Abstract
Mitochondrial diseases are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, and exposure to toxins (including some prescription medications). Normal mitochondrial physiology is responsible, in part, for the aging process itself, as free radical production within the mitochondria results in a lifetime burden of oxidative damage to DNA, especially the mitochondrial DNA that, in turn, replicate the mutational burden in future copies of itself, and lipid membranes. Primary mitochondrial diseases are those caused by mutations in genes that encode for mitochondrial structural and enzymatic proteins, and those proteins required for mitochondrial assembly and maintenance. A number of common adult maladies are associated with defective mitochondrial energy production and function, including diabetes, obesity, hyperthyroidism, hypothyroidism, and hyperlipidemia. Mitochondrial dysfunction has been demonstrated in many neurodegenerative disorders, including Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis, and some cancers. Polymorphisms in mitochondrial DNA have been linked to disease susceptibility, including death from sepsis and survival after head injury. There is considerable overlap in symptoms caused by primary mitochondrial diseases and those illnesses that affect mitochondrial function, but are not caused by primary mutations, as well as disorders that mimic mitochondrial diseases, but are caused by other identified mutations. Evaluation of these disorders is complex, expensive, and not without false-negative and false-positive results that can mislead the physician. Most of the common heritable mitochondrial disorders have been well-described in the literature, but can be overlooked by many clinicians if they are uneducated about these disorders. In general, the evaluation of the classic mitochondrial disorders has become straightforward if the clinician recognized the phenotype and orders appropriate confirmatory testing. However, the majority of patients referred for a mitochondrial evaluation do not have a clear presentation that allows for rapid identification and testing. This article provides introductory comments on mitochondrial structure, physiology, and genetics, but will focus on the presentation and evaluation of adults with mitochondrial symptoms, but who may not have a primary mitochondrial disease.
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References
DiMauro S, Bonilla E. Mitochondrial encephalomyopathies. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL (eds) The molecular and genetic basis of neurological disease. Butterworth-Heinemann, Boston, MA; 1997: pp. 201–235
Shoffner JM, Wallace DC. Oxidative phosphorylation diseases. In: Scriver CR, Beaudet AL, Sly WS, et al. (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York; 1995: pp. 1535–1610.
DiMauro S, Schon EA,.The mitochondrial respiratory chain and its disorders. In: DiMauro S, Hirano M, Schon EA (eds) Mitochondrial medicine. Informa Healthcare, Boca Raton, FL; 2006: pp. 7–26
Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol 2010;5:297–348.
Cooper JM, Clark JB. The structural organization of the mitochondrial respiratory chain. In: Schapira AHV, DiMauro S (eds) Mitochondrial disorders in neurology. Butterworth-Heinemann, Oxford; 1994; pp. 1–30.
Pagliarini DJ, Calvo SE, Chang B, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008;134:112–123.
Haas RH, Parikh S, Falk MH, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008;94:16–37.
Bernier FP, Boneh A, Dennett X, et al. Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 2002;59:1406–1411.
Wolf NI, Smeitink JA. Mitochondrial disorders: a proposal for consensus diagnostic criteria in infants and children. Neurology 2002;59:1402–1405.
Friedman SD, Shaw DW, Ishak G, Gropman AL, Saneto RP. The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev 2010;16:129–135.
Hammans SR, Morgan-Hughes JA. Mitochondrial myopathies: clinical features, investigation, treatment and genetic counseling. In: Schapira AHV, DiMauro S (eds) Mitochondrial disorders in neurology. Butterworth-Heinemann, Oxford; 1994: pp. 1–30.
Chinnery PF. Mitochondrial DNA polymerase-gamma and human disease. Hum Mol Genet 2006;15:R244-252.
Hinson JT, Fantin VR, Schönberger J, et al. Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. N Engl J Med 2007;356:809–819.
Schon EA. Mitochondrial DNA and the genetics of mitochondrial disease. In: Schapira AHV, DiMauro S (eds) Mitochondrial disorders in neurology. Butterworth-Heinemann, Oxford; 1994; pp. 31–48.
Fan W, Waymire KG, Narula N, et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 2008;319:958–962.
Stewart JD, Horvath R, Baruffini E, et al. Polymerase γ gene POLG determines the risk of sodium valproate-induced liver toxicity. Hepatology 2010;52:1791–1796.
Wallace DC. Mitochondrial DNA mutations and bioenergetic defects in aging and degenerative diseases. In: Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL (eds). The molecular and genetic basis of neurologic disease. Butterworth-Heinemann, Boston, MA; 1997: pp. 237–269
Melov S, Shoffner JM, Kaufman A, Wallace DC. Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle. Nucleic Acids Res 1995;23:4122–4126.
Andreu AL, Hanna MG, Reichmann H, et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med 1999;341:1037–1044.
Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 1993;4:289–294.
Corral-Debrinski M, Shoffner JM, Lott MT, Wallace DC. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res 1992;275:169–180.
Bird TD. Myotonic dystrophy type 1. In: Pagon RA, Bird TD, Dolan CR, et al. (eds) GeneReviews™. Available via http://www.ncbi.nlm.nih.gov/books/NBK1165/. Accessed 20 Mar 2013.
Brais B, Rouleau GA. Oculopharyngeal muscular dystrophy. In: Pagon RA, Bird TD, Dolan CR, et al. (eds) GeneReviews™. Available via http://www.ncbi.nlm.nih.gov/books/NBK1126/. Accessed 20 Mar 2013.
Gerrits KH, Voermans NC, de Haan A, van Engelen BG. Neuromuscular properties of the thigh muscles in patients with Ehlers-Danlos syndrome. Muscle Nerve 2013;47:96–104.
Celletti C, Galli M, Cimolin V, Castori M, Albertini G, Camerota F. Relationship between fatigue and gait abnormality in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type. Res Dev Disabil 2012;33:1914–1918.
Voermans NC, van Alfen N, Pillen S, Lammens M, Schalkwijk J, Zwarts MJ, et al. Neuromuscular involvement in various types of Ehlers-Danlos syndrome. Ann Neurol 2009;65:687–697.
Rosenberg H, Sambuughin N, Riazi S, et al. Malignant hyperthermia susceptibility. In: Pagon RA, Bird TD, Dolan CR, et al. (eds) GeneReviews™. Available via http://www.ncbi.nlm.nih.gov/books/NBK1146/. Accessed 20 Mar 2013.
Barbeau A. The syndrome of hereditary late-onset ptosis and dysphagia in French Canada. In: Kuhn E (ed.) Symposium über progressive muskeldystrophie. Springer-Verlag, Berlin; 1996: pp. 102–109.
Quinlivan R, Jungbluth H. Myopathic causes of exercise intolerance with rhabdomyolysis. Dev Med Child Neurol 2012;54:886–891.
Michot C, Hubert L, Romero NB, et al. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis 2012;35:1119–1128.
Pavlakis SG, Phillips PC, DiMauro S, DeVivo DC, Rowland LP. Mitochondrial myopathy, encephalomyopathy, lactic acidosis and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 1984;16:481–488.
Goto Y, Nonaka I, Horai S. A mutation in the tRNALeu(URR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348:653.
Bardosi A, Creutzfeldt W, DiMauro S, et al. Myo-, neuro-, gastrointestinal encephalomyopathy (MNGIE syndrome) due to partial deficiency of cytochrome c oxidase: a new mitochondrial multisystem disorder. Acta Neuropathol (Berl) 1987;74:(3)248–258.
Nishino I, Spinazzola A, Hirano M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 1999;283:689–692.
Zhang F, Wang S, Gan L, Vosler PS, Gao Y, Zigmond MJ, Chen J. Protective effects and mechanisms of sirtuins in the nervous system. Prog Neurobiol 2011;95:373–395.
Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol 2004;555:1–13.
Lietman PS. Mitochondrial protein synthesis: inhibition by emetine hydrochloride. Mol Pharmacol 1971;7:122–128.
Hirano M, Kaufmann P, De Vivo D, Tanji K. Mitochondrial neurology I: encephlopathies. In: DiMauro S, Hirano M, Schon EA (eds) Mitochondrial medicine. Informa Healthcare, Boca Raton, FL; 2006: pp. 27–44
Goodfellow JA, Dani K, Stewart W, Santosh C, McLean J, Mulhern S, Razvi S. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people. Postgrad Med J 2012;88:326–334.
Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G. Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem 2006;17:571–588.
Wong LJ. Mitochondrial syndromes with leukoencephalopathies. Semin Neurol 2012;32:55–61.
Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy. Epilepsia 2012;53(Suppl. 4):92–97.
Cohen BH, Naviaux RK. The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods 2010;51:364–373.
Cohen BH, Chinnery PF, Copeland WC. POLG-related disorders. In: Pagon RA, Bird TD, Dolan CR, et al. (eds) GeneReviews™. Available via http://www.ncbi.nlm.nih.gov/books/NBK26471/. Accessed XXX.
Saneto RP, Lee I-C, Koenig MK, Bao X, Weng SW, Naviaux RK, Wong L-J. POLG DNA testing as an emerging standard of care before instituting valproic acid therapy for pediatric seizure disorders. Seizure 2010;19:140–146.
Huang CC, Chu CC, Pang CY, Wei YH. Tissue mosaicism in the skeletal muscle and sural nerve biopsies in the MELAS syndrome. Acta Neurol Scand 1999; 99:125–129.
Peyronnard JM, Charron L, Bellavance A, Marchand L. Neuropathy and mitochondrial myopathy. Ann Neurol 1980;7:262–268.
Wenning GK, Stefanova N. Recent developments in multiple system atrophy. J Neurol 2009;256:1791–808.
Sekijima Y, Yoshida K, Tokuda T, et al. Familial transthyretin amyloidosis. In: Pagon RA, Bird TD, Dolan CR, et al. (eds) GeneReviews™. Available via http://www.ncbi.nlm.nih.gov/books/NBK1194/. Accessed 20 Mar 2013.
Kenny D, Wetherbee J. Kearns-Sayre syndrome in the elderly: mitochondrial myopathy with advanced heart block. Am Heart J 1990;120:440–443.
Mashima Y, Kigasawa K, Hasegawa H, Tani M, Oguchi Y. High incidence of pre-excitation syndrome in Japanese families with Leber’s hereditary optic neuropathy. Clin Genet 1996; 50:535–537.
Vydt TC, de Coo RF, Soliman OI, et al. Cardiac involvement in adults with m.3243A > G MELAS gene mutation. Am J Cardiol 2007;99:264–269.
Morris AAM. Mitochondrial respiratory chain disorders and the liver. Liver 1999;19:357–368.
Bindoff L. Mitochondrial gastroenterology. In: DiMauro S, Hirano M, Schon EA (eds) Mitochondrial medicine. Informa Healthcare, Boca Raton, FL; 2006: pp. 143–159
Vial G, Dubouchaud H, Leverve XM. Liver mitochondria and insulin resistance. Acta Biochim Pol 2010;57:389–392.
Serviddio G, Bellanti F, Vendemiale G, Altomare E. Mitochondrial dysfunction in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2011;5:233–244.
Wong L-J C, Naviaux RK, Brunetti-Pierri, N, et al. Molecular and clinical genetics of mitochondrial diseases due to POLG Mutations. Hum Mutat 2008;29:E150-172.
Schrier SA, Falk MJ. Mitochondrial disorders and the eye. Curr Opin Ophthalmol 2011;22:325–331.
Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol 2010;55:299–334.
Kerrison JB, Biousse V, Newman NJ. Retinopathy of NARP syndrome. Arch Ophthalmol 2000;118:298–299.
Smith PR, Bain SC, Good PA, et al. Pigmentary retinal dystrophy and the syndrome of maternally inherited diabetes and deafness cause by the mitochondrial DNA 3243 tRNA (Leu) A to G mutation. Ophthalmology 1999;106:1101–1108.
Sitarz KS, Chinnery PF, Yu-Wai-Man P. Disorders of the optic nerve in mitochondrial cytopathies: new ideas on pathogenesis and therapeutic targets. Curr Neurol Neurosci Rep 2012;12:308–317.
Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988;242:1427–1430.
Chalmers RM, Schapira AH. Clinical, biochemical and molecular genetic features of Leber’s hereditary optic neuropathy. Biochim Biophys Acta 1999;1410:147–158.
Zeviani M. OPA1 mutations and mitochondrial DNA damage: keeping the magic circle in shape. Brain 2008;131:314–317.
Leonard JV, Schapira AH. Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet 2000;335:299–304
McFarland R, Taylor RW, Chinnery PF et al. A novel sporadic mutation in cytochrome c oxidase subunit II as a cause of rhabdomyolysis. Neuromuscul Disord 2004;14:162–166.
Elliott HR, Samuels DC, Eden JA, Relton CL, Chinnery PF. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 2008;83:254–260.
Fischel-Ghodsian N. Mitochondrial genetics and hearing loss: the missing link between genotype and phenotype. Proc Soc Exp Biol Med 1998;218:1–6.
Jacobs HT. Mitochondrial deafness. Ann Med 1997;29:483–491.
Ballana E, Morales E, Rabionet R, et al. Mitochondrial 12S rRNA gene mutations affect RNA secondary structure and lead to variable penetrance in hearing impairment. Biochem Biophys Res Commun 2006;341:950–957.
Guan MX, Yan Q, Li X, et al. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am J Hum Genet 2006;79:291–302.
Niaudet P. Mitochondrial disorders and the kidney. Arch Dis Child 1998;78:387–390.
Niaudet P, Rotig A. The kidney in mitochondrial cytopathies. Kidney Int 1997;51:1000–1007.
Guéry B, Choukroun G, Noël LH, et al. The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol 2003;14:2099–2108.
Doleris LM, Hill GS, Chedin P, et al. Focal segmental glomerulosclerosis associated with mitochondrial cytopathy. Kidney Int 2000;58:1851–1858.
Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B. 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 1962;41:1776–1804.
Odawara M. Involvement of mitochondrial gene abnormalities in the pathogenesis of diabetes mellitus. Ann NY Acad Sci 1996; 786:72–81.
Gerbitz KD, van den Ouweland JM, Maassen JA, Jaksch M. Mitochondrial diabetes mellitus: a review. Biochim Biophys Acta 1995;1271:253–260.
van den Ouweland JM, Lemkes HH, et al. Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA (Leu(URR)) gene. Diabetes 1994;43:746–751.
Anon. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 34–1987. A 30-year-old woman with an ocular motility disturbance, myopathy, and hypocalcemia. N Engl J Med 1987;317:493–501
Yang CY, Lam HC, Lee HC, et al. MELAS syndrome associated with diabetes mellitus and hyperthyroidism: a case report from Taiwan. Clin Endocrinol 1995;43:235–239.
Finsterer J, Jarius C, Eichberger H. Phenotype variability in 130 adult patients with respiratory chain disorders. J Inherit Metab Dis 2001;24:560–576
Quade A, Zierz S, Klingmüller D. Endocrine abnormalities in mitochondrial myopathy with external ophthalmoplegia. Clin Invest 1992;70:396–402.
Chen CM, Huang CC. Gonadal dysfunction in mitochondrial encephalomyopathies. Eur Neurol 1995;35:281–286.
Harvey JN, Barnett D. Endocrine dysfunction in Kearns-Sayre syndrome. Clin Endocrinol 1992;37:97–103.
Matsuzaki M, Izumi T, Shishikura K, Suzuki H, Hirayama Y. Hypothalamic growth hormone deficiency and supplementary GH therapy in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. Neuropediatrics 2002;33:271–273.
Plioplys AV, Plioplys S. Serum levels of carnitine in chronic fatigue syndrome: clinical correlates. Neuropsychobiology 1995;32:132–138.
Kuratsune H, Yamaguti K, Takahashi M, Tagawa S, Kitani T. Acylcarnitine deficiency in chronic fatigue syndrome. Clin Infect Dis 1994;18(Suppl. 1):62–67.
Griggs RC, Karpati G. Muscle pain, fatigue, and mitochondriopathies. N Engl J Med 1999;341:1077–1078.
Smits B, van den Heuvel L, Knoop H, Küsters B, Janssen A, Borm G, et al. Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome. Mitochondrion 2011;11:735–738.
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Cohen, B.H. Neuromuscular and Systemic Presentations in Adults: diagnoses beyond MERRF and MELAS. Neurotherapeutics 10, 227–242 (2013). https://doi.org/10.1007/s13311-013-0188-3
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DOI: https://doi.org/10.1007/s13311-013-0188-3