RESUMO
Oxidative phosphorylation (OXPHOS) is responsible for producing much of the adenosine triphosphate that is required by cells. The OXPHOS pathway incorporates over 100 polypeptides whose genes are located in either the nuclear DNA or the mitochondrial DNA (mtDNA). The expression of these genes and the assembly of the five OXPHOS enzyme complexes (complexes I to V) is a highly ordered and coordinated process. A broad array of human diseases result from mutations in either the nuclear or mtDNA genes or even in the systems that coordinate their interactions. Consequently, OXPHOS diseases can have complex inheritance patterns and a wide spectrum of clinical presentations.
Assuntos
Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Educação Médica Continuada , Humanos , Doenças Neuromusculares/genética , Doenças Neuromusculares/metabolismoRESUMO
Oxidative phosphorylation (OXPHOS) diseases are caused by inherited or spontaneously occurring mutations in the mitochondrial DNA (mtDNA) or the nuclear DNA. Mutations in the mtDNA can be classified into two groups, rearrangements and point mutations. This unit describes a method for detecting rearrangements of the mtDNA, which involves Southern blot hybridization. Another protocol detects mtDNA point mutations using restriction analysis of polymerase chain reaction (PCR) products. The Southern blot method requires an mtDNA-specific probe.
Assuntos
Análise Mutacional de DNA/métodos , DNA Mitocondrial/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Fosforilação Oxidativa , Southern Blotting , Sondas de DNA , Rearranjo Gênico , Testes Genéticos , Genética Médica , Humanos , Mutação , Mutação Puntual , Reação em Cadeia da PolimeraseRESUMO
Oxidative phosphorylation (OXPHOS) accounts for approximately 95% of the adenosine triphosphate (ATP) produced by the cell. The central nervous system, peripheral nervous system, cardiac muscle, skeletal muscle, and smooth muscle are highly susceptible to dysfunction of this complex enzyme system. Although most OXPHOS diseases are multisystem disorders, the neuromuscular manifestations are often prominent and play an important role in patient diagnosis. To assist the neurologist in evaluating these complex patients, this article focuses on selected samples of OXPHOS diseases with identifiable neuromuscular abnormalities and presents an evaluation algorithm to facilitate patient diagnosis.
Assuntos
Miopatias Mitocondriais/diagnóstico , Algoritmos , DNA Mitocondrial/genética , Diagnóstico Diferencial , Humanos , Encefalomiopatias Mitocondriais/diagnóstico , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/fisiopatologia , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/fisiopatologia , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/genética , Doenças Neuromusculares/fisiopatologia , Fosforilação Oxidativa , FenótipoRESUMO
Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.
Assuntos
Demência/genética , Neurônios/química , Neurônios/patologia , Mutação Puntual , Proteínas tau/genética , Atrofia , Western Blotting , Canadá , Análise Mutacional de DNA , Sondas de DNA , Demência/patologia , Epitopos/genética , Saúde da Família , Feminino , França , Lobo Frontal/patologia , Humanos , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/química , Emaranhados Neurofibrilares/ultraestrutura , Lobo Parietal/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Linhagem , Reação em Cadeia da Polimerase , Mapeamento por Restrição , Solubilidade , Lobo Temporal/patologia , Proteínas tau/análiseRESUMO
Although the mtDNA encodes only 13 polypeptide subunits of the OXPHOS enzymes, approximately 1,000 proteins are estimated to be necessary for proper OXPHOS function. Over the past 10 years a wide variety of adult and pediatric OXPHOS diseases were found to be caused by or associated with mitochondrial DNA (mtDNA) mutations and nuclear DNA mutations. These advances enhanced the ability to definitively diagnose patients, develop management plans, and provide genetic counseling. Recently described nuclear DNA and mtDNA mutations are enhancing our understanding of this complex group of diseases. The impact of these advances on our understanding of OXPHOS disease pathogenesis will be reviewed.
Assuntos
Encefalopatias Metabólicas Congênitas/genética , DNA Mitocondrial/genética , Miopatias Mitocondriais/genética , Fosforilação Oxidativa , Adulto , Encefalopatias Metabólicas Congênitas/diagnóstico , Criança , Aconselhamento Genético , Humanos , Miopatias Mitocondriais/diagnósticoRESUMO
Although the mitochondrial (mtDNA) encodes only 13 polypeptide subunits of the oxidative phosphorylation (OXPHOS) enzymes, approximately 1,000 proteins are estimated to be necessary for proper OXPHOS function. Over the past ten years, a wide variety of adult and pediatric OXPHOS diseases were found to be caused by or associated with mtDNA mutations and nuclear DNA mutations. These advances enhanced the ability to definitively diagnose patients, develop management plans, and provide genetic counseling. However, in most individuals, diagnosing OXPHOS diseases is difficult and depends on assessing complex data derived from clinical, neuroradiologic, metabolic, biochemical, and pathologic evaluations. As understanding of nuclear OXPHOS genes grows, a more coherent approach to diagnosis, management, and treatment is likely to emerge. This article reviews major classes of OXPHOS diseases, a diagnostic algorithm, and recent advances in this complex field.
Assuntos
Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/metabolismo , Fosforilação Oxidativa , Algoritmos , Núcleo Celular/metabolismo , DNA/genética , DNA Mitocondrial/genética , Humanos , Mutação , Doenças do Sistema Nervoso/genéticaRESUMO
Abnormalities in cellular bioenergetics have been identified in patients with Alzheimer's disease (AD) as well as in patients with other neurodegenerative diseases. The most commonly reported enzyme abnormalities are in the pyruvate dehydrogenase complex, the alpha-ketoglutarate dehydrogenase complex, and oxidative phosphorylation (OXPHOS). Although genetic evidence supporting primary OXPHOS defects as a cause for AD is weak, functionally important reductions in OXPHOS enzyme activities appear to occur in AD and may be related to beta-amyloid accumulation or other neurodegenerative processes. Since reduced neuronal ATP may enhance susceptibility to glutamate toxicity, OXPHOS defects could play an important role in the pathophysiology of AD.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Fosforilação Oxidativa , Peptídeos beta-Amiloides/genética , DNA Mitocondrial , Complexo IV da Cadeia de Transporte de Elétrons/genética , Ácido Glutâmico/genética , Humanos , Modelos Biológicos , MutaçãoRESUMO
PURPOSE: To describe the results of strabismus surgery on three patients with chronic progressive external ophthalmoplegia, a group of rare disorders characterized by ptosis and slowly progressive ophthalmoparesis that has been shown to result from defects in mitochondrial DNA. METHODS: Strabismus surgery using the adjustable suture technique was performed in three patients with strabismus and chronic progressive external ophthalmoplegia confirmed by clinical, biochemical, histopathologic, and genetic criteria. All three patients had mitochondrial DNA deletions. Two patients were exotropic; one patient was esotropic. RESULTS: Rectus muscle recessions were initially unsuccessful in correcting strabismus in one patient, although a subsequent procedure employing rectus muscle resections was successful in alleviating a significant head turn and improved ocular alignment. In the two other patients, a single procedure consisting of rectus muscle recessions combined with large rectus muscle resections successfully achieved good postoperative alignment. The amount of surgery performed in these three patients exceeded that predicted in standard strabismus tables. CONCLUSIONS: The myopathic process that results in chronic progressive external ophthalmoplegia renders rectus muscle recessions less effective compared with resections for correcting the associated strabismus seen in these patients. Rectus muscle resections therefore should be an integral procedure in the surgical management of the strabismus associated with chronic progressive external ophthalmoplegia.
Assuntos
Miopatias Mitocondriais/etiologia , Oftalmoplegia/complicações , Estrabismo/etiologia , Adulto , Doença Crônica , DNA Mitocondrial/genética , Progressão da Doença , Feminino , Deleção de Genes , Humanos , Pessoa de Meia-Idade , Miopatias Mitocondriais/patologia , Estrabismo/cirurgia , Resultado do TratamentoRESUMO
Mitochondrial DNA is more susceptible than nuclear DNA to mutations. Mitochondrial mutations have been associated with a range of disorders, some of which can be inherited maternally as well as by mendelian patterns. The oxidative phosphorylation diseases are a group of such disorders characterised by a complex phenotype; the Kearns-Sayre syndrome, for example, can include cardiac abnormalities, diabetes mellitus, cerebellar ataxia, and deafness. An understanding of the genetic and biochemical basis of these disorders will help in the adoption of a systematic approach to their diagnosis and to patient management.
Assuntos
DNA Mitocondrial/genética , Herança Extracromossômica , Fosforilação Oxidativa , DNA/genética , Feminino , Rearranjo Gênico , Humanos , Síndrome de Kearns-Sayre/genética , Doença de Leigh/genética , Síndrome MELAS/genética , Síndrome MERRF/genética , Encefalomiopatias Mitocondriais/genética , Miopatias Mitocondriais/genética , Mutação , Mutação PuntualRESUMO
An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.
Assuntos
Acidose Láctica/metabolismo , Hormônio Adrenocorticotrópico/deficiência , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias Musculares/metabolismo , Fosforilação Oxidativa , Acidose Láctica/complicações , Acidose Láctica/tratamento farmacológico , Catarata/complicações , Ácido Dicloroacético/uso terapêutico , Feminino , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/complicações , FenótipoRESUMO
Maternally inherited diabetes and deafness (MIDD) is a form of diabetes associated with mutation of mitochondrial DNA (mtDNA) that occurs in 1% to 2% of individuals with diabetes. Understanding the clinical course and abnormalities in insulin secretion and action in affected individuals should allow better understanding of how this genetic defect alter glucose metabolism. We report the clinical course of three individuals with mtDNA mutations and deafness. Subjects no. 1 and 2 had diabetes not yet requiring insulin therapy, and subject no. 3, the son of subject no. 2, had normal glucose tolerance. Defective oxidative phosphorylation (OXPHOS) based on OXPHOS enzymology of skeletal muscle biopsy of subjects no. 1 and 2 showed activity of less than 5% of the tolerance level in complex III for subject no. 1 and in complexes I, I + III, and IV for subject no. 2. Assessing insulin secretion using insulin response to intravenous glucose and insulin sensitivity based on minimal model analysis of an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT), first-phase insulin secretion was abnormal in subjects no. 1 and 2 and normal in subject no. 3 (AUC, 57, 93, and 1,235 pmol/L, respectively). In contrast, all three subjects had low insulin sensitivity indices (0.04, 0.14, and 0.27 x 10-4 x min/pmol/L, respectively). Subject no. 2, who underwent three FSIGT studies over a 16-month interval, showed transient improvement in insulin release in response to modification of diet and exercise (first-phase insulin AUC, 57 pmol/min v 287 pmol/min 10 months later; fasting insulin, 97 pmol/L v 237 pmol/L 10 months later), but by 16 months, first-phase insulin release and fasting insulin had decreased (AUC, 64 and 136 pmol/L, respectively) despite higher fasting glucose. We conclude that in our subjects with MIDD, insulin resistance is present and appears to precede defects in insulin release.
Assuntos
DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/fisiologia , Adolescente , Adulto , Biópsia , Glicemia/análise , DNA Mitocondrial/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Insulina/metabolismo , Síndrome MELAS/genética , Masculino , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Mutação , FosforilaçãoRESUMO
A heteroplasmic G-to-A transition at nucleotide pair (np) 14459 within the mitochondrial DNA (mtDNA)-encoded NADH dehydrogenase subunit 6 (ND6) gene has been identified as the cause of Leber hereditary optic neuropathy (LHON) and/or pediatric-onset dystonia in three unrelated families. This ND6 np 14459 mutation changes a moderately conserved alanine to a valine at amino acid position 72 of the ND6 protein. Enzymologic analysis of mitochondrial NADH dehydrogenase (complex I) with submitochondrial particles isolated from Epstein-Barr virus-transformed lymphoblasts revealed a 60% reduction (P < 0.005) of complex I-specific activity in patient cell lines compared with controls, with no differences in enzymatic activity for complexes II plus III, III and IV. This biochemical defect was assigned to the ND6 np 14459 mutation by using transmitochondrial cybrids in which patient Epstein-Barr virus-transformed lymphoblast cell lines were enucleated and the cytoplasts were fused to a mtDNA-deficient (p 0) lymphoblastoid recipient cell line. Cybrids harboring the np 14459 mutation exhibited a 39% reduction (p < 0.02) in complex I-specific activity relative to wild-type cybrid lines but normal activity for the other complexes. Kinetic analysis of the np 14459 mutant complex I revealed that the Vmax of the enzyme was reduced while the Km remained the same as that of wild type. Furthermore, specific activity was inhibited by increasing concentrations of the reduced coenzyme Q analog decylubiquinol. These observations suggest that the np 14459 mutation may alter the coenzyme Q-binding site of complex I.
Assuntos
DNA Mitocondrial/genética , NADH Desidrogenase/genética , Atrofias Ópticas Hereditárias/genética , Linhagem Celular Transformada , Herpesvirus Humano 4 , Humanos , Células Híbridas , Mutação , Atrofias Ópticas Hereditárias/enzimologiaRESUMO
The mitochondrial DNA (mtDNA) sequence was determined on 3 patients with Alzheimer's disease (AD) exhibiting AD plus Parkinson's disease (PD) neuropathologic changes and one patient with PD. Patient mtDNA sequences were compared to the standard Cambridge sequence to identify base changes. In the first AD+PD patient, 2 of the 15 nucleotide substitutions may contribute to the neuropathology, a nucleotide pair (np) 4336 transition in the tRNA(Gln) gene found 7.4 times more frequently in patients than in controls, and a unique np 721 transition in the 12S rRNA gene which was not found in 70 other patients or 905 controls. In the second AD+PD patient, 27 nucleotide substitutions were detected, including an np 3397 transition in the ND1 gene which converts a conserved methionine to a valine. In the third AD+PD patient, 2 polymorphic base substitutions frequently found at increased frequency in Leber's hereditary optic neuropathy patients were observed, an np 4216 transition in ND1 and an np 13708 transition in the ND5 gene. For the PD patient, 2 novel variants were observed among 25 base substitutions, an np 1709 substitution in the 16S rRNA gene and an np 15851 missense mutation in the cytb gene. Further studies will be required to demonstrate a causal role for these base substitutions in neurodegenerative disease.
Assuntos
Doença de Alzheimer/genética , DNA Mitocondrial/química , Doença de Parkinson/genética , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Mutação , Análise de Sequência de DNARESUMO
Mitochondrial DNA mutations are important causes of movement disorders and are often associated with basal ganglia degeneration. Leigh's disease and a form of generalized dystonia are caused by mitochondrial DNA mutations. Recent biochemical and genetic evidence suggests that some cases of Parkinson's disease may be caused by oxidative phosphorylation defects.
Assuntos
Doenças dos Gânglios da Base/metabolismo , Mitocôndrias/metabolismo , Humanos , Transtornos dos Movimentos/metabolismo , Fosforilação OxidativaRESUMO
Several reports have shown that individual mitochondrial DNA (mtDNA) deletions accumulate with age. However, the overall extent of somatic mtDNA damage with age remains unclear. We have utilized full-length PCR to concurrently screen for multiple mtDNA rearrangements in total DNA extracted from skeletal muscle derived from physiologically normal individuals (n = 35). This revealed that both the number and variety of mtDNA rearrangements increases dramatically between young and old individuals (P < 0.0001). We further examined the mtDNA from both the younger and older subjects by Southern blot analysis and observed an age-related increase in mtDNA(s) comparable in size to mtDNA products unique to patients with known mtDNA deletions. These data imply that a wide spectrum of mtDNA rearrangements accumulate in old individuals, which correlates with the marked age related decrease in OXPHOS capacity observed in post-mitotic tissues.
Assuntos
Envelhecimento/genética , DNA Mitocondrial/genética , Rearranjo Gênico/genética , Músculo Esquelético/fisiologia , Adulto , Idoso , DNA Mitocondrial/química , Humanos , Pessoa de Meia-Idade , Peso Molecular , Reação em Cadeia da Polimerase/métodos , Deleção de SequênciaRESUMO
To determine if somatic mtDNA mutations might contribute to the neurodegeneration observed in Huntington's disease (HD), we quantitated the amount of the common mitochondrial 4977 nucleotide pair deletion (mtDNA4977) in cortex and putamen of HD patients and age-matched controls by the serial dilution-polymerase chain reaction method. Cortical deletion levels were analyzed in the temporal, frontal, and occipital lobes. HD temporal lobes had an 11-fold greater mean mtDNA4977 deletion level than age-matched controls, and HD frontal lobes had fivefold greater levels. HD occipital lobe and putamen deletion levels were comparable with control levels. These results support the hypothesis that HD is associated with elevated cortical mtDNA damage.
Assuntos
Córtex Cerebral/química , DNA Mitocondrial/análise , Doença de Huntington/genética , Adulto , Sequência de Bases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido NucleicoRESUMO
A novel point mutation in the ND6 subunit of complex I at position 14,459 of the mitochondrial DNA (MTND6*LDY T14459A) was identified as a candidate mutation for the highly tissue-specific disease. Leber's hereditary optic neuropathy plus dystonia. Since the MTND6*LDYT14459A mutation was identified in a single family, other pedigrees with the mutation are needed to confirm its association with the disease. Clinical, biochemical, and genetic characterization is reported in two additional pedigrees. Leber's hereditary optic neuropathy developed in two family members in one pedigree. The daughter had clinically silent basal ganglia lesions. In a second pedigree, a single individual presented with childhood-onset generalized dystonia and bilateral basal ganglia lesions. Patient groups that included individuals with Leigh's disease, dystonia plus complex neurodegeneration, and Leber's hereditary optic neuropathy did not harbor the MTND6*LDYT14459A mutation, suggesting that this mutation displays a high degree of tissue specificity, thus producing a narrow phenotypic range. These results confirm the association of the MTND6*LDYT14459A mutation with Leber's hereditary optic neuropathy and/or dystonia. As the first genetic abnormality that has been identified to cause generalized dystonia, this mutation suggests that nuclear DNA or mitochondrial DNA mutations in oxidative phosphorylation genes are important considerations in the pathogenesis of dystonia.
Assuntos
DNA Mitocondrial/genética , Distonia/genética , Atrofias Ópticas Hereditárias/genética , Mutação Puntual , Adolescente , Adulto , Distonia/enzimologia , Feminino , Humanos , Pessoa de Meia-Idade , Atrofias Ópticas Hereditárias/enzimologiaRESUMO
A wide variety of mitochondrial DNA (mtDNA) mutations have recently been identified in degenerative diseases of the brain, heart, skeletal muscle, kidney and endocrine system. Generally, individuals inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during childhood, mid-life, or old age depending on the severity of the maternally-inherited mtDNA mutation; and then undergo a progressive decline. These novel features of mtDNA disease are proposed to be the product of the high dependence of the target organs on mitochondrial bioenergetics, and the cumulative oxidative phosphorylation (OXPHOS) defect caused by the inherited mtDNA mutation together with the age-related accumulation mtDNA mutations in post-mitotic tissues.
Assuntos
Envelhecimento/genética , Evolução Biológica , DNA Mitocondrial/genética , Mitocôndrias/metabolismo , Miopatias Mitocondriais/genética , Mutação , Atrofias Ópticas Hereditárias/genética , Mutação Puntual , Adulto , Idoso , Sequência de Aminoácidos , Animais , Criança , Sequência Conservada , Metabolismo Energético , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/metabolismo , Dados de Sequência Molecular , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Atrofias Ópticas Hereditárias/metabolismo , Fosforilação Oxidativa , Linhagem , Homologia de Sequência de AminoácidosRESUMO
The clinical manifestations of mitochondrial DNA (mtDNA) mutations depend on a variety of factors including ratios of normal to abnormal mtDNA and tissue-specific differences in ATP production by oxidative phosphorylation (OXPHOS). In order to investigate the effects of OXPHOS defects on renal tubule function, we characterized sodium-coupled transport processes in six individuals with OXPHOS diseases. Pathogenic mtDNA mutations were identified in five of these individuals. Sodium coupled transport processes were evaluated by determining fractional excretions of amino acids, glucose, lactate, urate, and phosphate in patients and controls. Four of the six individuals had high fractional excretions of neutral amino acids, indicating abnormal renal tubule reabsorbtion of these amino acids. Abnormalities in fractional excretions of lactate, glucose, urate, and phosphate were less pronounced. These results demonstrate that sodium-coupled transport processes in the kidney are sensitive to OXPHOS impairment. When abnormalities in these processes are encountered, an OXPHOS disease should be included in the differential diagnosis.
Assuntos
Aminoácidos/metabolismo , DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/metabolismo , Túbulos Renais Proximais/metabolismo , Síndrome MERRF/metabolismo , Miopatias Mitocondriais/metabolismo , Fosforilação Oxidativa , Trifosfato de Adenosina/biossíntese , Adulto , Idoso , Aminoácidos/genética , Sequência de Bases , Biópsia , Southern Blotting , DNA Mitocondrial/metabolismo , Feminino , Humanos , Transporte de Íons , Síndrome de Kearns-Sayre/genética , Túbulos Renais Proximais/fisiopatologia , Síndrome MERRF/genética , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/genética , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Sódio/metabolismoRESUMO
The investigation of pathogenic mitochondrial DNA (mtDNA) mutations has revealed a complex relation between patient genotype and phenotype. For unknown reasons, some mtDNA mutations produce specific clinical manifestations such as chronic progressive external ophthalmoplegia; myoclonic epilepsy and ragged-red fiber disease (MERRF); and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). To enhance our understanding of the association between genotype and phenotype, we investigated a patient with mitochondrial encephalomyopathy and severe cerebral calcifications for a mtDNA mutation. There was a deletion of one of three T:A nucleotide pairs in the tRNALeu(UUR) gene of the mtDNA involving positions 3271 to 3273. Pedigree analysis suggested that this mutation may have occurred spontaneously in the proband. This analysis represents the smallest mtDNA deletion observed to date and is the first deletion identified within a mitochondrial tRNA. This observation emphasizes the importance of delineating the precise mutation responsible for an oxidative phosphorylation disease for patient diagnosis as well as for genetic counseling of maternal lineage relatives.