Developmental Disabilities Research Reviews最新文献

Mitochondrial oxidative phosphorylation (OXPHOS) represents the final step in the conversion of nutrients into cellular energy. Genetic defects in the OXPHOS system have an incidence between 1:5,000 and 1:10,000 live births. Inherited isolated deficiency of the first complex (CI) of this system, a multisubunit assembly of 45 different proteins, occurs most frequently and originates from mutations in either the nuclear DNA, encoding 38 structural subunits and several assembly factors, or the mitochondrial DNA, encoding 7 structural subunits. The deficiency is associated with devastating multisystemic disorders, often affecting the brain, with onset in early childhood. There are currently no rational treatment strategies. Here, we present an overview of the genetic origins and cellular consequences of this deficiency and discuss how these insights might aid future development of treatment strategies. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:175–182.

The extensive conservation of mitochondrial structure, composition, and function across evolution offers a unique opportunity to expand our understanding of human mitochondrial biology and disease. By investigating the biology of much simpler model organisms, it is often possible to answer questions that are unreachable at the clinical level. Here, we review the relative utility of four different model organisms, namely the bacterium Escherichia coli, the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster, in studying the role of mitochondrial proteins relevant to human disease. E. coli are single cell, prokaryotic bacteria that have proven to be a useful model system in which to investigate mitochondrial respiratory chain protein structure and function. S. cerevisiae is a single-celled eukaryote that can grow equally well by mitochondrial-dependent respiration or by ethanol fermentation, a property that has proven to be a veritable boon for investigating mitochondrial functionality. C. elegans is a multicellular, microscopic worm that is organized into five major tissues and has proven to be a robust model animal for in vitro and in vivo studies of primary respiratory chain dysfunction and its potential therapies in humans. Studied for over a century, D. melanogaster is a classic metazoan model system offering an abundance of genetic tools and reagents that facilitates investigations of mitochondrial biology using both forward and reverse genetics. The respective strengths and limitations of each species relative to mitochondrial studies are explored. In addition, an overview is provided of major discoveries made in mitochondrial biology in each of these four model systems. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:200–218.

Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:129–135.

Coenzyme Q₁₀ (CoQ₁₀) is an essential electron carrier in the mitochondrial respiratory chain and an important antioxidant. Deficiency of CoQ₁₀ is a clinically and molecularly heterogeneous syndrome, which, to date, has been found to be autosomal recessive in inheritance and generally responsive to CoQ₁₀ supplementation. CoQ₁₀ deficiency has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ₁₀ (primary CoQ₁₀ deficiencies) or in genes not directly related to CoQ₁₀ biosynthesis (secondary CoQ₁₀ deficiencies). Respiratory chain defects, ROS production, and apoptosis contribute to the pathogenesis of primary CoQ₁₀ deficiencies. In vitro and in vivo studies are necessary to further understand the pathogenesis of the disease and to develop more effective therapies. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:183–188.

The vast majority of energy necessary for cellular function is produced in mitochondria. Free-radical production and apoptosis are other critical mitochondrial functions. The complex structure, electrochemical properties of the inner mitochondrial membrane (IMM), and genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) are some of the unique features that explain why the mitochondria are vulnerable to environmental injury. Because of similarity to bacterial translational machinery, mtDNA translation is likewise vulnerable to inhibition by some antibiotics. The mechanism of mtDNA replication, which is required for normal mitochondrial maintenance and duplication, is inhibited by a relatively new class of drugs used to treat AIDS. The electrochemical gradient maintained by the IMM is vulnerable to many drugs that are weak organic acids at physiological pH, resulting in excessive free-radical generation and uncoupling of oxidative phosphorylation. Many of these drugs can cause clinical injury in otherwise healthy people, but there are also examples where particular gene mutations may predispose to increased drug toxicity. The spectrum of drug-induced mitochondrial dysfunction extends across many drug classes. It is hoped that preclinical pharmacogenetic and functional studies of mitochondrial toxicity, along with personalized genomic medicine, will improve both our understanding of mitochondrial drug toxicity and patient safety. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:189–199.

Autism spectrum disorder (ASD) as defined by the revised Diagnostic and Statistical Manual of Mental Disorders: DSM IVTR criteria (American Psychiatric Association [2000] Washington, DC: American Psychiatric Publishing) as impairment before the age of 3 in language development and socialization with the development of repetitive behaviors, appears to be increased in incidence and prevalence. Similarly, mitochondrial disorders are increasingly recognized. Although overlap between these disorders is to be expected, accumulating clinical, genetic, and biochemical evidence suggests that mitochondrial dysfunction in ASD is more commonly seen than expected. Some patients with ASD phenotypes clearly have genetic-based primary mitochondrial disease. This review will examine the data linking autism and mitochondria. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:144–153.

The nervous system contains some of the body's most metabolically demanding cells that are highly dependent on ATP produced via mitochondrial oxidative phosphorylation. Thus, the neurological system is consistently involved in patients with mitochondrial disease. Symptoms differ depending on the part of the nervous system affected. Although almost any neurological symptom can be due to mitochondrial disease, there are select symptoms that are more suggestive of a mitochondrial problem. Certain symptoms that have become sine qua non with underlying mitochondrial cytopathies can serve as diagnostic “red-flags.” Here, the typical and atypical presentations of mitochondrial disease in the nervous system are reviewed, focusing on “red flag” neurological symptoms as well as associated symptoms that can occur in, but are not specific to, mitochondrial disease. The multitudes of mitochondrial syndromes are not reviewed in-depth, though a select few are discussed in some detail. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:120–128.

Mitochondrial diseases are very heterogeneous and can affect different tissues and organs. Moreover, they can be caused by genetic defects in either nuclear or mitochondrial DNA as well as by environmental factors. All of these factors have made the development of therapies difficult. In this review article, we will discuss emerging approaches to the therapy of mitochondrial disorders, some of which are targeted to specific conditions whereas others may be applicable to a more diverse group of patients. © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:219–229.

Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA replication, transcription, and translation, all require nuclear-encoded genes. In this review, primary molecular defects in the mitochondrial genome and major classes of nuclear genes causing mitochondrial RCDs, including genes underlying mitochondrial DNA (mtDNA) depletion syndrome, as well as genes encoding RC subunits, complex assembly genes, and translation factors, are described. Diagnostic methodologies used to detect common point mutations, large deletions, and unknown point mutations in the mtDNA and to quantify mutation heteroplasmy are also discussed. Finally, the selection of nuclear genes for gold standard sequence analysis, application of novel technologies including oligonucleotide array comparative genomic hybridization, and massive parallel sequencing of target genes are reviewed. © © 2010 Wiley-Liss, Inc. Dev Disabil Res Rev 2010;16:154–162.