Volume 20, Number 3
September 2013
Introduction he first clinical and biochemical description of mitochondrial (mt) disease was reported by Luft et al.1 Only 2 patients with Luft disease have been described to date.2 Both were interesting examples of intellectually normal adult women with a rare form of mt hyperfunction associated with high oxygen consumption rates, hypermetabolism, heat intolerance, resting tachycardia, hyperhidrosis, and death in middle age from respiratory muscle failure.3 Although mitochondria (mt) were first reported to contain their own DNA in 1963 by Nass and Nass,4 it was another 25 years before the first DNA mutations were found that caused mt disease, when in 1988, Wallace et al5 reported the first mtDNA mutation associated with Leber’s optic neuropathy. In the same year, Holt et al6 and Zeviani et al7 reported the first disease-associated deletions in mtDNA. Today, we know of more than 300 biochemically or molecularly distinct forms of mt disease.3 The principal function of mt is to provide the cell with adenosine triphosphate (ATP), by a process called oxidative phosphorylation (OXPHOS). In this process, the reduced forms of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) formed during fatty acid oxidation, glycolysis, and in the citric acid cycle are oxidized to NADþ and FAD, while the free energy of these reactions is indirectly used for the phosphorylation of adenosine diphosphate to ATP. The enzymes involved in OXPHOS are arranged as 5 discrete multiprotein-lipid complexes that are embedded in the inner mt membrane.8 They are: (1) NADH: ubiquinone oxidoreductase or complex I, (2) succinate: ubiquinone oxidoreductase or complex II, (3) ubiquinol: ferricytochrome c oxidoreductase or complex III, (4) ferrocytochrome c: oxygen oxidoreductase (cytochrome c oxidase) or complex IV, and (5) ATP synthase (F1F0-ATPase) or complex V.8 The first 4 complexes are electronically connected by smaller components, coenzyme Q (synonymous to ubiquinone) and cytochrome c. Together, they make up the mt respiratory chain, which transfers electrons from the coenzymes NADH and FADH2 to molecular oxygen in a series of oxidation-reduction reactions; therefore, it is also called electron transport chain or ETC.8 Mt diseases are basically defined as conditions with dysfunction of the metabolic process of OXPHOS. The epidemiology of mt disease has evolved rapidly over the past 15 years. The first estimates of its prevalence were as low as 1:33,000.9 More recent figures available state that 1 in 2000 children born each
T
1071-9091/13/$-see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spen.2013.10.009
year in the United States will develop definite mt disease in their lifetimes.10 However, when Elliott et al11 studied the frequency of 10 mtDNA point mutations in 3168 neonatalcord-blood samples, they found that at least 1 in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially could cause disease in the offspring of female carriers; the most common was the MELAS A3243G. Approximately 15% of pediatric mt disease is caused by mtDNA mutations, and 85% is caused by nuclear DNA mutations that are inherited in a Mendelian fashion.3 During the past few years, the biochemical composition of the respiratory chain complexes has been described, and their genetic regulation by mtDNA and nuclear DNA has been defined. Only 13 subunits of the respiratory chain are mtDNA encoded, whereas nuclear DNA encodes the remaining of the 74 subunits of complexes I-V. Therefore, the clinical characteristics of mt diseases have been better described and the diagnostic suspicion of mt disease has been emphasized.12,13 Mt disorders are systemic conditions; however, they most commonly affect the organ systems requiring the most ATP to function properly. Therefore, the energy-demanding nervous system is frequently involved, especially in childhood. Brain and muscle, along with vision and hearing, are typically compromised, bringing that child to the attention of the child neurologist. However, mt disease should be included in the differential diagnosis for almost any neurologic symptom.13 The mt role in neurologic conditions requires further studies with the latest genetic technology, bioinformatics, and biochemical assays, which would help to determine the prevalence and type of mt defects in diverse neurologic diseases. In particular, the development of Next Generation Sequencing (NGS) has revolutionized the diagnostic approach. Using massive parallel sequencing (MPS) analysis of the entire mt genome, mtDNA point mutations and deletions can be detected and quantified in a single step.14 This is very exciting because, early and accurate diagnosis opens the door for possible therapeutic trials, including gene therapy,15 in spite of previous unsuccessful attempts.16 Even though the advances in the study of mt and mt disease during the past few years has been impressive, as discussed previously, recently a new aspect of mt disease has developed. Mt dysfunction has been associated with the aging process and a large variety of human disorders, such as cardiovascular diseases, cancer, infertility, kidney and liver disease, and
161
A. Legido
162
We want to take advantage of this opportunity to thank the Department of Pediatrics of DUCOM, SCHC administration, and St. Christopher's Foundation for their constant support of our Mitochondria Disorders Program. Also, we are particularly indebted to the late Ms Elizabeth Engell for her generous contribution to establish the SCHC Mitochondrial Disorders Fund to support our Laboratory. Finally, it is our honor to dedicate this issue to the late Dr Warren Grover and Leon Salganicoff, PhD, who created both the Mitochondrial Clinical Program and the Laboratory, which continue to stimulate all of us to provide outstanding clinical care and research opportunities to our children with mt disorders, and their families. Agustín Legido, MD, PhD, MBA Guest Editor
Warren D. Grover, MD 1928–2013
References
Leon Salganicoff, Ph.D 1924–2013
neurologic conditions, including migraine, neurodegenerative disorders, and brain tumors.17 The epidemiologic and pathogenetic data of such interaction are limited. Furthermore, the study of the relationship between mt disease and neurologic disorders in children is starting. However, this is a fascinating area of great clinical and research interest, as if we believe Edeas and Weissig, “the future of medicine will come through mitochondria.”17 The goal of this issue of Seminars in Pediatric Neurology is to review the current knowledge about the link between mt dysfunction and several pediatric neurologic diseases. They include autism, epilepsy, migraine, demyelinating diseases (multiple sclerosis and X-linked adrenoleukodystrophy), neuromuscular disorders, and gliomas. All the leading authors are faculty from the Section of Neurology at St. Christopher’s Hospital for Children (SCHC)/Drexel University College of Medicine (DUCOM) and provide their experience in mt disorders developed in our institution during the past 25 years. We also contribute personal data in the chapters of Autism and Epilepsy, as the use of the technique of buccal swabs has allowed us during the past few years to study ETC complexes I and IV in buccal cells of large series of patients with these diseases.
1. Luft R, Ikkos D, Palmieri G, et al: A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: A correlated clinical, biochemical, and morphological study. J Clin Invest 41:1776-1804, 1962 2. DiMauro S, Bonilla E, Lee CP, et al: Luft's disease: Further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci 27:217-232, 1976 3. Naviaux RK: Mitochondria and autism spectrum disorders. In: Buxbaum JD, Hof PR (eds): The Neuroscience of Autism Spectrum Disorders. Amsterdam, Academic Press, 179-193, 2013 4. Nass MM, Nass S: Intramitochondrial fibers with DNA characteristics. I. Fixation and electron staining reactions. J Cell Biol 19:593-611, 1963 5. Wallace DC, Zheng XX, Lott MT, et al: Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427-1430, 1988 6. Holt IJ, Harding AE, Morgan-Hughes JA: Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717-719, 1988 7. Zeviani M, Moraes CT, DiMauro S, et al: Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339-1346, 1988 8. Taanman JW, Williams SL: Structure and function of mitochondrial oxidative phosphorylation system. In: AH Schapira, DiMauro S (eds): Mitochondrial Disorders in Neurology 2. Boston, Butterworth Heinemann, 1-34, 2002 9. Applegarth DA, Toone JR, Lowry RB: Incidence of inborn errors of metabolism in British Columbia, 1969-1976. Pediatrics 105:e10, 2000 10. Naviaux RK: Developing a systematic approach to the diagnosis and classification of mitochondrial disease. Mitochondrion 4:351-361, 2004 11. Elliott HR, Samuels DC, Eden JA, et al: Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 83:254-260, 2008 12. DeBrosse S, Parikh S: Neurologic disorders due to mitochondrial DNA mutations. Semin Pediatr Neurol 19:194-202, 2012 13. Goldstein A, Bhatia P, Vento JM: Update on nuclear mitochondrial genes and neurologic disorders. Semin Pediatr Neurol 19:181-193, 2012 14. Wong LJC: Next generation molecular diagnosis of mitochondrial disorders. Mitochondrion 13:379-387, 2013 15. Adhya S, Mahato B, Jash S, et al: Mitochondrial gene therapy: The tortuous path from bench to bedside. Mitochondrion 11:839-844, 2011 16. Stacpoole PW: Why are there no proven therapies for genetic mitochondrial diseases? Mitochondrion 11:679-685, 2011 17. Edeas M, Weissig V: Targeting mitochondria: Strategies, innovations and challenges. The future of medicine will come through mitochondria. Mitochondrion 13:389-390, 2013
September 2013
Introduction he first clinical and biochemical description of mitochondrial (mt) disease was reported by Luft et al.1 Only 2 patients with Luft disease have been described to date.2 Both were interesting examples of intellectually normal adult women with a rare form of mt hyperfunction associated with high oxygen consumption rates, hypermetabolism, heat intolerance, resting tachycardia, hyperhidrosis, and death in middle age from respiratory muscle failure.3 Although mitochondria (mt) were first reported to contain their own DNA in 1963 by Nass and Nass,4 it was another 25 years before the first DNA mutations were found that caused mt disease, when in 1988, Wallace et al5 reported the first mtDNA mutation associated with Leber’s optic neuropathy. In the same year, Holt et al6 and Zeviani et al7 reported the first disease-associated deletions in mtDNA. Today, we know of more than 300 biochemically or molecularly distinct forms of mt disease.3 The principal function of mt is to provide the cell with adenosine triphosphate (ATP), by a process called oxidative phosphorylation (OXPHOS). In this process, the reduced forms of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) formed during fatty acid oxidation, glycolysis, and in the citric acid cycle are oxidized to NADþ and FAD, while the free energy of these reactions is indirectly used for the phosphorylation of adenosine diphosphate to ATP. The enzymes involved in OXPHOS are arranged as 5 discrete multiprotein-lipid complexes that are embedded in the inner mt membrane.8 They are: (1) NADH: ubiquinone oxidoreductase or complex I, (2) succinate: ubiquinone oxidoreductase or complex II, (3) ubiquinol: ferricytochrome c oxidoreductase or complex III, (4) ferrocytochrome c: oxygen oxidoreductase (cytochrome c oxidase) or complex IV, and (5) ATP synthase (F1F0-ATPase) or complex V.8 The first 4 complexes are electronically connected by smaller components, coenzyme Q (synonymous to ubiquinone) and cytochrome c. Together, they make up the mt respiratory chain, which transfers electrons from the coenzymes NADH and FADH2 to molecular oxygen in a series of oxidation-reduction reactions; therefore, it is also called electron transport chain or ETC.8 Mt diseases are basically defined as conditions with dysfunction of the metabolic process of OXPHOS. The epidemiology of mt disease has evolved rapidly over the past 15 years. The first estimates of its prevalence were as low as 1:33,000.9 More recent figures available state that 1 in 2000 children born each
T
1071-9091/13/$-see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spen.2013.10.009
year in the United States will develop definite mt disease in their lifetimes.10 However, when Elliott et al11 studied the frequency of 10 mtDNA point mutations in 3168 neonatalcord-blood samples, they found that at least 1 in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially could cause disease in the offspring of female carriers; the most common was the MELAS A3243G. Approximately 15% of pediatric mt disease is caused by mtDNA mutations, and 85% is caused by nuclear DNA mutations that are inherited in a Mendelian fashion.3 During the past few years, the biochemical composition of the respiratory chain complexes has been described, and their genetic regulation by mtDNA and nuclear DNA has been defined. Only 13 subunits of the respiratory chain are mtDNA encoded, whereas nuclear DNA encodes the remaining of the 74 subunits of complexes I-V. Therefore, the clinical characteristics of mt diseases have been better described and the diagnostic suspicion of mt disease has been emphasized.12,13 Mt disorders are systemic conditions; however, they most commonly affect the organ systems requiring the most ATP to function properly. Therefore, the energy-demanding nervous system is frequently involved, especially in childhood. Brain and muscle, along with vision and hearing, are typically compromised, bringing that child to the attention of the child neurologist. However, mt disease should be included in the differential diagnosis for almost any neurologic symptom.13 The mt role in neurologic conditions requires further studies with the latest genetic technology, bioinformatics, and biochemical assays, which would help to determine the prevalence and type of mt defects in diverse neurologic diseases. In particular, the development of Next Generation Sequencing (NGS) has revolutionized the diagnostic approach. Using massive parallel sequencing (MPS) analysis of the entire mt genome, mtDNA point mutations and deletions can be detected and quantified in a single step.14 This is very exciting because, early and accurate diagnosis opens the door for possible therapeutic trials, including gene therapy,15 in spite of previous unsuccessful attempts.16 Even though the advances in the study of mt and mt disease during the past few years has been impressive, as discussed previously, recently a new aspect of mt disease has developed. Mt dysfunction has been associated with the aging process and a large variety of human disorders, such as cardiovascular diseases, cancer, infertility, kidney and liver disease, and
161
A. Legido
162
We want to take advantage of this opportunity to thank the Department of Pediatrics of DUCOM, SCHC administration, and St. Christopher's Foundation for their constant support of our Mitochondria Disorders Program. Also, we are particularly indebted to the late Ms Elizabeth Engell for her generous contribution to establish the SCHC Mitochondrial Disorders Fund to support our Laboratory. Finally, it is our honor to dedicate this issue to the late Dr Warren Grover and Leon Salganicoff, PhD, who created both the Mitochondrial Clinical Program and the Laboratory, which continue to stimulate all of us to provide outstanding clinical care and research opportunities to our children with mt disorders, and their families. Agustín Legido, MD, PhD, MBA Guest Editor
Warren D. Grover, MD 1928–2013
References
Leon Salganicoff, Ph.D 1924–2013
neurologic conditions, including migraine, neurodegenerative disorders, and brain tumors.17 The epidemiologic and pathogenetic data of such interaction are limited. Furthermore, the study of the relationship between mt disease and neurologic disorders in children is starting. However, this is a fascinating area of great clinical and research interest, as if we believe Edeas and Weissig, “the future of medicine will come through mitochondria.”17 The goal of this issue of Seminars in Pediatric Neurology is to review the current knowledge about the link between mt dysfunction and several pediatric neurologic diseases. They include autism, epilepsy, migraine, demyelinating diseases (multiple sclerosis and X-linked adrenoleukodystrophy), neuromuscular disorders, and gliomas. All the leading authors are faculty from the Section of Neurology at St. Christopher’s Hospital for Children (SCHC)/Drexel University College of Medicine (DUCOM) and provide their experience in mt disorders developed in our institution during the past 25 years. We also contribute personal data in the chapters of Autism and Epilepsy, as the use of the technique of buccal swabs has allowed us during the past few years to study ETC complexes I and IV in buccal cells of large series of patients with these diseases.
1. Luft R, Ikkos D, Palmieri G, et al: A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: A correlated clinical, biochemical, and morphological study. J Clin Invest 41:1776-1804, 1962 2. DiMauro S, Bonilla E, Lee CP, et al: Luft's disease: Further biochemical and ultrastructural studies of skeletal muscle in the second case. J Neurol Sci 27:217-232, 1976 3. Naviaux RK: Mitochondria and autism spectrum disorders. In: Buxbaum JD, Hof PR (eds): The Neuroscience of Autism Spectrum Disorders. Amsterdam, Academic Press, 179-193, 2013 4. Nass MM, Nass S: Intramitochondrial fibers with DNA characteristics. I. Fixation and electron staining reactions. J Cell Biol 19:593-611, 1963 5. Wallace DC, Zheng XX, Lott MT, et al: Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427-1430, 1988 6. Holt IJ, Harding AE, Morgan-Hughes JA: Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331:717-719, 1988 7. Zeviani M, Moraes CT, DiMauro S, et al: Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 38:1339-1346, 1988 8. Taanman JW, Williams SL: Structure and function of mitochondrial oxidative phosphorylation system. In: AH Schapira, DiMauro S (eds): Mitochondrial Disorders in Neurology 2. Boston, Butterworth Heinemann, 1-34, 2002 9. Applegarth DA, Toone JR, Lowry RB: Incidence of inborn errors of metabolism in British Columbia, 1969-1976. Pediatrics 105:e10, 2000 10. Naviaux RK: Developing a systematic approach to the diagnosis and classification of mitochondrial disease. Mitochondrion 4:351-361, 2004 11. Elliott HR, Samuels DC, Eden JA, et al: Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 83:254-260, 2008 12. DeBrosse S, Parikh S: Neurologic disorders due to mitochondrial DNA mutations. Semin Pediatr Neurol 19:194-202, 2012 13. Goldstein A, Bhatia P, Vento JM: Update on nuclear mitochondrial genes and neurologic disorders. Semin Pediatr Neurol 19:181-193, 2012 14. Wong LJC: Next generation molecular diagnosis of mitochondrial disorders. Mitochondrion 13:379-387, 2013 15. Adhya S, Mahato B, Jash S, et al: Mitochondrial gene therapy: The tortuous path from bench to bedside. Mitochondrion 11:839-844, 2011 16. Stacpoole PW: Why are there no proven therapies for genetic mitochondrial diseases? Mitochondrion 11:679-685, 2011 17. Edeas M, Weissig V: Targeting mitochondria: Strategies, innovations and challenges. The future of medicine will come through mitochondria. Mitochondrion 13:389-390, 2013
