Leber hereditary optic neuropathy – Therapeutic challenges and early promise

AbstractLeber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the general population. It is an important cause of severe, usually irreversible, visual loss among young adults with a peak age of onset in the second and third decades of life. Management is currently mostly supportive but recent developments in LHON research are pointing the way towards more effective treatments for this blinding mitochondrial disorder

Modifying Mitochondrial tRNAs: Delivering What the Cell Needs

Protein synthesis is critically dependent on transfer (t)-RNAs, but the factors regulating tRNA function are poorly understood. In this issue of Cell Metabolism, Wei et al. (2015) show that Cdk5 regulatory subunit-associated protein-like-1 synchronizes mitochondrial and cytosolic translation in response to external stress, providing key insight into the pathogenesis of a common inherited mitochondrial disease

Disorders of the Optic Nerve in Mitochondrial Cytopathies: New Ideas on Pathogenesis and Therapeutic Targets

Mitochondrial cytopathies are a heterogeneous group of human disorders triggered by disturbed mitochondrial function. This can be due to primary mitochondrial DNA mutations or nuclear defects affecting key components of the mitochondrial machinery. Optic neuropathy is a frequent disease manifestation and the degree of visual failure can be profound, with a severe impact on the patient’s quality of life. This review focuses on the major mitochondrial disorders exhibiting optic nerve involvement, either as the defining clinical feature or as an additional component of a more extensive phenotype. Over the past decade, significant progress has been achieved in our basic understanding of Leber hereditary optic neuropathy and autosomal-dominant optic atrophy—the two classical paradigms for these mitochondrial optic neuropathies. There are currently limited treatments for these blinding ocular disorders and, ultimately, the aim is to translate these major advances into tangible benefits for patients and their families

Genetic variation in the methylenetetrahydrofolate reductase gene, MTHFR, does not alter the risk of visual failure in Leber’s hereditary optic neuropathy

Focal neurodegeneration of the optic nerve in Leber hereditary optic neuropathy (LHON) is primarily due to a maternally inherited mitochondrial DNA mutation. However, the markedly reduced penetrance of LHON and segregation pattern of visual failure within families implicates an interacting nuclear genetic locus modulating the phenotype. Folate deficiency is known to cause bilateral optic neuropathy, and defects of folate metabolism have been associated with nonarteritic ischemic optic neuropathy

Mitochondrial DNA Heteroplasmy and Purifying Selection in the Mammalian Female Germ Line.

Inherited mutations in the mitochondrial (mt)DNA are a major cause of human disease, with approximately 1 in 5000 people affected by one of the hundreds of identified pathogenic mtDNA point mutations or deletions. Due to the severe, and often untreatable, symptoms of many mitochondrial diseases, identifying how these mutations are inherited from one generation to the next has been an area of intense research in recent years. Despite large advances in our understanding of this complex process, many questions remain unanswered, with one of the most hotly debated being whether or not purifying selection acts against pathogenic mutations during germline development

Cell reprogramming shapes the mitochondrial DNA landscape.

Individual induced pluripotent stem cells (iPSCs) show considerable phenotypic heterogeneity, but the reasons for this are not fully understood. Comprehensively analysing the mitochondrial genome (mtDNA) in 146 iPSC and fibroblast lines from 151 donors, we show that most age-related fibroblast mtDNA mutations are lost during reprogramming. However, iPSC-specific mutations are seen in 76.6% (108/141) of iPSC lines at a mutation rate of 8.62 × 10-5/base pair. The mutations observed in iPSC lines affect a higher proportion of mtDNA molecules, favouring non-synonymous protein-coding and tRNA variants, including known disease-causing mutations. Analysing 11,538 single cells shows stable heteroplasmy in sub-clones derived from the original donor during differentiation, with mtDNA variants influencing the expression of key genes involved in mitochondrial metabolism and epidermal cell differentiation. Thus, the dynamic mtDNA landscape contributes to the heterogeneity of human iPSCs and should be considered when using reprogrammed cells experimentally or as a therapy

Oldies but Goldies mtDNA Population Variants and Neurodegenerative Diseases

mtDNA is transmitted through the maternal line and its sequence variability, which is population specific, is assumed to be phenotypically neutral. However, several studies have shown associations between the variants defining some genetic backgrounds and the susceptibility to several pathogenic phenotypes, including neurodegenerative diseases. Many of these studies have found that some of these variants impact many of these phenotypes, including the ones defining the Caucasian haplogroups H, J, and Uk, while others, such as the ones defining the T haplogroup, have phenotype specific associations. In this review, we will focus on those that have shown a pleiotropic effect in population studies in neurological diseases. We will also explore their bioenergetic and genomic characteristics in order to provide an insight into the role of these variants in disease. Given the importance of mitochondrial population variants in neurodegenerative diseases a deeper analysis of their effects might unravel new mechanisms of disease and help design new strategies for successful treatments

Prevalence of neurogenetic disorders in the North of England.

OBJECTIVE: Genetic disorders enter the differential diagnosis of common neurologic diseases, but their overall prevalence is not known. We set out to determine their minimum prevalence. METHODS: Meta-analysis of epidemiologic data gathered from the same geographic region in the North of England. RESULTS: Monogenic neurologic disorders affect at least 90.9/100,000 (95% confidence interval 87.6-94.3), or 1 in 1,100 of the population in Northern England. CONCLUSION: As a group, neurogenetic disorders are not rare. These findings have implications for clinical service delivery

Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations.

Inherited mitochondrial DNA (mtDNA) mutations have emerged as a common cause of human disease, with mutations occurring multiple times in the world population. The clinical presentation of three pathogenic mtDNA mutations is strongly associated with a background mtDNA haplogroup, but it is not clear whether this is limited to a handful of examples or is a more general phenomenon. To address this, we determined the characteristics of 30,506 mtDNA sequences sampled globally. After performing several quality control steps, we ascribed an established pathogenicity score to the major alleles for each sequence. The mean pathogenicity score for known disease-causing mutations was significantly different between mtDNA macro-haplogroups. Several mutations were observed across all haplogroup backgrounds, whereas others were only observed on specific clades. In some instances this reflected a founder effect, but in others, the mutation recurred but only within the same phylogenetic cluster. Sequence diversity estimates showed that disease-causing mutations were more frequent on young sequences, and genomes with two or more disease-causing mutations were more common than expected by chance. These findings implicate the mtDNA background more generally in recurrent mutation events that have been purified through natural selection in older populations. This provides an explanation for the low frequency of mtDNA disease reported in specific ethnic groups