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BioFactors (Oxford, England) 2008Coenzyme Q10 (CoQ10 or ubiquinone) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. A major function of CoQ10 is to...
Coenzyme Q10 (CoQ10 or ubiquinone) is a lipid-soluble component of virtually all cell membranes and has multiple metabolic functions. A major function of CoQ10 is to transport electrons from complexes I and II to complex III in the respiratory chain which resides in the mitochondrial inner membrane. Deficiencies of CoQ10 (MIM 607426) have been associated with four major clinical phenotypes: 1) encephalomyopathy characterized by a triad of recurrent myoglobinuria, brain involvement, and ragged-red fibers; 2) infantile multisystemic disease typically with prominent nephropathy and encephalopathy; 3) cerebellar ataxia with marked cerebellar atrophy; and 4) pure myopathy. Primary CoQ10 deficiencies due to mutations in ubiquinone biosynthetic genes (COQ2, PDSS1, PDSS2, and ADCK3 [CABC1]) have been identified in patients with the infantile multisystemic and cerebellar ataxic phenotypes. In contrast, secondary CoQ10 deficiencies, due to mutations in genes not directly related to ubiquinone biosynthesis (APTX, ETFDH, and BRAF), have been identified in patients with cerebellar ataxia, pure myopathy, and cardiofaciocutaneous syndrome. In many patients with CoQ10 deficiencies, the causative molecular genetic defects remain unknown; therefore, it is likely that mutations in additional genes will be identified as causes of CoQ10 deficiencies.
Topics: Cerebellar Ataxia; Humans; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Syndrome; Ubiquinone
PubMed: 19096106
DOI: 10.1002/biof.5520320113 -
CoDAS 2021Mitochondrial myopathy is caused by the absence and/or insufficiency of L-carnitine, a quaternary enzyme responsible for transporting free fatty acids into the...
Mitochondrial myopathy is caused by the absence and/or insufficiency of L-carnitine, a quaternary enzyme responsible for transporting free fatty acids into the mitochondria. The primary function of the mitochondria is to produce energy, contributing to proper cell functioning. Muscular lipidosis causes abnormalities in enzymes that metabolize fat, resulting in the accumulation of harmful amounts of fats in tissues. The aim of this study was to present the case study of patient B.D., a 37-year-old woman diagnosed with muscular lipidosis with L-carnitine deficiency at 6 years old, and describe the speech-language follow-up performed at a hearing care clinic. The first entry in the patient's medical chart was on 03/05/1989, with continuous use of 2g/day of L-carnitine prescribed by a neurologist. The mother reported that B.D. had difficulty hearing and was inattentive, which became more evident when she started school. In 1988 the patient was diagnosed with moderate bilateral sensorineural hearing loss and began using behind-the-ear (BTE) hearing aids in 1989, after which her academic performance and communication improved. In 1998 she switched to Completely in Canal (CIC) hearing aids, which are more discreet, provided better sound localization and greater high frequency gain, although her hearing thresholds worsened slightly. She completed her graduate studies and currently works at a large financial institution. It was concluded that early neurological diagnosis and speech-language intervention enabled adequate language development in the patient.
Topics: Adult; Child; Female; Hearing Aids; Hearing Loss, Bilateral; Hearing Loss, Sensorineural; Humans; Mitochondrial Myopathies; Sound Localization; Speech Perception
PubMed: 34406262
DOI: 10.1590/2317-1782/20202020021 -
Pediatric Nephrology (Berlin, Germany) Jan 2021Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria.... (Review)
Review
Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson's marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.
Topics: DNA, Mitochondrial; Humans; Kearns-Sayre Syndrome; Mitochondria; Mitochondrial Myopathies; Mutation; Nephritis, Interstitial
PubMed: 31925537
DOI: 10.1007/s00467-019-04404-6 -
Journal of Neuromuscular Diseases 2022Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders.... (Review)
Review
Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: < 2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.
Topics: Animals; Child; DNA, Mitochondrial; Humans; Mice; Mitochondrial Myopathies; Muscular Diseases; Thymidine Kinase
PubMed: 35094997
DOI: 10.3233/JND-210786 -
Annals of Medicine Feb 2013Mitochondrial disorders are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain. Muscle tissue is highly metabolically active,... (Review)
Review
Mitochondrial disorders are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain. Muscle tissue is highly metabolically active, and therefore myopathy is a common element of the clinical presentation of these disorders, although this may be overshadowed by central neurological features. This review is aimed at a general medical and neurologist readership and provides a clinical approach to the recognition, investigation, and treatment of mitochondrial myopathies. Emphasis is placed on practical management considerations while including some recent updates in the field.
Topics: Biopsy; Cytochrome-c Oxidase Deficiency; Deglutition Disorders; Dietary Supplements; Endocrine System Diseases; Exercise Test; Exercise Therapy; Hearing Disorders; Heart Diseases; Humans; Mitochondrial Myopathies; Muscle, Skeletal; Ubiquinone; Vision Disorders; Vitamins
PubMed: 21867371
DOI: 10.3109/07853890.2011.605389 -
Neurology India Jun 2002The mitochondrial cytopathies are genetically and phenotypically heterogeneous group of disorders caused by structural and functional abnormalities in mitochondria. To...
The mitochondrial cytopathies are genetically and phenotypically heterogeneous group of disorders caused by structural and functional abnormalities in mitochondria. To the best of our knowledge, there are very few studies published from India till date. Selected and confirmed fourteen cases of neurological mitochondrial cytopathies with different clinical syndromes admitted between 1997 and 2000 are being reported. There were 8 male and 6 female patients. The mean age was 24.42+/-11.18 years (range 4-40 years). Twelve patients could be categorized into well-defined syndromes, while two belonged to undefined group. In the defined syndrome categories, three patients had MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like episodes), three had MERRF (myoclonic epilepsy and ragged red fibre myopathy), three cases had KSS (Kearns-Sayre Syndrome) and three were diagnosed to be suffering from mitochondrial myopathy. In the uncategorized group, one case presented with paroxysmal kinesogenic dystonia and the other manifested with generalized chorea alone. Serum lactic acid level was significantly increased in all the patients (fasting 28.96+/-4.59 mg%, post exercise 41.02+/-4.93 mg%). Muscle biopsy was done in all cases. Succinic dehydrogenase staining of muscle tissue showed subsarcolemmal accumulation of mitochondria in 12 cases. Mitochondrial DNA study could be performed in one case only and it did not reveal any mutation at nucleotides 3243 and 8344. MRI brain showed multiple infarcts in MELAS, hyperintensities in putaminal areas in chorea and bilateral cerebellar atrophy in MERRF.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; India; Kearns-Sayre Syndrome; MELAS Syndrome; MERRF Syndrome; Male; Mitochondrial Myopathies
PubMed: 12134180
DOI: No ID Found -
Medicine Feb 2015The mitochondrial myopathies include a diverse group of disorders characterized by morphological abnormalities of muscle mitochondria. Little is reported about spinal... (Review)
Review
The mitochondrial myopathies include a diverse group of disorders characterized by morphological abnormalities of muscle mitochondria. Little is reported about spinal deformity associated with this syndrome.This study presents a case of scoliosis occurring in the setting of mitochondrial myopathies and explores the possible mechanisms between the 2 diseases.A previously unreported scoliosis in mitochondrial myopathies is described. The patient was a 16-year-old Chinese adolescent boy undergoing a posterior correction at thoracic 2-lumbar 3 (T2-L3) levels using the Moss-SI spinal system. At 48-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of deformity correction. After evaluating 60 mitochondrial myopathies, patients referred to Peking Union Medical College Hospital from February 2009 to May 2013, the prevalence of scoliosis among patients with mitochondrial myopathies was 5% (3/60), much higher than that among general population (2%).The scoliosis in mitochondrial myopathies is usually extensive and progressively aggravated and the correction of the associated spinal deformities is generally difficult. Therefore, the exact role of mitochondrial myopathy in the development of scoliosis requires further study for a better understanding of the disease, as well as adequate and effective patient care.
Topics: Adolescent; Humans; Lumbar Vertebrae; Male; Mitochondrial Myopathies; Scoliosis; Syndrome; Thoracic Vertebrae
PubMed: 25674747
DOI: 10.1097/MD.0000000000000513 -
EMBO Molecular Medicine Jul 2023Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly...
Mitochondrial diseases are a heterogeneous group of monogenic disorders that result from impaired oxidative phosphorylation (OXPHOS). As neuromuscular tissues are highly energy-dependent, mitochondrial diseases often affect skeletal muscle. Although genetic and bioenergetic causes of OXPHOS impairment in human mitochondrial myopathies are well established, there is a limited understanding of metabolic drivers of muscle degeneration. This knowledge gap contributes to the lack of effective treatments for these disorders. Here, we discovered fundamental muscle metabolic remodeling mechanisms shared by mitochondrial disease patients and a mouse model of mitochondrial myopathy. This metabolic remodeling is triggered by a starvation-like response that evokes accelerated oxidation of amino acids through a truncated Krebs cycle. While initially adaptive, this response evolves in an integrated multiorgan catabolic signaling, lipid store mobilization, and intramuscular lipid accumulation. We show that this multiorgan feed-forward metabolic response involves leptin and glucocorticoid signaling. This study elucidates systemic metabolic dyshomeostasis mechanisms that underlie human mitochondrial myopathies and identifies potential new targets for metabolic intervention.
Topics: Mice; Animals; Humans; Mitochondrial Myopathies; Muscle, Skeletal; Energy Metabolism; Mitochondrial Diseases; Lipids
PubMed: 37222423
DOI: 10.15252/emmm.202216951 -
JAMA Neurology Jun 2017YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However,... (Observational Study)
Observational Study
IMPORTANCE
YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders.
OBJECTIVES
To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant.
DESIGN, SETTING, AND PARTICIPANTS
An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015.
MAIN OUTCOME AND MEASURES
The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants.
RESULTS
Seventeen patients (median [interquartile range] age at onset, 1.5 [9.8] years) with YARS2-related mitochondrial myopathy were identified. Fifteen individuals (88%) exhibited an elevated blood lactate level accompanied by generalized myopathy; only 12 patients (71%) manifested with sideroblastic anemia. Hypertrophic cardiomyopathy (9 [53%]) and respiratory insufficiency (8 [47%]) were also prominent clinical features. Central nervous system involvement was rare. Muscle studies showed global cytochrome-c oxidase deficiency in all patients tested and severe, combined respiratory chain complex activity deficiencies. Microsatellite genotyping demonstrated a common founder effect shared between 3 Scottish patients with a p.Leu392Ser variant. Immunoblotting from fibroblasts and myoblasts of an affected Scottish patient showed normal YARS2 protein levels and mild respiratory chain complex defects. Yeast modeling of novel missense YARS2 variants closely correlated with the severity of clinical phenotypes.
CONCLUSIONS AND RELEVANCE
The p.Leu392Ser variant is likely a newly identified founder YARS2 mutation. Testing for pathogenic YARS2 variants should be considered in patients presenting with mitochondrial myopathy, characterized by exercise intolerance and muscle weakness even in the absence of sideroblastic anemia irrespective of ethnicity. Regular surveillance and early treatment for cardiomyopathy and respiratory muscle weakness is advocated because early treatment may mitigate the significant morbidity and mortality associated with this genetic disorder.
Topics: Acidosis, Lactic; Adult; Aged; Anemia, Sideroblastic; Cardiomyopathies; England; Female; Humans; Male; Middle Aged; Mitochondrial Myopathies; Muscle Weakness; Mutation; Prognosis; Respiratory Insufficiency; Scotland; Tyrosine-tRNA Ligase
PubMed: 28395030
DOI: 10.1001/jamaneurol.2016.4357 -
Proceedings of the National Academy of... Sep 1994Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was... (Review)
Review
Primary defects in mitochondrial function are implicated in over 100 diseases, and the list continues to grow. Yet the first mitochondrial defect--a myopathy--was demonstrated only 35 years ago. The field's dramatic expansion reflects growth of knowledge in three areas: (i) characterization of mitochondrial structure and function, (ii) elucidation of the steps involved in mitochondrial biosynthesis, and (iii) discovery of specific mitochondrial DNA. Many mitochondrial diseases are accompanied by mutations in this DNA. Inheritance is by maternal transmission. The metabolic defects encompass the electron transport complexes, intermediates of the tricarboxylic acid cycle, and substrate transport. The clinical manifestations are protean, most often involving skeletal muscle and the central nervous system. In addition to being a primary cause of disease, mitochondrial DNA mutations and impaired oxidation have now been found to occur as secondary phenomena in aging as well as in age-related degenerative diseases such as Parkinson, Alzheimer, and Huntington diseases, amyotrophic lateral sclerosis and cardiomyopathies, atherosclerosis, and diabetes mellitus. Manifestations of both the primary and secondary mitochondrial diseases are thought to result from the production of oxygen free radicals. With increased understanding of the mechanisms underlying the mitochondrial dysfunctions has come the beginnings of therapeutic strategies, based mostly on the administration of antioxidants, replacement of cofactors, and provision of nutrients. At the present accelerating pace of development of what may be called mitochondrial medicine, much more is likely to be achieved within the next few years.
Topics: Aging; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Oxidative Phosphorylation
PubMed: 8090715
DOI: 10.1073/pnas.91.19.8731