Mitochondrial Disorder

Mitochondrial disorders (MDs) are a very complex group of neurometabolic and neurodegenerative diseases caused by impairment of the mitochondrial respiratory chain (the oxidative phosphorylation system) [1].

From: Clinical Bioenergetics, 2021

Mitochondrial disorders

N. Couser, M. Gucsavas-Calikoglu, in Biomarkers in Inborn Errors of Metabolism, 2017

Abstract

Mitochondrial disorders represent a heterogeneous group of diseases caused by a dysfunction of oxidative phosphorylation in the mitochondria, the double membrane-bound organelles that generate energy in eukaryotic cells. This group collectively may involve any mode of inheritance, may present from the neonatal period to adulthood, and can clinically affect nearly every organ system. Symptoms are variable and evolve over time and may include developmental delay, myopathy, encephalopathy, seizures, ataxia, sensorineural hearing loss, ophthalmoplegia, retinopathy, diabetes mellitus, liver failure, cardiomyopathy, exercise intolerance, and gastric dysmotility. Given the variability of clinical presentations, establishing the diagnosis of a mitochondrial disorder is frequently challenging. Diagnostic delay or misdiagnosis is common. Mutations in 37 mitochondrial genes or over 100 nuclear genes can result in overlapping phenotypes. The reverse is also true with the same genetic mutation causing different clinical presentations. Not uncommonly, extensive laboratory evaluation is required including lactate and pyruvate levels, plasma amino acid profiles, urine organic acid profiles, plasma acylcarnitine profiles, and specific enzymatic analysis of skin and muscle. Neuroimaging is often needed. Recent developments in whole-exome sequencing have revolutionized diagnosis and expanded the molecular spectrum with discovery of new conditions. Although some symptomatic improvement may be achieved by the use of specialized vitamin and cofactor therapies as well as supportive illness management, there is no cure for these conditions and some can be fatal. Improvements in quality of life and survival can be achieved with multidisciplinary clinical management.

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Mitochondrial disorders

Jaya Ganesh, Fernando Scaglia, in Handbook of Clinical Adult Genetics and Genomics, 2020

Laboratory testing

The laboratory investigation of mitochondrial disease is complex, and a multipronged approach including clinical and functional studies as well as genetic testing is employed. When a mitochondrial disorder is suspected, biochemical studies in blood, urine, and cerebrospinal fluid (CSF) are performed as initial screening studies as these are minimally invasive and may help to direct more invasive or expensive testing.

The initial evaluation in blood for mitochondrial disease should include complete blood count, creatine phosphokinase, liver and kidney function studies, lactate and pyruvate, plasma amino acids, acylcarnitine profile, and quantitative urinary organic acid analysis. A complete blood count may reveal megaloblastic or sideroblastic anemia, neutropenia, and thrombocytopenia or pancytopenia if the bone marrow is affected. Elevations of plasma aspartate and alanine aminotransferases, hypoalbuminemia, and coagulopathy may indicate hepatic involvement. Metabolic acidosis and lactic acidosis may be seen. Persistent elevation of blood lactate (>3 mM/L) suggests the presence of mitochondrial dysfunction and indicates impaired utilization of pyruvate generated during glycolysis. However, lactate is a nonspecific biomarker, and elevations are often spurious and associated with difficult phlebotomy or poor sample processing or may be due to secondary mitochondrial dysfunction that can be seen in poor perfusion states or other inborn errors of metabolism. More importantly, many patients with primary mitochondrial disorders do not have elevations in serum lactate. Pyruvate elevation, specifically in the presence of lactate elevation, points to defects of pyruvate metabolism [24,25].

If CSF is obtained, a specimen should be sent for amino acids, lactate, pyruvate and 5-methyltetrahydrofolate measurements. 5-Methyltetrahydrofolate levels are reported to be low in mtDNA deletion syndromes [26]. Elevated CSF lactate is not specific to mitochondrial disease and may be seen in seizure disorders, stroke, central nervous system (CNS) infection, or malignancy

Alterations to the cellular redox status due to OXPHOS dysfunction result in biochemical abnormalities including abnormal plasma amino acid profile with elevated alanine or proline, glycine or threonine. Elevated urinary amino acids indicate renal tubular impairment. Abnormal acylcarnitine profile reflective of altered fatty acid and ketone metabolism and abnormal urine organic acid profile with elevations of dicarboxylic acids, 3 methylglutaconic acid, intermediaries of the Krebs cycle are often seen [27]. Evidence of rhabdomyolysis with elevated serum creatinine kinase levels has been seen in some mitochondrial myopathies [28]

Newer technologies such as whole transcriptome sequencing (RNAseq) using RNA from affected tissues will be helpful in unsolved cases and will facilitate the interpretation of variants identified by whole-exome sequencing (WES) and whole-genome sequencing (WGS). Transcriptomic analysis might also reveal biomarkers of mitochondrial disease. Fibroblast growth factor 21 (FGF21) and growth and differentiation factor (GDF15) have been shown to be useful biomarkers in mitochondrial disorders [29,30].

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Genetic Approaches to Cardiovascular Disease

Carl J. Vaughan, Craig T. Basson, in Molecular Basis of Cardiovascular Disease (Second Edition), 2004

Mitochondrial Inheritance

Mitochondrial disorders are maternally inherited because the egg, not the sperm, transmits cytoplasmic mitochondrial DNA to offspring.4,5 Because each germ and somatic cell can contain different amounts of mitochondrial DNA, the risk of disease transmission to offspring is difficult to predict. This results in a non-Mendelian pattern of inheritance (Figure 8-1D). The severity and often highly variable expressivity of the phenotype in a mitochondrial disorder is often related to the ratio of mutant to normal mitochondrial DNA (mtDNA) in a cell. Organs with high-energy requirements (muscles, eyes, and kidneys) appear to be more susceptible to mitochondrial disorders.6 An example of a mitochondrial disorder is MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and the inheritance pattern of such mitochondrial disorders is seen in Figure 8-1D.

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Hyperkinetic Movement Disorders

Andreas Moustris, ... Kailash P. Bhatia, in Handbook of Clinical Neurology, 2011

Conclusions

Mitochondrial disorders present a major dilemma to the clinician, given their massive heterogeneity and the lack of simple diagnostic tests even when the diagnosis is considered. Movement disorders are clearly a common component of mitochondrial disorders, and again heterogeneity of movement disorder phenotype is common, even in patients with the same underlying genetic mutation. The peculiarities of mitochondrial genetics may account in part for this phenomenon, but nuclear background and environmental factors appear to have a role as well.

Mitochondrial disorders only very rarely present as an isolated movement disorder, and are even less likely to remain as an isolated movement disorder over time. There are occasional exceptions to this (for example, female carriers of MTS presenting with isolated dystonia), but in such cases a family history of a more typical presentation of a “full-blown” mitochondrial disorder is usually seen. Movement disorder clinicians need to suspect mitochondrial disorders mainly in the setting of a complex progressive clinical picture where the movement disorder is just part of a more generalized nervous system (and perhaps systemic) dysfunction. A familiarity with the “classic” mitochondrial phenotypes outlined here is helpful in guiding appropriate investigations, always bearing in mind the phenotypic and genetic heterogeneity of mitochondrial disorders. LS and LLS appear to be the mitochondrial syndromes associated with the widest spectrum of movement disorders, dystonia being the most common. Dystonia is also a prominent feature of MTS and occasionally of LHON. Myoclonus is also very common in mitochondrial diseases, particularly in MERRF, where it is frequently the presenting symptom. POLG mutations are also frequently associated with myoclonus and parkinsonism. While the correct diagnosis of these disorders does not lead to specific treatment, the last two decades have seen an exponential increase in our knowledge of genes associated with mitochondrial disorders, although much remains to be learnt. With elucidation of their molecular pathophysiology it is hoped that there will be a step change in the development of effective therapeutic strategies.

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Mitochondrial Disorders Due to Mutations in the Nuclear Genome

Patrick F. Chinnery, in Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015

Abstract

Mitochondrial disorders are caused by mutations in nuclear DNA and mitochondrial DNA (mtDNA). Nuclear-encoded mitochondrial disorders have emerged as a major cause of inherited neurometabolic disease. As with mitochondrial DNA-encoded disorders, they characteristically affect multiple neurological systems, and also often involve other non-neurological organs and tissues. They can present at any age, from early-onset severe encephalomyopathies in children, through to late-onset, slowly progressive adult neurodegenerative disorders.

Nuclear-encoded mitochondrial disorders can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive trait. The recessive forms are more common in consanguineous individuals but usually appear as isolated cases in an outbred population. This inheritance pattern contrasts with mitochondrial DNA-encoded mitochondrial disorders, which are inherited down the maternal line.

Some nuclear-encoded mitochondrial disorders have the characteristic clinical phenotype, prompting early genetic testing of specific nuclear genes. However, given the overlapping spectrum for clinical phenotypes, a systematic approach is advocated in all but the most obvious cases. This should incorporate clinical investigations aimed at building a clear picture of the phenotype, and biochemical studies in an affected tissue, which guides nuclear genetic testing. The impact of exome and whole-genome sequencing will dramatically change the diagnostic approach in the near future.

Current research activity is focused on providing a comprehensive molecular diagnosis to enable reliable genetic counseling and prenatal testing. Genetically defined cohorts are being assembled throughout the world, enabling the first natural history studies and treatment trials in mitochondrial disease. It is likely that new treatments will become available in the near future.

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New therapeutics to modulate mitochondrial energy metabolism in neurodegenerative disorders

Daniele Orsucci, ... Michelangelo Mancuso, in Clinical Bioenergetics, 2021

Abstract

Mitochondrial disorders are a group of neurometabolic and neurodegenerative diseases caused by impairment of the mitochondrial respiratory chain. There is no clear evidence supporting any pharmacological interventions for the majority of mitochondrial disorders, except Leber hereditary optic neuropathy, coenzyme Q10 deficiencies, and mitochondrial neurogastrointestinal encephalomyopathy. Furthermore, some drugs may have detrimental effects on mitochondrial function. Drugs known to be “mitochondrion-toxic” should be avoided whenever possible in these patients. In this chapter, we discuss the new therapeutics to modulate mitochondrial energy metabolism in neurodegenerative disorders, with special attention to mitochondrial diseases. We will also briefly discuss their potential role in more “conventional” neurodegenerative disorders.

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Neurogenetics, Part I

Ryan L. Davis, ... Carolyn M. Sue, in Handbook of Clinical Neurology, 2018

Introduction

Mitochondrial disorders are the most common group of inherited metabolic diseases. They have protean clinical symptoms, variable ages of onset, diverse patterns of disease course, and varying modes of inheritance. As such, mitochondrial diseases often present a diagnostic challenge to the clinician and may be unrecognized or misdiagnosed for long periods of time. Because the mitochondrion's main function is to produce energy for the cell, clinical manifestations typically involve organs with high energy requirements. Tissues commonly affected include brain, muscle, heart, retina, and cochlea. Loss of mitochondrial function can occur in many different types of cells within tissues, and there are often specific “signatures” of clinical manifestations that can provide clues to the diagnosis of a mitochondrial disorder. The age of onset of mitochondrial disorders may range from very early in the neonatal period to very late in adulthood. Some symptoms may be precipitated by external or environmental factors, but at times, the natural course of the illness can be slowly progressive, or punctuated with periods of good health. Mitochondrial diseases can result from genetic mutations in either the mitochondrial or nuclear genome, and thus may be transmitted by either maternal or Mendelian inheritance patterns.

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Pediatric Liver Disease and Inherited, Metabolic, and Developmental Disorders of the Pediatric and Adult Liver

MAY ARROYO, JAMES M. CRAWFORD, in Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas (Second Edition), 2009

CLINICAL FEATURES

Mitochondrial disorders are an extraordinarily diverse array of diseases that can progress rapidly from apparent normality at birth to overt liver failure.111 Included in this category are respiratory chain mutations112–114 and defects of long-chain fatty acid transport115 and fatty acid oxidation.15, 116 Acute liver failure and acute multiorgan failure have been described in CDGS Ib (phosphomannose iso-merase deficiency).117 Liver failure can also complicate CDGS Ia (phosphomannomutase deficiency), Pearson marrow pancreas syndrome (caused by mitochondrial DNA deletions), and Alpers' progressive poliodystrophy.117 Defects that arise from mutations in nuclear genes are inherited as an autosomal trait, whereas defects in genes that are encoded by mitochondrial DNA are inherited maternally.

The general functional defect of mitochondrial disorders occurs in mitochondrial production of adenosine triphosphate (ATP), although other biochemical abnormalities may also occur, such as increased intracellular production of reactive oxygen species and defective β-oxidation, related to the specific underlying genetic mutation. Liver disease may present clinically during the first week of life. In this setting, sudden death may be wrongly attributed to sepsis. Alternatively, patients may have transient hypoglycemia, lactic acidosis, severe neurologic impairment with hypotonia, myoclonic seizures, developmental delay, and cardiomyopathy, which can lead to a rapidly fatal course.117 In a second group of patients, the onset of symptoms is delayed from 2 to 18 months of age and liver disease and neurologic impairment are initially less severe.4 Although liver failure may still occur, in its absence, some patients survive into adulthood. Because many infants with mitochondrial disorders exhibit abnormalities before birth, prenatal diagnosis may be possible.

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Neuropathology

Maria J. Molnar, Gabor G. Kovacs, in Handbook of Clinical Neurology, 2018

Abstract

Mitochondrial disorders represent a major challenge in medicine. Most of the mitochondrial proteins are encoded by the nuclear DNA (nDNA), whereas a very small fraction is encoded by the mitochondrial DNA (mtDNA). Mutations in mtDNA or mitochondria-related nDNA genes can result in mitochondrial dysfunction. The disease usually affects multiple organs in varying locations and severity; however, there are some forms which affect a single organ. The diagnosis of mitochondrial disorders is based on clinical examination, biochemical and histopathologic examinations, functional studies, and molecular genetic testing. Neuropathologic alterations of the muscle are variable and can range from striking abnormalities, such as cytochrome oxidase-negative and ragged red fibers, to nonspecific or minimal changes. Neuropathologic alterations in the brain show common features in disorders with different genetic background. These are characterized by various degrees of vacuolation in the white and gray matter, regional neurodegeneration with reactive astrogliosis, loss of oligodendrocytes, presence of macrophages and microgliosis, capillary proliferation, and mineralization of vessel walls. The advent of molecular genetics, the discovery of biomarkers and new sequencing platforms to perform targeted exome and whole-genome sequencing have changed traditional approaches to diagnose mitochondrial diseases.

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Diagnosis of Hydrops and Multiple Malformation Syndromes

Tessa Homfray, in Twining's Textbook of Fetal Abnormalities (Third Edition), 2015

Fetal Cardiomyopathy: Dilated and Hypertrophic

There are multiple causes of fetal cardiomyopathy. The fetus of a poorly controlled diabetic mother will have increased glycogen in the myocardium which may lead to a hypertrophic myocardium.31 Infection with cytomegalovirus, congential syphilis, fetal rubella and coxsackie infection may cause a dilated cardiomyopathy. Improving diabetic control and treating congenital syphilis may cure these babies although the prognosis for the others is very poor.

Genetic Causes of Cardiomyopathy

Mitochondrial disorders of oxidative phosphorylation can cause a severe cardiomyopathy. Barth syndrome is an X-linked syndrome associated with mutations in tefazzin. It more commonly presents with a postnatal cardiomyopathy but a prenatal presentation with hydrops has been recorded. Non-compaction of the left ventricle in a male fetus should raise the suspicion of Barth syndrome.32

Other metabolic syndromes may be associated with a cardiomyopathy and will be discussed below.

Noonan syndrome can have hypertrophic cardiomyopathy without pulmonary stenosis and pleural effusions may occur in the absence of other features of hydrops. Pulmonary stenosis in Noonan syndrome can be progressive and it may not be possible to identify this at the second trimester scan.30

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