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1.
Orphanet J Rare Dis ; 14(1): 100, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060578

RESUMO

BACKGROUND: TK2 gene encodes for mitochondrial thymidine kinase, which phosphorylates the pyrimidine nucleosides thymidine and deoxycytidine. Recessive mutations in the TK2 gene are responsible for the 'myopathic form' of the mitochondrial depletion/multiple deletions syndrome, with a wide spectrum of severity. METHODS: We describe 18 patients with mitochondrial myopathy due to mutations in the TK2 gene with absence of clinical symptoms until the age of 12. RESULTS: The mean age of onset was 31 years. The first symptom was muscle limb weakness in 10/18, eyelid ptosis in 6/18, and respiratory insufficiency in 2/18. All patients developed variable muscle weakness during the evolution of the disease. Half of patients presented difficulty in swallowing. All patients showed evidence of respiratory muscle weakness, with need for non-invasive Mechanical Ventilation in 12/18. Four patients had deceased, all of them due to respiratory insufficiency. We identified common radiological features in muscle magnetic resonance, where the most severely affected muscles were the gluteus maximus, semitendinosus and sartorius. On muscle biopsies typical signs of mitochondrial dysfunction were associated with dystrophic changes. All mutations identified were previously reported, being the most frequent the in-frame deletion p.Lys202del. All cases showed multiple mtDNA deletions but mtDNA depletion was present only in two patients. CONCLUSIONS: The late-onset is the less frequent form of presentation of the TK2 deficiency and its natural history is not well known. Patients with late onset TK2 deficiency have a consistent and recognizable clinical phenotype and a poor prognosis, due to the high risk of early and progressive respiratory insufficiency.


Assuntos
Miopatias Mitocondriais/enzimologia , Timidina Quinase/deficiência , Adolescente , Adulto , Criança , DNA Mitocondrial/genética , Feminino , Humanos , Transtornos de Início Tardio/enzimologia , Transtornos de Início Tardio/metabolismo , Transtornos de Início Tardio/patologia , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/genética , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/enzimologia , Doenças Musculares/genética , Mutação/genética , Estudos Retrospectivos , Timidina Quinase/genética , Adulto Jovem
2.
Biochem Biophys Res Commun ; 494(1-2): 133-137, 2017 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-29054413

RESUMO

Mitochondrial (mt) DNA-associated NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) syndrome is due to mutation in the MT-ATP6 gene. We report the case of a 18-year-old man who presented with deafness, a myoclonic epilepsy, muscle weakness since the age of 10 and further developed a retinitis pigmentosa and ataxia. The whole mtDNA analysis by next-generation sequencing revealed the presence of the 2 bp microdeletion m.9127-9128 del AT in the ATP6 gene at 82% heteroplasmy in muscle and to a lower load in blood (10-20%) and fibroblasts (50%). Using the patient's fibroblasts, we demonstrated a 60% reduction of the oligomycin-sensitive ATPase hydrolytic activity, a 40% decrease in the ATP synthesis and determination of the mitochondrial membrane potential using the fluorescent probe tetramethylrhodamine, ethyl ester indicated a significant reduction in oligomycin sensitivity. In conclusion, we demonstrated that this novel AT deletion in the ATP6 gene is pathogenic and responsible for the NARP syndrome.


Assuntos
Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Retinite Pigmentosa/enzimologia , Retinite Pigmentosa/genética , Deleção de Sequência , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Sequência de Bases , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Análise Mutacional de DNA , DNA Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Oligomicinas/farmacologia , Síndrome , Adulto Jovem
3.
FEBS J ; 282(24): 4714-26, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26408230

RESUMO

Mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies are fatty acid oxidation disorders biochemically characterized by tissue accumulation of long-chain fatty acids and derivatives, including the monocarboxylic long-chain 3-hydroxy fatty acids (LCHFAs) 3-hydroxytetradecanoic acid (3HTA) and 3-hydroxypalmitic acid (3HPA). Patients commonly present severe cardiomyopathy for which the pathogenesis is still poorly established. We investigated the effects of 3HTA and 3HPA, the major metabolites accumulating in these disorders, on important parameters of mitochondrial homeostasis in Ca(2+) -loaded heart mitochondria. 3HTA and 3HPA significantly decreased mitochondrial membrane potential, the matrix NAD(P)H pool and Ca(2+) retention capacity, and also induced mitochondrial swelling. These fatty acids also provoked a marked decrease of ATP production reflecting severe energy dysfunction. Furthermore, 3HTA-induced mitochondrial alterations were completely prevented by the classical mitochondrial permeability transition (mPT) inhibitors cyclosporin A and ADP, as well as by ruthenium red, a Ca(2+) uptake blocker, indicating that LCHFAs induced Ca(2+)-dependent mPT pore opening. Milder effects only achieved at higher doses of LCHFAs were observed in brain mitochondria, implying a higher vulnerability of heart to these fatty acids. By contrast, 3HTA and docosanoic acids did not change mitochondrial homeostasis, indicating selective effects for monocarboxylic LCHFAs. The present data indicate that the major LCHFAs accumulating in mitochondrial trifunctional protein and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiencies induce mPT pore opening, compromising Ca(2+) homeostasis and oxidative phosphorylation more intensely in the heart. It is proposed that these pathomechanisms may contribute at least in part to the severe cardiac alterations characteristic of patients affected by these diseases.


Assuntos
Sinalização do Cálcio , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa/metabolismo , Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Ácidos Mirísticos/metabolismo , Fosforilação Oxidativa , Ácidos Palmíticos/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatias/enzimologia , Cardiomiopatias/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/metabolismo , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa/deficiência , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/enzimologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Proteína Mitocondrial Trifuncional/deficiência , Proteína Mitocondrial Trifuncional/metabolismo , NADP/metabolismo , Doenças do Sistema Nervoso/enzimologia , Doenças do Sistema Nervoso/metabolismo , Especificidade de Órgãos , Fosforilação Oxidativa/efeitos dos fármacos , Ratos Wistar , Rabdomiólise/enzimologia , Rabdomiólise/metabolismo
5.
Eur J Pediatr ; 174(12): 1593-602, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26074369

RESUMO

UNLABELLED: Pearson marrow-pancreas syndrome (PS) is a rare mitochondrial disorder. Impaired mitochondrial respiratory chain complexes (MRCC) differ among individuals and organs, which accounts for variable clinical pictures. A subset of PS patients develop 3-methylglutaconic aciduria (3-MGA-uria), but the characteristic symptoms and impaired MRCC remain unknown. Our patient, a girl, developed pancytopenia, hyperlactatemia, steatorrhea, insulin-dependent diabetes mellitus, liver dysfunction, Fanconi syndrome, and 3-MGA-uria. She died from cerebral hemorrhage at 3 years of age. We identified a novel 5.4-kbp deletion of mitochondrial DNA. The enzymatic activities of MRCC I and IV were markedly reduced in the liver and muscle and mildly reduced in skin fibroblasts and the heart. To date, urine organic acid analysis has been performed on 29 PS patients, including our case. Eight patients had 3-MGA-uria, while only one patient did not. The remaining 20 patients were not reported to have 3-MGA-uria. In this paper, we included these 20 patients as PS patients without 3-MGA-uria. PS patients with and without 3-MGA-uria have similar manifestations. Only a few studies have examined the enzymatic activities of MRCC. CONCLUSION: No clinical characteristics distinguish between PS patients with and without 3-MGA-uria. The correlation between 3-MGA-uria and the enzymatic activities of MRCC remains to be elucidated. WHAT IS KNOWN: • The clinical characteristics of patients with Pearson marrow-pancreas syndrome and 3-methylglutaconic aciduria remain unknown. WHAT IS NEW: • No clinical characteristics distinguish between Pearson marrow-pancreas syndrome patients with and without 3-methylglutaconic aciduria.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Musculares/enzimologia , Doenças Mitocondriais/diagnóstico , Miopatias Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/genética , Southern Blotting , Pré-Escolar , DNA Mitocondrial/genética , Evolução Fatal , Feminino , Fibroblastos/enzimologia , Deleção de Genes , Humanos , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/genética , Mitocôndrias Cardíacas/enzimologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/genética , Doenças Musculares/enzimologia , Doenças Musculares/genética , Reação em Cadeia da Polimerase , Pele/citologia
6.
Clin Sci (Lond) ; 128(12): 895-904, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25626417

RESUMO

Complex I (CI) is the largest of the five multi-subunit complexes constituting the human oxidative phosphorylation (OXPHOS) system. Seven of its catalytic core subunits are encoded by mitochondrial DNA (ND (NADH dehydrogenase)1-6, ND4L (NADH dehydrogenase subunit 4L)), with mutations in all seven having been reported in association with isolated CI deficiency. We investigated two unrelated adult patients presenting with marked exercise intolerance, persistent lactic acidaemia and severe muscle-restricted isolated CI deficiency associated with sub-sarcolemmal mitochondrial accumulation. Screening of the mitochondrial genome detected novel mutations in the MTND1 (NADH dehydrogenase subunit 1) gene, encoding subunit of CI [Patient 1, m.3365T>C predicting p.(Leu20Pro); Patient 2, m.4175G>A predicting p.(Trp290*)] at high levels of mitochondrial DNA heteroplasmy in skeletal muscle. We evaluated the effect of these novel MTND1 mutations on complex assembly showing that CI assembly, although markedly reduced, was viable in the absence of detectable ND1 signal. Real-time PCR and Western blotting showed overexpression of different CI assembly factor transcripts and proteins in patient tissue. Together, our data indicate that the mechanism underlying the expression of the biochemical defect may involve a compensatory response to the novel MTND1 gene mutations, promoting assembly factor up-regulation and stabilization of respiratory chain super-complexes, resulting in partial rescue of the clinical phenotype.


Assuntos
Complexo I de Transporte de Elétrons/deficiência , Tolerância ao Exercício/genética , Miopatias Mitocondriais/genética , Mutação , NADH Desidrogenase/genética , Adolescente , DNA Mitocondrial/genética , Teste de Esforço/métodos , Feminino , Humanos , Miopatias Mitocondriais/enzimologia , Músculo Esquelético/enzimologia , Linhagem , Adulto Jovem
7.
J Inherit Metab Dis ; 38(2): 315-22, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25141826

RESUMO

Children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) have a defect in the degradation of long-chain fatty acids and are at risk of hypoketotic hypoglycemia and insufficient energy production as well as accumulation of toxic fatty acid intermediates. Knowledge on substrate metabolism in children with LCHAD deficiency during fasting is limited. Treatment guidelines differ between centers, both as far as length of fasting periods and need for night feeds are concerned. To increase the understanding of fasting intolerance and improve treatment recommendations, children with LCHAD deficiency were investigated with stable isotope technique, microdialysis, and indirect calometry, in order to assess lipolysis and glucose production during 6 h of fasting. We found an early and increased lipolysis and accumulation of long chain acylcarnitines after 4 h of fasting, albeit no patients developed hypoglycemia. The rate of glycerol production, reflecting lipolysis, averaged 7.7 ± 1.6 µmol/kg/min, which is higher compared to that of peers. The rate of glucose production was normal for age; 19.6 ± 3.4 µmol/kg/min (3.5 ± 0.6 mg/kg/min). Resting energy expenditure was also normal, even though the respiratory quotient was increased indicating mainly glucose oxidation. The results show that lipolysis and accumulation of long chain acylcarnitines occurs before hypoglycemia in fasting children with LCHAD, which may indicate more limited fasting tolerance than previously suggested.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Cardiomiopatias/enzimologia , Metabolismo Energético , Jejum/sangue , Erros Inatos do Metabolismo Lipídico/enzimologia , Lipólise , Miopatias Mitocondriais/enzimologia , Doenças do Sistema Nervoso/enzimologia , Rabdomiólise/enzimologia , 3-Hidroxiacil-CoA Desidrogenases/sangue , Fatores Etários , Biomarcadores/sangue , Glicemia/metabolismo , Calorimetria Indireta , Cardiomiopatias/sangue , Cardiomiopatias/diagnóstico , Cardiomiopatias/dietoterapia , Carnitina/análogos & derivados , Carnitina/sangue , Criança , Pré-Escolar , Feminino , Glicerol/sangue , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/enzimologia , Marcação por Isótopo , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/dietoterapia , Masculino , Microdiálise , Miopatias Mitocondriais/sangue , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/dietoterapia , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/dietoterapia , Período Pós-Prandial , Rabdomiólise/sangue , Rabdomiólise/diagnóstico , Rabdomiólise/dietoterapia , Fatores de Tempo
9.
J Clin Neuromuscul Dis ; 16(2): 69-73, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25415517

RESUMO

Mitochondrial disorders resulting from an isolated deficiency of complex II of the respiratory chain is rarely reported. The phenotypic spectrum associated with these disorders is heterogeneous and still expanding. This report describes a patient who presented with myopathy, dilated cardiomyopathy, and pontine signal changes on magnetic resonance imaging. Muscle biopsy showed total absence of succinate dehydrogenase on enzyme histochemistry, negative succinate dehydrogenase subunit A (SDHA) activity on immunohistochemistry, and ultrastructural evidence of mitochondrial aggregates of varying sizes confirming the diagnosis of complex II deficiency. A unique phenotype with complex II deficiency is reported.


Assuntos
Encefalopatias Metabólicas/etiologia , Cardiomiopatias/etiologia , Complexo II de Transporte de Elétrons/deficiência , Miopatias Mitocondriais/patologia , Ponte/patologia , Encefalopatias Metabólicas/patologia , Feminino , Humanos , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/fisiopatologia , Adulto Jovem
10.
Am J Hum Genet ; 92(2): 293-300, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23352259

RESUMO

Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity. The autosomal-dominant form of PEO is genetically heterogeneous. Recently, causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B). Despite these findings, putative mutations remain unknown in half of the subjects with PEO. We report the identification, by exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA. DNA2 encodes a helicase/nuclease family member that is most likely involved in mtDNA replication, as well as in the long-patch base-excision repair (LP-BER) pathway. In vitro biochemical analysis of purified mutant proteins revealed a severe impairment of nuclease, helicase, and ATPase activities. These results implicate human DNA2 and the LP-BER pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance.


Assuntos
DNA Helicases/genética , DNA Mitocondrial/genética , Instabilidade Genômica/genética , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/genética , Mutação/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Sequência Conservada/genética , DNA Helicases/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Músculos/patologia , Polimorfismo de Nucleotídeo Único/genética
11.
Ann Med ; 45(1): 4-16, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21867371

RESUMO

Mitochondrial disorders are a heterogeneous group of disorders resulting from primary dysfunction of the respiratory chain. Muscle tissue is highly metabolically active, and therefore myopathy is a common element of the clinical presentation of these disorders, although this may be overshadowed by central neurological features. This review is aimed at a general medical and neurologist readership and provides a clinical approach to the recognition, investigation, and treatment of mitochondrial myopathies. Emphasis is placed on practical management considerations while including some recent updates in the field.


Assuntos
Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/terapia , Músculo Esquelético/patologia , Ubiquinona/análogos & derivados , Biópsia , Deficiência de Citocromo-c Oxidase/complicações , Transtornos de Deglutição/complicações , Suplementos Nutricionais , Doenças do Sistema Endócrino/complicações , Doenças do Sistema Endócrino/tratamento farmacológico , Teste de Esforço , Terapia por Exercício , Transtornos da Audição/complicações , Cardiopatias/complicações , Cardiopatias/diagnóstico , Cardiopatias/tratamento farmacológico , Humanos , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/enzimologia , Músculo Esquelético/enzimologia , Ubiquinona/deficiência , Ubiquinona/uso terapêutico , Transtornos da Visão/complicações , Vitaminas/uso terapêutico
12.
Gene ; 515(2): 372-5, 2013 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-23266623

RESUMO

The archetypal NARP syndrome is almost exclusively associated with the m.8993T>C/G mutation in the sixth subunit of the mitochondrial ATP synthase, whereas other mutations in the MT-ATP6 gene primarily associate with Leigh syndrome or Leber's hereditary optic neuropathy (LHON). We report a novel mitochondrial point mutation, m.8989G>C, in a patient presenting with neuropathy, ataxia and retinitis pigmentosa constituting the classical NARP phenotype. This mutation alters the amino acid right next to canonical NARP mutation. We suggest that classic NARP syndrome relates to a defined dysfunction of p.MT-ATP6.


Assuntos
Miopatias Mitocondriais/diagnóstico , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação de Sentido Incorreto , Retinite Pigmentosa/diagnóstico , Sequência de Bases , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/enzimologia , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/genética , Retinite Pigmentosa/enzimologia , Retinite Pigmentosa/genética
13.
Mol Genet Metab ; 107(3): 409-15, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22980518

RESUMO

Mitochondrial DNA depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterised by a quantitative reduction of the mitochondrial DNA copy number. Three main clinical forms of MDS: myopathic, encephalomyopathic and hepatocerebral have been defined, although patients may present with other MDS associated clinical symptoms and signs that cover a wide spectrum of onset age and disease. We studied 52 paediatric individuals suspected to have MDS. These patients have been divided into three different groups, and the appropriate MDS genes have been screened according to their clinical and biochemical phenotypes. Mutational study of DGUOK, MPV17, SUCLA2, SUCLG1 and POLG allowed us to identify 3 novel mutations (c.1048G>A and c.1049G>T in SUCLA2 and c.531+4A>T in SUCLG1) and 7 already known mutations in 10 patients (8 families). Seventeen patients presented with mtDNA depletion in liver or muscle, but the cause of mtDNA depletion still remains unknown in 8 of them. When possible, we quantified mtDNA/nDNA and CS activity in the same tissue sample, providing an additional tool for the study of MDS. The ratio (mtDNA/nDNA)/CS has shed some light in the discrepant results between the mtDNA copy number and the enzymatic respiratory chain activities of some cases.


Assuntos
Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Miopatias Mitocondriais/genética , Doenças Musculares/genética , Succinato-CoA Ligases/genética , Adolescente , Criança , Citrato (si)-Sintase/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Polimerase do DNA Mitocondrial , DNA Mitocondrial/genética , DNA Polimerase Dirigida por DNA/genética , Esclerose Cerebral Difusa de Schilder/diagnóstico , Esclerose Cerebral Difusa de Schilder/enzimologia , Esclerose Cerebral Difusa de Schilder/genética , Feminino , Humanos , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/enzimologia , Mitocôndrias/enzimologia , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/enzimologia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/enzimologia , Doenças Musculares/diagnóstico , Doenças Musculares/enzimologia , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adulto Jovem
14.
Hum Mol Genet ; 21(3): 526-35, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22012983

RESUMO

Mitochondrial dysfunction is an important cause of metabolic disorders of children and adults, with no effective therapy options. Recently, induction of mitochondrial biogenesis, by transgenic overexpression of PGC1-alpha [peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1-alpha], was reported to delay progression of early-onset cytochrome-c-oxidase (COX) deficiency in skeletal muscle of two mouse models: a muscle-specific knock-out of COX10 (COX10-mKO) and a constitutive knock-out of Surf1 (Surf1-KO). A pan-PPAR agonist, bezafibrate, could similarly delay myopathy progression in COX10-mKOs, but not in SURF1-KOs. We asked whether bezafibrate affected disease progression in late-onset adult-type mitochondrial myopathy mice. These 'Deletor mice' express a dominant patient mutation in Twinkle-helicase, leading to accumulation of multiple mtDNA deletions and subsequent progressive respiratory chain (RC) deficiency with COX-negative muscle fibers at 12 months of age. The primary and secondary molecular findings in Deletor mice mimic closely those in patients with Twinkle myopathy. We applied 0.5% bezafibrate diet to Deletors for 22 weeks, starting at disease manifestation, mimicking patient treatment after diagnosis. Bezafibrate delayed significantly the accumulation of COX-negative fibers and multiple mtDNA deletions. However, mitochondrial biogenesis was not induced: mitochondrial DNA copy number, transcript and RC protein amounts decreased in both Deletors and wild-type mice. Furthermore, bezafibrate induced severe lipid oxidation effects, with hepatomegaly and loss of adipose tissue, the mechanism involving lipid mobilization by high hepatic expression of FGF21 cytokine. However, as bezafibrate has been tolerated well by humans, the beneficial muscle findings in Deletor mice support consideration of bezafibrate trials on adult patients with mitochondrial myopathy.


Assuntos
Bezafibrato/uso terapêutico , Miopatias Mitocondriais/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Animais , Temperatura Corporal/efeitos dos fármacos , DNA Helicases/genética , DNA Mitocondrial/análise , Progressão da Doença , Complexo IV da Cadeia de Transporte de Elétrons/análise , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Hepatomegalia/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Mitocôndrias/metabolismo , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Fibras Musculares Esqueléticas/enzimologia , Mutação , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição , Perda de Peso
15.
Clin Exp Ophthalmol ; 40(5): 497-502, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22044520

RESUMO

INTRODUCTION: Orbicularis oculi (OO) muscle has recently proposed as a suitable muscle for biopsy to diagnose mitochondrial cyopathy: METHODS: Enzyme histochemical and immunohistochemical studies were performed on OO muscle obtained from 18 patients aged 37-87 years (median 64 years), 6 males, 12 females, who were undergoing routine upper blepharoplasty surgery. RESULTS: We confirmed the marked type II fibre (fast myosin heavy chain) predominance (89%) but also noted a different proportion and distribution of mitochondria in these fibres with occasional pseudo-'ragged-red' fibres with prominent subsarcolemmal and cytoplasmic aggregation of mitochondria. Cytochrome oxidase-negative fibres and true 'ragged-red' fibres were found at all ages over 40 years at levels that approach those used for diagnosis of mitochondrial cytopathy in peripheral or limb skeletal muscles. CONCLUSION: We would therefore urge caution in the use of OO as muscle biopsy for diagnosis of mitochondrial cytopathy and advise concomitant biopsy of limb skeletal muscle and/or supplementary genetic studies.


Assuntos
Mitocôndrias Musculares/patologia , Miopatias Mitocondriais/diagnóstico , Músculos Oculomotores/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Blefaroplastia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/enzimologia , Miopatias Mitocondriais/enzimologia , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Rápida/patologia , Músculo Esquelético/patologia , Cadeias Pesadas de Miosina/metabolismo , Músculos Oculomotores/enzimologia , Isoformas de Proteínas
16.
Curr Opin Neurol ; 24(5): 449-56, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21844807

RESUMO

PURPOSE OF REVIEW: Coenzyme Q (CoQ) is a vital component of the mitochondrial respiratory chain. A number of patients with CoQ deficiency presented with different clinical phenotypes, often affecting skeletal muscle, and responded well to CoQ supplementation. We discuss recent advances in this field with special attention to muscle involvement. RECENT FINDINGS: The identification of genetic defects causing CoQ deficiency has allowed to distinguish primary forms, due to mutations in biosynthetic genes, from secondary defects caused either by mutations in genes unrelated to CoQ biosynthesis or by nongenetic factors. To date, none of the patients with genetically proven primary deficiency presented with an exclusively (or prominently) myopathic phenotype. Most patients with myopathy were found to harbor other genetic defects (mutations in electron-transferring-flavoprotein dehydrogenase or mitochondrial DNA). The majority of patients with CoQ deficiency still lack a genetic diagnosis. The pathogenesis of CoQ deficiency cannot be attributed solely to the bioenergetic defect, suggesting that other roles of CoQ, including its antioxidant properties or its role in pyrimidine metabolism, may also play crucial roles. SUMMARY: Early recognition of CoQ deficiency is essential to institute appropriate and timely treatment, thus avoiding irreversible tissue damage.


Assuntos
Doenças Metabólicas/enzimologia , Músculo Esquelético/enzimologia , Doenças Musculares/enzimologia , Ubiquinona/deficiência , Humanos , Doenças Metabólicas/patologia , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/patologia , Músculo Esquelético/patologia , Doenças Musculares/patologia , Ubiquinona/genética
17.
J Neurol ; 258(3): 440-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20953793

RESUMO

Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual-spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss.


Assuntos
Heterogeneidade Genética , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/patologia , Mutação Puntual/genética , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Adolescente , Adulto , Ataxia/enzimologia , Ataxia/genética , Ataxia/patologia , DNA Mitocondrial/genética , Feminino , Humanos , Pessoa de Meia-Idade , Miopatias Mitocondriais/enzimologia , ATPases Mitocondriais Próton-Translocadoras/genética , Fatores Acopladores da Fosforilação Oxidativa/genética , Fenótipo , Retinite Pigmentosa/enzimologia , Adulto Jovem
18.
J Inherit Metab Dis ; 33 Suppl 3: S373-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20814823

RESUMO

Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is associated with c.1528G>C substitution in the HADHA gene, since most patients have the prevalent mutation on at least one allele. As it is known that the disease is relatively frequent in Europe, especially around the Baltic Sea, and that the majority of Polish LCHADD patients originate from the coastal Pomeranian province, partly inhabited by an ancient ethnic group, the Kashubians, we aimed to determine the carrier frequency of the prevalent HADHA mutation in various districts of Poland with special focus on the Kashubian district. A total of 6,854 neonatal dried blood samples from the entire country, including 2,976 Pomeranian neonates of Kashubian origin, were c.1528G>C genotyped. Fifty-nine heterozygous carriers for the prevalent c.1528G>C substitution (41 Pomeranian children) were detected in the studied group. Our data reveal a geographically skewed distribution of the c.1528C allele in the Polish population; in the northern Pomeranian province the carrier frequency is 1:73, which is the highest frequency ever reported, whereas in the remaining regions it is 1:217. Hence, the incidence of LCHADD in Poland is predicted to be 1:118,336 versus 1:16,900 in the Pomeranian district. Despite the relative rarity of the disease, screening for LCHADD in neonates born in the northern part of Poland, especially those of Kashubian origin, is justified. Our data allow us to suggest a probable Kashubian origin of the prevalent c.1528G>C mutation.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Cardiomiopatias/epidemiologia , Cardiomiopatias/genética , Erros Inatos do Metabolismo Lipídico/epidemiologia , Erros Inatos do Metabolismo Lipídico/genética , Miopatias Mitocondriais/epidemiologia , Miopatias Mitocondriais/genética , Subunidade alfa da Proteína Mitocondrial Trifuncional/deficiência , Subunidade alfa da Proteína Mitocondrial Trifuncional/genética , Mutação , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/genética , Rabdomiólise/epidemiologia , Rabdomiólise/genética , 3-Hidroxiacil-CoA Desidrogenases/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/enzimologia , Análise Mutacional de DNA , Teste em Amostras de Sangue Seco , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/enzimologia , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/enzimologia , Proteína Mitocondrial Trifuncional/deficiência , Triagem Neonatal/métodos , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/enzimologia , Fenótipo , Polônia/epidemiologia , Valor Preditivo dos Testes , Prevalência , Características de Residência , Rabdomiólise/diagnóstico , Rabdomiólise/enzimologia
19.
J Inherit Metab Dis ; 33 Suppl 3: S219-26, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20458543

RESUMO

Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18 months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8 years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNA(Leu(UUR)) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected families.


Assuntos
Miopatias Mitocondriais/genética , Mutação , RNA de Transferência/genética , RNA/genética , Idade de Início , Biópsia , Células Cultivadas , Criança , Análise Mutacional de DNA , Progressão da Doença , Metabolismo Energético , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/fisiopatologia , Miopatias Mitocondriais/terapia , Debilidade Muscular/enzimologia , Debilidade Muscular/genética , Fosforilação Oxidativa , Linhagem , Fenótipo , Músculo Quadríceps/enzimologia , Músculo Quadríceps/fisiopatologia , RNA Mitocondrial , Índice de Gravidade de Doença
20.
J Inherit Metab Dis ; 33 Suppl 3: S95-104, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20135231

RESUMO

Mitochondrial disorders are frequently encountered inherited diseases characterized by unexplained multisystem involvement with a chronic, intermittent, or progressive nature. The objective of this paper is to describe the profile of patients with mitochondrial disorders in South Africa. Patients with possible mitochondrial disorders were accessed over 10 years. Analyses for respiratory chain and pyruvate dehydrogenase complex enzymes were performed on muscle. A diagnosis of a mitochondrial disorder was accepted only if an enzyme activity was deficient. Sixty-three patients were diagnosed with a mitochondrial disorder, including 40 African, 20 Caucasian, one mixed ancestry, and two Indian patients. The most important findings were the difference between African patients and other ethnicities: respiratory chain enzyme complexes CI+III or CII+III deficiencies were found in 52.5% of African patients, being of statistical significance (p value = 0.0061). They also presented predominantly with myopathy (p value = 0.0018); the male:female ratio was 1:1.2. Twenty-five (62.5%) African patients presented with varying degrees of a myopathy accompanied by a myopathic face, high palate, and scoliosis. Fourteen of these 25 also had ptosis and/or progressive external ophthalmoplegia. No patients of other ethnicities presented with this specific myopathic phenotype. Caucasian patients (16/20) presented predominantly with central nervous system involvement. Of the South African pediatric neurology patients, Africans are more likely to present with myopathy and CII+III deficiency, and Caucasian patients are more likely to present with encephalopathy or encephalomyopathy.


Assuntos
Grupo com Ancestrais do Continente Africano , Grupo com Ancestrais do Continente Europeu , Doenças Mitocondriais/etnologia , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Complexo de Proteínas da Cadeia de Transporte de Elétrons/deficiência , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/enzimologia , Encefalomiopatias Mitocondriais/etnologia , Encefalomiopatias Mitocondriais/genética , Miopatias Mitocondriais/enzimologia , Miopatias Mitocondriais/etnologia , Miopatias Mitocondriais/genética , Músculo Esquelético/enzimologia , Fenótipo , Prognóstico , Complexo Piruvato Desidrogenase/genética , Complexo Piruvato Desidrogenase/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/enzimologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/etnologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Fatores de Risco , África do Sul/epidemiologia , Adulto Jovem
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