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Molecular Genetics and Metabolism Jul 2023Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the... (Review)
Review
Sengers syndrome (OMIM# 212350) is a rare autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the AGK gene, which encodes the acylglycerol kinase enzyme. The syndrome was originally defined as a "triad" of hypertrophic cardiomyopathy, cataracts, and lactic acidosis, with or without skeletal myopathy. The clinical manifestation of Sengers Syndrome exhibits substantial heterogeneity, with mild and severe/infantile forms reported. Further, biallelic AGK pathogenic variants have also been identified in a familial case of non-syndromic isolated cataract (OMIM# 614691), expanding our understanding of the gene's influence beyond the originally defined syndrome. In this study, we provide a systematic review of molecularly confirmed cases with biallelic AGK pathogenic variants (Supplementary Table 1). Our analysis demonstrates the variable expressivity and penetrance of the central features of Sengers syndrome, as follows: cataracts (98%), cardiomyopathy (88%), lactic acidosis (adjusted 88%), and skeletal myopathy (adjusted 74%) (Table 1). Furthermore, we investigate the associations between genotype, biochemical profiles, and clinical outcomes, with a particular focus on infantile mortality. Our findings reveal that patients carrying homozygous nonsense variants have a higher incidence of infant mortality and a lower median age of death (p = 0.005 and p = 0.02, Table 2a). However, the location of pathogenic variants within the AGK domains was not significantly associated with infantile death (p = 0.62, Table 2b). Additionally, we observe a borderline association between the absence of lactic acidosis and longer survival (p = 0.053, Table 2c). Overall, our systematic review sheds light on the diverse clinical manifestations of AGK-related disorders and highlights potential factors that influence its prognosis. These provide important implications for the diagnosis, treatment, and counseling of affected individuals and families.
Topics: Infant; Humans; Acidosis, Lactic; Cardiomyopathies; Cataract; Muscular Diseases; Biological Variation, Population; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 37354892
DOI: 10.1016/j.ymgme.2023.107626 -
Journal of Clinical Neuromuscular... Dec 2019Whether asymptomatic hyper-CKemia (AHCE) should prompt a thorough work-up for muscle disease or not is controversially discussed. This review aims at summarizing and...
OBJECTIVES
Whether asymptomatic hyper-CKemia (AHCE) should prompt a thorough work-up for muscle disease or not is controversially discussed. This review aims at summarizing and discussing recent findings concerning the cause, frequency, evolution, and work-up of conditions manifesting as AHCE and normal or abnormal electromyography (EMG) respectively muscle biopsy.
METHODS
Systematic PubMed search.
RESULTS
There are numerous primary (hereditary) and acquired myopathies that manifest with permanent, recurrent, or temporary AHCE with/without myopathic EMG or muscle biopsy. AHCE particularly occurs at onset of these conditions, which include dystrophinopathies, myotilinopathies, calpainopathy, caveolinopathy, dysferlinopathy, central core disease, multicore disease, desminopathy, MD1, MD2, hypoPP, malignant hyperthermia susceptibility, Pompe disease, McArdle disease, myoadenylate deaminase-deficiency, CPT2-deficiency, mitochondrial disorders, or myopathy with tubular aggregates. Most likely, other primary myopathies manifest with AHCE as well, without having been reported. Patients with AHCE should be taken seriously and repeated CK determination must be conducted. If hyper-CKemia is persisting or recurrent, these patients should undergo an EMG and eventually muscle biopsy. If noninformative, genetic work-up by a panel or whole exome sequencing should be initiated, irrespective of the family history. Patients with AHCE should avoid excessive exercise, require sufficient hydration, require counseling with regard to the risk of malignant hyperthermia, and should inform anesthesiologists and surgeons about their condition before elective surgery.
CONCLUSIONS
Recurrent AHCE should be taken seriously and managed with conventional work-up. If noninformative, genetic work-up should follow irrespective of the family history.
Topics: Creatine Kinase; Humans; Mass Screening; Mitochondrial Diseases; Muscular Diseases
PubMed: 31743252
DOI: 10.1097/CND.0000000000000269 -
Journal of the Neurological Sciences May 2020One of the most frequent cerebral lesions in mitochondrial disorders(MIDs) on imaging is the stroke-like lesion(SLL) clinically manifesting as stroke-like episode (SLE,... (Review)
Review
OBJECTIVES
One of the most frequent cerebral lesions in mitochondrial disorders(MIDs) on imaging is the stroke-like lesion(SLL) clinically manifesting as stroke-like episode (SLE, metabolic stroke). This review aims at discussing recent advances concerning the presentation, diagnosis, and treatment of SLLs.
METHODS
Systematic literature review using appropriate search terms.
RESULTS
SLLs are the hallmark of MELAS but occasionally occur in other MIDs. SLLs are best identified on multimodal, cerebral MRI. SLLs may present as uni-/multilocular, symmetric/asymmetric, cortical/subcortical, supra-/infratentorial condition, initially resembling a cytotoxic edema and later a vasogenic edema, or a variable mix between them. SLLs run through an acute and a chronic stage. The acute stage is characterised by a progressively expanding lesion over days, weeks, or months, showing up as increasing hyperintensity on T2/FLAIR, DWI, and PWI and by hyperperfusion, that does not conform to a vascular territory. ADC maps are initially hypointens to become hyperintens during the course. More rarely, a variable mixture of hyper- and hypointensities may be found. The chronic stage is characterised by hypoperfusion, gadolinium enhancement, and regression of hyperintensities to various endpoints. SLLs originate from an initial cortical lesion due to focal metabolic breakdown, which either remains stable or expands within the cortex or to subcortical areas. Some SLLs show spontaneous reversibility (fleeing cortical lesions) suggesting that neuronal/glial damage does not reach the threshold of irreversible cell death.
CONCLUSIONS
SLLs are a unique feature of various MIDs in particular MELAS. SLLs are dynamic and change their appearance over time. SLLs are accessible to treatment.
Topics: Contrast Media; Gadolinium; Humans; MELAS Syndrome; Magnetic Resonance Imaging; Stroke
PubMed: 32088469
DOI: 10.1016/j.jns.2020.116726 -
Journal of Inherited Metabolic Disease Nov 2014Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a... (Meta-Analysis)
Meta-Analysis Review
Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases.
Topics: 3-Hydroxyacyl CoA Dehydrogenases; Amino Acid Metabolism, Inborn Errors; Brain Diseases, Metabolic; Cardiomyopathies; England; Glutaryl-CoA Dehydrogenase; Homocystinuria; Humans; Infant, Newborn; Isovaleryl-CoA Dehydrogenase; Lipid Metabolism, Inborn Errors; Maple Syrup Urine Disease; Mitochondrial Myopathies; Mitochondrial Trifunctional Protein; Neonatal Screening; Nervous System Diseases; Rhabdomyolysis; Tandem Mass Spectrometry
PubMed: 25022222
DOI: 10.1007/s10545-014-9729-0 -
Molecular Biology Reports Dec 2020The mitochondrial encephalomyopathies represent a clinically heterogeneous group of neurodegenerative disorders. The clinical phenotype of patients could be explained by... (Review)
Review
The mitochondrial encephalomyopathies represent a clinically heterogeneous group of neurodegenerative disorders. The clinical phenotype of patients could be explained by mutations of mitochondria-related genes, notably SUCLG1 and SUCLA2. Here, we presented a 5-year-old boy with clinical features of mitochondrial encephalomyopathy from Iran. Also, a systematic review was performed to explore the involvement of SUCLG1 mutations in published mitochondrial encephalomyopathies cases. Genotyping was performed by implementing whole-exome sequencing. Moreover, quantification of the mtDNA content was performed by real-time qPCR. We identified a novel, homozygote missense variant chr2: 84676796 A > T (hg19) in the SUCLG1 gene. This mutation substitutes Cys with Ser at the 60-position of the SUCLG1 protein. Furthermore, the in-silico analysis revealed that the mutated position in the genome is well conserved in mammalians, that implies mutation in this residue would possibly result in phenotypic consequences. Here, we identified a novel, homozygote missense variant chr2: 84676796 A > T in the SUCLG1 gene. Using a range of experimental and in silico analysis, we found that the mutation might explain the observed phenotype in the family.
Topics: Child, Preschool; DNA, Mitochondrial; Homozygote; Humans; Iran; Male; Mitochondria; Mitochondrial Encephalomyopathies; Mutation, Missense; Succinate-CoA Ligases
PubMed: 33230783
DOI: 10.1007/s11033-020-05999-y -
American Journal of Medical Genetics.... Jan 2023Biallelic pathogenic variants in the TARS2 gene cause combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial...
Biallelic pathogenic variants in the TARS2 gene cause combined oxidative phosphorylation deficiency, subtype 21 (COXPD21, MIM #615918), which is a rare mitochondrial encephalomyopathy (ME) characterized by early-onset severe axial hypotonia, limb hypertonia, delayed psychomotor development, epilepsy, and brain anomalies. Currently, eight COXPD21 patients have been reported in the literature, and 11 pathogenic variants in TARS2 have been identified. Here, we report a 2-year-6-month-old Chinese female who presented with severe dystonia, developmental regression, absent speech, and intractable epilepsy. Laboratory examination showed persistently increased serum lactate. Brain MRI showed that the head of the caudate and partial lenticular nucleus were bilateral symmetrical T2-weighted imaging (T2WI) hyperintense and the corpus callosum was very thin. The clinical characteristics pointed to a ME. Trio-based whole-exome sequencing (WES) was employed to detect the causative variants. WES revealed novel compound heterozygous variants, c.470G>C (p.Thr157Arg) and c.2051C>T (p.Arg684Gln), in TARS2 in our patient that were inherited from the mother and father, respectively. Next, we systematically reviewed the available clinical features of COXPD21 patients and noticed that the reduced fetal movement observed in our patient may be a novel phenotype of COXPD21. These findings expand the mutation spectrum of TARS2 and provide insights into the genotype-phenotype relationship in COXPD21 as well as a foundation for its genetic counseling, diagnosis and treatment.
Topics: Humans; Female; Mitochondrial Encephalomyopathies; East Asian People; Exome Sequencing; Phenotype; Mutation
PubMed: 36218002
DOI: 10.1002/ajmg.a.62988 -
Zeitschrift Fur Rheumatologie Feb 2024The objectives of this study are to analyze the association between anti-mitochondrial antibody (AMA) and cardiac involvement in idiopathic inflammatory myopathy (IIM)... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The objectives of this study are to analyze the association between anti-mitochondrial antibody (AMA) and cardiac involvement in idiopathic inflammatory myopathy (IIM) and to evaluate the diagnostic value of AMA for cardiac involvement in IIM patients.
METHODS
We conducted a comprehensive search in PubMed, Web of Science, EMBASE, and the Cochrane Library to identify English-language studies published before November 19, 2021. Stata 12.0 software (Stata Corp., College Station, TX, USA) was used for the statistical analyses. We used the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and summary receiver operating characteristic (SROC) curve to evaluate the diagnostic value of AMA for cardiac involvement in IIM patients. Statistical heterogeneity of studies was assessed using the I statistic with 95% confidence intervals (95% CIs).
RESULTS
Seven studies were included in the final analyses, with a total of 2308 IIM patients (including 171 AMA-positive and 2137 AMA-negative patients). The pooled sensitivity of AMA for cardiac involvement in IIM patients was 0.29 (95% CI: 0.19-0.43) and specificity was 0.92 (95% CI: 0.88-0.96). The pooled PLR was 3.9 (95% CI: 2.82-5.38), NLR was 0.76 (95% CI: 0.66-0.88), and the diagnostic odds ratio (DOR) was 5 (95% CI: 3-7). The area under the SROC curve was 0.76 (95% CI: 0.72-0.79).
CONCLUSION
The overall diagnostic value of AMA may not be very high for cardiac involvement in IIM patients.
Topics: Humans; ROC Curve; Myositis; Sensitivity and Specificity
PubMed: 35575829
DOI: 10.1007/s00393-022-01216-2 -
Journal of Neuroradiology = Journal de... Sep 2021Major cerebral vessels have been proposed as a target of defective mitochondrial metabolism in patients with mitochondrial encephalopathy, lactic acidosis, and... (Review)
Review
Major cerebral vessels have been proposed as a target of defective mitochondrial metabolism in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS). Cerebral angiographic techniques are not routinely performed in MELAS patients. A systematic literature review was performed to identify studies describing major vessel caliber alterations in MELAS. Twenty-three studies reporting on 46 MELAS patients were included. Alterations in major caliber vessels were present in 59% (27/46) of patients. Dilation occurred in 37% (17/46) of patients, and in 88% (15/17) of them during a stroke-like episode (SLE). Stenosis was reported in 24% (11/46) of patients: 36% (4/11) related to an SLE and 64% (7/11) to dissections or degenerative changes. During an SLE, identification of intracranial vessels dilation or stenosis could be a selection tool for new treatment protocols. Outside SLE, identification of major cerebral vessels dissections and degenerative changes may help to prevent subsequent complications.
Topics: Cerebral Angiography; Humans; MELAS Syndrome; Radionuclide Imaging; Stroke
PubMed: 33596430
DOI: 10.1016/j.neurad.2021.02.002 -
International Journal of Cardiology Feb 2015Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterised by onset before the age of 20years, progressive external ophthalmoplegia, and pigmentary... (Review)
Review
Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterised by onset before the age of 20years, progressive external ophthalmoplegia, and pigmentary retinopathy, accompanied by either cardiac conduction defects, elevated cerebrospinal fluid protein or cerebellar ataxia. 50% of patients with KSS develop cardiac complications. The most common cardiac manifestation is conduction disease which may progress to complete atrioventricular block or bradycardia-related polymorphic ventricular tachycardia (PMVT). The management of cardiac electrical disease associated with KSS and mitochondrial cytopathy is systematically reviewed including the case of a 23year-old female patient with KSS who developed a constellation of cardiac arrhythmias including rapidly progressive conduction system disease and monomorphic ventricular tachycardia with myocardial scarring. The emerging role of cardiac magnetic resonance imaging (CMR) in detecting subclinical cardiac involvement is also highlighted. This review illustrates the need for cardiologists to be informed about this rare but emerging condition.
Topics: Electrocardiography; Female; Humans; Kearns-Sayre Syndrome; Mitochondrial Myopathies; Young Adult
PubMed: 25540845
DOI: 10.1016/j.ijcard.2014.12.038 -
Frontiers in Physiology 2022Blood flow restriction exercise (BFRE) has become a common method to increase skeletal muscle strength and hypertrophy for individuals with a variety of conditions. A...
Blood flow restriction exercise (BFRE) has become a common method to increase skeletal muscle strength and hypertrophy for individuals with a variety of conditions. A substantial literature of BFRE in older adults exists in which significant gains in strength and functional performance have been observed without report of adverse events. Research examining the effects of BFRE in heart disease (HD) and heart failure (HF) appears to be increasing for which reason the Muscle Hypothesis of Chronic Heart Failure (MHCHF) will be used to fully elucidate the effects BFRE may have in patients with HD and HF highlighted in the MHCHF. A comprehensive literature review was performed in PubMed and the Cochrane library through February 2022. Inclusion criteria were: 1) the study was original research conducted in human subjects older than 18 years of age and diagnosed with either HD or HF, 2) study participants performed BFRE, and 3) post-intervention outcome measures of cardiovascular function, physical performance, skeletal muscle function and structure, and/or systemic biomarkers were provided. Exclusion criteria included review articles and articles on viewpoints and opinions of BFRE, book chapters, theses, dissertations, and case study articles. Seven BFRE studies in HD and two BFRE studies in HF were found of which four of the HD and the two HF studies examined a variety of measures reflected within the MHCHF over a period of 8-24 weeks. No adverse events were reported in any of the studies and significant improvements in skeletal muscle strength, endurance, and work as well as cardiorespiratory performance, mitochondrial function, exercise tolerance, functional performance, immune humoral function, and possibly cardiac performance were observed in one or more of the reviewed studies. In view of the above systematic review, BFRE has been performed safely with no report of adverse event in patients with a variety of different types of HD and in patients with HF. The components of the MHCHF that can be potentially improved with BFRE include left ventricular dysfunction, inflammatory markers, inactivity, a catabolic state, skeletal and possibly respiratory muscle myopathy, dyspnea and fatigue, ANS activity, and peripheral blood flow. Furthermore, investigation of feasibility, acceptability, adherence, adverse effects, and symptoms during and after BFRE is needed since very few studies have examined these important issues comprehensively in patients with HD and HF.
PubMed: 35874535
DOI: 10.3389/fphys.2022.924557