Phenotypes of single mtDNA deletions may unequivocally suggest mitochondrial disease

2019 ◽  
Author(s):  
Josef Finsterer
Keyword(s):  
Mitochondrial Disease ◽  
Mtdna Deletions

scholarly journals Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice

2005 ◽  
Vol 102 (49) ◽  
pp. 17687-17692 ◽  
Author(s):  
H. Tyynismaa ◽  
K. P. Mjosund ◽  
S. Wanrooij ◽  
I. Lappalainen ◽  
E. Ylikallio ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Late Onset ◽  
Mtdna Deletions

scholarly journals Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease

2017 ◽  
Vol 3 (3) ◽  
pp. e149 ◽  
Author(s):  
Enrico Bugiardini ◽  
Olivia V. Poole ◽  
Andreea Manole ◽  
Alan M. Pittman ◽  
Alejandro Horga ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Mitochondrial Disease ◽  
Haplotype Analysis ◽  
Progressive External Ophthalmoplegia ◽  
Mtdna Deletions ◽  
Clinical Presentations ◽  
Human Rnase ◽  
Disease Haplotype ◽  
Founder Event ◽  
Pathophysiologic Mechanisms

Objective:Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations.Methods:RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring RNASEH1 mutations was subsequently undertaken.Results:Pathogenic c.424G>A p.Val142Ile RNASEH1 mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, RNASEH1 genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further RNASEH1 mutations were confirmed. RNASEH1-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported RNASEH1-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families.Conclusions:In our cohort, RNASEH1 mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in POLG, RRM2B, and TWNK. RNASEH1 genetic analysis should also be considered in all patients with POLG-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.

scholarly journals Hybrid gel electrophoresis using skin fibroblasts to aid in diagnosing mitochondrial disease

2019 ◽  
Vol 5 (3) ◽  
pp. e336 ◽  
Author(s):  
Christopher Newell ◽  
Aneal Khan ◽  
David Sinasac ◽  
John Shoffner ◽  
Marisa W. Friederich ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Biopsy ◽  
Mitochondrial Disease ◽  
Gel Electrophoresis ◽  
Polyacrylamide Gel Electrophoresis ◽  
Skin Fibroblasts ◽  
Mtdna Deletions ◽  
Transport Chain ◽  
Long Range Pcr ◽  
Blue Native

ObjectiveWe developed a novel, hybrid method combining both blue-native (BN-PAGE) and clear-native (CN-PAGE) polyacrylamide gel electrophoresis, termed BCN-PAGE, to perform in-gel activity stains on the mitochondrial electron transport chain (ETC) complexes in skin fibroblasts.MethodsFour patients aged 46–65 years were seen in the Metabolic Clinic at Alberta Children's Hospital and investigated for mitochondrial disease and had BN-PAGE or CN-PAGE on skeletal muscle that showed incomplete assembly of complex V (CV) in each patient. Long-range PCR performed on muscle-extracted DNA identified 4 unique mitochondrial DNA (mtDNA) deletions spanning the ATP6 gene of CV. We developed a BCN-PAGE method in skin fibroblasts taken from the patients at the same time and compared the findings with those in skeletal muscle.ResultsIn all 4 cases, BCN-PAGE in skin fibroblasts confirmed the abnormal CV activity found from muscle biopsy, suggesting that the mtDNA deletions involving ATP6 were most likely germline mutations that are associated with a clinical phenotype of mitochondrial disease.ConclusionsThe BCN-PAGE method in skin fibroblasts has a potential to be a less-invasive tool compared with muscle biopsy to screen patients for abnormalities in CV and other mitochondrial ETC complexes.

scholarly journals Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0214250 ◽  
Author(s):  
Amanda H. Kahn-Kirby ◽  
Akiko Amagata ◽  
Celine I. Maeder ◽  
Janet J. Mei ◽  
Steve Sideris ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Therapeutic Strategy ◽  
Novel Therapeutic

scholarly journals General anesthesia with remimazolam in a patient with mitochondrial encephalomyopathy: a case report

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuji Suzuki ◽  
Matsuyuki Doi ◽  
Yoshiki Nakajima
Keyword(s):  
Lactic Acidosis ◽  
General Anesthesia ◽  
Mitochondrial Disease ◽  
Muscle Relaxation ◽  
Anesthetic Management ◽  
Perioperative Period ◽  
Mitochondrial Encephalomyopathy ◽  
Anesthesia Induction ◽  
General Anesthetic ◽  
Anesthetic Agents

Abstract Background Systemic anesthetic management of patients with mitochondrial disease requires careful preoperative preparation to administer adequate anesthesia and address potential disease-related complications. The appropriate general anesthetic agents to use in these patients remain controversial. Case presentation A 54-year-old woman (height, 145 cm; weight, 43 kg) diagnosed with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes underwent elective cochlear implantation. Infusions of intravenous remimazolam and remifentanil guided by patient state index monitoring were used for anesthesia induction and maintenance. Neither lactic acidosis nor prolonged muscle relaxation occurred in the perioperative period. At the end of surgery, flumazenil was administered to antagonize sedation, which rapidly resulted in consciousness. Conclusions Remimazolam administration and reversal with flumazenil were successfully used for general anesthesia in a patient with mitochondrial disease.

scholarly journals Risk of cardiac manifestations in adult mitochondrial disease caused by nuclear genetic defects

Open Heart ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. e001510
Author(s):  
Albert Zishen Lim ◽  
Daniel M Jones ◽  
Matthew G D Bates ◽  
Andrew M Schaefer ◽  
John O'Sullivan ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Nuclear Dna ◽  
Laboratory Data ◽  
Nuclear Genome ◽  
Nuclear Gene ◽  
Left Ventricular ◽  
Adult Patients ◽  
Limited Information ◽  
Cardiac Abnormalities ◽  
Cardiac Manifestations

ObjectiveRegular cardiac surveillance is advocated for patients with primary mitochondrial DNA disease. However, there is limited information to guide clinical practice in mitochondrial conditions caused by nuclear DNA defects. We sought to determine the frequency and spectrum of cardiac abnormalities identified in adult mitochondrial disease originated from the nuclear genome.MethodsAdult patients with a genetically confirmed mitochondrial disease were identified and followed up at the national clinical service for mitochondrial disease in Newcastle upon Tyne, UK (January 2009 to December 2018). Case notes, molecular genetics reports, laboratory data and cardiac investigations, including serial electrocardiograms and echocardiograms, were reviewed.ResultsIn this cohort-based observational study, we included 146 adult patients (92 women) (mean age 53.6±18.7 years, 95% CI 50.6 to 56.7) with a mean follow-up duration of 7.9±5.1 years (95% CI 7.0 to 8.8). Eleven different nuclear genotypes were identified: TWNK, POLG, RRM2B, OPA1, GFER, YARS2, TYMP, ETFDH, SDHA, TRIT1 and AGK. Cardiac abnormalities were detected in 14 patients (9.6%). Seven of these patients (4.8%) had early-onset cardiac manifestations: hypertrophic cardiomyopathy required cardiac transplantation (AGK; n=2/2), left ventricular (LV) hypertrophy and bifascicular heart block (GFER; n=2/3) and mild LV dysfunction (GFER; n=1/3, YARS2; n=1/2, TWNK; n=1/41). The remaining seven patients had acquired heart disease most likely related to conventional cardiovascular risk factors and presented later in life (14.6±12.8 vs 55.1±8.9 years, p<0.0001).ConclusionsOur findings demonstrate that the risk of cardiac involvement is genotype specific, suggesting that routine cardiac screening is not indicated for most adult patients with nuclear gene-related mitochondrial disease.

scholarly journals Imaging mass cytometry reveals generalised deficiency in OXPHOS complexes in Parkinson’s disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Chun Chen ◽  
David McDonald ◽  
Alasdair Blain ◽  
Ashwin Sachdeva ◽  
Laura Bone ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Dopaminergic Neurons ◽  
Neuronal Response ◽  
Proteomic Profiling ◽  
Mass Cytometry ◽  
And Control

AbstractHere we report the application of a mass spectrometry-based technology, imaging mass cytometry, to perform in-depth proteomic profiling of mitochondrial complexes in single neurons, using metal-conjugated antibodies to label post-mortem human midbrain sections. Mitochondrial dysfunction, particularly deficiency in complex I has previously been associated with the degeneration of dopaminergic neurons in Parkinson’s disease. To further our understanding of the nature of this dysfunction, and to identify Parkinson’s disease specific changes, we validated a panel of antibodies targeting subunits of all five mitochondrial oxidative phosphorylation complexes in dopaminergic neurons from Parkinson’s disease, mitochondrial disease, and control cases. Detailed analysis of the expression profile of these proteins, highlighted heterogeneity between individuals. There is a widespread decrease in expression of all complexes in Parkinson’s neurons, although more severe in mitochondrial disease neurons, however, the combination of affected complexes varies between the two groups. We also provide evidence of a potential neuronal response to mitochondrial dysfunction through a compensatory increase in mitochondrial mass. This study highlights the use of imaging mass cytometry in the assessment and analysis of expression of oxidative phosphorylation proteins, revealing the complexity of deficiencies of these proteins within individual neurons which may contribute to and drive neurodegeneration in Parkinson’s disease.

Sign in / Sign up

Export Citation Format

Share Document