillance are strategies to try to reduce morbidity and mortality by timely treatment of organ-specific complications...

The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative phosphorylation. Therefore, neurodegeneration is a hallmark of mitochondrial diseases. The nervous system of affected individuals typically shows selective regional vulnerability leading to distinct patterns of tissue damage. A classic example is Leigh syndrome, which causes symmetric alterations of basal ganglia and brain stem. Leigh syndrome can be caused by different genetic defects (>75 known disease genes) with variable disease onset ranging from infancy to adulthood...

Clinical variability and substantial overlap between mitochondrial disorders and other genetic disorders and inborn errors make the clinical and metabolic diagnosis of mitochondrial disorders quite challenging. Evaluating specific laboratory markers is essential in the diagnostic process, but mitochondrial disease can be present in the absence of any abnormal metabolic markers. In this chapter, we share the current consensus guidelines for metabolic investigations, including investigations in blood, urine, and the cerebral spinal fluid and discuss different diagnostic approaches...

Mitochondrial diseases are a genetically and phenotypically variable set of monogenic disorders. The main characteristic of mitochondrial diseases is a defective oxidative phosphorylation. Both nuclear and mitochondrial DNA encode the approximately 1500 mitochondrial proteins. Since identification of the first mitochondrial disease gene in 1988 a total of 425 genes have been associated with mitochondrial diseases. Mitochondrial dysfunctions can be caused both by pathogenic variants in the mitochondrial DNA or the nuclear DNA...

A multidisciplinary approach to the laboratory diagnosis of mitochondrial disease has long been applied, with crucial information provided by deep clinical phenotyping, blood investigations, and biomarker screening as well as histopathological and biochemical testing of biopsy material to support molecular genetic screening. In an era of second and third generation sequencing technologies, traditional diagnostic algorithms for mitochondrial disease have been replaced by gene agnostic, genomic strategies including whole-exome sequencing (WES) and whole-genome sequencing (WGS), increasingly supported by other 'omics technologies (Alston et al...

Mitochondrial diseases typically involve organs highly dependent on aerobic metabolism and are often progressive with high morbidity and mortality. In the previous chapters of this book, classical mitochondrial phenotypes and syndromes are extensively described. However, these well-known clinical pictures are more the exception rather than the rule in mitochondrial medicine. In fact, more complex, unspecified, incomplete, and/or overlap clinical entities may be even more frequent, with multisystem appearance or progression...

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