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Mitochondria are present in every cell in the human body, except red blood cells. In addition to their main role providing aerobically derived ATP, they are also involved in reactive oxygen species generation, apoptosis, and calciumbuffering.

Mark A. Tarnopolsky ABSTRACT
Mitochondrial cytopathies represent a heterogenous group of disorders with abnormal mitochondrial structure or function as the defining entity and with clinical onset across all age groups. Given that the mitochondria provide the majority of cellular adenosine 50 -triphosphate (ATP), the clinical symptoms can manifest with a myriad of presentations. Cellular pathology includes a reduction in aerobic energy transduction, an increase in anaerobic energy utilization (lactate production), and, in some cases, higher oxidative stress. Diagnostic criteria include history (classic multisystem involvement), blood test abnormalities (elevated lactate, alanine, and creatine kinase activity), urine organic acids (3-methylglutaconic acid, ethylmalonic acid, fumarate), muscle enzymology (reduction in activity), exercise testing (low maximum ˙ oxygen consumption [VO2max], early lactate production) and other ancillary tests, including MRI, MR spectroscopy, and near-infrared spectroscopy. Treatment is multifactorial and supportive, including optimization of nutrition and deficiency (folate and vitamin B12) replacement, gastrostomy tube if necessary (failure to thrive), treatment of secondary neurologic issues, vitamin and cofactor therapy (creatine monohydrate, coenzyme Q10, -lipoic acid, etc), and exercise.
Continuum Lifelong Learning Neurol 2009;15(6):98–125.


INTRODUCTION Mitochondria are essential to the functional integrity and energy metabolism of all cells (except red blood cells) and can be directly implicated in human disease (mitochondrial cytopathies) or as contributors to health (mitochondrial proliferation in muscle cells of elite athletes) and disease (mitochondrial dysfunction in ischemic tissue, neurodegenerative diseases, and critical illness). Mitochondrial diseases manifest across the full spectrum from infancy to old age. Children with severe early-

onset mitochondrial cytopathies are surviving into adulthood, and intrafamilial variability in age at onset and clinical manifestations of inherited mitochondrial conditions have implications for the care of all family members. This chapter will provide an overview of mitochondrial biology and will discuss the most common forms of mitochondrial cytopathies in children and adults. Discussion of the contributions of secondary mitochondrial dysfunction in other neurologic or systemic diseases is beyond the scope of this chapter.

Relationship Disclosure: Dr Tarnopolsky has received personal compensation for speaking engagements with Transgenomic, Inc., has received personal compensation in an editorial capacity from Medicine & Science in Sports & Exercise, and has received research support from ApoPharma, Inc., and Gilead. Unlabeled Use of Products/Investigational Use Disclosure: Dr Tarnopolsky has nothing to disclose.

Copyright # 2009, American Academy of Neurology. All rights reserved.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

MITOCHONDRIAL BIOLOGY PRIMER Mitochondria are the main ‘‘powerhouse’’ for all cells in the body except red blood cells. The mitochondria are considered an evolutionary parasite evolved from purple photosynthetic bacteria that invaded proto-eukaryotic cells approximately 11/2 billion years ago. This symbiotic relationship is felt to confer selective advantage through enhanced aerobic adenosine 50 -triphosphate (ATP) delivery and oxygen detoxification given the steep oxygen gradient evolving in the earth’s atmosphere. Over 11/2 billion years of evolution, all of the proteins involved in mitochondrial DNA (mtDNA) replication and maintenance were transferred to the nuclear genome, and the bacterialike circular mitochondrial genome retains only 16,569 base pairs encoding for 13 polypeptide subunits, 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and a small noncoding region. The circular genome is composed of an outer heavy strand (predominately purines [adenine and guanine]) and an inner light strand (predominantly pyrimidines [cytosine and thymine]). Bacterialike polycistronic replication of mitochondria is triggered by cellular signals sensed through a variety of mechanisms (reactive oxygen species, protein kinase, energy charge) that increase gene expression of a variety of nuclear-encoded mitochondrial proteins and mitochondrial transcription factor A (mtTFA) under coregulation with peroxisome proliferator-activated receptor -coactivator-1 ( Wu et al, 1999). mtTFA binds to regulatory elements in the mitochondrial genome, initiating replication of mtDNA. mtDNA encodes for seven subunits of complex I, one subunit of complex III, three subunits of complex IV, and two subunits of complex V. Consequently, mtDNA encodes for a component of each of the major enzyme complexes involved

in the core series circuit of the electron transport chain (I, III, IV) and the adenosine triphosphatase (ATPase) function ( V ). There can be two to several dozens of mtDNA copies per mitochondria, and in certain cells, such as a multinucleate muscle cell, there may be many thousands of mitochondria. The purpose of the mitochondria is to provide aerobically derived ATP for a variety of cellular energy processes. Fat, protein, and carbohydrate are all oxidized in the mitochondria through a variety of different pathways that ultimately converge on the electron transport chain. Nicotinamide adenine dinucleotide (reduced form) (NADH) + H+ ( proton) derived from

Flavin adenine dinucleotide (reduced)2 provides reducing equivalents to complex II from . where a proton is pumped from the mitochondrial matrix to the intermembrane of space. and electrons are passed onto coenzyme Q10.-oxidation or the tricarboxylic acid (TCA) cycle provides reducing equivalents to complex I.

.15(6) 99 Copyright @ American Academy of Neurology. and a final proton is pumped. analogous to the potential energy from a waterfall captured by a turbine.-oxidation or the TCA cycle. The accumulated protons in the intermembrane space flow through a dynamic turbinelike system at complex V (ATPase synthase) toward the matrix and generate ATP. Electrons then flow to complex III. The potential energy from the reducing equivalents is created by the relatively impermeable inner mitochondrial membrane leading to a buildup of a proton motive force and the development of a membrane potential ($ M). and onto complex IV. where proton pumping occurs. A unique aspect of mtDNA is a concept termed heteroplasmy. mtDNA is maternally inherited. which is the terminal oxygen acceptor. and both male and female offspring will inherit mtDNA from their mother. Unauthorized reproduction of this article is prohibited. referring to the relative proportion of mutant to wild Continuum Lifelong Learning Neurol 2009. and electrons are also passed to coenzyme Q10.

the clinical symptoms of mitochondrial dysfunction can be predicted from the relative reliance of different tissues on aerobic energy and random expansion in different tissues within the developing embryo and fetus after going through an embryologic bottleneck. It is estimated that the minimal prevalence of mitochondrial cytopathies is 1:6000 individuals (Chinnery et al. lactic acidosis. Consequently. however. 100 type mitochondrial genomes within a cell.html). 2000. 2008). hypoacusis) and muscle (weakness. and again this is likely to increase as new genes are being discovered for phenotypes not previously considered to be mitochondrial in origin (eg. mitomap. The largest representation of nuclear mutations directly affecting the electron transport chain subunits are Copyright @ American Academy of Neurology. the proportion of mutant:wild type heteroplasmy in different tissues can vary from 99:1 to 1:99. the identification of pathogenic point mutations in mtDNA has exploded in recent years. org/cgi-bin/tbl9gen.mitomap. with 165 rRNA/tRNA mutations reported on Mitomap (www. encephalopathy. and with the ability to rapidly sequence mtDNA. the incidence and prevalence of mitochondrial cytopathies is increasing dramatically because of increased recognition of these conditions and the discovery of genes responsible for the . MILS = maternally inherited Leigh disease). To some extent. IOSCA = infantile onset spino cerebellar ataxia. fatigue) as common symptoms of mitochondrial cytopathies. Higher levels of mutant heteroplasmy are generally associated with more severe mitochondrial dysfunction. Unauthorized reproduction of this article is prohibited. The latter process is called replicative segregation. blindness. Singh et al. For example." MITOCHONDRIAL CYTOPATHIES KEY POINT A It is estimated that the minimal prevalence of mitochondrial cytopathies is 1:6000 individuals and this is likely to increase as new genes are being discovered for phenotypes not previously considered to be mitochondrial in origin. 1989). a transition mutation (3243 A>G) as a cause for mitochondrial myopathy. ¨ 2004). Although once considered rare. and consequently a set level of mutant heteroplasmy cannot be uniformly ascribed as the threshold. in which the heteroplasmy in the oocyte undergoes and strokelike episodes (MELAS). Since these original descriptions. Any somatic or mtDNA gene mutation that leads to a breakdown in the complex and carefully orchestrated electron transport chain energy circuit can lead to a reduction in energy transduction and have tissue-specific deleterious consequences. a mother with a specific transition mutation (A>G) at position 3243 in the mtDNA that was 30% mutant and 70% wild type would pass on the 3243 mutation in varying ratios to her offspring and each child would have different ratios in each tissue. contraction.mitomap. the percent of heteroplasmy that results in mitochondrial dysfunction is highly variable and mutation specific. Schaefer et al. MERRF = myoclonus epilepsy and ragged red fibers. and 194 reported mutations in coding and control regions (www.15(6) of large-scale mtDNA deletions as the cause of Kearns-Sayre syndrome. The latter fact provides some rationale for the frequent involvement of the CNS (strokes. Many of the mitochondrial disorder names have followed in the tradition of an acronym describing the clinical phenotype (eg. An increasing number of nuclearencoded mitochondrial function and structural genes are clearly associated with mitochondrial cytopathies (www. mfn2 resulting in Charcot-MarieTooth disease type 2) (Zuchner et al. and a transition mutation (11778 G>A) as a cause of Leber hereditary optic neuropathy (Holt et al. seizures. developmental delay. MITOCHONDRIAL DNA MUTATIONS AND DISEASE The explosion of knowledge in the area of mitochondrial cytopathies and the emergence of mitochondrial medicine began in 1988 to 1989 with a discovery Continuum Lifelong Learning Neurol 2009.

2003b. 2003a. Unauthorized reproduction of this article is prohibited. White et al. Autosomal dominant mutations have been described in the succinate dehydrogenase (SDHB. A significant advantage derived from the discovery of nuclear gene mutations is the ability to provide accurate prenatal diagnosis and genetic counseling. a number of genes have been implicated in Leigh disease (SURF-1. 2008). 2001a). heteroplasmic transmission from mother to child always leads to uncertainty regarding the relative risk to the fetus of inheriting a high proportion of mutated to wild type mitochondria. Lebon et al. MITOCHONDRIAL MYOPATHY DIAGNOSIS History Given that the mitochondria are very important in terminally differentiated tissues. . 8993 T>C/G) (Dahl et al. and mitofusin 2 (mfn2) gene mutations result in an autosomal dominant predominately axonal myopathy called Charcot-Marie-Tooth disease type 2 ( Verhoeven et al. such as maternally inherited Leigh disease (MILS. mitochondrial cytopathies commonly involve these tissues. 2006). Although prenatal counseling can be given for some of the mtDNA mutations. 2007). strokelike episodes. Involvement in skeletal muscle can lead to hypotonia in younger children with gross motor delay. while manifestations in older children. 2000. Other stability factors including ANT1 and C10ORF2 (Twinkle) are associated with CPEO. 2001). which result in hepatocerebral and myopathic mtDNA depletion syndrome. Mitochondrial dysfunction in brain can result in developmental delay. C. Antonicka et al. and adults tend to include muscle weakness and Continuum Lifelong Learning Neurol 2009. and mutations in the ECGF1 (thymidine phosphorylase) gene result in a severe disorder called myoneurogastrointestinal encephalomyopathy (MNGIE). spinocerebellar ataxia. respectively. 101 Copyright @ American Academy of Neurology. which is a dynamin-related protein resulting in autosomal dominant optic atrophy and associated with encephalopathy (Amati-Bonneau et al.the complex I defects resulting in the clinical picture of Leigh disease (Hoefs et al. and BCS1L) or cardioencephalomyopathy and hypertrophic cardiomyopathy (SCO2) and hypertrophic cardiomyopathy (COX10. seizures. The largest subgroup is the polymerase gamma (POLG) mutations responsible for a variety of syndromes including Alpers syndrome (hepatic encephalomyopathy). chronic progressive external ophthalmoplegia (CPEO). Horvath et al. failure to thrive). visual loss.15(6) KEY POINT A A history of fluctuating symptoms affecting multiple tissues or organs should prompt consideration of a mitochondrial cytopathy in any age group. LRPPRC. and hypoacusis. 3-methylglutatonic aciduria. heart. as the transmission follows mendelian genetics. and muscle. 2008. including brain. For example. It is likely that the number of nuclear genes responsible for mitochondrial disorders will increase dramatically in the years to come. and sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO). Tafazzin gene mutations result in an X-linked condition associated with cardiolipin defects causing Barth syndrome (noncompaction cardiomyopathy. Genes affecting mitochondrial integrity include OPA1. 1999). hypotonia. adolescents. Two genes implicated in maintenance of the deoxynucleotide triphosphate pool include DGUOK and TK2. Some of the more common mitochondrial disorders are summarized in Table 6-1. D) gene. Mitochondrial genes implicated in mtDNA stability represent the largest group of nuclear mutations involved in mitochondrial cytopathy. Other autosomal recessively inherited mutations have been described in association with complex II subunit (SDHA) and complex III subunit (UQCRB)associated Leigh disease. 2006. COX15) (Antonicka et al. A large number of mutations characterized to date affecting nonstructural nuclear genomes implicated mitochondrial disease. Jaksch et al. COX15. usually resulting in paraganglionoma and pheochromocytoma (Astuti et al.

sporadic) Leigh disease Complex I. pigmentary retinopathy. 2004). ophthalmoplegia. can also have early-onset cognitive decline. ataxia. encephalopathy. optic atrophy. 1999.8 kb) of mtDNA (Often sporadic) CPEO Deletions of mtDNA (AD and AR. tingling. . polymerase gamma. tingling. AD = autosomal dominant. lactic acidosis. hypoacusis. Cardiomyopathy is usually hypertrophic. hypoacusis. CPEO = chronic progressive external ophthalmoplegia. GastroinContinuum Lifelong Learning Neurol 2009. hypoacusis. Numbness. also noted are psychomotor retardation. 2001. Twinkle and ANT mutations. IV. cognitive decline. including intestinal pseudoobstruction (MELAS syndrome) or severe gastrointestinal dysfunction (MNGIE syndrome). and recurrent vomiting. including irritable bowellike symptoms and constipation in MELAS syndrome and other mitochondrial cytopathies.3 kb–8. muscle weakness/atrophy. MERRF = myoclonic epilepsy and ragged red fibers. strokelike episodes. chorea). and manifest as cardiomyopathy later in life. and sensory ataxia are common in SANDO syndrome seen Copyright @ American Academy of Neurology. neuropathy. proximal muscle weakness. distal weakness) are seen frequently in MNGIE syndrome and may be misdiagnosed as Charcot-Marie-Tooth disease. Symptoms of peripheral neuropathy (numbness. II.15(6) testinal symptoms can be mild and nonspecific. lactic acidosis. ataxia. mtDNA = mitochondrial DNA. and ataxia MERRF 8344 A>G 8356 T>C 8363 G>A (Maternal) Kearns-Sayre syndrome Deletion (1. muscle weakness. optic atrophy. ataxia. optic atrophy Childhood and adult: (variable pattern and age of onset) generalized epilepsy (myoclonic and tonic-clonic). pyruvate dehydrogenase deficiency. type 2 diabetes. Unauthorized reproduction of this article is prohibited. and multiple endocrinopathies Adult: slowly progressive weakness of muscles involved in horizontal eye movements and eyelid opening. abnormal movements (dystonia. but dilated forms or left ventricular noncompaction can also occur (Scaglia et al. resulting in a progressive and symmetric external ophthalmoplegia with bilateral ptosis Infancy and childhood: (often fatal at less than 5 years of age) hypotonia failure to thrive due to poor feeding and suck reflex. 2004). 8993 mutations MELAS = mitochondrial myopathy. myoclonus. spasticity. head and neck lipomas. Naviaux and Nguyen. and strokelike episodes. 102 exercise intolerance. psychiatric disorders Childhood and adult: progressive external ophthalmoplegia. or can be more severe. AR = autosomal recessive. contribute to exercise intolerance at any age. cognitive decline. myopathy." MITOCHONDRIAL CYTOPATHIES TABLE 6-1 Disease MELAS Examples of Common Types of Mitochondrial Disorders in Children and Adults Genetics 3423 A>G 3271 T>C 3260 A>G (Maternal) Clinical Presentation/Features Infancy: rare (less than 1% of cases) Childhood and adult: (variable pattern and age of onset) encephalopathy. Cardiac involvement can manifest in infancy with cyanosis and cardiac failure (SCO2 gene mutations). and cardiac conduction block. Liver involvement is most commonly seen with Alpers syndrome (POLG mutations) and mtDNA depletion due to dGUOK gene mutations (Mandel et al. Naviaux et al.

with POLG and Twinkle gene mutations (Gago et al. 2003). leading to an increase in the generation of lactate through anaerobic pathways. 2005). however. and in mitochondrial recessive ataxia syndrome (MIRAS). 2005). but who use excessive isometric muscle contraction. early cardiac death. and pervasive developmental symptoms. SCO2 mutations. and hypoacusis. however. Neurologic examination of both parents and all siblings is always an important aspect of the family investigation. Finally. CMT2A2 [mfn2 gene]. MERRF 8363. Lactate elevation in blood is also very common in upset or struggling children who not only may have their arm held firmly (tourniquet effect). An elevated lactate level is also not specific for mitochondrial disease and can be seen in adults with type 2 diabetes or if the individual has not been fasting. short stature. Unauthorized reproduction of this article is prohibited. POLG. visual loss. MNGIE syndrome). The lactate/ pyruvate ratio can also be obtained in CSF or in culture medium from tissue culture where the absolute lactate level and the lactate/pyruvate ratio may be helpful in differentiating pyruvate dehydrogenase deficiency from primary mitochondrial cytopathies. depression (Twinkle). hypotonia. A strong maternal inheritance pattern is suggestive of mtDNA mutation. muscle discomfort or exercise intolerance. including autosomal recessive (NDUF-and SURF-1-associated Leigh disease. have been described. The family history is also helpful in diagnosing mitochondrial myopathy. Thus. autosomal dominant (OPA-1. including autism. the sensitivity is only approximately 60% (Tarnopolsky et al. Both of these conditions lead to mtDNA depletion in the brain and liver with complex I deficiency seen only in large neurons (Hakonen et al. We have seen a number of patients with adolescent-onset or later-onset psychosis as part of the clinical manifestations of mitochondrial disease (MELAS 3271. Twinkle). 2008). Blood and Urine Testing An elevated serum lactate level raises the suspicion of mitochondrial cytopathy. Nikali et al. Barth syndrome. Absence of maternal inheritance does not rule out mitochondrial cytopathy. Plasma amino acid profiles are helpful in ruling out primary aminoacidopathies and may show elevated alanine in mitochondrial cytopathies. and X-linked (PDHA1associated Leigh disease. Hudson et al. seizures. It is extremely important to specifically ask for a history of deafness. . 2008). Many families do not appreciate these conditions as manifestations of inherited mitochondrial disease and do not mention them in the context of an ill child. 2007. 103 Copyright @ American Academy of Neurology. accurate determination of lactate requires proper sample handling: samples must be collected and placed immediately on ice (as red blood cells are obligate anaerobes and thus will generate lactate unless their metabolism is inhibited by cooling) followed by prompt centrifugation. IOSCA has been associated with mutations in Twinkle (Hakonen et al. mtDNA depletion.and ANT1associated CPEO. a normal lactate level cannot be used to exclude mitochondrial cytopathy. strokelike episodes. Twinkle-associated SANDO and CPEO). Ataxia is a common symptom in children with Leigh disease and is particularly prominent in a syndrome termed infantile-onset spinocerebellar ataxia (IOSCA). or early-onset diabetes. and DDP gene mutations causing deafness and dystonia). especially those with a myopathic presentation.15(6) KEY POINT A Mitochondrial dysfunction in the brain can result in developmental delay. Serum creatine kinase activity may be elevated in some mitochondrial cytopathies. 2006. they cannot be used for ruling in or ruling out mitochondrial cytopathies. A very high level of creatine Continuum Lifelong Learning Neurol 2009. Nuclear inheritance patterns are represented in all types of mitochondrial cytopathy. Psychiatric symptoms of dementia (MELAS). Involvement of skeletal muscle can lead to hypotonia/ motor delay in children and weakness/ exercise intolerance in adolescents and adults. and MIRAS is usually associated with mutations in the POLG gene (Hakonen et al. Cardiac involvement can manifest in infancy with cyanosis and cardiac failure (SCO2 mutations) and as cardiomyopathy anytime later in life.

2008). oral communication. Specific testing for thymidine levels showing massive elevations is characteristic of MNGIE syndrome." MITOCHONDRIAL CYTOPATHIES KEY POINT A A muscle biopsy for suspected mitochondrial disease must include microscopic analysis (light and electron) with two other pieces collected into liquid nitrogen or dry ice and stored at À808C for enzyme and molecular or protein analysis. Unauthorized reproduction of this article is prohibited. 104 kinase in the absence of rhabdomyolysis would. point one more toward primary dystrophy evaluation. ragged red fibers (RRFs) tend to accumulate with age. Specifically. malate) (Barshop. particularly in teenagers in whom diet may not be optimal. PhD. 2006). another piece must be placed in liquid nitrogen or immediately on dry ice and transported to the laboratory for enzyme assessment. DiMauro. In general. and glutamyl transferase can be seen in Alpers syndrome and hepatic mtDNA depletion (dGUOK mutations).15(6) drial cytopathy. and readers may refer to specific reviews (Bourgeois and Tarnopolsky. In addition to preparing a frozen section with an optimal cutting temperature embedding medium and placing a piece of tissue into chilled glutaraldehyde. it is prudent to check levels in patients. 2004. or vitamin E in serum. Muscle biopsies for suspected mitochondrial disease should be performed in a facility with a metabolic laboratory. but high levels should also prompt consideration of ataxia telangiectasia in children and/or an underlying tumor in children or adults. Muscle Biopsy A muscle biopsy is important in the investigation of suspected mitochonContinuum Lifelong Learning Neurol 2009. . A detailed description of all of the pathologic consequences of mitochondrial cytopathies is beyond the scope of this chapter. 2004). 2004). High 3-methylglutaconic acid levels should prompt investigation into tafazzin mutations responsible for Barth syndrome. Urine analysis for organic acids can also be quite helpful with a pattern showing 3-methylglutaconic acid and various TCA cycle intermediates (fumarate. CSF studies are also helpful in ruling out mitochondrial mimics such as CSF neurotransmitter defects or disorders of CSF folate metabolism. High levels of isolated ethylmalonic acid should prompt investigation into the ETHE1 gene responsible for encephalopathy. In my experience. Given that deficiencies in each of these vitamins can cause neuropathy and ataxia. A uniform reduction in cytochrome c oxidase (COX) staining Copyright @ American Academy of Neurology. Elevation of liver aminotransferase (alanine aminotransferase and aspartate aminotransferase) bilirubin. A muscle biopsy can be obtained with a modified needle technique or an open technique (Bourgeois and Tarnopolsky. MD. Pineda et al. or at least with well-trained staff familiar with proper technique. red blood cell folate. 1992). RRFs often indicate a tRNA defect in mtDNA. Moraes et al. A needle biopsy can be obtained in less than 20 minutes in the clinic from most people aged 12 or older. Cerebral folate deficiency has also been seen as a nonspecific consequence of mitochondrial cytopathy (Garcia-Cazorla et al. in younger children or young adults who are very anxious. alterations apparent on light microscopy are less prevalent in children than in adults. Irrespective of whether an open or needle biopsy technique is used. RRFs can be present in otherwise healthy older adults. 2008. Modifications to needle biopsy tools have aided in the ability to obtain adequate sample sizes for light and electron microscopic evaluation as well as DNA and enzyme studies. approximately 10% to 13% of the patients with mitochondrial cytopathy have a coincidental deficiency of vitamin B12. however. While the presence of RRFs is one of the classic patterns of mitochondrial disease (visualized on routine muscle histochemistry by the modified Gomori trichrome stain). An early sign of Alpers syndrome may be the elevation of -fetoprotein (Robert Naviaux. a short propofol infusion (children) or lorazepam (young adults) is often required. 2006. it is imperative that the sample be handled appropriately.

The electron transport chain enzyme analysis is an essential component of the workup for suspected mitochondrial disease. while in MELAS the RRFs are COX positive. and MERFF syndrome and highlight as ‘‘ragged blue’’ fibers when combined with succinate dehydrogenase (SDH) staining (see later discussion). Paracrystalline inclusions represent upregulation of mitochondrial creatine kinase for dimeric crystalline structures in the presence of peroxynitrite (oxidative stress). Markedly pleomorphic mitochondria are seen in POLG muta- tions. however. this aspect of the analysis can be performed from fibroblasts (it is suggested that one obtain a small skin biopsy from the muscle biopsy site. These crystalline structures accumulate in the intermembrane space and disrupt the three-dimensional relationship between the inner and outer mitochondrial membrane and alter contact sites important for energy transduction.15(6) KEY POINT A A skin biopsy taken at the time of the muscle biopsy can be used for fibroblast analysis if muscle samples are limited. 2004). heteroplasmy determinations for specific mutations and deletion/ depletion analysis can also be done on the sample. usually parallel the changes with Gomori trichrome. and CPEO. and large mitochondria with homogenous matrix staining with paucity of cristae can be seen in the mtDNA depletion syndrome (Bourgeois and Tarnopolsky.can be seen in SCO2 deficiency (cardiomyopathy. type 2 diabetes). COX-negative RRFs are characteristic of MERFF. however. Other stains. 2006). For frozen sample analysis. the diagnostic yield in skeletal muscle is usually higher. Although paracrystalline inclusion is one of the hallmarks of mitochondrial dysfunction. PhD. and clinical suspicion would lead to mutation analysis of ATPase 6 and 8 genes in such cases (eg. Paracrystalline inclusions can also be seen in nonmitochondrial cytopathies due to secondary mitochondrial dysfunction (HIV medications. it is important that the tissue is frozen rapidly on dry ice or liquid nitrogen and stored in either liquid nitrogen or at less than À808C before analysis. 105 Copyright @ American Academy of Neurology. and then grow the fibroblasts for analysis). COX-negative fibers are seen in aging (older than 65 years). Kearns-Sayre syndrome. oral communication. given that histologic analysis. Significant abnormalities may not be apparent with any histologic stains. pleomorphism. The complex V assay is the only one that must be done on fresh mitochondria. Unauthorized reproduction of this article is prohibited. it is more likely in older patients and may be absent in the pediatric age group. In spite of the ongoing debate about fresh isolated mitochondrial preparations and frozen muscle. Some laboratories have found that fibroblast analysis is helpful. and strongly SDH-positive blood vessels are seen predominately in MELAS syndrome. Dr David Thorburn has extensive experience with frozen tissue analysis and has presented data showing longterm (greater than 5 years) stability of electron transport chain enzyme activity in a single large muscle sample kept at less than À808C (David Thorburn. . and changes such as paracrystalline inclusions. although the SDH stain is useful in highlighting mitochondrial proliferation in blood vessels. Furthermore. including SDH and NADH. Skeletal muscle is an ideal tissue for sampling. Electron microscopy is imperative in the evaluation of pediatric mitochondrial cytopathies. CPEO. the most important issue is that the enzyme analysis is done in an experienced laboratory and that normal reference ranges are available for that specific laboratory. spinal muscular atrophy–like syndrome) or SURF1 mutations (Leigh disease). maternally inherited Leigh disease. place the skin in sterile fibroblast culture medium. many of the conditions affecting complex V have characteristic features. and alterations of mitochondrial cristae structure may be very evident on electron microscopy without any histopathologic correlate. Continuum Lifelong Learning Neurol 2009. MELAS.

the key to diagnosis of a patient with suspected mitochondrial disease rests on direct communication with the pathology department staff member obtaining the specimen. 2002). Furthermore. MRI. SCO-1. A variety of testing protocols available have been developed and validated in adults. such as ataxia or spasticity. while complex I and IV deficiencies are seen in the mtDNA-encoded tRNA mutations. and extensive details regarding principles and practice of exercise testing have been described elsewhere (Taivassalo and Haller. with the medical director of the mitochondrial laboratory. Muscle biopsy results often guide genetic investigations. Large single deletions can be seen in Kearns-Sayre syndrome or cases of later-onset CPEO with and without other neurologic features (CPEO plus). and with a metabolic genetics team. Near-infrared spectroscopy evaluates the oxygenation/deoxygenation status of hemoglobin and myoglobin. 2004. or COX-15 mutation. Savoiardo et al. and MR spectroscopy Continuum Lifelong Learning Neurol 2009. . ataxia. The exception is in a Leighlike presentation in which enzymatic evidence of complex I deficiency is associated with an increasing number of nuclear mutations (NDUF nuclearencoded complex I subunits). Tarnopolsky. with progression to bilateral striatal necrosis sometimes seen. Laboratories must establish their own normative data. or OPA1 mutations. A pattern of strokelike lesions crossing vascular territories with a propensity for the occipital cortex should prompt investigations for MELAS syndromes. Miscellaneous Tests A variety of other ancillary tests." MITOCHONDRIAL CYTOPATHIES KEY POINT A Exercise testing may reveal a low maximal oxygen consumption ˙ (V O2max) and/or a high respiratory exchange ratio. Consequently. the peripheral extraction of oxygen by the mitochondria during exercise normally leads to deoxygenation but fails to do so in patients with mitochondrial disease (Taivassalo and Haller. An isolated complex I deficiency is the most common abnormality in pediatric enzyme assessment. 2005). Tarnopolsky and Raha. 2005). Deletions in mtDNA can be seen in a variety of conditions and be detected using long-range PCR or Southern blotting. The patterns of Leigh disease on MRI are fairly characteristic with high T2 signal in the basal ganglia ( primarily the putamen) and the brainstem as the more common findings (Saneto et al. The MRI evaluation of the brain is extremely helpful in the diagnostic evaluation of a child with suspected mitochondrial disease. Unauthorized reproduction of this article is prohibited. and retinitis pigmentosa). a definitive pathogenic mutation is often not found. In most cases of isolated complex I deficiency.15(6) (MRS) may be useful in the diagnosis of mitochondrial cytopathies. A severe COX deficiency in a child with cardiomyopathy or spinal muscular atrophy pattern would be consistent with a SCO-2. Twinkle. 2005. 2008. however. have nonspecific periventricular white Copyright @ American Academy of Neurology. near-infrared spectroscopy. Global reductions in many enzymes can be seen in the mtDNA depletion syndromes. and an isolated COX deficiency in a child with a Leighlike presentation would be most consistent with a SURF-1 mutation. For most neurologists. often cannot complete exercise protocols. The principle of exercise testing is that a primary mitochondrial disorder will generally reduce the maximal oxygen consump˙ tion per unit time ( VO2) of a person and ˙ lower the VO2max during exercise and/or increase the rate of lactate/CO2 production ( high peak respiratory ratio during exercise). including exercise testing. Multiple deletions are often seen in POLG. ANT1. 106 neurogenic muscle weakness. A downside to the use of exercise testing in children with mitochondrial disease is that most children under 6 years of age cannot comply with testing or the equipment is not suitable for them. Most patients with mitochondrial encephalopathy. thymidine phosphorylase (ECGF1). children with cognitive issues and major neurologic impairments.

dystonia. a normal scan does not rule out mitochondrial disease. demyelination. It is clear that the diagnostic criteria for each of the aforementioned templates is influenced by the strengths of the clinic/ laboratory making the proposal. It is very important to entertain the possibility of alternative diagnoses until arriving at a definitive diagnosis. Consequently. Leigh disease is associated with complex I (approximately 35%). . it is important for a given center to adopt the criteria that best fit with the available testing methods. and posterior columns of the spinal cord in a child with a neurodegenerative disease (Morava et al. 2004). chromosomal anomalies. can be misleading. ataxia. individuals have proposed several diagnostic criteria for mitochondrial disease (Bernier et al. Importantly. such as electron transport chain enzyme activities. and/or respiratory abnormalities (apnea/hypopnea). particularly if the MRS voxel is placed in an area of involvement (basal ganglia or abnormal white matter) (Sijens et al. and we have seen many children who have had abnormal mitochondrial electron transport chain enzyme tests (especially complex I deficiency) in whom subsequent testing confirmed an alternative diagnosis (eg. 2003. or pyruvate dehydrogenase (approximately 15%) deficiencies. and mtDNA mutations (approximately 20%) (Berger et al. SPECIFIC PEDIATRIC MITOCHONDRIAL DISORDERS Leigh Disease Leigh disease was first described by Dennis Leigh in 1951 based on neuropathologic findings of cystic cavitation. MRS using proton (1H) spectroscopy can show elevated lactate in brain parenchyma. For example. Vilarinho et al. 2007). optic atrophy. chromosomal deletion. 2002. 2008. consequently. tremor. if the local laboratory uses frozen muscle for electron transport chain assessment. optic atrophy. Thorburn et al. Comprehensive analyses of the MRI and MRS findings associated with mitochondrial cytopathies have been published (Farina et al. Most children with Leigh disease do not survive beyond age 5. 2008). Krabbe]. 2002. and definite mitochondrial disease for these patients. The progression of neurologic dysfunction can be rapid. 2006. ataxia. Valanne et al. Leigh disease is a rapidly progressive encephalopathy occurring in infancy or childhood with a mean age of onset of approximately 2 years. ophthalmoplegia. spasticity. congenital muscular dystrophy). Saneto et al. many pediatric neurologic disorders can have clinical features that mimic mitochondrial disease (Rett syndrome. complex III (approximately 5%). and neuronal loss predominately in the thalamus. Zhang et al. 107 Copyright @ American Academy of Neurology. The diagnosis of mitochondrial disorders is ultimately based on a composite of several tests. Given the treatment and counseling implications. Munoz ˜ et al.matter high signal on T2 and fluidattenuated inversion recovery imaging. brainstem. Unauthorized reproduction of this article is prohibited. probable. and respiratory changes. dystonia. spasticity. Rett syndrome. metachromatic. 1997. complex IV (approximately 20%). Phosphorus31 MRS ( 31P-MRS) can show a reduced brain phosphocreatine and/or a low phosphocreatine/inorganic phosphate ratio. The neurologic deterioration is often more apparent during periods of concurrent illness and other metabolic stressors. For example. 1998). ophthalmoplegia.15(6) KEY POINT A Leigh disease often presents before age 2 with psychomotor regression. complex II (approximately 5%). it would not be useful to use criteria based on isolated mitochondria from a fresh biopsy. and sole reliance on a single test. Manifestations include developmental delay or psychomotor regression. Sijens et al. leukodystrophies [eg. Prader-Willi syndrome. 2008. Kirby et al. Continuum Lifelong Learning Neurol 2009. vascular proliferation. we have found it useful to use the labels possible. etc). 2008. with compromised respiratory status being the main indication for intensive care admission. 1999. and children with a previously normal scan may demonstrate abnormalities only during acute decompensation.

as should point mutation analysis for ATPase mutations associated with Leigh disease (9176 T>G/C. At our institution we have provided prenatal testing for previously documented Leigh disease–associated mutations in three separate families and have had successful outcomes (not affected) in all three cases. complex IV = SURF-1. pyruvate dehydrogenase analysis should be considered." MITOCHONDRIAL CYTOPATHIES Schiff et al. 2007. Motor examination demonstrated mild hypotonia and thin muscle bulk. normal is less than 2. 9185 T>C. . with a recent study showing that 40% of children with mitochondrial cytopathies had cardiomyopathy (Scaglia et al. never attained the ability to ambulate. children with mitochondrial cytopathy manifesting solely with skeletal Case 6-1 A 13-month-old boy presented with a 2-month history of decreased eating and falling off the growth curve for weight. 29% had dilated cardiomyopathy. Specific mutation analysis is also very helpful from a genetic counseling and prenatal diagnostic perspective (Case 6-1). A diagnosis of complex IV deficiency Leigh disease was confirmed by the finding of a homozygous SURF1 mutation 845-846 delCT (Ser272cys). This case demonstrates the often ominous outcome in children presenting with developmental regression. 14459 G>A). LRPPRC). On neurologic examination. If the electron transport chain enzyme activity for complexes I through IV are normal. He was unable to initiate voluntary eye movements to an object of interest. Developmental history indicated that he started to cruise on furniture at 12 months but appeared weak. particularly in the ventral aspect of the medulla. Serum lactate levels were mildly elevated on two of three blood draws (3. The nonspecificity of the weight loss and the absence of neurologic symptoms until several months into the disease course diverted diagnostic attention initially toward more of a gastrointestinal-focused investigation. He would look at his mother and father to command but did so by moving his head to gain visual fixation. and 13% showed echocardiographic evidence of left ventricular noncompaction. and head circumference. he was alert and demonstrated age-appropriate stranger anxiety.2 mmol/L and 2. 2006. Comment. and subsequently lost his ability to stand. Most patients had hypertrophic cardiomyopathy (58%). and the plantar response was flexor. Prenatal counseling for the family was offered. with a survival rate of only 18% by age 16. Unauthorized reproduction of this article is prohibited. The diagnosis of cardiomyopathy in a child with mitochondrial cytopathy implies a poor prognosis. Cranial MRI demonstrated symmetric hyperintensity and increased fluid-attenuated inversion recovery signal bilaterally in the brainstem. mtDNA (10158 T>C. 2004). 11777 C>A. Parents were devastated by the diagnosis and then revealed that the mother was 10 weeks pregnant with their second child. Zhu et al. 108 Continuum Lifelong Learning Neurol 2009. In contrast. Muscle biopsy demonstrated COX enzyme activity less than 5% of normal. consistent with ocular motor apraxia. 1998). Zhang et al. Impaired swallowing necessitated a percutaneous gastrostomy tube. The marked changes on MRI showing much more extensive changes than are revealed by the clinical examination are a common feature in patients with Leigh disease. Muscle stretch reflexes were normal with no clonus.15(6) Copyright @ American Academy of Neurology.2 mmol/L).8 mmol/L. Cardiomyopathies Cardiomyopathy is a common finding in pediatric and adult mitochondrial cytopathy. Optimism was very high for prenatal diagnosis given that the SURF1 mutation is nuclear. 8993 T>C/G). height. A muscle biopsy with electron transport chain enzyme activity analysis is helpful to target definitive mutational analysis (complex I = NDUF mutations. which was associated with rapid weight gain and improved neurologic function and alertness. 10191 T>C. MRS demonstrated a lactate peak in the basal ganglia.

and some can present with a spinal muscular atrophy (lower motor neuron disease) picture (Mancuso et al. In addition. Cardiomyopathy can be a part of the phenotype in MELAS 3243 A>G or the predominant symptom in other mtDNA mutations (1555 A>G. 2008. More recently. 2001).myopathy experienced a survival rate by age 16 of 95% (Scaglia et al.15(6) KEY POINT A Cardiomyopathy may be a subclinical comorbidity in some mitochondrial disorders (ie. and many succumb in the first few months of life ( Jaksch et al. mtDNA depletion is characterized by a reduction in mtDNA copy number. and the clinical features can overlap with TK2-associated mtDNA depletion. Hypertrophic cardiomyopathy may be the predominant and/or exclusive feature in children with defects in COX assembly. These mutations interrupt the deoxyribose nucleotide pathway and inhibit incorporation of the deoxynucleotide triphosphates into the mtDNA. afterload reduction) and prognostication. resulting in mtDNA depletion. 2001b). 1555 A>G. For example. A cardiomyopathy is often asymptomatic and usually picked up as part of the workup in a child with suspected mitochondrial disease. 2004). Most children with SCO2 deficiency die before 2 years of age. 3260 A>G. Most children with SCO2 deficiency also show significant hypotonia owing to alpha motor neuron involvement. Although conduction disturbances can be seen in the cardiomyopathies. 2007. SCO2). including SCO2. 4320 C>T. 4330 A>G. but dilated and noncompacted forms of cardiomyopathy may also occur. 2001. 4295 and 4269 A>G. 2002. 2001). 8296 A>G. 2003. patients rarely require pacemakers. mutations in POLG. and mutations have been demonstrated in the deoxyguanosine kinase (dGUOK) gene in patients with the hepato-encephalopathic form (Mandel et al. Jaksch et al. 2001). and POLG mutations manifest with Alpers syndrome (Mandel et al. Unauthorized reproduction of this article is prohibited. Hudson et al. although those with Kearns-Sayre syndrome often show progressive conduction block requiring pacing in the absence of cardiomyopathy. and OPA1 (Amati-Bonneau et al. The dGUOK mutations usually present with progressive hepatic failure. Hudson et al. MELAS) or can be the defining feature (ie. . and approximately 20% of patients with the encephalomyopathic form have TK2 mutations (Carrozzo et al. 2001). These children can be indistinguishable at onset from those with Werdnig-Hoffman disease (spinal muscular atrophy type I). Hakonen et al. The mtDNA depletion syndromes often present in the first few months of life and frequently have a rapidly progressive and fatal outcome. mutations in TK2 can present with encephalopathy and hypotonia. Mandel et al. 2003a. 2001b). 2001). 8363 G>A. 109 Copyright @ American Academy of Neurology. Saada et al. Continuum Lifelong Learning Neurol 2009. Mitochondrial DNA Depletion mtDNA depletion syndromes are categorized into two groups: an enceph- alomyopathic form and a hepatoencephalopathic form. and COX15 mutations (Antonicka et al. Twinkle. Significant clinical heterogeneity occurs for any given mutation. 2005. 3260 A>G. Saada et al. The discovery of these specific mutations is helpful in understanding pathogenesis of the syndrome and for accurate genetic and prenatal counseling. COX10. and thymidine kinase (TK2) in children with the encephalomyopathic form of mitochondrial depletion syndrome (Saada et al. Mutations in dGUOK are found in approximately 10% to 15% of all patients with the hepato-encephalopathic form of mtDNA depletion. Most cases of cardiomyopathy in mitochondrial diseases are hypertrophic. 2008) have also been associated with mtDNA depletion. A major distinguishing feature between spinal muscular atrophy type 1 and SCO2 mutations is presence of high lactate concentration in serum/plasma seen in SCO2. and 15243 G>A) (Case 6-2). Every child with mitochondrial cytopathy should be screened for cardiomyopathy using echocardiography given the opportunity for therapeutic intervention (ie. 9997 T>C.

The comprehensive family pedigree highlights the extreme clinical heterogeneity that can arise from a single point mutation (cardiomyopathy. 110 children can present with a renal Fanconi syndrome. Genetic analysis revealed a 3260 A>G transition mutation with high heteroplasmy in heart tissue and skeletal muscle (mutant 90%). In spite of afterload reduction. congestive heart failure. Cardiovascular workup revealed a hypertrophic cardiomyopathy with very low ejection fraction. the disease can present with psychomotor regression and/or progressive weakness in childhood. such treatment ensures timely and complete delivery of prescribed medications. seizures. seizures.’’ One maternal uncle had severe migraines and exercise-induced rhabdomyolysis. had resting lactic acidemia. and progressive external ophthalmoContinuum Lifelong Learning Neurol 2009. . Exercise-induced deafness was reported by the mother to her family physician. and progressive emaciation. All children born to the maternal aunts had lactic acidemia and exercise intolerance. while the two children of the maternal uncle were asymptomatic and had normal resting lactate levels." MITOCHONDRIAL CYTOPATHIES Case 6-2 An 8-year-old girl presented with shortness of breath on exertion and cyanosis. Occasionally. The maternal grandmother died at age 42 with ‘‘encephalitis. and increased exercise capacity with activities of daily living.8 kg of weight. Comment.15(6) plegia. without further investigation. who found her hearing to be normal at rest and dismissed the symptom as odd. Seizures were managed with carbamazepine. although no family members were hypertensive or hypercholesterolemic. gained 1. In addition. exercise-induced rhabdomyolysis. Pathologic examination of the native heart demonstrated mitochondrial proliferation of pleomorphic mitochondria with paracrystalline inclusions. In the postoperative period she was encephalopathic. Copyright @ American Academy of Neurology. seizures. The proband went on to develop multiple strokelike episodes with incomplete neurologic recovery. migraines. strokelike episodes. Evaluation of family members revealed two siblings with lactic acidemia (6 mmol/L to 8 mmol/L) and moderate to severe exercise intolerance. Unauthorized reproduction of this article is prohibited. as valproic acid is contraindicated in patients with mitochondrial disease (valproic acid impairs mitochondrial carnitine transport). This case also illustrates the clinical improvement that is often seen in patients with mitochondrial cytopathy when adequate nutrition and hydration are provided. and another aunt also had migraines. The mother experienced exercise-induced deafness. and had suffered a severe strokelike episode at age 42. Of particular relevance is the fact that it was not until the proband presented with cardiac failure that the true nature of the familial disorder was revealed. hypoacusis. heart failure worsened rapidly and she received a cardiac transplant. and the early onset of strokes was thought to be related to cholesterol or blood pressure. Migraines are a common neurologic disorder. had less abdominal pain. a maternal aunt also had migraines and had experienced a single strokelike episode at age 38. Serum lactate levels rose to over 20 mmol/L (normal is less than 2 mmol/L). She had a percutaneous gastrostomy tube placed and over the ensuing year had marked improvement in neurologic function. and intestinal pseudo-obstruction).

2000). 111 Copyright @ American Academy of Neurology. 15990 C>T). Unauthorized reproduction of this article is prohibited. The three common mutations (11778 G>A = 69%. MERRF can present as isolated myoclonic epilepsy with and without ataxia. Targeted PCR-restriction fragment length polymorphism is the most common method used to screen for the ‘‘common’’ mutations. and skeletal muscle showing depletion in the encephalomyopathic form. and 14484 T>C = 13%) account for the majority of cases. including severe obsessive-compulsive disorder. and type 2 diabetes. exercise intolerance. strokelike episodes. denaturing high-performance Continuum Lifelong Learning Neurol 2009. mtDNA depletion is very often tissue specific with liver being the criterion standard for the hepato-encephalopathic The age of onset can range from childhood to middle age (forties) and usually a progressive decline in function occurs. Mitochondrial DNA Disorders mtDNA disorders are maternally inherited and arise from specific point mutations in either tRNA or specific subunit regions of the mtDNA. Some of the LHON mutations can present with a multiple sclerosis–like syndrome. Other LHON mutations have been associated with dystonia. isolated myopathy (618 T>CC. 15084 G> are common. The progression of MELAS can resemble multiple sclerosis and be chronically progressive or relapsing and remitting. 15924 A>G). more adults than children are identified with mtDNA point mutations. . proximal myopathy. myopathy. 13513 G>A. In our experience. In general. complex I deficiency Leigh disease (10191 T>C. especially the 14459 G>A mutation (Tarnopolsky et al. encephalopathy. 2004). Leber hereditary optic neuropathy (LHON) usually results in painless. 3460 G>A = 13%. peripheral neuropathy. 18S). and exercise intolerance (predominately cytochrome b mutations such as 14846 G>A. 3250 T>C.mitomap. dementia. ataxia. An updated list of all reported pathogenic and polymorphic mtDNA sequence variants can be found on Mitomap (www. with more men carrying the mutation developing symptoms (40% to 70%) as compared with women (20% to 30%). and psychotic features. 3302 A>G. depression. including hypoacusis. The age at onset of symptoms is as variable as the clinical phenotypes with presentations starting in infancy and up to adult age groups (Case 6-2). 14459 G>A). Several other mtDNA mutations that can present in the pediatric age group include lethal infantile mitochondrial disorder (15923 A>G. as well as type 2 diabetes.15(6) KEY POINT A mtDNA disorders are maternally inherited and arise from specific point mutations in either tRNA or specific subunit regions of the mtDNA. Point mutations in the tRNA regions of mtDNA often result in variable combinations of electron transport chain enzyme activity reduction. rapidly and 15615 G>A) (www.mtDNA depletion is measured using real time PCR for the copy number of mtDNA relative to a nuclear DNA housekeeping gene (eg. and multiple lipomas ( particularly in the head and neck). neuropsychiatric manifestations. 12320 A>G. ophthalmoplegia. including the most common 11778 G>A mutation (Vanopdenbosch et al. 10158 T>C. 12706 T>C. complex I = ND subunits. whereas isolated enzyme activity reductions can point to specific protein subunit DNA regions (eg. 5521 G>A. A marked sex difference is found. whereas exploratory analysis for new mutations can be done with DNA sequencing. MELAS syndrome is the most common of the mtDNA point mutations and can show an extremely wide range of phenotypic manifestations. mitomap. Mutations exist in essentially every region of the mtDNA with over 100 specific point mutations now considered pathogenic and over 200 more reported and awaiting confirmation. 15059 G>A. Mutations exist in essentially every region of the mtDNA with over 100 specific point mutations now considered pathogenic and over 200 more reported and awaiting confirmation. visual loss with centrocecal scotoma in teenagers or young adults. complex III = cytochrome b).

The associated peripheral neuropathy may be the presenting feature. myocerebrohepatopathy. Patients will show very elevated levels of plasma thymidine. hypoacusis. and often multiple mtDNA deletions or depletion in skeletal muscle. The evaluation of these patients will show variably elevated serum lactate levels and a demyelinating peripheral neuropathy. The specific nuclear gene responsible for this condition has not yet been identified. Most of the reported mutations have been associated with progressive external ophthalmoplegia in adults. 1994). leukodystrophic changes on MRI. coma.niehs. Coenzyme Q10 (CoQ10) deficiency has been reported in a variety of clinical syndromes. nih. elevated CSF protein. Miscellaneous Conditions Kearns-Sayre syndrome is a multisystem mitochondrial disorder characterized by progressive external ophthalmoplegia. and other infantile hepatocerebral syndromes associated with mtDNA depletion in children. These patients usually have high lactate levels in plasma. malabsorption. Mutations in the POLG gene have also been seen in children with Leigh disease. Myoneurogastrointestinal Encephalomyopathy Syndrome MNGIE is an autosomal recessive condition associated with severe abdominal pain. including childhood-onset ataxia with cerebellar atrophy. POLG is the sole polymerase for mtDNA replication. Unauthorized reproduction of this article is prohibited. and other ataxia-neuropathy syndromes resembling Friedreich ataxia. The gene responsible for this disorder is ECGF1. which encodes thymidine phosphorylase involved in the degradation pathway of thymidine (Nishino et al. myocerebrohepatopathy. ataxia. 2004) (Case 6-4). neuropathy. a variable reduction in electron transport chain enzyme activity. SANDO." MITOCHONDRIAL CYTOPATHIES KEY POINT A Most POLG mutations are associated with progressive external ophthalmoplegia in adults. ataxia. and the diagnosis is based on the clinical and muscle biopsy features. Polymerase Gamma Mutations and Alpers Syndrome The explosion of information regarding polymerase gamma mutations began when Naviaux discovered low POLG activity in a child with fatal seizures. 1999). but the ETC enzyme activity in skeletal muscle may be normal. and an exonuclease domain.15(6) be variably symptomatic or even asymptomatic (Hirano et al. and ophthalmoplegia with the A467T and W748S POLG mutations has also been described (Tzoulis et al. heart block. Close to 100 mutations have been reported in each of the three main regions and have been listed in the Human DNA Polymerase Gamma Database (http://tools.977 bp) in muscle (not white blood cells) detected by long-range PCR or Southern blot. hepatopathy. headache. liquid chromatography. . The POLG protein has a polymerase domain. Alpers syndrome. and onset before the age of 25. and weight loss. myopathy. a linker region. A teenage-onset disorder with seizures. Charcot-Marie-Tooth neuropathy. myoclonus. 112 Copyright @ American Academy of Neurology. and muscle biopsy shows RRFs. The leukodystrophy may become apparent during periods of concurrent illness in which a delirium/encephalopathic picture can appear. The age of onset is usually in the early to late teenage years with progression of the gastrointestinal problems leading to a feeding tube and eventually total parental nutritional requirement. and white blood cell preparations can be used to demonstrate the reduced thymidine phosphorylase activity (Marti et al. Alpers syndrome. MIRAS. and sequencing microarrays. and a single large-scale deletion (4. and lactic acidosis (Alpers syndrome) (Naviaux et al. but the associated leukoencephalopathy may Continuum Lifelong Learning Neurol 2009. 1999). encephalopathy and seizures. 2006) (Case 6-3). and other infantile hepatocerebral syndromes associated with mtDNA depletion in children. Mutations in POLG result in mtDNA depletion and sometimes deletions (especially in adult-onset cases). retinitis pigmentosa.

Examination showed normal mental status. 8. He was fine otherwise with a negative functional inquiry. Serum lactate was elevated at 3. power. Comment. did not smoke. and pathologic reflexes were absent. and previous reports have demonstrated ataxia and epilepsy in an adult (age 55) positive for the W748S +/À mutation (Tzoulis et al. vitamin B12. C-reactive protein. Muscle stretch reflexes were normal. Dysmetria was noted in both arms and legs. 2.15(6) Copyright @ American Academy of Neurology. He first noticed this while playing soccer when he had difficulty turning suddenly and would bump into people. 6. This case describes the value of muscle biopsy with enzyme workup as well as full mitochondrial screening. Continuum Lifelong Learning Neurol 2009. and worked in a university employee relations office. NARPP 8993 and LHON 11778. aprataxin and SCA 1. autoimmune workup. and his symptomatic brother was being screened for the mutation. 2008). CABC1. and scanning speech. Several reports have documented pediatric-onset seizures in ataxia with W748S homozygous state (Engelsen et al. He had no allergies. cranial nerves were otherwise normal. including lactate and urine organic acids in atypical cases of ataxia. IV normal and citrate synthase slightly high. thyrotropin. He could not perform tandem gait. 3. Two other brothers were reportedly without symptoms. 2006). including mitochondrial parahydroxybenzoid-polyprenyltransferase (CoQ2). vitamin E. 7. Lamperti et al. Cranial MRI showed nonspecific high signal and periventricular white matter with no cerebellar atrophy. Family history revealed that his mother had balance problems for as long as he could remember. APTX. and tone proximally and distally in the upper and lower extremities. Point mutation analysis from muscle-derived DNA was normal for MELAS 3243. his brother reported similar symptoms when asked specifically and was evaluated by a neurologist at another center who found similar clinical findings. for initially his brother was reported to have no symptoms but after 1 year he clearly had identical symptoms. and complete blood count values were normal. Mutation analysis revealed a 2243 G>C heterozygous mutation in POLG1 gene causing a Trp748Ser mutation (W748S +/À). indicative of mitochondrial proliferation. his past history was positive for a three-vessel bypass in 1995 for atherosclerotic heart disease secondary to hypercholesterolemia. antigliadin antibodies. folate. 3271. Motor examination showed normal bulk. rarely consumed ethanol. Amino acids. He had been on statin medications for 14 years prior to presentation. 2006. and isolated myopathy (Horvath et al. Unauthorized reproduction of this article is prohibited. The sequence variant was not found in either of the two asymptomatic children. Several genes have been found in association with CoQ10 deficiency.Case 6-3 A 56-year-old man presented with a several-year history of feeling a bit off balance. 17 gene mutations. This also shows the value of ongoing follow-up in patients. red blood cell. Electron transport chain enzyme activities showed a slight reduction in complex I + III relative to citrate synthase (8% ratio) with complex II + III. One brother died from cancer at age 65 and had no reported problems. . Diagnosis can be elusive as highlighted by the relatively normal MRI and the absence of any classic mitochondrial changes on muscle biopsy with histology and electron microscopy. Urine organic acid showed a large elevation of 3-methylglutaconic acid and the moderate elevation of ethylmalonic acid. 113 cardiomyopathy and renal failure.2 mmol/L). Of interest also is the fact that subsequent lactates have been normal (hence the value of three lactates taken at different times in suspected cases of mitochondrial cytopathy). He also had a difficult time suddenly trying to get out of the way of the ball when it was coming at him. Vastus lateralis muscle biopsy showed borderline type II fiber atrophy and prominent lipid droplets on electron microscopy. In the preceding 2 months he had noted some slurring of his words. This also shows that having a single allele mutation for the W748S mutation can lead to later-onset neurologic symptoms. His 29-year-old son and 31-year-old daughter had no neurologic symptoms.0 mmol/L (normal is less than 2. EMG and nerve conduction studies were normal. 2003) CoQ10 is the electron acceptor for complexes I and II and transfers electrons to complex III of the electron transport chain. and prenyl (decaprenyl) diphosphate synthase subunit 2 gene (PDSS2) or PDSS1 (DiMauro et al. Sensory examination was normal. horizontal nystagmus. During the course of the workup.

stated that the patient should be admitted to the adult care hospital. because common tests such as lactate and muscle structure were normal. who was not familiar with the family. Plasma thymidine levels were markedly elevated (5. A muscle biopsy of the vastus lateralis showed normal histology and ultrastructure and no mtDNA deletions. Of particular relevance are the issues faced in caring for a young terminally ill adult with a rare pediatric-onset disease. normal range less than 0. Copyright @ American Academy of Neurology. He arranged compassionate admission to the pediatric care facility. vitamin B12. He also described some nausea and had lost approximately 0. and borderline slowing of nerve conduction studies in the peroneal nerve. mild pes cavus. Genetic testing for CMT1A and CMTX was negative. and thymidine phosphorylase activity in white blood cells was very low (50. His muscles were generally thin with mild distal atrophy in the intrinsic foot muscles and 4/5 weakness of dorsiflexion and eversion. the patient continued to lose weight and developed persistent abdominal pain. confirmed to be pneumonia at his local emergency department.15(6) tration in skeletal muscle to below 50% of healthy controls. p. The pediatric facility on-call physician. 2007). Vibration sensation was reduced in the lower extremities. Lopez-Martin et al. and feeling off balance. Over the ensuing 3 years he developed severe abdominal pain and gastroparesis requiring total parenteral nutrition.7.254 T>P mutation in the ECGF1 gene. as were lactate. was profoundly weak in all four limbs. The parents and the patient were frantic and called their neurologist at home. Comment. Family history was negative for confirmed mitochondrial disease. Unauthorized reproduction of this article is prohibited. This case discussion highlights the characteristic picture of MNGIE syndrome. Nerve conduction study confirmed a motor and sensory axonal neuropathy.05 mol/L). stubbing his toe. In the preceding few months he had increasing problems tripping. where the patient died from sepsis following a prolonged stay in the intensive care unit. 114 2007. He developed increasing respiratory distress. His parents requested transfer of care to the pediatric facility.91 kg over the same time period. he weighed 34 kg. At age 18. He was areflexic in the upper and lower extremities." MITOCHONDRIAL CYTOPATHIES Case 6-4 A 12-year-old boy presented with a several-month history of weakness and clumsiness. . The attending adult care physician told the family that he had never even heard of MNGIE. A diagnosis of MNGIE was confirmed with mutation analysis showing homozygosity for the c. This condition is suspected when linked muscle enzyme assays (I and III. Many pediatric facilities will extend their age of care for patients with such disorders. then transition of care should occur well before the 18th birthday to ensure that the adult facility will have a comprehensive medical record that includes detailed plans of care. although his mother had absent ankle reflexes. and pain and temperature sensation were reduced in a stocking distribution. 2003). and his teachers noted that he had difficulty in maintaining concentration. Over the following 6 weeks. but this care plan must be discussed prior to age 18 years. Investigations for common forms of leukodystrophy were negative. and very long-chain free fatty acids. An MRI revealed confluent white matter high signal on T2-weighted images. The importance of making the diagnosis comes from the fact that some of the children have shown a clinical response to very high doses of CoQ10 (Lamperti et al. Examination revealed a thin boy with normal mental status and cranial nerve examination.770 A>C. yet the individual components do not show reductions and are confirmed by showing reduced CoQ10 concenContinuum Lifelong Learning Neurol 2009. The case also highlights the challenges in making a diagnosis of mitochondrial disorder. where he received all care until he reached the age of 18. as well as the diagnostic challenges. and II and III) show low activity. normal range = 634 +/À 237 ng/h/mg protein). If admission for young adults is not permissible at the pediatric facility. and letters documenting approval for admission as an adult must be in the medical record as well as in the family’s possession. and was dependent for all aspects of care.

Given that propofol only induces conscious sedation. cholestasis. Cornstarch. 2009. Unauthorized reproduction of this article is prohibited. Care must be taken not to clog percutaneous endoscopic and gastrostomy tubes when using cornstarch. Hinson et al. 2007). the addition of complex carbohydrates such as Polycose or cornstarch may be required. in general. however. In addition to Leigh disease described earlier in this chapter. optic atrophy. ataxia. 2007). progressive external ophthalmoplegia. given the potential benefit from the ketosis. . amino aciduria. From an anesthetic perspective. It is important to maintain normothermia throughout the anesthetic period to avoid an increase in shiveringinduced thermogenesis. cristae organization). we always use local anesthesia. it is important to postpone any surgical procedure during a period of even minor concurrent illness. 2007). Gastrostomy tube placement should be considered early in any child or adult with weight loss. The myopathy is characterized by RRFs and COXve fibers and multiple mtDNA deletions (Amati-Bonneau et al. 2008). early death (GRACILE syndrome). or lumbar puncture we have found that propofol and local anesthesia have been well tolerated without a single adverse reaction in several hundred procedures. however. With respect to specific anesthetic agents. is difficult to add to formula but can be mixed into baby foods. It is also important to postpone any surgical procedure during a period of even minor concurrent illness. TREATMENT OF MITOCHONDRIAL DISORDERS General Care Issues From a nutritional perspective. In patients with mitochondrial disease.Recently CPEO plus ataxia phenotypes and multiple sclerosis–like phenotypes have been described in adults with mutations in OPA1 (Hudson et al. Fellman et al. energy expenditure can be quite low and care must be taken to not overfeed children and induce obesity. Since many infants and children have limited exercise capacity. A 115 Copyright @ American Academy of Neurology. or creatine monohydrate. malignant hyperthermia-like situations can arise with a metabolic crisis induced by additional metabolic stress that then can mimic some aspects of malignant hyperthermia. there does not appear to be a particular predisposition toward true malignant hyperthermia in patients with mitochondrial cytopathy. lactic acidosis. axonal motor-sensory neuropathy. as persistently inadequate caloric intake directly compromises residual mitochondrial function and exacerbates neurologic and multiorgan failure. Polycose. and Bjornstad syndrome (sensorineural hearing loss and pili torti) have been reported (Hinson et al. which can further impair mobility and lead to other chronic health care issues. one of the most important issues is to avoid prolonged periods of fasting. often with preapplication of a topical anaesthetic such as a eutectic mixture of local anesthetics (EMLA) cream 60 minutes before the procedure. and. 2008. especially when severe seizures are a feature. 2008). The provision from 10% aqueous dextrose solution (D10W) and/or total parenteral nutrition is important to prevent a fasting-induced metabolic stress. A high-fat diet may be of benefit in complex I deficiency. Although traditionally associated with isolated optic atrophy (Alavi et al. cases of growth retardation. OPA1 is a dynamin-related GTPase that is involved in mitochondrial maintenance (fission. 2008).15(6) KEY POINTS A Nutritional support for all patients with mitochondrial disease is critical. These conditions are all associated with a reduced complex III activity and mutations in the BCS1L gene. Verny et al. more frequent meals throughout the day are preferable. Several disorders have been associated with mutations in the BCS1L gene involved in complex III assembly (Blazquez et al. iron overload. 2008. and myopathy starting in childhood or young adulthood (Amati-Bonneau et al. For brief procedures such as a needle muscle biopsy. Polycose is generally much easier to blend into food but does not have as long a duration of action as cornstarch. most children do not tolerate prolonged periods of fasting. several groups have described hypoacusis. Continuum Lifelong Learning Neurol 2009. In some cases. EMG.

and in children with a seizure disorder. simethicone can be introduced. Gabapentin is often well tolerated and one of the first-line therapies for neuropathic pain. with the potential for aspiration. These symptoms may be improved with elemental diets or total parenteral nutrition if necessary. followed by stool softeners. A high degree of anxiety and marital strife may occur in families affected by maternally inherited disorders. For severe spasticity. most notably in children with POLG mutations (McFarland et al. we have had success with pregabalin in patients who cannot tolerate gabapentin. and the complexities and intensity of care. with individuals blaming themselves or their spouse for the condition. Seizures are common in children with mitochondrial cytopathy. Psychological and emotional support for the caregivers is very important. A number of patients experience gastrointestinal problems particularly. Uusimaa et al. with MNGIE syndrome in which abdominal Continuum Lifelong Learning Neurol 2009. is quite common and can lead to serious chemical pneumonitis. and diarrhea predominate. patients. occupational therapy and physiotherapy may help to prevent and treat contractures. botulinum toxin injections can be of benefit. can be seen. and their families. benzodiazepines are quite helpful. lactulose. More recently. As children get older and gain insight into their disorder. Some patients may benefit from tizanidine with varying levels of success. 2008). We have also found that a combination of capsaicin cream and EMLA (50/50 mix) is often effective for mild to moderate dysesthesias from peripheral neuropathy and has the advantage of being nonsystemic. Topiramate is particularly sedating in children with mitochondrial cytopathy but still can be used in selective cases. which has a great deal of educational information (eg. standard anticonvulsants for the given seizure types should be employed albeit with a few caveats. especially in MNGIE syndrome and SANDO. severe constipation. multiple hospitalizations. In general. ." MITOCHONDRIAL CYTOPATHIES 116 Peripheral neuropathy and other types of neurogenic pain can be a feature of mitochondrial cytopathy. In children with severe spasticity limiting hygiene or activities of daily living. Mineral oil–based laxatives should not be used because reflux. Psychological support is important for patients with mitochondrial cytopathy and their families. depression and despair may develop. Early intervention with counseling and possibly antidepressant medications may Copyright @ American Academy of Neurology. and often people find comfort and support through a group such as the United Mitochondrial Disease Foundation. High-fluid and high-fiber intake is the first-line therapy. in some cases leading to intestinal pseudo-obstruction. MITO 101: A Primer for Physicians and Patients) and conducts a yearly conference for scientists. Buscopcan may be helpful in alleviating abdominal cramps and pain. Valproic acid should not be used except as a last resort because it may trigger Reye syndrome– like hepatic dysfunction in children with mitochondrial cytopathy. 2008. glycerin suppositories if no bowel movement occurs in 3 days. In a variety of other conditions ( particularly MELAS). A high degree of stress in the families of children with severe mitochondrial cytopathy is also posed by the need for medical appointments. particularly in those who experienced the death from mitochondrial cytopathy of an older sibling or other family members.15(6) pain. The use of dantrolene should be avoided in patients with mitochondrial disorders because it can result in muscle weakness and fatigue. and if excess gas production is present. it is best to start gabapentin in the evening and gradually titrate the dose to avoid somnolence. cramps. Baclofen is a good first-line medication for spasticity. Unauthorized reproduction of this article is prohibited. however.

botulinum toxin [focal]. In general. B12. zinc. avoid valproic acid).htm). the overall efficacy has not been dramatic. encephalopathy.umdf. If children fall off growth curves and show signs or symptoms of undernutrition and do not respond to a nutritionist’s suggestions. avoid aspirin and triptans in mitochondrial myopathy. E. calcium. Tarnopolsky and Raha. They should not exercise in the fasted state or with a concomitant illness. magnesium).be of benefit. lactic acidosis. botulinum toxin [focal]. and a high-fat diet may also be of some benefit in pyruvate dehydrogenase mutations. A more complete discussion of each of these compounds can be found in review papers (Murphy et al. (3) Alternative energy sources such as creatine monohydrate increase intracellular phosphocreatine stores with some evidence of success in vivo and in vitro (Hultman et al. Fever should be treated with acetaminophen (10 mg/kg every 4 hours to 15 mg/kg every 4 hours). riboflavin. folate for red blood cells). however.15(6) Copyright @ American Academy of Neurology. Tarnopolsky et al. trihexyphenidyl). -lipoic acid). CoQ10. 2001). Several trials have been completed. Avoid prolonged (greater than 12 hours) TABLE 6-2 General Principles of Treatment " Treat Underlying Neurologic Issues Seizures (antiepileptic drugs. calcium blockers. Cofactors. (2) Enhance electron transport chain flux and/or bypass a specific defect (succinate. and thiamine). consider a feeding tube (also helpful for medications and mitochondrial cocktail). and Drugs The rationale for treatment of mitochondrial disorders is derived from the pathologic consequences of the disease as described earlier in this chapter: (1) Increase antioxidant capacity (vitamin E. selenium. Shivering is metabolically expensive and should be avoided. 2008. CoQ10. 2008. particularly with difficult-to-control seizures. 117 c. most clinicians recommend a combination of several of the above-mentioned compounds as a ‘‘mitochondrial cocktail. Dystonia (diazepam. 2002).dnJEKLNqFoG/b. (5) Levocarnitine is sometimes used because a secondary carnitine deficiency can occur in the absence of primary carnitine deficiency. riboflavin. 1997). Antioxidants. -lipoic acid). 1996. minerals (iron. coenzyme Q10. " Avoid Metabolic Stressors Extremes of heat and cold are not well tolerated. D. 2005) and in MITO-101: A Primer for Physicians and Patients links from the United Mitochondrial Disease Foundation (www. Identify and treat deficiencies in vitamins (vitamins A. and protein calorie (albumin. Unauthorized reproduction of this article is prohibited. avoid dantrolene if liver is involved). chronic: amitriptyline. . Some general suggestions for care are found in Table 6-2.C6AC/MITO_ 101. (4) A high-fat diet may increase the flux through complex II in patients with a complex I defect (Roef et al. " Identify and Treat Nutritional Deficiencies Growth curves are imperative to identify suboptimal nutrition. prealbumin). Spasticity (baclofen. Continuum Lifelong Learning Neurol 2009. Headache (acute: nonsteroidal anti-inflammatory drugs and acetaminophen. and strokelike episodes [MELAS]. A list of some of the treatments and their doses is presented in Table 6-3. Tarnopolsky. Dichloroacetate has been proposed as a treatment for mitochondrial cytopathies since it reduces serum lactate concentrations by activating the pyruvate dehydrogenase complex.’’ with the rationale of providing compounds that target the final common pathways of cellular dysfunction in mitochondrial cytopathies (Tarnopolsky and Beal.4585961/k. vitamin C. Patients should avoid unaccustomed strenuous exercise. in which ketogenesis may be secondarily useful as an antiseizure intervention.

however. 2000. CoQ10 and creatine monohydrate probably have been most extensively investigated (Haas.15(6) a complete mitochondrial cocktail strategy capable of targeting multiple final common pathways of cellular dysfunction induced by mitochondrial disorders. Liquid or hydrosoluble forms of coenzyme Q10 appear to be better absorbed than powdered capsule forms. neuroprotection Pyruvate dehydrogenase cofactor Bypass complex I defects Antioxidant Antioxidant Treating secondary deficiencies Bypass complex I defects Antioxidant Medication Coenzyme Q10 Coenzyme Q10 Creatine monohydrate Thiamine Riboflavin Vitamin E Vitamin C Levocarnitine Succinate -Lipoic acid Dose Range 5 mg/kg/d to 10 mg/kg/d 75 mg/kg/d to 150 mg/kg/d 100 mg/kg/d 3 mg/kg/d to 9 mg/kg/d 3 mg/kg/d to 5 mg/kg/d 5 mg/kg/d to 10 mg/kg/d 7 mg/kg/d to 15 mg/kg/d 30 mg/kg/d to 50 mg/kg/d 30 mg/kg/d to 70 mg/kg/d 5 mg/kg/d to 7 mg/kg/d It is important to start with a single compound at the lower end of the dosing range for a few days and to add in a new compound one at a time. Matthews et al. using a prospective randomized double-blind methodology." MITOCHONDRIAL CYTOPATHIES TABLE 6-3 Examples of Commonly Used Vitamins. Tarnopolsky et al. The difficulty. 2009. Other Therapies No genetic therapies for mitochondrial cytopathies are currently available. on balance. Rodriguez et al. and Other Nutraceuticals Mechanism of Action Bypass complexes I and II (Coenzyme Q10 deficiency) Energy source. As single agents. will be to evaluate the infinite possible combinations in a heterogeneous group of individuals. The main side effect with all of the above medications is gastrointestinal upset. 2007. Klopstock et al. 2002. titrating the dose to the desired effect as tolerated. 2001). In summary. Mahoney et al. Our approach has been to use dichloroacetate in cases of acute metabolic crisis for short periods of time. 2007). Further studies are required to develop Continuum Lifelong Learning Neurol 2009. 1993. 2006). 2007. Cofactors. which can often be treated by dividing the dose into a 2-times-perday or 3-times-per-day dosing regimen and taking the medication with meals. The development of animal models of mitochondrial disease will certainly be useful in identifying combination therapies for mitochondrial cytopathies to advance the development of clinical studies (Torraco et al. and. and many of the components have been well tolerated (Haas. 1997). 118 and one of the side effects is the development of peripheral neuropathy (Kaufmann et al. most of the constituents of the mitochondrial cocktail are based on biological rationale (Tarnopolsky and Beal. 2007). Wenz et al. there does appear to be some degree of efficacy when the two are combined with -lipoic acid (Rodriguez et al. only when serum lactate concentrations are elevated above 10 mmol/L. although in vitro approaches using mutation-specific peptide nucleic acids for mtDNA mutations and deletions have Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. . 2009).

genetic counselors. including physicians (geneticists. optic atrophy. with considerable clinical and genetic heterogeneity. and most people are better able to tolerate activities of daily living without adverse affects. With careful and progressive increases in activity. and long-term care of patients with mitochondrial cytopathies is extremely complicated and requires a dedicated team of specialists. et al.130(pt 4): 1029–1042. karate. occupational and physical therapists. 119 REFERENCES Alavi MV. and ballet are particularly helpful in children with dyscoordination and/or ataxia. With an increasing recognition of nuclear DNA mutations. 2005). and even exerciseinduced deafness with overexertion. The age of onset of the mitochondrial cytopathies can range from infancy to adults older than 65 years. Valentino ML. pulmonologists. Activities such as tai chi. At the genetic level. OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. 2008. hypoacusis. and specifically trained nutritionists. The difficulty with exercise in the pediatric population is that compliance and accessibility to appropriate exercise methods are challenging.’’ which can reduce the percentage of mutant heteroplasmy in the skeletal muscle (Murphy et al. 2006. we advise people to ‘‘listen to their body’’ and progress slowly and cautiously. the threshold for the onset of these symptoms is increased. nurses. Taivassalo and Haller. the diagnosis. or encephalopathic features. Bette S. ptosis. et al. 1997). Unauthorized reproduction of this article is prohibited. . Schimpf S. ophthalmoplegia. treatment. Taivassalo et al. gastroenterologists.shown some promise (Taylor et al. nausea. vomiting. We have had several patients who have experienced vertigo. provided that they work within their limit and not push to the point where they get nausea. Brain 2007. For these reasons. KEY POINT A Exercise has been demonstrated to be of benefit in mitochondrial cytopathies. 1999). physiatrists. Reynier P. with endurance and resistance types of exercise showing evidence of efficacy.15(6) Copyright @ American Academy of Neurology. muscle fatigue) or shows evidence of both neurologic and other systemic involvement should be investigated for the possibility of a mitochondrial cytopathy. cardiologists. In general. the potential for viral vector and other DNA-based strategies as well as possible short interfering RNA strategies may be greater in the future. Both endurance and resistance exercise has also been demonstrated to be of benefit in mitochondrial cytopathies in adults (Taivassalo et al. Brain 2008. vomiting. the sporadic mitochondrial mutation may be more amenable to therapy for exercise-induced muscle damage and can activate satellite cells that often show no or very low levels of mutational burden. social workers. We usually advise that they do not perform any vigorous physical activity if they are experiencing a migraine headache or have a concurrent illness such as an upper respiratory tract infection. Continuum Lifelong Learning Neurol 2009. A patient who presents with neurologic symptoms commonly seen in mitochondrial cytopathies (eg. Amati-Bonneau P. In summary. neurologists. we recommend that children be as active as possible in school-based and play-based activities. psychiatrists). in order to deal with all of the complexities of mitochondrial cytopathies. The activation of the satellite cells results in mtDNA ‘‘shifting.131(pt 2):338–351. A splice site mutation in the murine Opa1 gene features pathology of autosomal dominant optic atrophy.

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