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Journal of Clinical Medicine Mar 2021In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to... (Review)
Review
In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype-phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.
PubMed: 33802970
DOI: 10.3390/jcm10061249 -
Nutrients Dec 2021The clinical consequences of obesity on the kidneys, with or without metabolic abnormalities, involve both renal function and structures. The mechanisms linking obesity... (Review)
Review
The clinical consequences of obesity on the kidneys, with or without metabolic abnormalities, involve both renal function and structures. The mechanisms linking obesity and renal damage are well understood, including several effector mechanisms with interconnected pathways. Higher prevalence of urinary albumin excretion, sub-nephrotic syndrome, nephrolithiasis, increased risk of developing CKD, and progression to ESKD have been identified as being associated with obesity and having a relevant clinical impact. Moreover, renal replacement therapy and kidney transplantation are also influenced by obesity. Losing weight is key in limiting the impact that obesity produces on the kidneys by reducing albuminuria/proteinuria, declining rate of eGFR deterioration, delaying the development of CKD and ESKD, and improving the outcome of a renal transplant. Weight reduction may also contribute to appropriate control of cardiometabolic risk factors such as hypertension, metabolic syndrome, diabetes, and dyslipidemia which may be protective not only in renal damage but also cardiovascular disease. Lifestyle changes, some drugs, and bariatric surgery have demonstrated the benefits.
Topics: Dialysis; Humans; Kidney Diseases; Kidney Transplantation; Obesity; Risk Factors
PubMed: 34960033
DOI: 10.3390/nu13124482 -
Journal of Internal Medicine Jun 2020Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent... (Review)
Review
Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype-phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy-dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.
Topics: Adult; DNA Repair; DNA, Mitochondrial; Genome, Mitochondrial; Humans; MELAS Syndrome; Mitochondria; Mitochondrial Diseases; Mutation
PubMed: 32463135
DOI: 10.1111/joim.13064 -
Cureus Dec 2021Charles Darwin, the famous naturalist, suffered relapsing, debilitating illness for most of his adult life with a plethora of symptoms. The diagnosis favoured here for... (Review)
Review
Charles Darwin, the famous naturalist, suffered relapsing, debilitating illness for most of his adult life with a plethora of symptoms. The diagnosis favoured here for this illness is that of an adult-onset mitochondrial disorder due to a maternally inherited, pathological mitochondrial DNA mutation clinically manifesting as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome. This diagnosis accounts for Darwin's primary symptoms; in addition, it accounts for the various unusual illnesses that afflicted his siblings and maternal (Wedgwood) ancestors. Symptoms of Darwin's illness may be related to dysfunction of cells with high energy requirements; this includes cells constituting the cardiac conduction system, cerebral endothelial cells, neurons, neuroepithelial cells of the vestibular apparatus, and, as proposed here, central and peripheral neuroendocrine cells. Although Darwin's episodes of sudden facial flushing, his nocturnal panic attacks, and his severe gastrointestinal symptoms are not readily explained, these symptoms may relate to neuroendocrine dysfunction, either an uncontrolled release of stimulatory hormone or impaired inhibitory control. It is also conceivable that the autonomic system had been involved. A study of Darwin's illness may benefit those who suffer from similar symptoms today.
PubMed: 34966625
DOI: 10.7759/cureus.20689 -
Medicina (Kaunas, Lithuania) May 2022a stroke-like lesion, the morphological equivalent of a stroke-like episode and the hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes...
OBJECTIVES
a stroke-like lesion, the morphological equivalent of a stroke-like episode and the hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, have not been reported as manifestations of thiamine deficiency.
CASE REPORT
a 62-year-old man with a history of chronic alcoholism was admitted after a series of epileptic seizures. Upon waking up from the coma, he presented with disorientation, confusion, confabulation, psychomotor agitation, aggressiveness, right hemianopsia, aphasia, and right hemineglect over weeks. Electroencephalography showed a questionable focal status epilepticus over the left hemisphere, responsive to lorazepam and oxcarbazepine. Follow-up electroencephalographies no longer recorded epileptiform discharges. Cerebral magnetic resonance imaging (MRI) revealed T2-/diffusion weighted imaging (DWI) hyperintensity in the left occipito-temporal region that was not congruent to a vascular territory which persisted for at least nine weeks. Since a lactate-peak could be seen in this lesion by magnetic resonance-spectroscopy, this was interpreted as a stroke-like lesion. Since thiamine was reduced, the stroke-like lesion was attributed to thiamine deficiency after the exclusion of differential diseases, including MELAS and status epilepticus. The patient's behavioural and cognitive dysfunctions largely resolved upon vitamin-B1 substitution.
CONCLUSIONS
the case suggests that thiamine deficiency presumably causes mitochondrial dysfunction with cerebrospinal fluid lactic acidosis and a stroke-like lesion mimicking MELAS syndrome. It should be further studied whether nutritional deficits, such as thiamine deficiency, could give rise to secondary stroke-like lesions.
Topics: Acidosis, Lactic; Humans; MELAS Syndrome; Male; Middle Aged; Mitochondrial Encephalomyopathies; Status Epilepticus; Stroke; Thiamine Deficiency; Wernicke Encephalopathy
PubMed: 35630076
DOI: 10.3390/medicina58050660 -
Molecular and Cellular Neurosciences Sep 2023Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways... (Review)
Review
Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.
Topics: Animals; Glutamine; MELAS Syndrome; Mitochondria; Neurodegenerative Diseases; Mitochondrial Diseases
PubMed: 37586651
DOI: 10.1016/j.mcn.2023.103887 -
Metabolites Sep 2022Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in... (Review)
Review
Stroke-like episodes (SLEs) are significant clinical manifestations of metabolic disorders affecting the central nervous system. Morphological equivalents presented in neuroimaging procedures are described as stroke-like lesions (SLLs). It is crucial to distinguish SLEs from cerebral infarction or intracerebral hemorrhage, mainly due to the variety in management. Another significant issue to underline is the meaning of the main pathogenetic hypotheses in the development of SLEs. The diagnostic process is based on the patient's medical history, physical and neurological examination, neuroimaging techniques and laboratory and genetic testing. Implementation of treatment is generally symptomatic and includes L-arginine supplementation and adequate antiepileptic management. The main aim of the current review was to summarize the basic and actual knowledge about the occurrence of SLEs in various inherited neurometabolic disorders, discuss the possible pathomechanism of their development, underline the role of neuroimaging in the detection of SLLs and identification of the electroencephalographic patterns as well as histological abnormalities in inherited disorders of metabolism.
PubMed: 36295831
DOI: 10.3390/metabo12100929 -
Current Neurology and Neuroscience... Jun 2023Uncommon causes of stroke merit specific attention; when clinicians have less common etiologies of stoke in mind, the diagnosis may come more easily. This is key, as... (Review)
Review
PURPOSE OF REVIEW
Uncommon causes of stroke merit specific attention; when clinicians have less common etiologies of stoke in mind, the diagnosis may come more easily. This is key, as optimal management will in many cases differs significantly from "standard" care.
RECENT FINDINGS
Randomized controlled trials (RCT) on the best medical therapy in the treatment of cervical artery dissection (CeAD) have demonstrated low rates of ischemia with both antiplatelet and vitamin K antagonism. RCT evidence supports the use of anticoagulation with vitamin K antagonism in "high-risk" patients with antiphospholipid antibody syndrome (APLAS), and there is new evidence supporting the utilization of direct oral anticoagulation in malignancy-associated thrombosis. Migraine with aura has been more conclusively linked not only with increased risk of ischemic and hemorrhagic stroke, but also with cardiovascular mortality. Recent literature has surprisingly not provided support the utilization of L-arginine in the treatment of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); however, there is evidence at this time that support use of enzyme replacement in patients with Fabry disease. Additional triggers for reversible cerebral vasoconstriction syndrome (RCVS) have been identified, such as capsaicin. Imaging of cerebral blood vessel walls utilizing contrast-enhanced MRA is an emerging modality that may ultimately prove to be very useful in the evaluation of patients with uncommon causes of stroke. A plethora of associations between cerebrovascular disease and COVID-19 have been described. Where pertinent, authors provide additional tips and guidance. Less commonly encountered conditions with updates in diagnosis, and management along with clinical tips are reviewed.
Topics: Humans; COVID-19; Stroke; Migraine Disorders; Anticoagulants; Fibrinolytic Agents; Vitamin K
PubMed: 37247169
DOI: 10.1007/s11910-023-01269-z -
Ideggyogyaszati Szemle Jan 2023
Objective – Stroke-like lesions (SLLs) are pathognomonic for mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes... (Review)
Review
Objective – Stroke-like lesions (SLLs) are pathognomonic for mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome but occur in other mitochondrial and non-mitochondrial disorders as well. This mini-review aims at summarising and discussing recent findings to open up future perspectives how to manage this fleeting phenomenon.
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Results – Typically, SLLs are dynamic lesions, which increase in size and intensity to regress after a nadir. SLLs are incongruent with a vascular territory, originate frequently from the cortex to spread subcortically, can be monofocal or multifocal, run through an acute (attack) and chronic (remission) stage, and may either completely disappear or end up as laminar cortical necrosis, white matter lesion, subcortical atrophy, cyst, or the toenail sign. On cerebral CT, SLLs are hypodense. SLLs can be best visualized on multimodal MRI showing up as hyperintensity on T2, FLAIR, DWI, and PWI, and as hypointensity on OEF-MRI. On MR-spectroscopy, SLLs typically present with a decreased N-acetyl-aspartate peak and an increased lactate peak. DTI in acute SLLs reveals reduced connectivity, increased global efficiency, and reduced focal efficiency. Tc-HMPAO SPECT of SLLs indicates hyperperfusion and L-iomazenil SPECT reduced tracer uptake. FDG-PET typically shows hypometabolism within a SLL.
Conclusion – SLLs present with typical findings on various imaging modalities but the combination of cerebral CT, multimodal MRI, MRS, and PET clearly delineate a SLL from other acute or chronic cerebral lesions.Topics: Humans; Stroke; MELAS Syndrome; Magnetic Resonance Imaging; Tomography, Emission-Computed, Single-Photon; Positron-Emission Tomography; Brain
PubMed: 36892301
DOI: 10.18071/isz.76.0005 -
Iranian Journal of Child Neurology 2020Autism spectrum disorder (ASD) is a category of neurodevelopmental disorders characterized by social and communication impairment and restricted or repetitive behaviors.... (Review)
Review
Autism spectrum disorder (ASD) is a category of neurodevelopmental disorders characterized by social and communication impairment and restricted or repetitive behaviors. The pathogenesis of ASD is not well understood and it's proved that genetic is strongly associated with ASD in 5 to 25% of cases. Inborn errors of metabolism(IEMs), defined by a vast array of disorders that are caused by specific enzyme deficiencies or transport protein defects, is as frequent as in 1 in 800 births. IEMs can manifest several psychiatric or behavioral manifestations such as self-injuriesincreased activity and aggression, personality changes, paranoia, depression, catatonia, and psychosis. IEMs underlie autistic symptoms in less than 5% of cases. The literature on the association between ASD and respiratory chain abnormalities is growing, including complex III/IV deficiency and MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome, as well as glucose-6-phosphate dehydrogenase deficiency. Google Scholar, Pubmed, and SCOPUS databases were searched using a combination of the following keywords: "autism spectrum disorder", "autism spectrum", "autistic feature" and "inborn error of metabolism", " IEM", "congenital error of metabolism". Initially, 655 articles were found and our expert and methodologist altogether selected 187 articles based on the titles, relevance, and text language. After reading full texts, 37 studies were selected for review. We think it's best to consider IEMs in children with syndromic ASD and/or if there is a strong familial history of autism or parental consanguineous marriage.
PubMed: 33193781
DOI: No ID Found