Gait impairment in Parkinson's disease (PD) persists despite the use of dopaminergic therapy. Motor phenotype associated with greater postural instability and gait difficulty is related to a greater risk of motor decline and may be... more
Gait impairment in Parkinson's disease (PD) persists despite the use of dopaminergic therapy. Motor phenotype associated with greater postural instability and gait difficulty is related to a greater risk of motor decline and may be influenced by non-dopaminergic pathology. This study documents the progression of gait impairment over 18 months in an incident cohort of PD with regard to phenotype and medication. Gait characteristics were measured in 121 PD and 184 controls, and 18 months later in 108 PD participants. Sixteen gait characteristics were examined with respect to five broad domains for PD and motor phenotype. Correlations between change in levodopa (l-dopa) equivalent daily dose and gait were used to identify dopa-responsive and nonresponsive characteristics. Pace and rhythm deteriorated over 18 months in people with PD, with other gait domains remaining stable. People with a postural instability and gait difficulty phenotype had more impaired gait at baseline compared...
Research Interests: Cognitive Science, Medicine, Movement disorders, Gait, Humans, and 15 moreFemale, Male, Incidence, Levodopa, Phenotype, Clinical Sciences, Aged, Middle Aged, Disease Progression, Parkinson Disease, Cognition disorders, Cohort Studies, Neuropsychological Tests, Disability Evaluation, and dopaminergic
To report investigations performed in children with progressive neurodegenerative diseases reported to this UK study. Since 1997 paediatric surveillance for variant Creutzfeldt-Jakob disease (vCJD) has been performed by identifying... more
To report investigations performed in children with progressive neurodegenerative diseases reported to this UK study. Since 1997 paediatric surveillance for variant Creutzfeldt-Jakob disease (vCJD) has been performed by identifying children aged less than 16 years with progressive intellectual and neurological deterioration (PIND) and searching for vCJD among them. The PIND Study obtains case details from paediatricians who notify via the British Paediatric Surveillance Unit. Between May 1997 and October 2017, a total of 2050 cases meeting PIND criteria had been notified and investigated. Six children had vCJD. 1819 children had other diagnoses, made in 12 cases by antemortem brain biopsy and in 15 by postmortem investigations. 225 children were undiagnosed: only 3 had antemortem brain biopsies and only 14 of the 108 who died were known to have had autopsies; postmortem neuropathological studies were carried out in just 10% (11/108) and only two had prion protein staining of brain t...
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Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits... more
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectromet...
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Recessively-inherited variants in AARS2 (NM_020745.2) encoding mitochondrial alanyl-tRNA synthetase (mt-AlaRS) were first described in patients presenting with fatal infantile cardiomyopathy and multiple oxidative phosphorylation defects.... more
Recessively-inherited variants in AARS2 (NM_020745.2) encoding mitochondrial alanyl-tRNA synthetase (mt-AlaRS) were first described in patients presenting with fatal infantile cardiomyopathy and multiple oxidative phosphorylation defects. To date, all described patients with AARS2-related fatal infantile cardiomyopathy are united by either a homozygous or compound heterozygous c.1774C>T (p.Arg592Trp) missense founder mutation that is absent in patients with other AARS2-related phenotypes. We describe the clinical, biochemical and molecular investigations of two unrelated boys presenting with fatal infantile cardiomyopathy, lactic acidosis and respiratory failure. Oxidative histochemistry showed cytochrome c oxidase (COX)-deficient fibres in skeletal and cardiac muscle. Biochemical studies showed markedly decreased activities of mitochondrial respiratory chain complexes I and IV with a mild decrease of complex III activity in skeletal and cardiac muscle. Using next-generation sequ...
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Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the... more
Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy.
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Alpers' syndrome is an early-onset neurodegenerative disorder often caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG) which is essential for mitochondrial DNA (mtDNA)... more
Alpers' syndrome is an early-onset neurodegenerative disorder often caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG) which is essential for mitochondrial DNA (mtDNA) replication. Alpers' syndrome is characterised by intractable epilepsy, developmental regression and liver failure which typically affects children aged 6 months - 3 years. Although later onset variants are now recognised, they differ in that they are primarily an epileptic encephalopathy with ataxia. The disorder is progressive, without cure and inevitably leads to death from drug-resistant status epilepticus, often with concomitant liver failure. Since our understanding of the mechanisms contributing the neurological features in Alpers' syndrome is rudimentary, we performed a detailed and quantitative neuropathological study on 13 patients with clinically and histologically-defined Alpers' syndrome with ages ranging from 2 months to 18 years....
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Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed... more
Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood = 231, urine = 235, skeletal muscle = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine ( = 0.61-0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G-harbouring individuals; increasing age and heteroplasmy contribute ( = 0.27, < 0.001). In muscle, heteroplasmy, age and mtDNA copy ...
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Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of... more
Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory ...
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Objective:To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a... more
Objective:To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder.Methods:A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies.Results:After excluding candidate variants for an autosomal recessive mitochondrial disorder, re-evaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo.Conclusions:We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondr...
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YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular... more
YARS2 mutations have been associated with a clinical triad of myopathy, lactic acidosis, and sideroblastic anemia in predominantly Middle Eastern populations. However, the identification of new patients expands the clinical and molecular spectrum of mitochondrial disorders. To review the clinical, molecular, and genetic features of YARS2-related mitochondrial disease and to demonstrate a new Scottish founder variant. An observational case series study was conducted at a national diagnostic center for mitochondrial disease in Newcastle upon Tyne, England, and review of cases published in the literature. Six adults in a well-defined mitochondrial disease cohort and 11 additional cases described in the literature were identified with YARS2 variants between January 1, 2000, and January 31, 2015. The spectrum of clinical features and disease progression in unreported and reported patients with pathogenic YARS2 variants. Seventeen patients (median [interquartile range] age at onset, 1.5 [...
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Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural... more
Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with mitochondrial diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including mitoch...
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Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia... more
Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondrial respiratory chain deficiencies associated with a marked loss of mitochondrial DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked ...
Research Interests: Genetics, Biology, Medicine, Biological Sciences, Mitochondrial DNA, and 15 moreHumans, Child, Female, Male, Mitochondrial disease, Infant, Electron Transport, Mitochondrial Diseases, Isoenzymes, Age of Onset, Exome, Adenosine Triphosphate, Adenosine Diphosphate, Child preschool, and Medical and Health Sciences
Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing... more
Mitochondrial diseases collectively represent one of the most heterogeneous group of metabolic disorders. Symptoms can manifest at any age, presenting with isolated or multiple-organ involvement. Advances in next-generation sequencing strategies have greatly enhanced the diagnosis of patients with mitochondrial disease, particularly where a mitochondrial aetiology is strongly suspected yet OXPHOS activities in biopsied tissue samples appear normal. We used whole exome sequencing (WES) to identify the molecular basis of an early-onset mitochondrial syndrome-pathogenic biallelic variants in the HTRA2 gene, encoding a mitochondria-localised serine protease-in five subjects from two unrelated families characterised by seizures, neutropenia, hypotonia and cardio-respiratory problems. A unifying feature in all affected children was 3-methylglutaconic aciduria (3-MGA-uria), a common biochemical marker observed in some patients with mitochondrial dysfunction. Although functional studies of ...
Research Interests: Genetics, Biology, Mitochondria, Medicine, Mitochondrial DNA, and 15 moreHumans, Child, Female, Inborn errors of metabolism, Male, Cell Death, Mitochondrial disease, Clinical Sciences, Mitochondrial Diseases, Serine Proteases, Genetic variation, Exome, Mitochondrion, Mitochondrial Proteins, and fibroblasts
Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for... more
Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many familial mtDNA point mutations to very low for sporadic, large-scale single mtDNA deletions. Comprehensive data are lacking for de novo mtDNA point mutations, often leading to misconceptions and incorrect counselling regarding recurrence risk and reproductive options. We aim to study the relevance and recurrence risk of apparently de novo mtDNA point mutations. Systematic study of prenatal diagnosis (PND) and recurrence of mtDNA point mutations in families with de novo cases, including new and published data. 'De novo' based on the absence of the mutation in multiple (postmitotic) maternal tissues is preferred, but mutations absent in maternal blood only were also included. In our series of 105 index patients (33 children and 72 adults) w...
Research Interests: Genetics, Medical Genetics, Biology, Medicine, Biological Sciences, and 15 moreGenetic counseling, Mitochondrial DNA, Humans, Child, genetic Counselling, Female, Male, Mitochondrial DNA mutation, Adult, Cytochrome B Gene, De Novo, Germline, Leigh syndrome, Medical and Health Sciences, and Maternal Inheritance
Nuclear gene mutations are being increasingly recognised as causes of mitochondrial disease. The nuclear gene RMND1 has recently been implicated in mitochondrial disease, but the spectrum of pathogenic variants and associated phenotype... more
Nuclear gene mutations are being increasingly recognised as causes of mitochondrial disease. The nuclear gene RMND1 has recently been implicated in mitochondrial disease, but the spectrum of pathogenic variants and associated phenotype for this gene, has not been fully elucidated. An 11-month-old boy presented with renal impairment associated with a truncal ataxia, bilateral sensorineural hearing loss, hypotonia, delayed visual maturation and global developmental delay. Over a 9-year period, he progressed to chronic kidney disease stage V and developed a dilated cardiomyopathy. Abnormalities in renal and muscle biopsy as well as cytochrome c oxidase activity prompted genetic testing. After exclusion of mitochondrial DNA defects, nuclear genetic studies identified compound heterozygous RMND1 (c.713A>G, p. Asn238Ser and c.565C>T, p.Gln189*) variants. We report RMND1 gene variants associated with end stage renal failure, dilated cardiomyopathy, deafness and neurological involveme...
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Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh... more
Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated familie...
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To determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle... more
To determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between Jan 1(st) 2005 and Jan 1(st) 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. The overall prevalence of epilepsy in the cohort was 23.1%. The mean age of epilepsy onset was 29.4 years. The 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 epilep...
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To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were... more
To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.3243A>G mutation died suddenly and unexpectedly. The m.3243A>G mutation is present in ∼1 in 400 of the population, although the recognized incidence of mitochondrial DNA (mtDNA) disease is ∼1 in 5000. Pathological studies including histochemistry and molecular genetic analyses performed on various post-mortem samples including cardiac tissues (atrium and ventricles) showed marked respiratory chain deficiency and high levels of the…
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Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is... more
Succinate dehydrogenase (SDH) is a crucial metabolic enzyme complex that is involved in ATP production, playing roles in both the tricarboxylic cycle and the mitochondrial respiratory chain (complex II). Isolated complex II deficiency is one of the rarest oxidative phosphorylation disorders with mutations described in three structural subunits and one of the assembly factors; just one case is attributed to recessively inherited SDHD mutations. We report the pathological, biochemical, histochemical and molecular genetic investigations of a male neonate who had left ventricular hypertrophy detected on antenatal scan and died on day one of life. Subsequent postmortem examination confirmed hypertrophic cardiomyopathy with left ventricular non-compaction. Biochemical analysis of his skeletal muscle biopsy revealed evidence of a severe isolated complex II deficiency and candidate gene sequencing revealed a novel homozygous c.275A>G, p.(Asp92Gly) SDHD mutation which was shown to be rece...
Research Interests: Genetics, Human Genetics, Complementary and Alternative Medicine, Biology, Medicine, and 11 moreCongenital Heart Defects, Humans, Mutation, Male, Mitochondrial Respiratory Chain, RM, Newborn Infant, Amino Acid Substitution Rates, Succinate Dehydrogenase, Mitochondrial Proteins, and Paediatrics and reproductive medicine
Objective: The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease has expanded significantly since the... more
Objective: The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease has expanded significantly since the original reports that associated classic clinical syndromes with mitochondrial (mt) DNA rearrangements and point mutations. The revolution in genetic technologies has allowed interrogation of the nuclear genome in a manner that has dramatically improved the diagnosis of mitochondrial disorders. We comprehensively assessed the prevalence of all forms of adult mitochondrial disease to include pathogenic mutations in both nuclear and mtDNA. Methods: Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center from 1990 to 2014. For the mid-year period of 2011, we evaluated the minimum prevalence of symptomatic nuclear DNA mutations and symptomatic and asymptomatic mtDNA mutations causing mitochondri...
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[No abstract available
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ABSTRACT Mitochondrial disease is a debilitating and often life-threatening condition that affects at least 1 in 5000 people in the UK. Clinical descriptions of the natural history of mitochondrial disease are largely anecdotal and there... more
ABSTRACT Mitochondrial disease is a debilitating and often life-threatening condition that affects at least 1 in 5000 people in the UK. Clinical descriptions of the natural history of mitochondrial disease are largely anecdotal and there have been no systematic attempts to study disease progression in a tightly defined patient cohort. The MRC has funded the Mitochondrial Cohort Study, a collaborative project involving the MRC Centre for Neuromuscular Diseases in London and Newcastle. It aims to create a national database of patients with genetically confirmed mitochondrial disease, make detailed clinico-pathological description of phenotype and correlate this with underlying genotype. The data will be crucial in providing accurate prognostic advice to patients and are prerequisite for assessing efficacy of clinical interventions. The cohort will help facilitate phase IIb and phase III drug trials and assessment of novel treatment strategies such as sequential resistance-endurance exercise. It will also provide the opportunity to assess various prevention strategies including those for cardiomyopathy, stroke-like episodes, migraine and epilepsy. The unprecedented access to family data including genotyping will also permit definitive studies on the transmission of mitochondrial DNA mutations and the effects of mitochondrial disease on female fertility and pregnancy.
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ABSTRACT Mitochondrial diseases are a heterogeneous group of genetic disorders, resulting in significant morbidity and disability. The molecular basis of many of the common mitochondrial disorders has been elucidated over the last decade;... more
ABSTRACT Mitochondrial diseases are a heterogeneous group of genetic disorders, resulting in significant morbidity and disability. The molecular basis of many of the common mitochondrial disorders has been elucidated over the last decade; yet currently there are no known cures and few effective treatments. This is compounded by the paucity of natural history studies and the lack of uniformity and relevance of outcome measures in therapeutic trials, research and clinical settings, in this patient population. Functional outcome measures have proven reliable measures to monitor natural history and interventions in other neurological conditions. We sought to evaluate the usefulness of validated functional outcome measures for patients with mitochondrial disease. Twenty-four patients and 12 sedentary controls were recruited to this case control observational study. This included the six minute timed walk (6MTW), 10 meter walk test (10MWT), Timed up and Go (TUG) and the 5 times sit to stand (5XSTS). These functional measures were compared to clinical measures of peak exercise capacity, proximal muscle strength and disease burden. All clinical measures used detected significant differences between patients and sedentary controls. Disease severity correlated with TUG (r=0.63, p=.02) and 10MTW (r=0.62, p=.001). Receiver Operating Curve analysis revealed 5XSTS to be the most responsive measure. The 10 MTW, 6 MTW, TUG and 5 XSTS are valid evaluative outcome measures in patients with mitochondrial disease. The 5XSTS can be used to discriminate between mitochondrial and sedentary controls with high accuracy and 10 MTW and TUG may serve as useful surrogate markers of disease severity.
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Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive mutations cause a spectrum of disease from infantile onset to... more
Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. The study was conducted by 42 investigators across 31 academic medical centres. We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate...
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Research Interests: Genetics, Survival Analysis, Molecular Genetics, Adolescent, Family history, and 22 moreMitochondrial DNA, Humans, Child, Mutation, genetic Counselling, Young Adult, Infant, Mitochondrial Respiratory Chain, Phenotype, Mitochondrial Genome, Enzyme, Newborn Infant, European, Mitochondrial Diseases, Cell nucleus, Spectrum, Adult, Autosomal Recessive, Clinical Presentation, Age of Onset, Inheritance Patterns, and Age at Onset
Research Interests: Genetics, Skeletal muscle biology, Magnetic Resonance Imaging, Molecular Genetics, Adolescent, and 16 moreBrain, Mitochondrial DNA, Humans, Child, genetic Counselling, Female, Inborn errors of metabolism, Infant, Mitochondrial Respiratory Chain, Electron Transport, Pedigree, Mitochondrial Genome, Mitochondrial Diseases, Consanguinity, Base Sequence, and Autosomal Recessive
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Research Interests: Intelligence, Magnetic Resonance Imaging, Adolescent, Prospective studies, Mitochondrial DNA, and 19 moreHumans, Child, Mutation, Female, Male, Population based study, Infant, Developmental disabilities, Differential Diagnosis, Newborn Infant, Prevalence, Mitochondrial Diseases, Great Britain, Basal ganglia, Seizures, Clinical Presentation, Lactic Acid, Nervous System Diseases, and Cognition disorders
Research Interests: Magnetic Resonance Imaging, Brain, Humans, Female, Male, and 4 moreInfant, Proline, Newborn Infant, and Adult
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Research Interests: Skeletal muscle biology, Family, Adolescent, Brain, Mitochondrial DNA, and 11 moreHumans, Child, Mutation, Female, Male, Young Adult, Phenotype, Aged, Middle Aged, Adult, and Cohort Studies
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Research Interests: Skeletal muscle biology, Adolescent, Biopsy, Brain, Mitochondrial DNA, and 33 moreHumans, Child, Mutation, genetic Counselling, Female, Muscular Dystrophies, Peripheral Nervous System, Male, DNA sequence design, Infant, Genetic determinism, Proteins, Gene, Gender Bias, Left Ventricular Dysfunction, Duchenne Muscular Dystrophy, Phenotype, Clinical Sciences, Mitochondrial Diseases, Middle Aged, Gen, Spectrum, Genotype, Adult, Sex Factors, Amino Acid Profile, Annals, Liver Failure, Clinical Presentation, Hypoventilation, Neurosciences, Age of Onset, and DNA sequence
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Diverse and variable clinical features, a loose genotype-phenotype relationship, and presentation to different medical specialties have all hindered attempts to gauge the epidemiological impact of mitochondrial DNA (mtDNA) disease.... more
Diverse and variable clinical features, a loose genotype-phenotype relationship, and presentation to different medical specialties have all hindered attempts to gauge the epidemiological impact of mitochondrial DNA (mtDNA) disease. Nevertheless, a clear understanding of its prevalence remains an important goal, particularly about planning appropriate clinical services. Consequently, the aim of this study was to accurately define the prevalence of mtDNA disease (primary mutation occurs in mtDNA) in the working-age population of the North East of England. Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center for investigation from 1990 to 2004. Those with pathogenic mtDNA mutations were identified and pedigree analysis performed. For the midyear period of 2001, we calculated the minimum point prevalence of mtDNA disease for adults of working age (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;16 and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;60/65 years for female/male patients, respectively). In this population, we found that 9.2 in 100,000 people have clinically manifest mtDNA disease, making this one of the commonest inherited neuromuscular disorders. In addition, a further 16.5 in 100,000 children and adults younger than retirement age are at risk for development of mtDNA disease. Through detailed pedigree analysis and active family tracing, we have been able to provide revised minimum prevalence figures for mtDNA disease. These estimates confirm that mtDNA disease is a common cause of chronic morbidity and is more prevalent than has been previously appreciated.
Research Interests: Adolescent, England, Mitochondrial DNA, Humans, Genetic Testing, and 18 moreMutation, Female, Male, Pedigree, Risk factors, Phenotype, Clinical Sciences, Aged, Prevalence, Mitochondrial Diseases, Middle Aged, Genotype, Adult, Age Factors, Risk Factors, Annals, Neurosciences, and Inheritance Patterns
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We have defined the genetic defect in a large family first described in one of the earliest reports of suspected mitochondrial myopathy, as the mutation T14709C in the mitochondrial transfer RNA(Glu) (mt-tRNA(Glu)) gene. Extraordinarily,... more
We have defined the genetic defect in a large family first described in one of the earliest reports of suspected mitochondrial myopathy, as the mutation T14709C in the mitochondrial transfer RNA(Glu) (mt-tRNA(Glu)) gene. Extraordinarily, this mutation has attained homoplasmy (100% mutated mt-tRNA(Glu)) on at least three independent occasions in this family and has done so in one individual who remains asymptomatic with no clinical evidence of disease. Heteroplasmy (dual populations of mutated and wild-type mtDNA) usually is regarded as one of the primary diagnostic criteria for pathogenicity and previous reports of the T14709C mutation detail heteroplasmy in a variety of tissues. In contrast, homoplasmy of mt-tRNA mutations generally has been regarded as evidence of a benign nature, with rare exceptions that result in organ-specific phenotypes. Discovering that T14709C, a common and severe mt-tRNA mutation, can attain homoplasmy without symptoms or clinical signs of disease has profound implications for the identification and prevalence of other pathogenic mt-tRNA mutations. Furthermore, variation in phenotype between homoplasmic individuals implies a crucial contribution from the nuclear genetic environment in determining the clinical outcome of mt-tRNA mutations.