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Neurology(R) Neuroimmunology &... Jul 2022Sporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been...
BACKGROUND AND OBJECTIVES
Sporadic late-onset nemaline myopathy (SLONM) is a treatable or otherwise fatal myopathy. Diagnosis of SLONM is still challenging, and no therapeutic consensus has been achieved. Here, we reported the clinicopathologic features and long-term follow-up data of SLONM in a Chinese cohort.
METHODS
We performed a retrospective evaluation of clinical, pathologic, and treatment outcomes of 17 patients with SLONM diagnosed between March 1986 and April 2021 at our neuromuscular center. Immunohistochemistry (IHC) with antibodies against 5 Z-disc-associated proteins was performed in the muscle biopsies of SLONM to identify a potential pathologic marker in aid of diagnosis. In comparison, we also performed muscle IHC in patients with selective type II fiber atrophy (n = 22), neurogenic atrophy (n = 22), mitochondrial myopathy (n = 5), immune-mediated necrotizing myopathy (n = 5), and normal controls (n = 5).
RESULTS
Most of the patients exhibited asymmetric limb muscles weakness (71%, 12/17) and neck extensor weakness (53%, 9/17). Immunofixation electrophoresis was performed in 11 patients, and 4 of them were identified with monoclonal gammopathy of undetermined significance (MGUS). EMG from 16 patients demonstrated a myopathic pattern with spontaneous activities in 69% (11/16) of them. Muscle MRI showed preferential involvement of paraspinal, gluteus minimus and medius, semimembranosus, and soleus muscles. Suspected nemaline bodies on modified Gomori trichrome were confirmed by IHC using anti-α-actinin antibody (100%, 17/17), anti-myotilin antibody (94%, 16/17), anti-desmin antibody (94%, 16/17), anti-α-B crystallin antibody (65%, 11/17), and anti-telethonin antibody (18%, 3/17) with various positive rates. Notably, anti-α-actinin IHC showed the highest percentage of strongly positive staining (77%, 13/17), being the only one without negative results. Moderate improvement following autologous stem cell transplantation (ASCT) was noted in 3/4 patients with MGUS; favorable outcomes were also achieved in 6/7 patients without MGUS, including 3 patients with complete recovery who were given a combined treatment of prednisone and another immunosuppressant.
DISCUSSION
SLONM is a treatable myopathy with ASCT or traditional immunotherapy, especially when combined with steroids and immunosuppressants. Anti-α-actinin immunostaining is the most reliable pathologic marker to identify rod-bearing fibers, and it should be performed routinely in adult patients with undiagnosed nonnecrotic myopathies.
Topics: Actinin; Adult; Atrophy; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Monoclonal Gammopathy of Undetermined Significance; Myopathies, Nemaline; Retrospective Studies; Transplantation, Autologous
PubMed: 35581006
DOI: 10.1212/NXI.0000000000001184 -
Frontiers in Physiology 2020In patients with mitochondrial DNA (mtDNA) mutation, a pathogenic mtDNA mutation is heteroplasmically distributed among tissues. The ratio between wild-type and mutated... (Review)
Review
In patients with mitochondrial DNA (mtDNA) mutation, a pathogenic mtDNA mutation is heteroplasmically distributed among tissues. The ratio between wild-type and mutated mtDNA copies determines the mtDNA mutation load of the tissue, which correlates inversively with oxidative capacity of the tissue. In patients with mtDNA mutation, the mutation load is often very high in skeletal muscle compared to other tissues. Additionally, skeletal muscle can increase its oxygen demand up to 100-fold from rest to exercise, which is unmatched by any other tissue. Thus, exercise intolerance is the most common symptom in patients with mtDNA mutation. The impaired oxidative capacity in skeletal muscle in patients with mtDNA mutation results in limitation in physical capacity that interferes with daily activities and impairs quality of life. Additionally, patients with mitochondrial disease due to mtDNA mutation often live a sedentary lifestyle, which further impair oxidative capacity and exercise tolerance. Since aerobic exercise training increase mitochondrial function and volume density in healthy individuals, studies have investigated if aerobic training could be used to counteract the progressive exercise intolerance in patients with mtDNA mutation. Overall studies investigating the effect of aerobic training in patients with mtDNA mutation have shown that aerobic training is an efficient way to improve oxidative capacity in this condition, and aerobic training seems to be safe even for patients with high mtDNA mutation in skeletal muscle.
PubMed: 32508662
DOI: 10.3389/fphys.2020.00349 -
Biochimica Et Biophysica Acta Jul 2016Complex I deficiency is the most frequently encountered single mitochondrial single enzyme deficiency in patients with a mitochondrial disorder. Although specific...
Complex I deficiency is the most frequently encountered single mitochondrial single enzyme deficiency in patients with a mitochondrial disorder. Although specific genotype-phenotype correlations are very difficult to identify, the majority of patients present with symptoms caused by leukodystrophy. The poor genotype-phenotype correlations can make establishing a diagnosis a challenge. The classical way to establish a complex I deficiency in patients is by performing spectrophotometric measurements of the enzyme in a muscle biopsy or other patient-derived material (liver or heart biopsy, cultured skin fibroblasts). Complex I is encoded by both the mtDNA and nuclear DNA and pathogenic mutations have been identified in the majority of the 44 genes encoding the structural subunits of complex I. In recent years, the increasing possibilities for diagnostic molecular genetic tests of large gene panels, exomes, and even entire genomes has led to the identification of many novel genetic defects causing complex I deficiency. Complex I mutations not only result in a reduced enzyme activity but also induce secondary effects at the cellular level, such as elevated reactive oxygen species production, altered membrane potential and mitochondrial morphology. At this moment there is no cure for complex I deficiency and the treatment options for complex I patients are restricted to symptomatic treatment. Recent developments, amongst others based on the treatment of the secondary effects of complex I deficiency, have shown to be promising as new therapeutic strategies in vitro and have entered clinical trials. This article is part of a Special Issue entitled Respiratory complex I, edited by Volker Zickermann and Ulrich Brandt.
Topics: Biomarkers; Cataract; Developmental Disabilities; Electron Transport Complex I; Enzyme Activation; Genetic Predisposition to Disease; Hearing Loss; Humans; Mitochondria; Mitochondrial Myopathies; Models, Chemical; Molecular Dynamics Simulation; Mutation; Protein Conformation
PubMed: 26906428
DOI: 10.1016/j.bbabio.2016.02.012 -
Cell Metabolism Nov 2018Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O. They have therefore been proposed as a...
Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O. They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout (KO) mouse with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared with KO alone. Decreased ROS production in KO-AOX versus KO mice led to impaired AMPK/PGC-1α signaling and PAX7/MYOD-dependent muscle regeneration, blunting compensatory responses. Importantly, the antioxidant N-acetylcysteine had a similar effect, decreasing the lifespan of KO mice. Our findings have major implications for understanding pathogenic mechanisms in mitochondrial diseases and for the design of therapies, highlighting the benefits of ROS signaling and the potential hazards of antioxidant treatment.
Topics: Animals; Autophagy; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Myopathies; Mitochondrial Proteins; Muscle, Skeletal; Organelle Biogenesis; Oxidation-Reduction; Oxidoreductases; Plant Proteins; Reactive Oxygen Species; Signal Transduction
PubMed: 30122554
DOI: 10.1016/j.cmet.2018.07.012 -
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 -
Acta Myologica : Myopathies and... Dec 2019Muscle and lower motor neuron diseases share a common denominator of perturbed muscle function, most often related to wasting and weakness of muscles. This leads to a... (Review)
Review
Muscle and lower motor neuron diseases share a common denominator of perturbed muscle function, most often related to wasting and weakness of muscles. This leads to a number of challenges, such as restricted mobility and respiratory difficulties. Currently there is no cure for these diseases. The purpose of this review is to present research that examines the effects of exercise in muscle and lower motor neuron diseases. Evidence indicates that moderate intensity aerobic- and strength exercise is advantageous for patients with muscle diseases, without causing harmful exercise-induced muscle damage. On the contrary, motor neuron diseases show a rather blunted response from exercise training. High-intensity training is a modality that seems safe and a promising exercise method, which may circumvent neural fatigue and provide effect to patients with motor neuron disease. Although we have come far in changing the view on exercise therapy in neuromuscular diseases to a positive one, much knowledge is still needed on what dose of time, intensity and duration should be implemented for different disease and how we should provide exercise therapy to very weak, non-ambulatory and wheelchair bound patients.
Topics: Electric Stimulation Therapy; Exercise; Exercise Therapy; Glycogen Storage Disease Type II; Glycogen Storage Disease Type V; Humans; Mitochondrial Myopathies; Motor Neuron Disease; Muscular Diseases; Muscular Dystrophies; Resistance Training
PubMed: 31970320
DOI: No ID Found -
International Journal of Molecular... Mar 2024MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with... (Review)
Review
MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.
Topics: Humans; MELAS Syndrome; Acidosis, Lactic; Arginine; Stroke; Dietary Supplements
PubMed: 38612442
DOI: 10.3390/ijms25073629 -
Brain : a Journal of Neurology Jun 2021Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases....
Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.
Topics: Animals; DNA Ligase ATP; Female; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Male; Mitochondrial Encephalomyopathies; Mutation; Pedigree; Poly-ADP-Ribose Binding Proteins; Zebrafish
PubMed: 33855352
DOI: 10.1093/brain/awab056 -
Nature Metabolism Dec 2023Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate...
Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate the cell and shift mtDNA heteroplasmy. Various technologies are available, but many suffer from limitations based on size and/or specificity. The use of ARCUS nucleases, derived from naturally occurring I-CreI, avoids these pitfalls due to their small size, single-component protein structure and high specificity resulting from a robust protein-engineering process. Here we describe the development of a mitochondrial-targeted ARCUS (mitoARCUS) nuclease designed to target one of the most common pathogenic mtDNA mutations, m.3243A>G. mitoARCUS robustly eliminated mutant mtDNA without cutting wild-type mtDNA, allowing for shifts in heteroplasmy and concomitant improvements in mitochondrial protein steady-state levels and respiration. In vivo efficacy was demonstrated using a m.3243A>G xenograft mouse model with mitoARCUS delivered systemically by adeno-associated virus. Together, these data support the development of mitoARCUS as an in vivo gene-editing therapeutic for m.3243A>G-associated diseases.
Topics: Humans; Animals; Mice; DNA, Mitochondrial; MELAS Syndrome; Mitochondria; Mutation
PubMed: 38036771
DOI: 10.1038/s42255-023-00932-6 -
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