Leigh Disease: A group of metabolic disorders primarily of infancy characterized by the subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, dysphagia, and lactic acidosis. Pathological features include spongy degeneration of the neuropile of the basal ganglia, thalamus, brain stem, and spinal cord. Patterns of inheritance include X-linked recessive, autosomal recessive, and mitochondrial. Leigh disease has been associated with mutations in genes for the PYRUVATE DEHYDROGENASE COMPLEX; CYTOCHROME-C OXIDASE; ATP synthase subunit 6; and subunits of mitochondrial complex I. (From Menkes, Textbook of Child Neurology, 5th ed, p850).Encephalomalacia: Softening or loss of brain tissue following CEREBRAL INFARCTION; cerebral ischemia (see BRAIN ISCHEMIA), infection, CRANIOCEREBRAL TRAUMA, or other injury. The term is often used during gross pathologic inspection to describe blurred cortical margins and decreased consistency of brain tissue following infarction. Multicystic encephalomalacia refers to the formation of multiple cystic cavities of various sizes in the cerebral cortex of neonates and infants following injury, most notably perinatal hypoxia-ischemic events. (From Davis et al., Textbook of Neuropathology, 2nd ed, p665; J Neuropathol Exp Neurol, 1995 Mar;54(2):268-75)Brain Diseases, Metabolic: Acquired or inborn metabolic diseases that produce brain dysfunction or damage. These include primary (i.e., disorders intrinsic to the brain) and secondary (i.e., extracranial) metabolic conditions that adversely affect cerebral function.Cytochrome-c Oxidase Deficiency: A disease that results from a congenital defect in ELECTRON TRANSPORT COMPLEX IV. Defects in ELECTRON TRANSPORT COMPLEX IV can be caused by mutations in the SURF1, SCO2, COX10, or SCO1 genes. ELECTRON TRANSPORT COMPLEX IV deficiency caused by mutation in SURF1 manifests itself as LEIGH DISEASE; that caused by mutation in SCO2 as fatal infantile cardioencephalomyopathy; that caused by mutation in COX10 as tubulopathy and leukodystrophy; and that caused by mutation in SCO1 as early-onset hepatic failure and neurologic disorder. (from Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/Omim, MIM#220110, May 17, 2001)Regression (Psychology): A return to earlier, especially to infantile, patterns of thought or behavior, or stage of functioning, e.g., feelings of helplessness and dependency in a patient with a serious physical illness. (From APA, Thesaurus of Psychological Index Terms, 1994).Encyclopedias as Topic: Works containing information articles on subjects in every field of knowledge, usually arranged in alphabetical order, or a similar work limited to a special field or subject. (From The ALA Glossary of Library and Information Science, 1983)Acrodynia: A condition seen primarily in childhood, most often resulting from chronic exposure to MERCURY COMPOUNDS which may result in encephalopathy and POLYNEUROPATHY. Clinical features include pain, swelling and pinkish discoloration of the fingers and toes, weakness in the extremities, extreme irritability, HYPERESTHESIA, and alterations in level of consciousness. (From Menkes, Textbook of Child Neurology, 5th ed, p603)Syndrome: A characteristic symptom complex.DNA, Mitochondrial: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system.LondonNeurosurgery: A surgical specialty concerned with the treatment of diseases and disorders of the brain, spinal cord, and peripheral and sympathetic nervous system.Diphtheria: A localized infection of mucous membranes or skin caused by toxigenic strains of CORYNEBACTERIUM DIPHTHERIAE. It is characterized by the presence of a pseudomembrane at the site of infection. DIPHTHERIA TOXIN, produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects.Military Medicine: The practice of medicine as applied to special circumstances associated with military operations.Muscle, Skeletal: A subtype of striated muscle, attached by TENDONS to the SKELETON. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles.MERRF Syndrome: A mitochondrial encephalomyopathy characterized clinically by a mixed seizure disorder, myoclonus, progressive ataxia, spasticity, and a mild myopathy. Dysarthria, optic atrophy, growth retardation, deafness, and dementia may also occur. This condition tends to present in childhood and to be transmitted via maternal lineage. Muscle biopsies reveal ragged-red fibers and respiratory chain enzymatic defects. (From Adams et al., Principles of Neurology, 6th ed, p986)Myocardial Stunning: Prolonged dysfunction of the myocardium after a brief episode of severe ischemia, with gradual return of contractile activity.Optic Atrophy, Hereditary, Leber: A maternally linked genetic disorder that presents in mid-life as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with missense mutations in the mtDNA, in genes for Complex I, III, and IV polypeptides, that can act autonomously or in association with each other to cause the disease. (from Online Mendelian Inheritance in Man, http://www.ncbi.nlm.nih.gov/Omim/, MIM#535000 (April 17, 2001))Optic Atrophies, Hereditary: Hereditary conditions that feature progressive visual loss in association with optic atrophy. Relatively common forms include autosomal dominant optic atrophy (OPTIC ATROPHY, AUTOSOMAL DOMINANT) and Leber hereditary optic atrophy (OPTIC ATROPHY, HEREDITARY, LEBER).Gene Expression Profiling: The determination of the pattern of genes expressed at the level of GENETIC TRANSCRIPTION, under specific circumstances or in a specific cell.NADH Dehydrogenase: A flavoprotein and iron sulfur-containing oxidoreductase that catalyzes the oxidation of NADH to NAD. In eukaryotes the enzyme can be found as a component of mitochondrial electron transport complex I. Under experimental conditions the enzyme can use CYTOCHROME C GROUP as the reducing cofactor. The enzyme was formerly listed as EC 1.6.2.1.Congenital Hyperinsulinism: A familial, nontransient HYPOGLYCEMIA with defects in negative feedback of GLUCOSE-regulated INSULIN release. Clinical phenotypes include HYPOGLYCEMIA; HYPERINSULINEMIA; SEIZURES; COMA; and often large BIRTH WEIGHT. Several sub-types exist with the most common, type 1, associated with mutations on an ATP-BINDING CASSETTE TRANSPORTERS (subfamily C, member 8).Science: The study of natural phenomena by observation, measurement, and experimentation.Universities: Educational institutions providing facilities for teaching and research and authorized to grant academic degrees.Research: Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. (Webster, 3d ed)Biological Science Disciplines: All of the divisions of the natural sciences dealing with the various aspects of the phenomena of life and vital processes. The concept includes anatomy and physiology, biochemistry and biophysics, and the biology of animals, plants, and microorganisms. It should be differentiated from BIOLOGY, one of its subdivisions, concerned specifically with the origin and life processes of living organisms.Technology: The application of scientific knowledge to practical purposes in any field. It includes methods, techniques, and instrumentation.Physiology: The biological science concerned with the life-supporting properties, functions, and processes of living organisms or their parts.Medical Missions, Official: Travel by a group of physicians for the purpose of making a special study or undertaking a special project of short-term duration.Cardiomyopathy, Hypertrophic: A form of CARDIAC MUSCLE disease, characterized by left and/or right ventricular hypertrophy (HYPERTROPHY, LEFT VENTRICULAR; HYPERTROPHY, RIGHT VENTRICULAR), frequent asymmetrical involvement of the HEART SEPTUM, and normal or reduced left ventricular volume. Risk factors include HYPERTENSION; AORTIC STENOSIS; and gene MUTATION; (FAMILIAL HYPERTROPHIC CARDIOMYOPATHY).Mitochondrial Proton-Translocating ATPases: Proton-translocating ATPases responsible for ADENOSINE TRIPHOSPHATE synthesis in the MITOCHONDRIA. They derive energy from the respiratory chain-driven reactions that develop high concentrations of protons within the intermembranous space of the mitochondria.Liver Failure, Acute: A form of rapid-onset LIVER FAILURE, also known as fulminant hepatic failure, caused by severe liver injury or massive loss of HEPATOCYTES. It is characterized by sudden development of liver dysfunction and JAUNDICE. Acute liver failure may progress to exhibit cerebral dysfunction even HEPATIC COMA depending on the etiology that includes hepatic ISCHEMIA, drug toxicity, malignant infiltration, and viral hepatitis such as post-transfusion HEPATITIS B and HEPATITIS C.Adenosine Triphosphatases: A group of enzymes which catalyze the hydrolysis of ATP. The hydrolysis reaction is usually coupled with another function such as transporting Ca(2+) across a membrane. These enzymes may be dependent on Ca(2+), Mg(2+), anions, H+, or DNA.Proton-Translocating ATPases: Multisubunit enzymes that reversibly synthesize ADENOSINE TRIPHOSPHATE. They are coupled to the transport of protons across a membrane.Atrazine: A selective triazine herbicide. Inhalation hazard is low and there are no apparent skin manifestations or other toxicity in humans. Acutely poisoned sheep and cattle may show muscular spasms, fasciculations, stiff gait, increased respiratory rates, adrenal degeneration, and congestion of the lungs, liver, and kidneys. (From The Merck Index, 11th ed)ATP Synthetase Complexes: Multisubunit enzyme complexes that synthesize ADENOSINE TRIPHOSPHATE from energy sources such as ions traveling through channels.Pyruvate Dehydrogenase Complex: A multienzyme complex responsible for the formation of ACETYL COENZYME A from pyruvate. The enzyme components are PYRUVATE DEHYDROGENASE (LIPOAMIDE); dihydrolipoamide acetyltransferase; and LIPOAMIDE DEHYDROGENASE. Pyruvate dehydrogenase complex is subject to three types of control: inhibited by acetyl-CoA and NADH; influenced by the energy state of the cell; and inhibited when a specific serine residue in the pyruvate decarboxylase is phosphorylated by ATP. PYRUVATE DEHYDROGENASE (LIPOAMIDE)-PHOSPHATASE catalyzes reactivation of the complex. (From Concise Encyclopedia Biochemistry and Molecular Biology, 3rd ed)Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds.Forensic Pathology: The application of pathology to questions of law.Autopsy: Postmortem examination of the body.BooksBioethics: A branch of applied ethics that studies the value implications of practices and developments in life sciences, medicine, and health care.Blogging: Using an INTERNET based personal journal which may consist of reflections, comments, and often hyperlinks.
  • The more recent history of this disorder, now designated Leigh syndrome (LS) in view of its heterogeneity, exemplifies the revolution in clinical neurosciences, culminating in the understanding of the consequences of multiple mitochondrial defects through fundamental insights derived from molecular genetics, and attributing LS to a tale of two genomes, that is, to mutations in the mitochondrial DNA (mtDNA) or to nuclear DNA. (bmj.com)
  • This is the first gene therapy trial for Parkinson's disease trial in which intra-operative MRI-guided monitoring was used," noted first author Chad Christine , MD, of the UCSF Department of Neurology and the Weill Institute for Neurosciences . (ucsf.edu)
  • Here, we present ALoFT (annotation of loss-of-function transcripts), a method to annotate and predict the disease-causing potential of loss-of-function variants. (nature.com)
  • Using data from Mendelian disease-gene discovery projects, we show that ALoFT can distinguish between loss-of-function variants that are deleterious as heterozygotes and those causing disease only in the homozygous state. (nature.com)
  • Investigation of variants discovered in healthy populations suggests that each individual carries at least two heterozygous premature stop alleles that could potentially lead to disease if present as homozygotes. (nature.com)
  • 6500 cancer exomes shows that putative loss-of-function variants predicted to be deleterious by ALoFT are enriched in known driver genes. (nature.com)
  • One of the most notable findings from personal genomics studies is that all individuals harbor loss-of-function (LoF) variants in some of their genes 1 . (nature.com)
  • Recently, a larger study aimed at elucidating rare LoF events in 2636 Icelanders generated a catalog of 1171 genes that contain either homozygous or compound heterozygous LoF variants with a minor allele frequency less than 2% 5 . (nature.com)
  • Whole-exome sequencing (WES) revealed the siblings shared compound heterozygous mutations in the COQ9 gene with both variants predicted to affect splicing. (springer.com)
  • Alternatively spliced transcript variants encoding different isoforms have been found for this gene. (genecards.org)
  • LS and LLS have been linked to pathogenic variants in over 60 different genes (Rahman 2015). (preventiongenetics.com)
  • The gene has been localized in humans to the 11th chromosome, with the specific location being 11p1.3. (wikipedia.org)
  • Under Hobert's guidance, post-docs and graduate students--and a handful of younger students like Leigh--are trying to figure out how neurons develop and differentiate in C. elegans , a microscopic worm whose nervous system is analogous in many ways to that of humans. (nsf.gov)
  • 19, 2011- Researchers have identified a gene associated with accelerated evolution in humans that may increase some women's risk to deliver their baby prematurely. (vanderbilt.edu)
  • The mitochondrial genome in humans has some 37 genes. (missouri.edu)
  • Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. (wikipedia.org)
  • 2. Mitochondrial encephalomyopathy (brain and muscle disease) - beginning in childhood or adulthood and involving variable symptom combinations which may include: eye muscle paralysis, pigmentary retinopathy (retinal color changes with loss of vision), hearing loss, sensory neuropathy (nerve damage involving the sense organs), seizures, dementia, ataxia (abnormal muscle coordination), and involuntary movements. (umdf.org)
  • abstract = "Purpose: To report a bull's-eye maculopathy-like fundus abnormality in an infant with Leigh disease. (elsevier.com)
  • An understanding of how they work could allow scientists to control the process of neuron development and, ultimately, find treatments for neurological diseases like Parkinson's, Alzheimer's and ALS. (nsf.gov)
  • I don't think anybody thought that these types of neurological diseases could be reversible. (newswise.com)
  • Dr A Denis Leigh in his office at the Maudsley Hospital, London, circa 1966. (bmj.com)
  • LS was named after Denis Leigh, the first man to describe this rare neuropathology of infants and young children, which caused death in the affected patients. (frontiersin.org)
  • In compassionate use cases and in an FDA Expanded Access protocol, children with Leigh syndrome treated with EPI-743 demonstrated objective signs of neurologic and neuromuscular improvement. (curefa.org)