RESUMEN
We describe sequence analysis of the mitochondrial DNA of five Hungarian patients diagnosed with probable LHON, who do not carry any of the three primary point mutations. We report three novel mutations, one of which might have a pathogenic role.
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Atrofia Óptica Hereditaria de Leber/genética , Mutación Puntual/genética , Sustitución de Aminoácidos , Grupo Citocromo b/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Complejo IV de Transporte de Electrones/genética , Humanos , HungríaRESUMEN
Neurons may be particularly susceptible to oxidative damage, which has been proposed to induce somatic mutations, particularly in mitochondrial DNA (mtDNA). Therefore, acquired mtDNA mutations might preferentially accumulate in the brain and could play a role in aging and neurodegenerative disorders. Recently, a somatic T to G mtDNA mutation at noncoding nucleotide position 414 was reported in fibroblasts specifically from elderly subjects, with mutational burdens of up to 50%. We screened for this mutation in brain-derived mtDNA from 8 Alzheimer's disease patients, 27 Parkinson's disease patients, 4 multiple system atrophy patients, and 44 controls using up to three RFLP analyses. A total of 73 of these subjects were over the age of 65. The 414 mutation was absent in all cases. Next, individual mtDNA fragments from 6 elderly subjects were cloned, and a total of 70 clones were sequenced. The 414 mutation was absent in all clones, though occasional sequence variations were identified at other sites in single clones. The 414 mutation also was absent in blood (n = 6) and fibroblasts (n = 11) from elderly subjects. Our data suggest that it is rare for any one particular acquired mtDNA mutation to reach levels in the brain that are functionally significant. This does not exclude the possibility that the cumulative burden of multiple, individually rare, acquired mutations impairs mitochondrial function.
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Encefalopatías/genética , ADN Mitocondrial/genética , Mutación Puntual , Anciano , Envejecimiento/genética , Enfermedad de Alzheimer/genética , Sangre , Análisis Mutacional de ADN , Fibroblastos , Frecuencia de los Genes/genética , Humanos , Estrés Oxidativo , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
PURPOSE: To define the prevalence of a panel of mitochondrial DNA (mtDNA) mutations associated with Leber's hereditary optic neuropathy (LHON) in the Turkish LHON population. LHON-associated mtDNA mutations have been found in LHON patients from around the world, but the Turkish LHON population has not been studied. METHODS: Thirty-two Turkish patients were defined clinically as having LHON on the basis of painless, subacute, bilateral optic neuropathy and the exclusion of other causes of subacute optic neuropathy. mtDNA was extracted from blood of the 32 probands and assayed for a panel of primary and secondary LHON-associated mtDNA mutations by polymerase chain reaction (PCR)-based methods. We studied three well-known LHON-associated primary mutations (at nucleotide positions 11778, 3460 and 14484) and one common secondary mutation (at nucleotide 15257) in all 32 probands. In addition to these mutations, 18 of the 32 probands were tested for the Complex IV, COX III gene, LHON associated 9804 and 9438 mutations and secondary LHON mutations at nucleotide positions 3394, 4160, 4216, 4917, 5244, 7444, 7706, 13708, 13730 and 15812. RESULTS: Among the 32 probands tested for four common LHON mutations, 3 carried the 14484 mutation, 1 carried the 11778 mutation, 1 carried the 3460 mutation and 1 carried the 15257 mutation. Among the 18 LHON patients who tested for additional mutations, 1 proband harboured the 9804 mutation and 4 carried the secondary mutations at nucleotide positions 4216, 4917 and 13708. CONCLUSION: The results of mtDNA analysis of the Turkish LHON patients appear to be different from those of previous reports.
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ADN Mitocondrial/genética , Atrofias Ópticas Hereditarias/genética , Mutación Puntual , Adolescente , Adulto , Niño , Análisis Mutacional de ADN/métodos , Complejo IV de Transporte de Electrones/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofias Ópticas Hereditarias/fisiopatología , Turquía , Agudeza Visual , Campos VisualesAsunto(s)
Catarata/genética , ADN Mitocondrial/genética , Distonía/genética , NADH NADPH Oxidorreductasas/genética , Secuencia de Bases , Western Blotting , Catarata/patología , Análisis Mutacional de ADN , ADN Mitocondrial/química , Distonía/patología , Salud de la Familia , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , NADH Deshidrogenasa/genética , NADH Deshidrogenasa/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , LinajeRESUMEN
Mitochondrial diseases are a heterogeneous group of disorders with widely varying clinical features, due to defects in mitochondrial function. Involvement of both muscle and nerve is common in mitochondrial disease. In some cases, this involvement is subclinical or a minor part of a multisystem disorder, but myopathy and neuropathy are a major, often presenting, feature of a number of mitochondrial syndromes. In addition, mitochondrial dysfunction may play a role in a number of classic neuromuscular diseases. This article reviews the role of mitochondrial dysfunction in neuromuscular disease and discusses a rational approach to diagnosis and treatment of patients presenting with a neuromuscular syndrome due to mitochondrial disease.
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Miopatías Mitocondriales/patología , Enfermedades Neuromusculares/patología , Humanos , Miopatías Mitocondriales/genética , Miopatías Mitocondriales/terapia , Enfermedades Neuromusculares/genética , Enfermedades Neuromusculares/terapiaRESUMEN
OBJECTIVE: To identify mitochondrial DNA (mtDNA) mutations that predispose to PD. BACKGROUND: Mitochondrial complex I activity is deficient in PD. mtDNA mutations may account for the defect, but the specific mutations have not been identified. METHODS: Complete sequencing was performed of all mtDNA-encoded complex I and transfer RNA (tRNA) genes in 28 PD patients and 8 control subjects, as well as screening of up to 243 additional PD patients and up to 209 control subjects by restriction digests for selected mutations. RESULTS: In the PD patients, 15 complex I missense mutations and 9 tRNA mutations were identified. After screening additional subjects, rare PD patients were found to carry complex I mutations that altered highly conserved amino acids. However, no significant differences were found in the frequencies of any mutations in PD versus control groups. The authors were unable to confirm previously reported associations of mutations at nucleotide positions (np) 4336, 5460, and 15927/8 with PD. Complex I mutations previously linked to Leber's hereditary optic neuropathy, one of which has been linked to atypical parkinsonism, were not associated with PD. CONCLUSIONS: mtDNA mutations with a high mutational burden (present in a high percentage of mtDNA molecules in an individual) in complex I or tRNA genes do not play a major role in the risk of PD in most PD patients. Further investigations are necessary to determine if any of the rare mtDNA mutations identified in PD patients play a role in the pathogenesis of PD in those few cases.
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ADN Mitocondrial/genética , Mutación Missense/genética , Enfermedad de Parkinson/genética , ARN de Transferencia/genética , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: To investigate a family with maternally inherited, adult-onset multisystem degeneration including prominent parkinsonism to determine whether clinical features can result from a mitochondrial DNA (mtDNA) mutation. The parkinsonism was levodopa responsive and was associated with the loss of pigmented neurons in the substantia nigra in at least one patient. BACKGROUND: Mitochondrial dysfunction is hypothesized to play a role in late-onset neurodegenerative diseases including PD and AD. Mitochondrial genetic mutations are hypothesized to account for these defects, but attempts to identify specific mtDNA mutations have been inconclusive. METHODS: Clinical examinations, DNA sequencing, and restriction digestion and biochemical analyses were performed. RESULTS: Maternal relatives harbor a G-to-A missense mutation, heteroplasmic in some patients, at nucleotide position 11778 of the mitochondrial ND4 gene of complex I that converts a highly conserved arginine to a histidine. Sequencing of the entire mitochondrial genome in an affected family member reveals no other mutations likely to be pathogenic. This mutation has been identified previously only in families with Leber's hereditary optic neuropathy-a disorder also linked to complex I dysfunction but usually limited clinically to optic atrophy. CONCLUSIONS: These data reveal previously unsuspected clinical heterogeneity of the G11778A mutation, and suggest that an inherited mtDNA mutation can contribute to the development of adult-onset parkinsonism and multisystem degeneration.
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ADN Mitocondrial/genética , Trastornos Parkinsonianos/genética , Mutación Puntual/genética , Secuencia de Bases/genética , Encéfalo/patología , Femenino , Genoma , Humanos , Masculino , Persona de Mediana Edad , Trastornos Parkinsonianos/patología , LinajeRESUMEN
A variety of neurologic phenotypes have been described in patients with mitochondrial disorders. We report a 32-year-old man in whom dystonia was the salient and presenting feature of a mitochondrial DNA mutation. He presented at age 23 with writer's cramp and progressed over 5 years to exhibit dystonia in facial muscles and lower limbs. He also has exercise intolerance, mild, bilateral ptosis, proximal muscle weakness, and sensorineural hearing loss. Molecular genetic analysis of blood, urine, and muscle biopsy demonstrated the presence of a heteroplasmic point mutation at nucleotide position 3243. The 3243 mtDNA mutation has pleomorphic manifestations, and dystonia should be added to the list of associated clinical features.
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ADN Mitocondrial/genética , Distonía/genética , Síndrome MELAS/genética , Mutación Puntual/genética , Adulto , Análisis Mutacional de ADN , Humanos , Masculino , FenotipoRESUMEN
BACKGROUND/AIMS: Leber's hereditary optic neuropathy (LHON) is a mitochondrial DNA mediated disease which causes severe visual deficits. Although expressivity of the disease is 100%, penetrance is variable, and environmental factors may influence risk of becoming symptomatic. The causative relation between cigarette smoking and disease penetrance was examined. METHODS: The incidence of smoking in 65 age matched family members of one LHON pedigree was retrospectively obtained. Smoking in groups which expressed disease was compared with those which did not. Male subgroups were analysed separately in addition to combined sex groups. RESULTS: The association between smoking and disease penetrance was significant in all subgroups (p values from p=0.0009 to p=0.0001, 95% confidence intervals). Disease penetrance was higher in males than females. The association was weaker in the male group than combined sex groups (p values from p=0.0146 to p=0.0008, 95% confidence intervals), probably because of elimination of female asymptomatic non-smokers in the comparison groups. The association was strengthened in older age groups and in groups which smoked more heavily. CONCLUSIONS: Smoking is significantly associated with disease penetrance in this LHON pedigree. Degree of smoking and number of years smoked correlate with increased risk of developing symptoms.
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Atrofias Ópticas Hereditarias/genética , Fumar/efectos adversos , Adulto , Femenino , Humanos , Masculino , Atrofias Ópticas Hereditarias/etiología , Linaje , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Encuestas y CuestionariosRESUMEN
Virtually all cells in humans depend on mitochondrial oxidative phosphorylation to generate energy, accounting for the remarkable diversity of clinical disorders associated with mitochondrial DNA mutations. However, certain tissues are particularly susceptible to mitochondrial dysfunction, resulting in recognizable clinical syndromes. Mitochondrial DNA mutations have been linked to seizures, strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, and other clinical features. Mitochondrial DNA mutations also may play an important role in aging, as well as in common age-related neurodegenerative disorders such as Parkinson's disease. Therefore, it is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.
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Mitocondrias/metabolismo , Envejecimiento/genética , Cardiomiopatías/genética , Trastornos Cerebrovasculares/genética , ADN Mitocondrial/genética , Diabetes Mellitus/genética , Asesoramiento Genético , Técnicas Genéticas , Pérdida Auditiva Sensorineural/genética , Humanos , Mitocondrias/genética , Encefalomiopatías Mitocondriales/genética , Miopatías Mitocondriales/genética , Mutación/genética , Enfermedades Neurodegenerativas/genética , Atrofias Ópticas Hereditarias/genética , Fosforilación Oxidativa , Enfermedad de Parkinson/genética , Convulsiones/genéticaRESUMEN
The A-to-G mutation at position 8344 in the transfer RNAlysine mitochondrial DNA gene is associated mostly with the myoclonic epilepsy and ragged red fibers syndrome. We describe a five-generation family with this mutation and 19 affected members with a variant neurologic syndrome of ataxia, myopathy, hearing loss, and neuropathy. Along with axial lipomas and diabetes mellitus, hypertension is a frequent somatic feature, suggesting that mitochondrial mutations may contribute to hypertension in these patients.
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ADN Mitocondrial/genética , Síndrome MERRF/genética , Mutación Puntual , ARN de Transferencia de Lisina/genética , Diabetes Mellitus/genética , Femenino , Humanos , Hipertensión/genética , Lipoma/genética , Lipoma/patología , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
An expedient, accurate, and cost-efficient test was developed to scan critical regions of the mitochondrial genome for all possible mutations by two-dimensional DNA electrophoresis. The test involves a two-step multiplex PCR amplification: a long-distance PCR to amplify almost the entire mitochondrial genome, which then serves as template for the amplification of 25 short PCR fragments in two multiplex groups corresponding to regions implicated in human diseases. The mixture of fragments was subsequently subjected to two-dimensional electrophoretic separation, first by size in a nondenaturant polyacrylamide gel and then on the basis of basepair sequence in a denaturing gradient polyacrylamide gel. This latter process of denaturing gradient gel electrophoresis is a most accurate form of mutation detection on the basis of differences in melting behavior of mutant and wildtype fragments. Evaluation of the method using samples with known homoplasmic and heteroplasmic mutations, as well as CEPH pedigrees to study segregation of polymorphic variants, indicated a very high accuracy; none of the previously identified mutations and polymorphisms escaped detection, and no erroneous segregation patterns of polymorphic variants were observed. In addition, two variants were found to be novel mutations when analyzed by sequence analysis. One of these novel mutations was a heteroplasmic mutation in the COXIII gene that was found to segregate to homoplasmy in the next generation. Heteroplasmic mutations as low as 1% of mtDNA could still be detected.
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ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Análisis Mutacional de ADN/métodos , Electroforesis en Gel Bidimensional/métodos , Humanos , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Síndrome MERRF/diagnóstico , Síndrome MERRF/genética , Peso Molecular , Desnaturalización de Ácido Nucleico , Ácidos Nucleicos Heterodúplex/análisis , Atrofias Ópticas Hereditarias/diagnóstico , Atrofias Ópticas Hereditarias/genética , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético , Sensibilidad y Especificidad , TemperaturaRESUMEN
A 14-year-old girl with the mitochondrial neurogastrointestinal encephalopathy syndrome had an 8-year history of intestinal pseudoobstruction with abdominal pain, persistent vomiting, gastric and duodenal dilatation, and duodenal diverticulosis. The child appeared chronically malnourished and had severe growth failure. Multisystem involvement was evident with the presence of ptosis, external ophthalmoplegia, muscle wasting, peripheral neuropathy, and diffuse white matter disease seen on magnetic resonance imaging. Lactic acidosis and increased cerebrospinal fluid protein were observed. Mitochondrial enzyme analysis of fresh-frozen skeletal muscle revealed a respiratory chain defect. Molecular genetic studies showed multiple mitochondrial DNA deletions. Pathologic findings in the intestine included atrophy of the external layer of the muscularis propria and an increased number of abnormal-appearing mitochondria in ganglion and smooth-muscle cells. Microvesicular steatosis was observed in liver, skeletal, and gastrointestinal smooth muscle, and Schwann cells of peripheral nerve. Brightly eosinophilic inclusions in the cytoplasm of gastrointestinal ganglion cells were visible by light microscopy, which were confirmed to be megamitochondria by ultrastructural studies. This is the first report of abnormal mitochondria observed in intestinal ganglion and smooth-muscle cells in this syndrome.
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Seudoobstrucción Intestinal/patología , Miopatías Mitocondriales/patología , Recto/patología , Adolescente , Biopsia/métodos , ADN Mitocondrial/análisis , Femenino , Humanos , Microscopía Electrónica , Músculos/patología , Recto/inervaciónRESUMEN
Four unrelated patients presented with a severe sensory ataxic neuropathy in association with dysarthria and chronic progressive external ophthalmoplegia. Electrophysiologic and pathologic studies showed severe axonal loss disproportionately affecting sensory nerves. Molecular genetic analysis revealed multiple mitochondrial DNA deletions in muscle and peripheral nerve. Sensory ataxic neuropathy may be the predominant and presenting manifestation of a mitochondrial disorder, and a mitochondrial etiology should be included in its differential diagnosis. The triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) may represent a novel mitochondrial disease associated with multiple mitochondrial DNA deletions.
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ADN Mitocondrial/ultraestructura , Disartria/genética , Miopatías Mitocondriales/patología , Oftalmoplejía/genética , Adulto , Secuencia de Bases , Disartria/fisiopatología , Femenino , Humanos , Masculino , Microscopía Electrónica , Datos de Secuencia Molecular , Oftalmoplejía/fisiopatologíaRESUMEN
Congenital fibrosis of the extraocular muscles is an autosomal dominant congenital disorder characterized by bilateral ptosis, restrictive external ophthalmoplegia with the eyes partially or completely fixed in an infraducted (downward) and strabismic position, and markedly limited and aberrant residual eye movements. It has been generally thought that these clinical abnormalities result from myopathic fibrosis of the extraocular muscles. We describe the intracranial and orbital pathology of 1 and the muscle pathology of 2 other affected members of a family with chromosome 12-linked congenital fibrosis of the extraocular muscles. There is an absence of the superior division of the oculomotor nerve and its corresponding alpha motor neurons, and abnormalities of the levator palpebrae superioris and rectus superior (the muscles innervated by the superior division of the oculomotor nerve). In addition, increased numbers of internal nuclei and central mitochondrial clumping are found in other extraocular muscles, suggesting that the muscle pathology extends beyond the muscles innervated by the superior division of cranial nerve III. This report presents evidence that congenital fibrosis of the extraocular muscles results from an abnormality in the development of the extraocular muscle lower motor neuron system.
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Anomalías Múltiples/diagnóstico , Músculos Oculomotores/anomalías , Nervio Oculomotor/anomalías , Oftalmoplejía/congénito , Anomalías Múltiples/genética , Adulto , Anciano , Ambliopía/rehabilitación , Biopsia , Encéfalo/patología , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 12 , Femenino , Fibrosis , Humanos , Recién Nacido , Masculino , Músculo Esquelético/patología , Músculos Oculomotores/patología , Linaje , Estrabismo/cirugíaRESUMEN
We evaluated 10 patients with histologically typical polymyositis except for an excess of muscle fibres with absent cytochrome oxidase (COX) staining. No biopsies had vacuoles or congophilic material in muscle fibres. All patients presented with a history of slowly progressive weakness. The average age of onset was 9 years older than a group of polymyositis patients with normal COX staining of muscle fibres. Selective weakness of knee extension was a prominent and disabling feature in most patients. Serum creatine kinase was usually mildly elevated (363 +/- 115 U/l) but at levels lower than those in other patients with polymyositis. Mitochondrial DNA analysis showed multiple deletions in 90% of muscles from patients with excessive numbers of COX-negative muscle fibres, a prevalence significantly greater than the 22% figure for controls (P = 0.005). As a group, the patients responded poorly to immunosuppressive therapy. We conclude that patients with polymyositis and an excess of COX-negative muscle fibres, but no inclusion bodies, have common features including selective quadriceps weakness, mitochondrial pathology by histochemical and DNA analysis and a poor response to immunosuppressive therapy. Some of these features are shared with inclusion body myositis (IBM) and this entity cannot be entirely excluded as vacuoles may not be present in all muscle tissue in IBM patients. Evaluation of the COX activity in muscle fibres of patients with inflammatory myopathies provides useful prognostic information regarding the likelihood of improved strength after immunosuppressive treatment.
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Complejo IV de Transporte de Electrones/metabolismo , Polimiositis/enzimología , ADN Mitocondrial/genética , Femenino , Eliminación de Gen , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/patología , Polimiositis/tratamiento farmacológico , Polimiositis/genética , Polimiositis/patología , Prednisona/uso terapéuticoAsunto(s)
ADN Mitocondrial/genética , Genoma Humano , Miopatías Mitocondriales/genética , Envejecimiento/genética , Enfermedad de Alzheimer/genética , Herencia Extracromosómica , Humanos , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/fisiopatología , Atrofias Ópticas Hereditarias/genética , Fosforilación Oxidativa , ARN de Transferencia/genéticaRESUMEN
Colchicine may induce a myoneuropathy in patients with renal insufficiency. To date, myotonia has not been described in this disorder. We recently studied 4 patients treated with routine doses of colchicine who, in the setting of renal insufficiency, developed a severe myoneuropathy characterized by prominent myotonic discharges on electromyography. In addition, 1 of the 4 patients had profound clinical myotonia. In the 3 patients in whom biopsies were performed, marked myopathic change with intracytoplasmic vacuolization was identified. All 4 patients improved rapidly with discontinuation of the medication. The patient in whom electrophysiologic studies were repeated had a complete resolution of the myotonic discharges. Colchicine myoneuropathy can present with prominent clinical and electrophysiologic myotonia that resolves completely with discontinuation of the medication.
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Colchicina/efectos adversos , Miotonía/inducido químicamente , Enfermedades Neuromusculares/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Colchicina/uso terapéutico , Electromiografía , Femenino , Humanos , Fallo Renal Crónico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Músculos/patología , Miotonía/patología , Miotonía/fisiopatología , Enfermedades Neuromusculares/patología , Enfermedades Neuromusculares/fisiopatologíaRESUMEN
Mitochondrial DNA from two genetically unrelated patients carrying the mutation at position 11778 that causes Leber's hereditary optic neuropathy has been transferred with mitochondria into human mtDNA-less rho0206 cells. As analyzed in several transmitochondrial cell lines thus obtained, the mutation, which is in the gene encoding subunit ND4 of the respiratory chain NADH dehydrogenase (ND), did not affect the synthesis, size, or stability of ND4, nor its incorporation into the enzyme complex. However, NADH dehydrogenase-dependent respiration, as measured in digitonin-permeabilized cells, was specifically decreased by approximately 40% in cells carrying the mutation. This decrease, which was significant at the 99.99% confidence level, was correlated with a significantly reduced ability of the mutant cells to grow in a medium containing galactose instead of glucose, indicating a clear impairment in their oxidative phosphorylation capacity. On the contrary, no decrease in rotenone-sensitive NADH dehydrogenase activity, using a water-soluble ubiquinone analogue as electron acceptor, was detected in disrupted mitochondrial membranes. This is the first cellular model exhibiting in a foreign nuclear background mitochondrial DNA-linked biochemical defects underlying the optic neuropathy phenotype.
Asunto(s)
ADN Mitocondrial , Mitocondrias/metabolismo , Mutación , Atrofias Ópticas Hereditarias/genética , Oxígeno/metabolismo , Adulto , División Celular , Línea Celular , Línea Celular Transformada , Transporte de Electrón , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/enzimología , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , NADH Deshidrogenasa/metabolismo , Atrofias Ópticas Hereditarias/metabolismo , Atrofias Ópticas Hereditarias/patología , Fosforilación OxidativaRESUMEN
Mitochondrial diseases include myopathies and multisystem disorders. They are characterized by morphologic and biochemical abnormalities of mitochondria. Their genetic characteristics-maternal inheritance, heteroplasmy, mitotic segregation, and threshold effect-are unique. The clinical phenotypes are considerably heterogeneous, but the clinical presentation in many cases is characteristic or suggestive. We review the clinical features of the most prevalent mitochondrial encephalomyopathy syndromes, their molecular genetic basis, isolated clinical symptoms, and uncommon presentations. Molecular genetic diagnosis is available for the common syndromes and has revolutionized their diagnosis. Future therapeutic advances, based on the precise genetic etiology, are anticipated. Mitochondrial dysfunction may be a more frequent pathogenetic mechanism than the prevalence of the classic mitochondrial syndromes would indicate, as there is an association between the accumulation of mitochondrial DNA mutations in postmitotic tissues and neurologic and systemic degenerative diseases.