RESUMO
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.
Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Doenças Mitocondriais , Doenças Musculares , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Humanos , Recém-Nascido , Japão/epidemiologia , Erros Inatos do Metabolismo Lipídico/epidemiologia , Doenças Mitocondriais/epidemiologia , Doenças Musculares/epidemiologia , Triagem Neonatal/métodosRESUMO
BACKGROUND AND OBJECTIVES: To identify factors associated with severe coronavirus disease 2019 (COVID-19), defined by hospitalization status, in patients with primary mitochondrial diseases (PMDs), thereby enabling future risk stratification and informed management decisions. METHODS: We undertook a cross-sectional, international, registry-based study. Data were extracted from the International Neuromuscular COVID-19 Database and collected between May 1, 2020, and May 31, 2021. The database included subjects with (1) PMD diagnosis (any age), clinically/histopathologically suspected and/or genetically confirmed; and (2) COVID-19 diagnosis classified as "confirmed", "probable", or "suspected" based on World Health Organization definitions. The primary outcome was hospitalization because of COVID-19. We collected demographic information, smoking status, coexisting comorbidities, outcomes after COVID-19 infection, and PMD genotype-phenotype. Baseline status was assessed using the modified Rankin scale (mRS) and the Newcastle Mitochondrial Disease Adult Scale (NMDAS). RESULTS: Seventy-nine subjects with PMDs from 10 countries were included (mean age 41.5 ± 18 years): 25 (32%) were hospitalized, 48 (61%) recovered fully, 28 (35%) improved with sequelae, and 3 (4%) died. Statistically significant differences in hospitalization status were observed in baseline status, including the NMDAS score (p = 0.003) and mRS (p = 0.001), presence of respiratory dysfunction (p < 0.001), neurologic involvement (p = 0.003), and more than 4 comorbidities (p = 0.002). In multivariable analysis, respiratory dysfunction was independently associated with COVID-19 hospitalization (odds ratio, 7.66; 95% CI, 2-28; p = 0.002). DISCUSSION: Respiratory dysfunction is an independent risk factor for severe COVID-19 in PMDs while high disease burden and coexisting comorbidities contribute toward COVID-19-related hospitalization. These findings will enable risk stratification and informed management decisions for this vulnerable population.
Assuntos
COVID-19 , Doenças Mitocondriais , COVID-19/epidemiologia , Teste para COVID-19 , Estudos Transversais , Hospitalização , Humanos , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/terapia , SARS-CoV-2RESUMO
Coenzyme Q10/ COQ10 , an essential cofactor in the electron-transport chain is involved in ATP production. Primary COQ10 deficiency is clinically and genetically a heterogeneous group of mitochondrial disorders caused by defects in the COQ10 synthesis pathway. Its mode of inheritance is autosomal recessive and it is characterized by metabolic abnormalities and multisystem involvement including neurological features. Mutations in 10 genes have been identified concerning this group of diseases, so far. Among those, variants of the COQ7 gene are very rare and confined to three patients with Asian ancestry. Here, we present the clinical features and results of whole-exome sequencing (WES) of three Iranian unrelated families affected by primary COQ10 deficiency. Three homozygous variants in COQ2, COQ4, and COQ7 genes were identified. Candidate variants of the COQ2 and COQ4 genes were novel and associated with the cerebellar signs and multisystem involvement, whereas, the known variant in COQ7 was associated with a mild phenotype that was initially diagnosed as hereditary spastic paraplegia (HSP). This variant has already been reported in a Canadian girl with similar presentations that also originated from Iran suggesting both patients may share a common ancestor. Due to extensive heterogeneity in this group of disorders, and overlap with other mitochondrial/neurological disorders, WES may be helpful to distinguish primary coenzyme Q10 deficiency from other similar conditions. Given that some features of primary coenzyme Q10 deficiency may improve with exogenous COQ10 , early diagnosis is very important.
Assuntos
Alquil e Aril Transferases/genética , Ataxia/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Oxigenases de Função Mista/genética , Debilidade Muscular/genética , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Ataxia/epidemiologia , Ataxia/patologia , Canadá/epidemiologia , Criança , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Irã (Geográfico)/epidemiologia , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/patologia , Debilidade Muscular/epidemiologia , Debilidade Muscular/patologia , Mutação/genética , Ubiquinona/genética , Sequenciamento do ExomaRESUMO
Mitochondrial diseases are the most common inheritable metabolic diseases, due to defects in oxidative phosphorylation. They are caused by mutations of nuclear or mitochondrial DNA in genes involved in mitochondrial function. The peculiarity of "mitochondrial DNA genetics rules" in part explains the marked phenotypic variability, the complexity of genotype-phenotype correlations and the challenge of genetic counseling. The new massive genetic sequencing technologies have changed the diagnostic approach, enhancing mitochondrial DNA-related syndromes diagnosis and often avoiding the need of a tissue biopsy. Here we present the most common phenotypes associated with a mitochondrial DNA mutation with the recent advances in diagnosis and in therapeutic perspectives.
Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/genética , Adulto , Humanos , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/patologiaRESUMO
Mitochondrial complex II (succinate:ubiquinone oxidoreductase) is the smallest complex of the oxidative phosphorylation system, a tetramer of just 140 kDa. Despite its diminutive size, it is a key complex in two coupled metabolic pathways - it oxidises succinate to fumarate in the tricarboxylic acid cycle and the electrons are used to reduce FAD to FADH2, ultimately reducing ubiquinone to ubiquinol in the respiratory chain. The biogenesis and assembly of complex II is facilitated by four ancillary proteins, all of which are autosomally-encoded. Numerous pathogenic defects have been reported which describe two broad clinical manifestations, either susceptibility to cancer in the case of single, heterozygous germline variants, or a mitochondrial disease presentation, almost exclusively due to bi-allelic recessive variants and associated with an isolated complex II deficiency. Here we present a compendium of pathogenic gene variants that have been documented in the literature in patients with an isolated mitochondrial complex II deficiency. To date, 61 patients are described, harbouring 32 different pathogenic variants in four distinct complex II genes: three structural subunit genes (SDHA, SDHB and SDHD) and one assembly factor gene (SDHAF1). Many pathogenic variants result in a null allele due to nonsense, frameshift or splicing defects however, the missense variants that do occur tend to induce substitutions at highly conserved residues in regions of the proteins that are critical for binding to other subunits or substrates. There is phenotypic heterogeneity associated with defects in each complex II gene, similar to other mitochondrial diseases.
Assuntos
Complexo II de Transporte de Elétrons/deficiência , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Succinato Desidrogenase/genética , Adolescente , Adulto , Criança , Pré-Escolar , Complexo II de Transporte de Elétrons/genética , Complexo II de Transporte de Elétrons/metabolismo , Feminino , Fumaratos/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Redes e Vias Metabólicas/genética , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/metabolismo , Pessoa de Meia-Idade , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/metabolismo , Fosforilação Oxidativa , Proteínas/genética , Ácido Succínico/metabolismoRESUMO
OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.
Assuntos
Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/epidemiologia , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Biomarcadores/sangue , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/epidemiologia , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Glutaril-CoA Desidrogenase/deficiência , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Incidência , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/epidemiologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Doenças Musculares/diagnóstico , Doenças Musculares/epidemiologia , Valor Preditivo dos Testes , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/epidemiologia , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Fatores de TempoRESUMO
Background Fatty acid ß-oxidation disorders (FAODs) include more than 15 distinct disorders and have a wide variety of symptoms, usually not evident between episodes of acute decompensation. After the introduction of newborn screening (NBS) using tandem mass spectrometry (MS/MS), early identification of FAODs has become feasible. We analyzed the MS/MS results in Tianjin, China during a six-year period to evaluate the incidence, disease spectrum, and genetic characteristics of FAODs. Methods We analyzed the MS/MS results for screening FAODs from May 2013 to December 2018 in Tianjin, China. Infants with positive screening results were confirmed through next-generation sequencing and validated by Sanger sequencing. Results A total of 220,443 infants were screened and 25 FAODs patients were identified (1:8,817). Primary carnitine deficiency (PCD) with an incidence rate up to 1:20,040 was the most common disorder among all FAODs. Recurrent mutations of relatively common diseases, like PCD and short-chain acyl-CoA dehydrogenase deficiency (SCADD), were identified. During the follow-up, two patients suffered from sudden death due to carnitine palmitoyl transferase-â ¡ deficiency (CPT â ¡) and very-long-chain acyl-CoA dehydrogenase deficiency (VLCAD). Conclusion Our data indicated that FAODs are relatively common in Tianjin and may even cause infant death in certain cases. The elucidated disease spectrum and genetic backgrounds elucidated in this study may contribute to the treatment and prenatal genetic counseling of FAODs.
Assuntos
Ácidos Graxos/metabolismo , Transtornos do Metabolismo dos Lipídeos/diagnóstico , Transtornos do Metabolismo dos Lipídeos/epidemiologia , Transtornos do Metabolismo dos Lipídeos/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/epidemiologia , Cardiomiopatias/genética , Carnitina/deficiência , Carnitina/genética , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , China/epidemiologia , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Feminino , Seguimentos , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/epidemiologia , Hiperamonemia/genética , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/epidemiologia , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/epidemiologia , Doenças Musculares/genética , Triagem Neonatal/métodos , Oxirredução , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: The diagnosis of childhood-onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire-based survey to identify the clinical characteristics of childhood-onset CA in the Japanese population. MATERIALS AND METHODS: Questionnaires were sent to 1,103 board-certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow-up secondary questionnaire requested additional clinical characteristics of the patients. RESULTS: The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan. CONCLUSIONS: The diagnostic rate of childhood-onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood-onset CA in the Japanese population.
Assuntos
Ataxia Cerebelar/epidemiologia , Erros Inatos do Metabolismo/epidemiologia , Ataxias Espinocerebelares/epidemiologia , Anormalidades Múltiplas/epidemiologia , Adolescente , Idade de Início , Ataxia Telangiectasia/epidemiologia , Ataxia Cerebelar/etiologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Encefalite/complicações , Encefalite/epidemiologia , Anormalidades do Olho/epidemiologia , Feminino , Humanos , Lactente , Japão/epidemiologia , Doenças Renais Císticas/epidemiologia , Masculino , Erros Inatos do Metabolismo/complicações , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/epidemiologia , Neurologistas , Síndrome de Opsoclonia-Mioclonia/epidemiologia , Pediatria , Prevalência , Retina/anormalidades , Degenerações Espinocerebelares/epidemiologia , Inquéritos e Questionários , Adulto JovemRESUMO
AIMS: We sought to determine if some unclassified renal cell carcinomas (RCCs) in children and young adults that are characterised by predominantly eosinophilic cytoplasm are related to the recently described succinate dehydrogenase (SDH)-deficient RCC, fumarate hydratase (FH)-deficient RCC or eosinophilic solid and cystic (ESC) RCC. METHODS AND RESULTS: We reviewed 33 unclassified RCCs with predominantly eosinophilic cytoplasm in patients aged 35 years or younger. Immunohistochemistry (IHC) for SDHB, FH and CK20 (a marker of ESC) was performed in all cases. IHC for 2-succinocysteine (2SC) was performed on RCC with loss of FH labelling. Four RCC (12%) (median age 18 years) demonstrated loss of FH labelling as well as aberrant 2SC labelling, and were thus classified as FH-deficient RCCs. Importantly, none of these cases demonstrated the characteristic macronucleoli typical of FH-deficient RCC. Eight RCC (24%) (median age 20.5 years) demonstrated loss of SDHB and were reclassified as SDH-deficient RCCs. Importantly, only four of eight SDH-deficient RCC demonstrated the characteristic cytoplasmic vacuoles and inclusions of typical SDH-deficient RCC. Ten RCC (30%) (median age 27 years) were reclassified as ESC RCCs. Four of 10 ESC RCC were multifocal (one bilateral), four of 10 ESC RCC occurred in males and one patient presented with liver and lung metastases, all not described previously in ESC. Eleven RCC (33%) remained unclassified. CONCLUSIONS: Pathologists should have a low threshold for performing FH, SDHB and CK20 IHC when confronted with unclassified eosinophilic RCC or 'oncocytoma' in young patients.
Assuntos
Carcinoma de Células Renais/patologia , Eosinófilos/patologia , Neoplasias Renais/patologia , Adolescente , Adulto , Carcinoma de Células Renais/classificação , Carcinoma de Células Renais/genética , Complexo II de Transporte de Elétrons/deficiência , Feminino , Fumarato Hidratase/deficiência , Humanos , Neoplasias Renais/classificação , Neoplasias Renais/genética , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/epidemiologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Hipotonia Muscular/complicações , Hipotonia Muscular/epidemiologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Transtornos Psicomotores/complicações , Transtornos Psicomotores/epidemiologia , Adulto JovemRESUMO
Chronic obstructive pulmonary disease (COPD) patients are at increased risk of developing nonsmall cell lung carcinoma, irrespective of their smoking history. Although the mechanisms behind this observation are not clear, established drivers of carcinogenesis in COPD include oxidative stress and sustained chronic inflammation. Mitochondria are critical in these two processes and recent evidence links increased oxidative stress in COPD patients to mitochondrial damage. We therefore postulate that mitochondrial damage in COPD patients leads to increased oxidative stress and chronic inflammation, thereby increasing the risk of carcinogenesis.The functional state of the mitochondrion is dependent on the balance between its biogenesis and degradation (mitophagy). Dysfunctional mitochondria are a source of oxidative stress and inflammasome activation. In COPD, there is impaired translocation of the ubiquitin-related degradation molecule Parkin following activation of the Pink1 mitophagy pathway, resulting in excessive dysfunctional mitochondria. We hypothesise that deranged pathways in mitochondrial biogenesis and mitophagy in COPD can account for the increased risk in carcinogenesis. To test this hypothesis, animal models exposed to cigarette smoke and developing emphysema and lung cancer should be developed. In the future, the use of mitochondria-based antioxidants should be studied as an adjunct with the aim of reducing the risk of COPD-associated cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Mitocôndrias/patologia , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/patologia , Dinâmica Mitocondrial , Mitofagia , Estresse Oxidativo , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Fatores de Risco , Transdução de Sinais , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Based on limited number of clinical trials, several agents aiming at enhancing mitochondrial function or treating the consequences of mitochondrial dysfunction have been used. Several agents are currently being evaluated for mitochondrial diseases. Therapeutic strategies for mitochondrial diseases include the use of agents enhancing electron transfer chain function (coenzyme Q10, idebenone, riboflavin, dichloroacetate, and thiamine), agents acting as energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), amino acids restoring nitric oxide production (arginine and citrulline), cardiolipin protector (elamipretide), agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide bypass therapy, liver transplantation, and gene therapy. Although, there is a lack of curative therapies for mitochondrial disorders at the current time, the increased number of clinical research evaluating agents that target different aspects of mitochondrial dysfunction is promising and is expected to generate more therapeutic options for these diseases in the future.
Assuntos
Ensaios Clínicos como Assunto , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/terapia , Animais , Antioxidantes/uso terapêutico , Arginina/metabolismo , Cardiolipinas/efeitos dos fármacos , Catequina/uso terapêutico , Transporte de Elétrons/efeitos dos fármacos , Terapia Genética , Humanos , Transplante de Fígado , Camundongos , Mitocôndrias/patologia , Mitocôndrias/fisiologia , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/fisiopatologia , Óxido Nítrico/metabolismo , Fosforilação Oxidativa , Triterpenos/uso terapêuticoRESUMO
Black individuals have a lower risk of hearing loss than do whites, possibly because of differences in cochlear melanocytes. Previous studies have suggested that darker-skinned individuals tend to have more inner ear melanin, and cochlear melanocytes are important in generating the endocochlear potential. We investigated the relationship between self-reported hearing loss and skin pigmentation by using hair color, skin tanning ability, and skin reaction to prolonged sun exposure as surrogate measures of pigmentation among 49,323 white women in the Nurses' Health Study. Cox proportional hazards regression models were used to adjust for potential confounders. During 1,190,170 person-years of follow-up (1982-2012), there was no association between risk of hearing loss and hair color (for black hair vs. red or blonde hair, multivariable-adjusted relative risk (RR) = 0.99, 95% confidence interval (CI): 0.90, 1.09), skin tanning ability (for dark tan vs. no tan, multivariable-adjusted RR = 0.98, 95% CI: 0.92, 1.05), skin reaction to prolonged sun exposure (for painful burn with blisters vs. practically no reaction, multivariable-adjusted RR = 1.01, 95% CI: 0.93, 1.08), or Fitzpatrick skin phototype (for type IV vs. type I, multivariable-adjusted RR = 0.99, 95% CI: 0.92, 1.05). In our cohort of white women, surrogates for skin pigmentation were not associated with risk of hearing loss.
Assuntos
Perda Auditiva/epidemiologia , Pigmentação da Pele , População Branca , Adulto , Fatores Etários , Consumo de Bebidas Alcoólicas/epidemiologia , Índice de Massa Corporal , Surdez/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Dieta , Exercício Físico , Feminino , Cor de Cabelo , Humanos , Hipertensão/epidemiologia , Pessoa de Meia-Idade , Doenças Mitocondriais/epidemiologia , Modelos de Riscos Proporcionais , Fumar/epidemiologia , BronzeadoRESUMO
There are indications that preexisting mitochondrial disorders or beta-oxidation defects predispose for propofol infusion syndrome. This review aimed at investigating if propofol infusion syndrome occurs exclusively in patients with mitochondrial disorder and if propofol can unmask a mitochondrial disorder. Propofol infusion syndrome has been reported in genetically confirmed mitochondrial disorder patients. In addition, muscle biopsy of patients with propofol infusion syndrome revealed complex IV or complex II deficiency. In animal studies propofol disrupted the electron flow along the respiratory chain and decreased complex I, complex II, and complex III of the respiratory chain. In addition, propofol disrupted the permeability transition pore and reduced the mitochondrial membrane potential. In conclusion, propofol is mitochondrion-toxic and mitochondrial disorder patients should not receive propofol in high dosages over a prolonged period of time. Short-term application of propofol should be safe even in mitochondrial disorder patients. Not only does propofol infusion syndrome occur in mitochondrial disorder patients, but mitochondrial disorder patients are likely at higher risk to develop propofol infusion syndrome. Patients who develop propofol infusion syndrome should be screened for mitochondrial disorder. Propofol infusion syndrome is preventable if risk factors are thoroughly assessed, and if long-term propofol is avoided in patients at risk for propofol infusion syndrome.
Assuntos
Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/metabolismo , Propofol/toxicidade , Animais , Humanos , Doenças Mitocondriais/epidemiologia , RiscoRESUMO
BACKGROUND: Nitrogen-bisphosphonates (N-BPs) are the most widely used drugs for bone fragility disorders. Long-term or high-dose N-BP use is associated with unusual serious side effects such as osteonecrosis of the jaw, musculoskeletal pain, and atypical fractures of long bones. It has escaped notice that the pathway N-BPs block is central for the endogenous synthesis of coenzyme Q10, an integral enzyme of the mitochondrial respiratory chain and an important lipid-soluble antioxidant. Our objective was to assess the coenzyme Q10 and antioxidant status in relation to N-BP exposure in women with postmenopausal osteoporosis. METHODS: Seventy-one postmenopausal women (age, 73.5 ± 5.5 y) with osteoporosis and no other malignancy were included in this cross-sectional study. Seventeen were treatment naive, 27 were on oral N-BP, and 27 were on i.v. N-BP. RESULTS: Vitamin E γ-tocopherol levels (µmol/mL) were significantly reduced in N-BP users [oral, H(2) = 18.5, P = .02; i.v., H(2) = 25.2, P < .001; mean rank comparisons after Kruskal-Wallis test). Length of time (days) of N-BP exposure, but not age, was inversely associated with the coenzyme Q10/cholesterol ratio (µmol/mol) (ß = -0.27; P = .025), which was particularly low for those on i.v. N-BP (mean difference = -35.0 ± 16.9; 95% confidence interval, -65.2 to -4.9; P = .02). CONCLUSION: The degree of N-BP exposure appears related to compromised coenzyme Q10 status and vitamin E γ-tocopherol levels in postmenopausal women with osteoporosis. This phenomenon may link to certain adverse N-BP-associated effects. Confirmation of this would suggest that therapeutic supplementation could prevent or reverse certain complications of long-term N-BP therapy for at-risk individuals.
Assuntos
Difosfonatos/uso terapêutico , Terapia de Reposição de Estrogênios/efeitos adversos , Nitrogênio/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Ubiquinona/análogos & derivados , Vitamina E/sangue , Idoso , Ataxia/induzido quimicamente , Ataxia/diagnóstico , Ataxia/epidemiologia , Estudos Transversais , Feminino , Humanos , Doenças Mitocondriais/induzido quimicamente , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/diagnóstico , Debilidade Muscular/epidemiologia , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/diagnóstico , Osteoporose Pós-Menopausa/epidemiologia , Pós-Menopausa/sangue , Pós-Menopausa/efeitos dos fármacos , Prognóstico , Ubiquinona/sangue , Ubiquinona/deficiência , Deficiência de Vitamina E/induzido quimicamente , Deficiência de Vitamina E/diagnóstico , Deficiência de Vitamina E/epidemiologiaRESUMO
Symmetrical polyneuropathy is a common feature of mitochondrial disease. Both axonal and demyelinating types are described, with Schwann cell abnormalities demonstrated on nerve biopsy. Some authors have also suggested an increased incidence of entrapment neuropathy. We identified 738 adult patients with proven mitochondrial disease seen in our centre in the past 25 years. One-hundred sixty seven of these patients had undergone nerve conduction studies as part of their routine clinical care, and the results of these studies were reviewed. We found an incidence rate of carpal tunnel syndrome (CTS) of 50.7 per 100,000 person-years; 32.5 per 100,000 person-years for men and 65.3 per 100,000 person-years for women. One other patient had evidence of ulnar neuropathy at the elbow. The incidence of CTS in mitochondrial disease is similar to published rates for the UK general population. We found no evidence that mitochondrial disease per se increases the risk of entrapment neuropathy. We suggest that the pathophysiological mechanisms for the development of polyneuropathy in mitochondrial disease are quite distinct from the pathophysiology of CTS. Furthermore, it is essential that patients with mitochondrial disease who present with upper limb paraesthesia be referred for neurophysiological testing, so that treatable CTS is not missed.
Assuntos
Síndrome do Túnel Carpal/complicações , Síndrome do Túnel Carpal/epidemiologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
AIM: To determine the epidemiology of chronic ataxia in children in Manitoba, Canada. METHOD: A retrospective study using multiple sources and disease codes identified children (age 0-16y) with chronic ataxia (>2mo duration or recurrent episodes of ataxia) seen at Winnipeg Children's Hospital from 1991 to 2008. Patients with isolated peripheral nerve diseases, vestibular disorders, or brain tumors were excluded. RESULTS: We identified 184 patients (males=females; mean age 15y, SD 7y 8mo) with chronic ataxia. Median age at the presenting symptom onset was 1 year 3 months and at ataxia onset 3 years 1 month. Median duration of follow-up was 6 years 5 months. During the study period, the crude incidence rate was 5.77 in 10,000; the crude prevalence rate was 6.59 in 10,000; and the crude mortality rate 0.446 in 10,000. The most common presenting symptoms were developmental delay, ataxia, or seizures. The most common diagnoses (known in 129) were Angelman syndrome (n=16), ataxia telangiectasia (n=13), mitochondrial disease (n=9), Friedreich ataxia (n=7), stroke (n=7), and familial/genetic episodic ataxia (n=7). INTERPRETATION: Chronic ataxia is a relatively common early-presenting symptom in childhood. A specific diagnosis is possible in 70% of patients after extensive investigations. The mortality rate is relatively low and the disease burden is high with significant comorbidities including developmental delay and epilepsy.
Assuntos
Síndrome de Angelman/complicações , Ataxia Telangiectasia/complicações , Ataxia/epidemiologia , Ataxia/etiologia , Doenças Mitocondriais/complicações , Adolescente , Idade de Início , Síndrome de Angelman/epidemiologia , Ataxia/mortalidade , Ataxia Telangiectasia/epidemiologia , Criança , Doença Crônica , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/etiologia , Progressão da Doença , Feminino , Humanos , Incidência , Masculino , Manitoba/epidemiologia , Doenças Mitocondriais/epidemiologia , Prevalência , Estudos Retrospectivos , Convulsões/epidemiologia , Convulsões/etiologia , Adulto JovemRESUMO
OBJECTIVES: there are indications that patients with a mitochondrial disorder (MID) develop malignomas or benign tumors more frequently than the general population. The aims of the study were to find out if the prevalence of tumors is actually increased in MID-patients and which of the malignomas or benign tumors are the most frequent. METHODS: The charts of MID-patients were retrospectively evaluated for the presence of malign or benign tumors. MID was diagnosed according to the modified Walker-criteria. RESULTS: Among the 475 MID-patients screened for tumors, at least a single malignoma was found in 65 patients (13.7%), and at least a single benign tumor in 35 patients (7.4%). Among those with malignancy, 22 were men and 43 women. Among those with a malignancy, 1 had definite MID, 9 probable MID, and 55 possible MID. The most common of the malignancies was breast cancer, followed by dermatological, gynecological, and gastrointestinal malignancies. The most frequent of the benign tumors was lipoma, followed by pituitary adenoma, meningeomas, carcinoids, and suprarenal adenomas. Compared to the general population, the prevalence of malignancies and of benign tumors was markedly increased. The female preponderance was explained by the frequent maternal inheritance of MIDs. CONCLUSIONS: Adult patients with a MID, particularly females, carry an increased risk to develop a malignancy or a benign tumor. Since malignancy is an important determinant for their outcome, these patients should be more accurately screened for neoplasms, not to overlook the point, at which an effective treatment can no longer be provided.
Assuntos
Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Neoplasias/epidemiologia , Neoplasias/etiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estudos RetrospectivosRESUMO
AIM: To reveal the frequency, characteristics and prognosis of chronic intestinal pseudo-obstruction (CIP) in mitochondrial disease patients. METHODS: Between January 2000 and December 2010, 31 patients (13 males and 18 females) were diagnosed with mitochondrial diseases at our hospital. We conducted a retrospective review of the patients' sex, subclass of mitochondrial disease, age at onset of mitochondrial disease, frequency of CIP and the age at its onset, and the duration of survival. The age at onset or at the first diagnosis of the disorder that led to the clinical suspicion of mitochondrial disease was also examined. RESULTS: Twenty patients were sub-classified with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), 8 with chronic progressive external ophthalmoplegia (CPEO), and 3 with myoclonus epilepsy associated with ragged-red fibers (MERRF). Nine patients were diagnosed with CIP, 8 of the 20 (40.0%) patients with MELAS, 0 of the 8 (0.0%) patients with CPEO, and 1 of the 3 (33.3%) patients with MERRF. The median age (range) at the diagnosis and the median age at onset of mitochondrial disease were 40 (17-69) and 25 (12-63) years in patients with CIP, and 49 (17-81) and 40 (11-71) years in patients without CIP. During the survey period, 5 patients (4 patients with MELAS and 1 with CPEO) died. The cause of death was cardiomyopathy in 2 patients with MELAS, cerebral infarction in 1 patient with MELAS, epilepsy and aspiration pneumonia in 1 patient with MELAS, and multiple metastases from gastric cancer and aspiration pneumonia in 1 patient with CPEO. CONCLUSION: Patients with CIP tend to have disorders that are suspected to be related to mitochondrial diseases at younger ages than are patients without CIP.
Assuntos
Enteropatias/diagnóstico , Enteropatias/epidemiologia , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/epidemiologia , Doenças Mitocondriais/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Doença Crônica , Comorbidade , Feminino , Humanos , Enteropatias/mortalidade , Pseudo-Obstrução Intestinal/mortalidade , Síndrome MELAS/epidemiologia , Masculino , Pessoa de Meia-Idade , Encefalomiopatias Mitocondriais/epidemiologia , Oftalmoplegia Externa Progressiva Crônica/epidemiologia , Prevalência , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (≈ 0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD.