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mtDNA Disease in the Primary Care Setting

mtDNA Disease in the Primary Care Setting Disorders of mitochondrial DNA (mtDNA) may commonly present to primary care physicians but go undiagnosed. A 36-year-old man with a 15-year history of psychosis, seizures, and sensorineural hearing loss and a family history of diabetes mellitus and heart disease presented to our hospital without a unifying diagnosis. Physiologic, biochemical, and genetic testing revealed deficient aerobic metabolism, a defect in mitochondrial electron transport, and the presence of an A-to-G point mutation at position 3243 of the mitochondrial leucine–transfer RNA gene, establishing the diagnosis of mitochondrial encephalopathy, lactic acidosis, and strokelike syndrome (MELAS). Diagnosing mtDNA disorders requires a careful integration of clinical signs and symptoms with pedigree analysis and multidisciplinary testing. Diagnosis is important to provide genetic counseling, avoid unnecessary evaluation, and facilitate therapy for symptomatic relief.The explosion in fundamental understanding of genetics and molecular biology promises to revolutionize medical practice, but it has not had a substantive effect on primary care internal medicine. However, the recent breakthroughs in understanding the biology of mitochondria have enabled clinicians to diagnose and treat patients with defects of mitochondrial DNA (mtDNA). Epidemiological studies have revealed that mtDNA disorders are far more common than previously believed. In patients with diabetes mellitus, hearing loss, or renal failure, the prevalence of MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike syndrome) has been estimated to be as high as 1% to 10%.Thus, internists will likely encounter patients with unrecognized mtDNA disorders. Herein, we describe a patient who had symptoms for 15 years prior to the diagnosis of MELAS, and we discuss the tools currently available to primary care physicians to diagnose and treat mtDNA disorders.REPORT OF A CASEA 36-year-old man with a 15-year history of psychosis, seizures, and sensorineural hearing loss presented to our institution without a unifying diagnosis. The patient had been seen frequently by health care professionals from several disciplines during this 15-year period. Family history was remarkable for multiple cases of type 2 diabetes mellitus, heart disease, psychiatric problems, and hearing loss (that was confirmed to be sensorineural in the proband's 2 siblings) (Figure 1). Results of the patient's examination were significant for a wide-based gait, diffuse muscle weakness, loss of reflexes, and a mild intention tremor. Pathologic, physiologic, and biochemical tests were performed to assess mitochondrial structure and function(Table 1). The results demonstrated decreased nicotinamide adenine dinucleotide (NADH)–cytochrome creductase activity with normal decylubiquinol–cytochrome creductase activity, consistent with a defect in complex I of the mitochondrial electron transport chain. Genetic analysis of the patient's leukocytes detected a 17% frequency of the A-to-G mutation at position 3243 (A3243G) in the mitochondrial leucine–transfer RNA gene.Family pedigree. Circles indicate female family members; squares, male family members. Shaded symbols indicate confirmed mitochondrial DNA disease (proband's siblings confirmed by history of genetic testing). The arrow points to the proband. DM indicates type 2 diabetes mellitus; Psych, bipolar disease or psychosis; Deaf, hearing loss; Card, heart failure; SZ, seizures; and OI, osteogenesis imperfecta.Table 1. Diagnostic Test Results*TestResultCommentsLaboratoryMuscle biopsyStructurally abnormal mitochondria (no ragged red fibers)"Ragged red fibers" are pathognomonic for mtDNA diseaseVenous lactate, mg/dL (mmol/L)Resting, 27.0 (3.0) Exercise, 44.1 (4.9)Normal, <23.4 (2.6)Lactate-pyruvate ratioResting, 19:1 Exercise, 38:1Ratio ≥20:1 at rest and increases with exercise; suggests mtDNA diseaseExercise testingMax VO2, L/min0.8332% of normalAnaerobic threshold, L/min0.532% of normalMaximum heart rate, beats/min9854% of normalMuscle biochemistry, µmol/min per gramComplex I and III assay (NADH–cytochrome creductase)0Control range, 0.2-4.7Early complex I (ferricyanide reductase)18.9Control range, 11.5-60.1Complex III (decylubiquinol–cytochrome creductase)21.6Control range, 6.9-35.2*The abnormal results in an assay of complex I and complex III, combined with normal findings of complex III and early complex I alone, indicate a defect isolated to the late components of complex I of the electron transport chain. mtDNA indicates mitochondrial DNA; NADH, nicotinamide adenine dinucleotide.COMMENTMitchondria are the principal producers of cellular energy, generating adenosine triphosphate via oxidative phosphorylation. Embryonic mitochondria originate almost exclusively from the ovum,and each mitochondrion contains multiple copies of mtDNA. Each copy of mtDNA contains genes encoding 13 polypeptides of the electron transport chain and each gene may contain polymorphisms or mutations. During cell division, the distribution of mitochondria to daughter cells is stochastic, so a mitotic cell can generate daughter cells with different populations of mtDNA. Cell divisions during embryogenesis thus result in a mosaic of mitochondrial genotypes in different stem cells, which subsequently divide to generate tissues with varying burdens of mtDNA polymorphisms and mutations, a phenomenon known as heteroplasmy.Furthermore, possibly due to a selective growth advantage of mitochondria with mutated mtDNA,the proportion of defective mitochondria within tissues can increase over time.Due to transmission of mitochondria via the ovum, pedigree analysis of patients with mtDNA disorders reveals maternal inheritance,as was seen in our patient (Figure 1). As a result of heteroplasmy, family members carrying the same mtDNA mutation can present with protean phenotypes.However, due to the fundamental role of mitochondria in generating adenosine triphosphate, clinically apparent disease tends to affect organs with high energy demands. Thus, disorders of mtDNA cause type 2 diabetes mellitus due to disease of the islets of Langerhans,blindness, headache, neuropsychiatric disorders, hearing loss and stroke due to neuronal damage,cardiomyopathy and exercise intolerance due to cardiac and striated muscle dysfunction,and renal tubularand glomerular diseasedue to renal epithelial dysfunction (Table 2).Table 2. Common Manifestations of Mitochondrial DNA DisordersNeuropsychiatric DefectsHeadacheDepressionStrokePsychosisDementiaSeizuresBlindnessAtaxiaDeafnessPeripheral neuropathyMuscle DefectsMyopathy (cardiac or skeletal muscle)Lactic acidosisExercise intoleranceWeakness/fatigueRenal DefectsProximal tubule dysfunctionGlomerulonephritisOther Systemic FindingsEpisodic nausea/vomitingDiabetes mellitusIntestinal pseudo-obstructionPancytopeniaShort body statureHypoparathyroidismOur patient's case illustrates the major diagnostic challenges of mtDNA disorders. First, manifestations of mtDNA disorders such as diabetes mellitus present identically to idiopathic disease. Only the clustering of multiple diseases of high-energy organs within a family allows distinction. Also, owing to an increased proportion of diseased mitochondria in tissue over time and the need for a threshold mutation frequency to yield phenotypic expression, inherited defects of mtDNA can be clinically silent until the adult years. Indeed, MELAS first presenting at the age of 60 years has been reported.Finally, diagnosis of mtDNA disease is hampered by the lack of a single, highly specific, widely available test.A simple screening test for mtDNA disorders is the ratio of serum concentrations of lactate to pyruvate measured at rest. Because of defects in oxidative phosphorylation, patients with mtDNA disorders are dependent on anaerobic metabolism, which results in a shunt of pyruvate to lactate. A high lactate level at rest is suggestive of an mtDNA disorder, and a lactate-pyruvate ratio of 20:1 or higher is often seen.Evaluation during exercise may add sensitivity to this test, as the serum lactate-pyruvate ratio may reach high levels with physical activity in patients with mtDNA defects.Exercise testing was particularly valuable for our patient, whose borderline lactate-pyruvate ratio of 19:1 doubled with exercise, bolstering the case for an mtDNA disorder. Exercise testing can also reveal abnormal oxidative metabolism by other markers, as typified by our patient's low anaerobic threshold, maximum usage of oxygen, and maximum heart rate (Table 1).Muscle biopsy findings can suggest the presence of an mtDNA disorder, revealing pathognomonic "ragged red fibers" caused by proliferation of abnormal mitochondria.However, owing to heteroplasmy, patients whose defective mitochondria are not concentrated in muscle may not have ragged red fibers.Muscle biopsy results are thus relatively specific, but not sensitive for mitochondrial disorders. Assays of components of the oxidative phosphorylation cascade allow identification of specific defects in biopsy material. In concordance with prior published results from patients with MELAS,biochemical assay of our patient's muscle tissue demonstrated a defect in the late components of electron transport chain complex I, despite the absence of ragged red fibers on microscopy (Table 1).Results of genetic testing in our patient revealed the presence of the point mutation most commonly associated with MELAS, A3243G of the mitochondrial leucine–transfer RNA gene.Although the mutation was found at a 17% frequency in our patient's blood, the correlation between mutation frequencies in blood and muscle are notoriously poor,so no inference can be made regarding the frequency of the mutation in our patient's muscle. Furthermore, because of heteroplasmy, qualitative genetic testing is nonspecific for clinical disease. Thus, patients can have the genetic mutation but be phenotypically normalor display characteristics of other mtDNA syndromes.As well, genetic testing is relatively insensitive: patients can have symptomatic mtDNA disorders with negative screen results for common mtDNA mutations.Presumably these latter patients have either genetic defects not yet describedor genetic defects focused in tissues not used to prepare the mtDNA for the assay.For example, if DNA is extracted from muscle tissue but the mutant mitochondria are concentrated in neuronal tissue, the assay may produce negative results. Thus, a clinical assessment of signs, symptoms, and family history must be integrated with diagnostic testing to ensure proper diagnosis.It has been suggested that early treatment of mtDNA disorders might prevent the development of irreversible disease, such as stroke, in affected patients.A variety of agents have been used for therapy of mtDNA disorders, including L-carnitine,idebenone,thiamine,nicotinamide,and most commonly, coenzyme Q (ubiquinone)or dichloroacetic acid.Coenzyme Q is a diffusible carrier of protons and electrons, and thus can theoretically bypass an upstream block in the electron transport chain. Conversely, dichloroacetic acid de-represses pyruvate dehydrogenase, which leads to an increased use of the Krebs cycle and decreases metabolism of pyruvate to lactate. Although symptomatic improvement has been reported with these agents,no large-scale, randomized trials have been completed, and their overall clinical efficacy is unknown. Nevertheless, given the reported improvements in symptoms and quality of life, treatment should be considered for individual patients, with adjustments to the regimen made based on objective assessment of response (eg, by changes in symptoms, serum lactate-pyruvate ratios, or exercise testing).CONCLUSIONSIn summary, we describe a patient with MELAS who illustrates the diagnostic challenge that mtDNA disorders present to the internist. Although these disorders can cause common conditions such as type 2 diabetes mellitus, seizures, psychosis, stroke, renal failure, heart failure, and hearing loss, primary care physicians may only rarely entertain the diagnosis of an mtDNA disorder. Given their surprisingly high prevalence in patients with common medical conditions, it must be assumed that clinically significant mtDNA disorders frequently go undiagnosed. The clustering of disease processes to organs with high energy requirements, especially if such diseases are common in an entire family, is a clue to the presence of an mtDNA disorder. Primary care physicians can screen for such diseases using tests for serum lactate and pyruvate concentrations, with a ratio of 20:1 or greater at rest being suggestive of the diagnosis. Confirmation requires performance of a muscle biopsy, biochemical assays, and/or genetic tests, which are probably most appropriately performed by a specialist. 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samples.Lancet.1991;337:1311-1313.SCollinsEByrneXDennettContrasting histochemical features of various mitochondrial syndromes.Acta Neurol Scand.1995;91:287-293.AMelbergPAkerlundRRaininkoMonozygotic twins with MELAS-like syndrome lacking ragged red fibers and lactacidaemia.Acta Neurol Scand.1996;94:233-241.MNishizawaKTanakaKShinozawaA mitochondrial encephalomyopathy with cardiomyopathy: a case revealing a defect of complex I in the respiratory chain.J Neurol Sci.1987;78:189-201.TIchikiMTanakaMNishikimiDeficiency of subunits of complex I and mitochondrial encephalomyopathy.Ann Neurol.1988;23:287-294.YKogaINonakaMKobayashiMTojyoKNiheiFindings in muscle in complex I (NADH coenzyme Q reductase) deficiency.Ann Neurol.1988;24:749-756.YGotoSHoraiTMatsuokaMitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation.Neurology.1992;42:545-550.YGotoINonakaSHoraiA mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.Nature.1990;348:651-653.ASuomalainenAMajanderHPihkoLPeltonenACSyvänenQuantification of tRNA3243(Leu) point mutation of mitochondrial DNA in MELAS patients and its effects on mitochondrial transcription.Hum Mol Genet.1993;2:525-534.KMajamaaJSMoilanenSUimonenEpidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population.Am J Hum Genet.1998;63:447-454.ECiafaloniERicciSShanskeMELAS: clinical features, biochemistry, and molecular genetics.Ann Neurol.1992;31:391-398.RSChenCCHuangCCLeeOverlapping syndrome of MERRF and MELAS: molecular and neuroradiological studies.Acta Neurol Scand.1993;87:494-498.TFolgerøTTorbergsenPOianThe 3243 MELAS mutation in a pedigree with MERRF.Eur Neurol.1995;35:168-171.GMFabriziECardaioliGSGriecoThe A to G transition at nt 3243 of the mitochondrial tRNALeu(UUR) may cause an MERRF syndrome.J Neurol Neurosurg Psychiatry.1996;61:47-51.FDegoulMDiryAPou-SerradellJLloretaCMarsacMyo-leukoencephalopathy in twins: study of 3243-myopathy, encephalopathy, lactic acidosis, and strokelike episodes mitochondrial DNA mutation.Ann Neurol.1994;35:365-370.MGHannaIPNelsonJAMorgan-HughesNWWoodMELAS: a new disease-associated mitochondrial DNA mutation and evidence for further genetic heterogeneity.J Neurol Neurosurg Psychiatry.1998;65:512-517.FMSantorelliKTanjiRKulikovaIdentification of a novel mutation in the mtDNA ND5 gene associated with MELAS.Biochem Biophys Res Commun.1997;238:326-328.IFdeCooEASistermansIJde WijsA mitochondrial tRNA(Val) gene mutation (G1642A) in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes.Neurology.1998;50:293-295.CCHuangRSChenNSChuCYPangYHWeiRandom mitotic segregation of mitochondrial DNA in MELAS syndrome.Acta Neurol Scand.1996;93:198-202.RWTaylorGATaylorCMMorrisJMEdwardsonDMTurnbullDiagnosis of mitochondrial disease: assessment of mitochondrial DNA heteroplasmy in blood.Biochem Biophys Res Commun.1998;251:883-887.YIharaRNambaSKurodaTSatoTShirabeMitochondrial encephalomyopathy (MELAS): pathological study and successful therapy with coenzyme Q10 and idebenone.J Neurol Sci.1989;90:263-271.LValléeMFontaineJPNuytsStroke, hemiparesis and deficient mitochondrial beta-oxidation.Eur J Pediatr.1994;153:598-603.YBarakSArnonBWolachMELAS syndrome: peripheral neuropathy and cytochrome c-oxidase deficiency: a case report and review of the literature.Isr J Med Sci.1995;31:224-229.YSatoMNakagawaIHiguchiMOsameENaitoKOizumiMitochondrial myopathy and familial thiamine deficiency.Muscle Nerve.2000;23:1069-1075.KMajamaaHRusanenAMRemesJPyhtinenIEHassinenIncrease of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome.Life Sci.1996;58:691-699.SGodaTHamadaSIshimotoTKobayashiIGotoYKuroiwaClinical improvement after administration of coenzyme Q10 in a patient with mitochondrial encephalomyopathy.J Neurol.1987;234:62-63.NBresolinLBetABindaClinical and biochemical correlations in mitochondrial myopathies treated with coenzyme Q10.Neurology.1988;38:892-899.KAbeYMatsuoJKadekawaSInoueTYanagiharaEffect of coenzyme Q10 in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): evaluation by noninvasive tissue oximetry.J Neurol Sci.1999;162:65-68.CWLiouCCHuangTKLinJLTsaiYHWeiCorrection of pancreatic beta-cell dysfunction with coenzyme Q(10) in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome and diabetes mellitus.Eur Neurol.2000;43:54-55.YKurodaMItoENaitoConcomitant administration of sodium dichloroacetate and vitamin B1 for lactic acidemia in children with MELAS syndrome.J Pediatr.1997;131:450-452.SSaitohMYMomoiTYamagataYMoriMImaiEffects of dichloroacetate in three patients with MELAS.Neurology.1998;50:531-534.Accepted for publication April 19, 2001.We would like to thank Salvatore DeMauro, MD, for genetic testing for the MELAS mutation and Charles Hoppel, MD, for the biochemical test results. We also thank Mark Munekata, MD, and Scott Filler, MD, for their thoughtful review of the manuscript.Corresponding author: Brad Spellberg, MD, Department of Medicine, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA 90509 (e-mail: bjs@humc.edu). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Internal Medicine American Medical Association

mtDNA Disease in the Primary Care Setting

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American Medical Association
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Copyright 2001 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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2168-6106
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Abstract

Disorders of mitochondrial DNA (mtDNA) may commonly present to primary care physicians but go undiagnosed. A 36-year-old man with a 15-year history of psychosis, seizures, and sensorineural hearing loss and a family history of diabetes mellitus and heart disease presented to our hospital without a unifying diagnosis. Physiologic, biochemical, and genetic testing revealed deficient aerobic metabolism, a defect in mitochondrial electron transport, and the presence of an A-to-G point mutation at position 3243 of the mitochondrial leucine–transfer RNA gene, establishing the diagnosis of mitochondrial encephalopathy, lactic acidosis, and strokelike syndrome (MELAS). Diagnosing mtDNA disorders requires a careful integration of clinical signs and symptoms with pedigree analysis and multidisciplinary testing. Diagnosis is important to provide genetic counseling, avoid unnecessary evaluation, and facilitate therapy for symptomatic relief.The explosion in fundamental understanding of genetics and molecular biology promises to revolutionize medical practice, but it has not had a substantive effect on primary care internal medicine. However, the recent breakthroughs in understanding the biology of mitochondria have enabled clinicians to diagnose and treat patients with defects of mitochondrial DNA (mtDNA). Epidemiological studies have revealed that mtDNA disorders are far more common than previously believed. In patients with diabetes mellitus, hearing loss, or renal failure, the prevalence of MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike syndrome) has been estimated to be as high as 1% to 10%.Thus, internists will likely encounter patients with unrecognized mtDNA disorders. Herein, we describe a patient who had symptoms for 15 years prior to the diagnosis of MELAS, and we discuss the tools currently available to primary care physicians to diagnose and treat mtDNA disorders.REPORT OF A CASEA 36-year-old man with a 15-year history of psychosis, seizures, and sensorineural hearing loss presented to our institution without a unifying diagnosis. The patient had been seen frequently by health care professionals from several disciplines during this 15-year period. Family history was remarkable for multiple cases of type 2 diabetes mellitus, heart disease, psychiatric problems, and hearing loss (that was confirmed to be sensorineural in the proband's 2 siblings) (Figure 1). Results of the patient's examination were significant for a wide-based gait, diffuse muscle weakness, loss of reflexes, and a mild intention tremor. Pathologic, physiologic, and biochemical tests were performed to assess mitochondrial structure and function(Table 1). The results demonstrated decreased nicotinamide adenine dinucleotide (NADH)–cytochrome creductase activity with normal decylubiquinol–cytochrome creductase activity, consistent with a defect in complex I of the mitochondrial electron transport chain. Genetic analysis of the patient's leukocytes detected a 17% frequency of the A-to-G mutation at position 3243 (A3243G) in the mitochondrial leucine–transfer RNA gene.Family pedigree. Circles indicate female family members; squares, male family members. Shaded symbols indicate confirmed mitochondrial DNA disease (proband's siblings confirmed by history of genetic testing). The arrow points to the proband. DM indicates type 2 diabetes mellitus; Psych, bipolar disease or psychosis; Deaf, hearing loss; Card, heart failure; SZ, seizures; and OI, osteogenesis imperfecta.Table 1. Diagnostic Test Results*TestResultCommentsLaboratoryMuscle biopsyStructurally abnormal mitochondria (no ragged red fibers)"Ragged red fibers" are pathognomonic for mtDNA diseaseVenous lactate, mg/dL (mmol/L)Resting, 27.0 (3.0) Exercise, 44.1 (4.9)Normal, <23.4 (2.6)Lactate-pyruvate ratioResting, 19:1 Exercise, 38:1Ratio ≥20:1 at rest and increases with exercise; suggests mtDNA diseaseExercise testingMax VO2, L/min0.8332% of normalAnaerobic threshold, L/min0.532% of normalMaximum heart rate, beats/min9854% of normalMuscle biochemistry, µmol/min per gramComplex I and III assay (NADH–cytochrome creductase)0Control range, 0.2-4.7Early complex I (ferricyanide reductase)18.9Control range, 11.5-60.1Complex III (decylubiquinol–cytochrome creductase)21.6Control range, 6.9-35.2*The abnormal results in an assay of complex I and complex III, combined with normal findings of complex III and early complex I alone, indicate a defect isolated to the late components of complex I of the electron transport chain. mtDNA indicates mitochondrial DNA; NADH, nicotinamide adenine dinucleotide.COMMENTMitchondria are the principal producers of cellular energy, generating adenosine triphosphate via oxidative phosphorylation. Embryonic mitochondria originate almost exclusively from the ovum,and each mitochondrion contains multiple copies of mtDNA. Each copy of mtDNA contains genes encoding 13 polypeptides of the electron transport chain and each gene may contain polymorphisms or mutations. During cell division, the distribution of mitochondria to daughter cells is stochastic, so a mitotic cell can generate daughter cells with different populations of mtDNA. Cell divisions during embryogenesis thus result in a mosaic of mitochondrial genotypes in different stem cells, which subsequently divide to generate tissues with varying burdens of mtDNA polymorphisms and mutations, a phenomenon known as heteroplasmy.Furthermore, possibly due to a selective growth advantage of mitochondria with mutated mtDNA,the proportion of defective mitochondria within tissues can increase over time.Due to transmission of mitochondria via the ovum, pedigree analysis of patients with mtDNA disorders reveals maternal inheritance,as was seen in our patient (Figure 1). As a result of heteroplasmy, family members carrying the same mtDNA mutation can present with protean phenotypes.However, due to the fundamental role of mitochondria in generating adenosine triphosphate, clinically apparent disease tends to affect organs with high energy demands. Thus, disorders of mtDNA cause type 2 diabetes mellitus due to disease of the islets of Langerhans,blindness, headache, neuropsychiatric disorders, hearing loss and stroke due to neuronal damage,cardiomyopathy and exercise intolerance due to cardiac and striated muscle dysfunction,and renal tubularand glomerular diseasedue to renal epithelial dysfunction (Table 2).Table 2. Common Manifestations of Mitochondrial DNA DisordersNeuropsychiatric DefectsHeadacheDepressionStrokePsychosisDementiaSeizuresBlindnessAtaxiaDeafnessPeripheral neuropathyMuscle DefectsMyopathy (cardiac or skeletal muscle)Lactic acidosisExercise intoleranceWeakness/fatigueRenal DefectsProximal tubule dysfunctionGlomerulonephritisOther Systemic FindingsEpisodic nausea/vomitingDiabetes mellitusIntestinal pseudo-obstructionPancytopeniaShort body statureHypoparathyroidismOur patient's case illustrates the major diagnostic challenges of mtDNA disorders. First, manifestations of mtDNA disorders such as diabetes mellitus present identically to idiopathic disease. Only the clustering of multiple diseases of high-energy organs within a family allows distinction. Also, owing to an increased proportion of diseased mitochondria in tissue over time and the need for a threshold mutation frequency to yield phenotypic expression, inherited defects of mtDNA can be clinically silent until the adult years. Indeed, MELAS first presenting at the age of 60 years has been reported.Finally, diagnosis of mtDNA disease is hampered by the lack of a single, highly specific, widely available test.A simple screening test for mtDNA disorders is the ratio of serum concentrations of lactate to pyruvate measured at rest. Because of defects in oxidative phosphorylation, patients with mtDNA disorders are dependent on anaerobic metabolism, which results in a shunt of pyruvate to lactate. A high lactate level at rest is suggestive of an mtDNA disorder, and a lactate-pyruvate ratio of 20:1 or higher is often seen.Evaluation during exercise may add sensitivity to this test, as the serum lactate-pyruvate ratio may reach high levels with physical activity in patients with mtDNA defects.Exercise testing was particularly valuable for our patient, whose borderline lactate-pyruvate ratio of 19:1 doubled with exercise, bolstering the case for an mtDNA disorder. Exercise testing can also reveal abnormal oxidative metabolism by other markers, as typified by our patient's low anaerobic threshold, maximum usage of oxygen, and maximum heart rate (Table 1).Muscle biopsy findings can suggest the presence of an mtDNA disorder, revealing pathognomonic "ragged red fibers" caused by proliferation of abnormal mitochondria.However, owing to heteroplasmy, patients whose defective mitochondria are not concentrated in muscle may not have ragged red fibers.Muscle biopsy results are thus relatively specific, but not sensitive for mitochondrial disorders. Assays of components of the oxidative phosphorylation cascade allow identification of specific defects in biopsy material. In concordance with prior published results from patients with MELAS,biochemical assay of our patient's muscle tissue demonstrated a defect in the late components of electron transport chain complex I, despite the absence of ragged red fibers on microscopy (Table 1).Results of genetic testing in our patient revealed the presence of the point mutation most commonly associated with MELAS, A3243G of the mitochondrial leucine–transfer RNA gene.Although the mutation was found at a 17% frequency in our patient's blood, the correlation between mutation frequencies in blood and muscle are notoriously poor,so no inference can be made regarding the frequency of the mutation in our patient's muscle. Furthermore, because of heteroplasmy, qualitative genetic testing is nonspecific for clinical disease. Thus, patients can have the genetic mutation but be phenotypically normalor display characteristics of other mtDNA syndromes.As well, genetic testing is relatively insensitive: patients can have symptomatic mtDNA disorders with negative screen results for common mtDNA mutations.Presumably these latter patients have either genetic defects not yet describedor genetic defects focused in tissues not used to prepare the mtDNA for the assay.For example, if DNA is extracted from muscle tissue but the mutant mitochondria are concentrated in neuronal tissue, the assay may produce negative results. Thus, a clinical assessment of signs, symptoms, and family history must be integrated with diagnostic testing to ensure proper diagnosis.It has been suggested that early treatment of mtDNA disorders might prevent the development of irreversible disease, such as stroke, in affected patients.A variety of agents have been used for therapy of mtDNA disorders, including L-carnitine,idebenone,thiamine,nicotinamide,and most commonly, coenzyme Q (ubiquinone)or dichloroacetic acid.Coenzyme Q is a diffusible carrier of protons and electrons, and thus can theoretically bypass an upstream block in the electron transport chain. Conversely, dichloroacetic acid de-represses pyruvate dehydrogenase, which leads to an increased use of the Krebs cycle and decreases metabolism of pyruvate to lactate. Although symptomatic improvement has been reported with these agents,no large-scale, randomized trials have been completed, and their overall clinical efficacy is unknown. Nevertheless, given the reported improvements in symptoms and quality of life, treatment should be considered for individual patients, with adjustments to the regimen made based on objective assessment of response (eg, by changes in symptoms, serum lactate-pyruvate ratios, or exercise testing).CONCLUSIONSIn summary, we describe a patient with MELAS who illustrates the diagnostic challenge that mtDNA disorders present to the internist. Although these disorders can cause common conditions such as type 2 diabetes mellitus, seizures, psychosis, stroke, renal failure, heart failure, and hearing loss, primary care physicians may only rarely entertain the diagnosis of an mtDNA disorder. Given their surprisingly high prevalence in patients with common medical conditions, it must be assumed that clinically significant mtDNA disorders frequently go undiagnosed. 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would like to thank Salvatore DeMauro, MD, for genetic testing for the MELAS mutation and Charles Hoppel, MD, for the biochemical test results. We also thank Mark Munekata, MD, and Scott Filler, MD, for their thoughtful review of the manuscript.Corresponding author: Brad Spellberg, MD, Department of Medicine, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA 90509 (e-mail: bjs@humc.edu).

Journal

JAMA Internal Medicine – American Medical Association

Published: Nov 12, 2001

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