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Ophthalmology. Retina Jan 2022To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease.
PURPOSE
To report the retinal phenotype and the associated genetic and systemic findings in patients with mitochondrial disease.
DESIGN
Retrospective case series.
PARTICIPANTS
Twenty-three patients with retinopathy and mitochondrial disease, including chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness (MIDD), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Kearns-Sayre syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and other systemic manifestations.
METHODS
Review of case notes, retinal imaging, electrophysiologic assessment, molecular genetic testing including protein modeling, and histologic analysis of muscle biopsy.
MAIN OUTCOME MEASURES
Phenotypic characteristics of mitochondrial retinopathy.
RESULTS
Genetic testing identified sporadic large-scale mitochondrial DNA deletions and variants in MT-TL1, MT-ATP6, MT-TK, MT-RNR1, or RRM2B. Based on retinal imaging, 3 phenotypes could be differentiated: type 1 with mild, focal pigmentary abnormalities; type 2 characterized by multifocal white-yellowish subretinal deposits and pigment changes limited to the posterior pole; and type 3 with widespread granular pigment alterations. Advanced type 2 and 3 retinopathy presented with chorioretinal atrophy that typically started in the peripapillary and paracentral areas with foveal sparing. Two patients exhibited a different phenotype: 1 revealed an occult retinopathy, and the patient with RRM2B-associated retinopathy showed no foveal sparing, no severe peripapillary involvement, and substantial photoreceptor atrophy before loss of the retinal pigment epithelium. Two patients with type 1 disease showed additional characteristics of mild macular telangiectasia type 2. Patients with type 1 and mild type 2 or 3 disease demonstrated good visual acuity and no symptoms associated with the retinopathy. In contrast, patients with advanced type 2 or 3 disease often reported vision problems in dim light conditions, reduced visual acuity, or both. Short-wavelength autofluorescence usually revealed a distinct pattern, and near-infrared autofluorescence may be severely reduced in type 3 disease. The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination.
CONCLUSIONS
Different types of mitochondrial retinopathy show characteristic features. Even in absence of visual symptoms, their recognition may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease.
Topics: Adolescent; Adult; Aged; Electroretinography; Female; Fluorescein Angiography; Fundus Oculi; Humans; Male; Middle Aged; Mitochondrial Diseases; Retinal Degeneration; Retinal Pigment Epithelium; Retrospective Studies; Visual Acuity; Young Adult
PubMed: 34257060
DOI: 10.1016/j.oret.2021.02.017 -
The Journal of Clinical Investigation Jan 2021Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and... (Clinical Trial)
Clinical Trial
Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.3243A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.3243A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, α-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, β-hydroxy acylcarnitines, and β-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine; Biomarkers; Child; Child, Preschool; Female; Growth Differentiation Factor 15; Humans; Hydroxybutyrates; Lactic Acid; MELAS Syndrome; Male; Middle Aged; Mutation; Severity of Illness Index
PubMed: 33463549
DOI: 10.1172/JCI136055 -
European Journal of Paediatric... Jan 2020Mitochondria are vital organelles within cells that undertake many important metabolic roles, the most significant of which is to generate energy to support organ... (Review)
Review
Mitochondria are vital organelles within cells that undertake many important metabolic roles, the most significant of which is to generate energy to support organ function. Dysfunction of the mitochondrion can lead to a wide range of clinical features, predominantly affecting organs with a high metabolic demand such as the brain. One of the main neurological manifestations of mitochondrial disease is metabolic epilepsies. These epileptic seizures are more frequently of posterior quadrant and occipital lobe onset, more likely to present with non-convulsive status epilepticus which may last months and be more resistant to treatment from the onset. The onset of can be of any age. Childhood onset epilepsy is a major phenotypic feature in mitochondrial disorders such as Alpers-Huttenlocher syndrome, pyruvate dehydrogenase complex deficiencies, and Leigh syndrome. Meanwhile, adults with classical mitochondrial disease syndrome such as MELAS, MERFF or POLG-related disorders could present with either focal or generalised seizures. There are no specific curative treatments for mitochondrial epilepsy. Generally, the epileptic seizures should be managed by specialist neurologist with appropriate use of anticonvulsants. As a general rule, especially in disorders associated with mutation in POLG, sodium valproate is best avoided because hepato-toxicity can be fulminant and fatal.
Topics: Anticonvulsants; Epilepsy; Humans; Mitochondrial Diseases
PubMed: 31973983
DOI: 10.1016/j.ejpn.2019.12.021 -
Genes Nov 2021Strokes are the main cause of death and long-term disability worldwide. A stroke is a heterogeneous multi-factorial condition, caused by a combination of environmental... (Review)
Review
Strokes are the main cause of death and long-term disability worldwide. A stroke is a heterogeneous multi-factorial condition, caused by a combination of environmental and genetic factors. Monogenic disorders account for about 1% to 5% of all stroke cases. The most common single-gene diseases connected with strokes are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Fabry disease, mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) and a lot of single-gene diseases associated particularly with cerebral small-vessel disease, such as syndrome, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). In this article the clinical phenotype for the most important single-gene disorders associated with strokes are presented. The monogenic causes of a stroke are rare, but early diagnosis is important in order to provide appropriate therapy when available.
Topics: Alopecia; CADASIL; Cerebral Infarction; Cerebral Small Vessel Diseases; Fabry Disease; Heredity; Humans; Leukoencephalopathies; Mutation; Phenotype; Spinal Diseases; Stroke
PubMed: 34946804
DOI: 10.3390/genes12121855 -
Cells Feb 2022Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling... (Review)
Review
Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA found in mitochondria themselves, and are termed mitochondrial DNA (mtDNA). Mutations striking either genome can lead to mitochondrial impairment, determining infantile, childhood or adult neurodegeneration. Mitochondrial disorders are complex neurological syndromes, and are often part of a multisystem disorder. In this paper, we divide the diseases into those caused by mtDNA defects and those that are due to mutations involving nuclear genes; from a clinical point of view, we discuss pediatric disorders in comparison to juvenile or adult-onset conditions. The complementary genetic contributions controlling organellar function and the complexity of the biochemical pathways present in the mitochondria justify the extreme genetic and phenotypic heterogeneity of this new area of inborn errors of metabolism known as 'mitochondrial medicine'.
Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Child; DNA, Mitochondrial; Humans; Mitochondria; Protons
PubMed: 35203288
DOI: 10.3390/cells11040637 -
Handbook of Clinical Neurology 2023The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative... (Review)
Review
The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative phosphorylation. Therefore, neurodegeneration is a hallmark of mitochondrial diseases. The nervous system of affected individuals typically shows selective regional vulnerability leading to distinct patterns of tissue damage. A classic example is Leigh syndrome, which causes symmetric alterations of basal ganglia and brain stem. Leigh syndrome can be caused by different genetic defects (>75 known disease genes) with variable disease onset ranging from infancy to adulthood. Other mitochondrial diseases are characterized by focal brain lesions, which is a core feature of MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Apart from gray matter, also white matter can be affected by mitochondrial dysfunction. White matter lesions vary depending on the underlying genetic defect and may progress into cystic cavities. In view of the recognizable patterns of brain damage in mitochondrial diseases, neuroimaging techniques play a key role in diagnostic work-up. In the clinical setting, magnetic resonance imaging (MRI) and MR spectroscopy (MRS) are the mainstay of diagnostic work-up. Apart from visualization of brain anatomy, MRS allows the detection of metabolites such as lactate, which is of specific interest in the context of mitochondrial dysfunction. However, it is important to note that findings like symmetric basal ganglia lesions on MRI or a lactate peak on MRS are not specific, and that there is a broad range of disorders that can mimic mitochondrial diseases on neuroimaging. In this chapter, we will review the spectrum of neuroimaging findings in mitochondrial diseases and discuss important differential diagnoses. Moreover, we will give an outlook on novel biomedical imaging tools that may provide interesting insights into mitochondrial disease pathophysiology.
Topics: Humans; Leigh Disease; Magnetic Resonance Imaging; Neuroimaging; Brain; Mitochondrial Diseases; MELAS Syndrome; Lactic Acid
PubMed: 36813312
DOI: 10.1016/B978-0-12-821751-1.00016-6 -
Herz Jun 2020Little is known about cardiac involvement in m.3243A>G variant carriers. Thus, this study aimed to assess type and frequency of cardiac disease in symptomatic and... (Review)
Review
OBJECTIVES
Little is known about cardiac involvement in m.3243A>G variant carriers. Thus, this study aimed to assess type and frequency of cardiac disease in symptomatic and asymptomatic m.3243A>G carriers.
METHODS
Systematic literature review.
RESULTS
The m.3243A>G variant may manifest phenotypically as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), myoclonic epilepsy with ragged red fiber (MERRF), Leigh syndrome, or MELAS/KSS (Kearns-Sayre syndrome) overlap. Only few systematic studies which prospectively investigated m.3243A>G carriers for cardiac involvement were found. Cardiac abnormalities reported in m.3243A>G carriers include myocardial abnormalities, arrhythmias, or conduction defects. Myocardial abnormalities include myocardial thickening, hypertrophic cardiomyopathy, dilated cardiomyopathy, noncompaction, myocardial fibrosis, systolic dysfunction, heart failure, or arterial hypertension. Arrhythmias reported in m.3243A>G carriers include paroxysmal supraventricular or ventricular arrhythmias, including sinus tachycardia, atrial fibrillation and nonsustained ventricular tachycardia, and sudden cardiac death. Conduction defects in this group of patients include Wolff-Parkinson-White syndrome and left/right bundle branch block. Asymptomatic m.3243A>G carriers usually do not develop clinical or subclinical cardiac disease.
CONCLUSIONS
Cardiac involvement in m.3243A>G carriers has been only rarely systematically studied, which is perhaps why the incidence of cardiac diseases in MELAS is lower than would be expected. Myocardial abnormalities are much more frequent than arrhythmias or conduction defects. All symptomatic and asymptomatic m.3243A>G carriers should be systematically investigated for cardiac disease.
Topics: DNA, Mitochondrial; Deafness; Diabetes Mellitus, Type 2; Heart Diseases; Humans; MELAS Syndrome; Mitochondrial Diseases; Myocardium
PubMed: 30128910
DOI: 10.1007/s00059-018-4739-6 -
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 -
Handbook of Clinical Neurology 2023Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures,... (Review)
Review
Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are prominent findings associated with stroke-like episodes, with a predilection for the posterior cerebral cortex. The most common cause of stroke-like episodes is the m.3243A>G variant in MT-TL1 gene followed by recessive POLG variants. This chapter aims to review the definition of stroke-like episode and delineate the clinical phenomenology, neuroimaging and EEG findings typically seen in patients. In addition, several lines of evidence supporting neuronal hyper-excitability as the key mechanism of stroke-like episodes are discussed. The management of stroke-like episodes should focus on aggressive seizure management and treatment for concomitant complications such as intestinal pseudo-obstruction. There is no robust evidence to prove the efficacy of l-arginine for both acute and prophylactic settings. Progressive brain atrophy and dementia are the sequalae of recurrent stroke-like episode, and the underlying genotype in part predicts prognosis.
Topics: Humans; Adult; MELAS Syndrome; Stroke; Mitochondrial Diseases; Mitochondria; Brain; Seizures
PubMed: 36813321
DOI: 10.1016/B978-0-12-821751-1.00005-1 -
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