RESUMO
Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported significantly more frequently in females than in males, and also showed an association with one of the chromosomal markers defining the POLG haplotype. In conclusion, our clinical results show that the homozygous p.Ala467Thr POLG mutation does not cause discrete phenotypes, as previously suggested, but rather there is a continuum of clinical symptoms. Our results suggest that the mitochondrial DNA background plays an important role in modifying the disease phenotype but nuclear modifiers, epigenetic and environmental factors may also influence the severity of disease.
Assuntos
DNA Polimerase Dirigida por DNA/genética , Esclerose Cerebral Difusa de Schilder/genética , Saúde da Família , Predisposição Genética para Doença/genética , Doenças Mitocondriais/genética , Mutação/genética , Oftalmoplegia Externa Progressiva Crônica/genética , Adolescente , Adulto , Idade de Início , Alanina/genética , Criança , Estudos de Coortes , Análise Mutacional de DNA , DNA Polimerase gama , Esclerose Cerebral Difusa de Schilder/mortalidade , Europa (Continente) , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/mortalidade , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/mortalidade , Estatística como Assunto , Estatísticas não Paramétricas , Treonina/genética , Adulto JovemRESUMO
A 26-year-old man developed a movement disorder characterised by bradyphrenia, bradykinesia, rigidity, tremor and dystonia, several years after having been shot by a gun in the hip. Laboratory investigations revealed anaemia and porphyria. The authors demonstrate that his neurological condition was a delayed manifestation of lead toxicity, caused by slow absorption of lead from persisting bullet fragments in the hip joint. Treatment with excision of the femoral head and debridement of the hip followed by a total hip, in combination with chelating therapy, led to a remarkable remission.
Assuntos
Lesões do Quadril/complicações , Intoxicação do Sistema Nervoso por Chumbo em Adultos/complicações , Transtornos dos Movimentos/etiologia , Ferimentos por Arma de Fogo/complicações , Adulto , Lesões do Quadril/diagnóstico por imagem , Humanos , Masculino , Radiografia , Descoloração de Dente/induzido quimicamente , Ferimentos por Arma de Fogo/diagnóstico por imagemRESUMO
OBJECTIVE: The mitochondrial energy-generating system (MEGS) encompasses the mitochondrial enzymatic reactions from oxidation of pyruvate to the export of adenosine triphosphate. It is investigated in intact muscle mitochondria by measuring the pyruvate oxidation and adenosine triphosphate production rates, which we refer to as the "MEGS capacity." Currently, little is known about MEGS pathology in patients with mutations in the mitochondrial DNA. Because MEGS capacity is an indicator for the overall mitochondrial function related to energy production, we searched for a correlation between MEGS capacity and 3243A-->G mutation load in muscle of patients with the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome. METHODS: In muscle tissue of 24 patients with the 3243A-->G mutation, we investigated the MEGS capacity, the respiratory chain enzymatic activities, and the 3243A-->G mutation load. To exclude coinciding mutations, we sequenced all 22 mitochondrial transfer RNA genes in the patients, if possible. RESULTS: We found highly significant differences between patients and control subjects with respect to the MEGS capacity and complex I, III, and IV activities. MEGS-related measurements correlated considerably better with the mutation load than respiratory chain enzyme activities. We found no additional mutations in the mitochondrial transfer RNA genes of the patients. INTERPRETATION: The results show that MEGS capacity has a greater sensitivity than respiratory chain enzymatic activities for detection of subtle mitochondrial dysfunction. This is important in the workup of patients with rare or new mitochondrial DNA mutations, and with low mutation loads. In these cases we suggest to determine the MEGS capacity.
Assuntos
DNA Mitocondrial/genética , Metabolismo Energético/genética , Mitocôndrias Musculares/genética , Músculo Esquelético/fisiologia , Mutação/genética , Adenosina/genética , Adolescente , Adulto , Criança , Pré-Escolar , DNA Mitocondrial/metabolismo , Transporte de Elétrons/genética , Feminino , Guanina/fisiologia , Humanos , Lactente , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Síndrome MELAS/metabolismo , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/patologiaRESUMO
In patients with a triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), the presenting features are mainly ataxia or ptosis. SANDO patients often have impaired balance and gait, which is not surprising considering the combination of sensory ataxic neuropathy, and additional symptoms like cerebellar ataxia and limb girdle weakness. We describe a SANDO patient who noticed an increasingly impaired balance and gait, without any dizziness. Neurological investigation revealed an external ophthalmeplegia and a cerebellar ataxia; the head impulse test was not reliable because of eye movement disorders. The caloric reflex tests showed lack of responses on both sides, compatible with severe bilateral vestibulopathy. Making the diagnosis of bilateral vestibulopathy in SANDO patients may have implications for the management of the patient, because specific vestibular rehabilitation can improve gaze and postural stability.
Assuntos
Vestibulopatia Bilateral/fisiopatologia , Disartria/fisiopatologia , Marcha/fisiologia , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Doenças Mitocondriais/fisiopatologia , Oftalmoplegia/fisiopatologia , Equilíbrio Postural/fisiologia , Vestibulopatia Bilateral/complicações , Disartria/complicações , Neuropatia Hereditária Motora e Sensorial/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Oftalmoplegia/complicaçõesRESUMO
We determined the extent of disease impact in 28 patients with genetically confirmed chronic progressive external ophthalmoplegia (CPEO) and compared the outcomes to those of matched myotonic dystrophy type I patients. CPEO patients reported a high frequency of severe fatigue (67.9%), pain (96.2%), depression (32.1%) and dependency in daily life (46.4%). The frequency and extent of depression were significantly higher than in DM1 patients (32.1% vs. 7.1%, p=0.040; mean Beck's depression inventory for primary care score 3.8±3.5 vs. 1.3±1.4, p=0.001), as were fatigue severity, pain intensity and extent of functional impairments. CPEO patients with polymerase gamma-1 mutations reported more functional impairments than those with mitochondrial DNA mutations. Disease impact was however not influenced by most clinical features. The present results help physicians to identify and to treat the factors that influence quality of life in CPEO patients and to provide symptomatic treatment where needed.
Assuntos
Olho/patologia , Oftalmoplegia/complicações , Atividades Cotidianas , Adulto , Idade de Início , Idoso , Doença Crônica , DNA Polimerase gama , DNA Mitocondrial/genética , DNA Polimerase Dirigida por DNA/genética , Depressão/etiologia , Fadiga/etiologia , Fadiga/psicologia , Feminino , Humanos , Vida Independente , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Distrofia Miotônica/complicações , Distrofia Miotônica/psicologia , Razão de Chances , Oftalmoplegia/psicologia , Dor/etiologia , Medição da Dor , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Chronic progressive external ophthalmoplegia (CPEO) is a relatively common mitochondrial disorder. Weakness of the extra-ocular, limb girdle and laryngeal muscles are established clinical features. Respiratory muscle involvement however has never been studied systematically, even though respiratory complications are one of the main causes of death. We therefore determined the prevalence and nature of respiratory muscle involvement in 23 patients with genetically confirmed CPEO. The main finding was decreased respiratory muscle strength, both expiratory (76.8% of predicted, p = 0.002) and inspiratory (79.5% of predicted, p = 0.004). Although the inspiratory vital capacity (92.5% of predicted, p = 0.021) and the forced expiratory volume in 1 s (89.3% of predicted, p = 0.002) were below predicted values, both were still within the normal range in the majority of patients. Expiratory weakness was associated with a decreased vital capacity (ρ = 0.502, p = 0.015) and decreased peak expiratory flow (ρ = 0.422, p = 0.045). Moreover, expiratory muscle strength was lower in patients with limb girdle weakness (62.6 ± 26.1% of predicted vs. 98.9 ± 22.5% in patients with normal limb girdle strength, p = 0.003), but was not associated with other clinical features, subjective respiratory complaints, disease severity or disease duration. Since respiratory involvement in CPEO is associated with severe morbidity and mortality, the present data justify periodic assessment of respiratory functions in all CPEO patients.
Assuntos
Síndrome de Kearns-Sayre/fisiopatologia , Músculos Respiratórios/fisiopatologia , Adolescente , Adulto , Idade de Início , Criança , Feminino , Humanos , Síndrome de Kearns-Sayre/complicações , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/fisiopatologia , Testes de Função Respiratória , Adulto JovemRESUMO
In order to investigate the consequences of stress susceptibility on vascular function, the authors assessed the respective contributions of nitric oxide (NO), prostanoids, and endothelium-derived hyperpolarizing factor to the vascular tone in rats with a constitutionally determined high and low susceptibility to behavioral stressors. In mesenteric resistance arteries mounted in a small vessel myograph and precontracted with l-phenylephrine hydrochloride (phenylephrine), the NO-synthase inhibitor N omega-nitro-l-arginine (l-NOARG, 100 microM) elicited a smaller increase of vascular tone in apomorphine-susceptible (APO-SUS) rats (P < 0.01). Addition of indomethacin (10 microM), in the presence of l-NOARG, resulted in a smaller decrease of vascular tone in APO-SUS rats (P < 0.01). Although acetylcholine-induced relaxation in phenylephrine-precontracted arteries was not different (P > 0.1), the individual components contributing to this relaxation were. In arteries precontracted with 125 mM K+, and incubated with indomethacin, acetylcholine-induced relaxation was not significantly different (pEC(50) and E(max): P > 0.1). Sensitivity (pEC(50): P < 0.05) and maximum relaxation (E(max): P < 0.001) to sodium nitroprusside, in the presence of 125 mM K+, was more pronounced in APO-SUS rats. In phenylephrine-precontracted arteries, in the presence of l-NOARG and indomethacin, maximum relaxation to ACh was reduced in APO-SUS rats (E(max): P < 0.05). This study showed that in rats with a high susceptibility to stressors, the contribution of NO to vascular tone was decreased as was the ratio of vasoconstrictor and vasodilator cyclooxygenase products in alpha-adrenergic precontracted arteries. End-organ sensitivity to NO was greater in APO-SUS rats, possibly due to up-regulation. Moreover, the contribution of endothelium-derived hyperpolarizing factor to acetylcholine-induced vasodilation was reduced in APO-SUS rat arteries.
Assuntos
Endotélio Vascular/metabolismo , Artérias Mesentéricas/metabolismo , Estresse Fisiológico/metabolismo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Animais , Apomorfina/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Characterized by the behavioral response to apomorphine, two outbred lines of Wistar rats can be recognized with constitutionally determined high (apomorphine susceptible, APO-SUS) or low (apomorphine unsusceptible, APO-UNSUS) adrenal responses to similar environmental stress. Within the accumbens nucleus, the APO-SUS and APO-UNSUS rats differ in alpha -adrenergic receptor responsiveness. This study explored whether these differences in adrenergic receptor sensitivity also exist in mesenteric resistance arteries. A Mulvany myograph was used to study the vasomotor responses of isolated mesenteric resistance arteries to adrenergic receptor stimulation. Phenylephrine (alpha1-agonist)-induced vasoconstriction did not differ between the two lines (pEC : 5.8 +/- 0.05 microM versus 5.8 +/- 0.04 microM and Emax: 36 +/- 2 kPa versus 33 +/- 1 kPa for APO-SUS, n = 9, and APO-UNSUS, n = 11, respectively, p > 0.1). After precontraction with phenylephrine, salbutamol (beta -agonist)-induced relaxation was less in APO-SUS rats (pEC50 4.9 +/- 0.06 versus 5.3 +/- 0.06M for APO-SUS, n = 9, and APO-UNSUS, n = 7, respectively, p < 0.001). Likewise, clonidine (alpha2-agonist)-induced relaxation was reduced in APO-SUS rats (pEC50: 6.7 +/- 0.07 versus 7.0 +/- 0.04, for APO-SUS, n = 9, and APO-UNSUS, n = 8, respectively; p < 0.01). In conclusion, constitutionally determined high susceptibility to stress is accompanied by an impaired vasorelaxation to adrenergic stimuli whereas vasoconstriction is unaffected. An unopposed vasoconstrictor action of norepinephrine may place the APO-SUS rats at increased risk for the development of hypertension, insulin resistance, and atherosclerosis.