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1.
Ann Neurol ; 86(2): 310-315, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187502

RESUMO

Distinct clinical syndromes have been associated with pathogenic MT-ATP6 variants. In this cohort study, we identified 125 individuals (60 families) including 88 clinically affected individuals and 37 asymptomatic carriers. Thirty-one individuals presented with Leigh syndrome and 7 with neuropathy ataxia retinitis pigmentosa. The remaining 50 patients presented with variable nonsyndromic features including ataxia, neuropathy, and learning disability. We confirmed maternal inheritance in 39 families and demonstrated that tissue segregation patterns and phenotypic threshold are variant dependent. Our findings suggest that MT-ATP6-related mitochondrial DNA disease is best conceptualized as a mitochondrial disease spectrum disorder and should be routinely included in genetic ataxia and neuropathy gene panels. ANN NEUROL 2019;86:310-315.

2.
J Med Genet ; 56(3): 123-130, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30683676

RESUMO

Primary genetic mitochondrial diseases are often difficult to diagnose, and the term 'possible' mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of 'possible' mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of 'diagnosis uncertain', together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.

3.
J Clin Med ; 6(8)2017 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-28825656

RESUMO

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients' FGF-21 results were assessed by the use of age-adjusted z-scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance (n = 32) and mtDNA rearrangements (n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations (n = 40) or mutations in other autosomal genes (n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z-score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway.

4.
JIMD Rep ; 26: 103-13, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26354038

RESUMO

INTRODUCTION: Mitochondrial diseases are a clinically, biochemically and genetically heterogeneous group of disorders with a variable age of onset and rate of disease progression. It might therefore be expected that this variation be reflected in the age and cause of death. However, to date, little has been reported regarding the 'end-of-life' period and causes of death in mitochondrial disease patients. For some specific syndromes, the associated clinical problems might predict the cause of death, but for many patients, it remains difficult to provide an accurate prognosis. AIMS: To describe a retrospective cohort of adult mitochondrial disease patients who had attended the NHS Highly Specialised Services for Rare Mitochondrial Diseases in Newcastle upon Tyne (UK), evaluate life expectancy and causes of death and assess the consequences for daily patient care. METHODS: All deceased adult patients cared for at this centre over a period of 10 years were included in the study. Patient history, data on laboratory findings, biochemical investigations and genetic studies were analysed retrospectively. RESULTS: A total of 30 adult mitochondrial patients died within the time period of the study. The main mitochondrial disease-related causes of death in this patient cohort were respiratory failure, cardiac failure and acute cerebral incidents such as seizures and strokes. In almost half of the patients, the cause of death remained unknown. Based on our study, we present recommendations regarding the care of patients with mitochondrial disease.

5.
Ann Neurol ; 78(6): 949-57, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26381753

RESUMO

OBJECTIVE: The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. METHODS: We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7-year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke-like episode, and death. RESULTS: Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke-like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83). INTERPRETATION: Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke-like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease.


Assuntos
DNA Mitocondrial/genética , Epilepsia/etiologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/genética , Acidente Vascular Cerebral/etiologia , Adolescente , Adulto , Idade de Início , Progressão da Doença , Epilepsia/epidemiologia , Epilepsia/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/mortalidade , Mutação , Prevalência , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Adulto Jovem
6.
Eur J Hum Genet ; 22(11): 1255-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24642831

RESUMO

Mitochondrial diseases affect >1 in 7500 live births and may be due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Genetic counselling for families with mitochondrial diseases, especially those due to mtDNA mutations, provides unique and difficult challenges particularly in relation to disease transmission and prevention. We have experienced an increasing demand for prenatal diagnostic testing from families affected by mitochondrial disease since we first offered this service in 2007. We review the diagnostic records of the 62 prenatal samples (17 mtDNA and 45 nDNA) analysed since 2007, the reasons for testing, mutation investigated and the clinical outcome. Our findings indicate that prenatal testing for mitochondrial disease is reliable and informative for the nuclear and selected mtDNA mutations we have tested. Where available, the results of mtDNA heteroplasmy analyses from other family members are helpful in interpreting the prenatal mtDNA test result. This is particularly important when the mutation is rare or the mtDNA heteroplasmy is observed at intermediate levels. At least 11 cases of mitochondrial disease were prevented following prenatal testing, 3 of which were mtDNA disease. On the basis of our results, we believe that prenatal testing for mitochondrial disease is an important option for couples where appropriate genetic analyses and pre/post-test counselling can be provided.


Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Diagnóstico Pré-Natal/métodos , Amostra da Vilosidade Coriônica/métodos , Aconselhamento Genético , Testes Genéticos/métodos , Humanos , Mitocôndrias/genética , Mutação
7.
Brain ; 137(Pt 2): 323-34, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24277717

RESUMO

Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression.


Assuntos
DNA Mitocondrial/genética , Progressão da Doença , Deleção de Genes , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , DNA Mitocondrial/antagonistas & inibidores , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
8.
J Neurol Neurosurg Psychiatry ; 84(8): 936-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23355809

RESUMO

BACKGROUND: Population-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with several clinical syndromes including mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), maternally inherited deafness and diabetes (MIDD) and progressive external ophthalmoplegia (PEO). Many patients affected by this mutation exhibit a clinical phenotype that does not fall within accepted criteria for the currently recognised classical mitochondrial syndromes. METHODS: We have defined the phenotypic spectrum associated with the m.3243A>G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK. RESULTS: 10% of patients exhibited a classical MELAS phenotype, 30% had MIDD, 6% MELAS/MIDD, 2% MELAS/chronic PEO (CPEO) and 5% MIDD/CPEO overlap syndromes. 6% had PEO and other features of mitochondrial disease not consistent with another recognised syndrome. Isolated sensorineural hearing loss occurred in 3%. 28% of patients demonstrated a panoply of clinical features, which were not consistent with any of the classical syndromes associated with the m.3243A>G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic. CONCLUSION: Following this study we propose guidelines for screening and for the management of confirmed cases.


Assuntos
Doenças Mitocondriais/genética , Mutação/genética , Adolescente , Adulto , Idoso , Cardiomiopatias/epidemiologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Criança , Pré-Escolar , Estudos de Coortes , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/genética , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Feminino , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/etiologia , Humanos , Lactente , Síndrome MELAS/epidemiologia , Síndrome MELAS/genética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/terapia , Encefalomiopatias Mitocondriais/epidemiologia , Encefalomiopatias Mitocondriais/etiologia , Encefalomiopatias Mitocondriais/genética , Reino Unido/epidemiologia , Adulto Jovem
9.
Dev Med Child Neurol ; 54(7): 612-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22500675

RESUMO

AIM: To describe the frequency and causes of death in children with epilepsy, ascertain the contribution of seizure disorder to cause of death, and compare with rates of sudden unexplained death in children without epilepsy. METHOD: This study was a retrospective review of clinical and death certificate records. It examined two UK population-based samples of deaths in children with epilepsy from 1 month to 18 years, together comprising the largest reported series of deaths in children with epilepsy (n=265). RESULTS: In approximately two-thirds, the death was not due to the seizure disorder. Rates of unexplained death were similar in the two samples at 7.3% and 9.7%: all were in children with symptomatic or presumed symptomatic epilepsy. There were no unexplained deaths in the children with idiopathic epilepsy. Four per cent of the deaths were of children experiencing acute symptomatic seizures as part of their final illness. The risk of unexpected, unexplained death in children with idiopathic epilepsy is not more than 65 per 100,000 child-years. INTERPRETATION: Epilepsy is associated with an increased risk of death in childhood but this risk is almost entirely confined to those with an associated neurodevelopmental disorder. The risk of unexpected, unexplained death in children with idiopathic epilepsy is extremely small.


Assuntos
Causas de Morte , Morte Súbita/etiologia , Epilepsia/complicações , Epilepsia/mortalidade , Adolescente , Criança , Pré-Escolar , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Masculino , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia
10.
Dev Med Child Neurol ; 54(6): 500-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22364517

RESUMO

Mitochondrial respiratory chain diseases represent one of the most common inherited neurometabolic disorders of childhood, affecting a minimum of 1 in 7500 live births. The marked clinical, biochemical, and genetic heterogeneity means that accurate genetic counselling relies heavily upon the identification of the underlying causative mutation in the individual and determination of carrier status in the parents. Isolated complex I deficiency is the most common respiratory chain defect observed in children, resulting in organ-specific or multisystem disease, but most often presenting as Leigh syndrome, for which mitochondrial DNA mutations are important causes. Several recurrent, pathogenic point mutations in the MTND3 gene - including m.10191T>C (p.Ser45Pro) - have been previously identified. In this short clinical review we evaluate the case reports of the m.10191T>C mutation causing complex I-deficient Leigh syndrome described in the literature, in addition to two new ones diagnosed in our laboratory. Both of these appear to have arisen de novo without transmission of the mutation from mother to offspring, illustrating the importance not only of fully characterizing the mitochondrial genome as part of the investigation of children with complex I-deficient Leigh syndrome but also of assessing maternal samples to provide crucial genetic advice for families.


Assuntos
Complexo I de Transporte de Elétrons/deficiência , Doença de Leigh/genética , Mutação Puntual/genética , Adulto , Encéfalo/patologia , Pré-Escolar , Complexo I de Transporte de Elétrons/genética , Feminino , Humanos , Lactente , Recém-Nascido , Doença de Leigh/complicações , Doença de Leigh/diagnóstico , Imagem por Ressonância Magnética , Masculino , Prolina/genética , Serina/genética
11.
J Neuropathol Exp Neurol ; 71(2): 148-61, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22249460

RESUMO

Cerebellar ataxia is a prominent clinical symptom in patients with mitochondrial DNA (mtDNA) disease. This is often progressive with onset in young adulthood. We performed a detailed neuropathologic investigation of the olivary-cerebellum in 14 genetically and clinically well-defined patients with mtDNA disease. Quantitative neuropathologic investigation showed varying levels of loss of Purkinje cells and neurons of the dentate nucleus and inferior olivary nuclei. Typically, focal Purkinje cell loss was present in patients with the m.3243A>G mutation caused by the presence of microinfarcts, with relative preservation of neuronal cell populations in the olivary and dentate nuclei. In contrast, patients with the m.8344A>G mutation or recessive POLG mutations showed extensive and global neuronal cell loss in all 3 olivary-cerebellum areas examined. Molecular analysis of mutated mtDNA heteroplasmy levels revealed that neuronal cell loss occurred independently of the level of mutated mtDNA present within surviving neurons. High levels of neuronal respiratory chain deficiency, particularly of complex I, were detected in surviving cells; levels of deficiency were greater in regions with extensive cell loss. We found a relationship between respiratory deficiency and neuronal cell density, indicating that neuronal cell death correlates with respiratory deficiency. These findings highlight the vulnerability of the olivary-cerebellum to mtDNA defects.


Assuntos
Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , DNA Polimerase Dirigida por DNA/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Mutação/genética , Adulto , Contagem de Células , Morte Celular/genética , Ataxia Cerebelar/complicações , Cerebelo/patologia , Polimerase do DNA Mitocondrial , DNA Mitocondrial/genética , Avaliação da Deficiência , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Gliose/etiologia , Gliose/patologia , Humanos , Microdissecção e Captura a Laser , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Neurônios/patologia , Núcleo Olivar/patologia , Succinato Desidrogenase/metabolismo , Adulto Jovem
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