Robert W Taylor

Publications (148)1059.17 Total impact

• Article: Incidence of carpal tunnel syndrome in adult patients with mitochondrial disease.

  Roger G Whittaker, Elizabeth Hall, Muhammad K Mansoor, Robert W Taylor, Douglass M Turnbull
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  ABSTRACT: 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.
  Journal of the Peripheral Nervous System 03/2013; 18(1):59-61. · 2.80 Impact Factor
• Article: Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNAGlu (MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study.

  Nichola Z Lax, Sharmilee Gnanapavan, Sarah J Dowson, Charlotte L Alston, Langping He, Tuomo M Polvikoski, Evelyn Jaros, Dominic G O'Donovan, John W Yarham, Douglass M Turnbull, Andrew F Dean, Robert W Taylor
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  ABSTRACT: Mitochondrial respiratory chain disease is associated with a spectrum of clinical presentations and considerable genetic heterogeneity. Here we report molecular genetic and neuropathologic findings from an adult with an unusual manifestation of mitochondrial DNA disease. Clinical features included early-onset cataracts, ataxia, and progressive paraparesis, with sequencing revealing the presence of a novel de novo m.14685G>A mitochondrial tRNA (MT-TE) gene mutation. Muscle biopsy showed that 13% and 34% of muscle fibers lacked cytochrome c oxidase activity and complex I subunit expression, respectively. Biochemical studies confirmed a marked decrease in complex I activity. Neuropathologic investigation revealed a large cystic lesion affecting the left putamen, caudate nucleus, and internal capsule, with evidence of marked microvacuolation, neuron loss, perivascular lacunae, and blood vessel mineralization. The internal capsule showed focal axonal loss, whereas brainstem and spinal cord showed descending anterograde degeneration in medullary pyramids and corticospinal tracts. In agreement with muscle biopsy findings, reduced complex I immunoreactivity was detected in the remaining neuronal populations, particularly in the basal ganglia and cerebellum, correlating with the neurologic dysfunction exhibited by the patient. This study emphasizes the importance of molecular genetic and postmortem neuropathologic analyses for furthering our understanding of underlying mechanisms of mitochondrial disorders.
  Journal of neuropathology and experimental neurology. 02/2013; 72(2):164-175.
• Article: The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation--implications for diagnosis and management.

  Victoria Nesbitt, Robert D S Pitceathly, Doug M Turnbull, Robert W Taylor, Mary G Sweeney, Ese E Mudanohwo, Shamima Rahman, Michael G Hanna, Robert McFarland
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  ABSTRACT: 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.
  Journal of neurology, neurosurgery, and psychiatry 01/2013; · 4.87 Impact Factor
• Article: Cardiomyopathies due to homoplasmic mitochondrial tRNA mutations: morphologic and molecular features.

  Carla Giordano, Elena Perli, Maurizia Orlandi, Annalinda Pisano, Helen A Tuppen, Langping He, Rocco Ierinò, Luciano Petruzziello, Amedeo Terzi, Camillo Autore, Vincenzo Petrozza, Pietro Gallo, Robert W Taylor, Giulia d'Amati
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  ABSTRACT: Isolated hypertrophic cardiomyopathy may represent the sole clinical feature of a mitochondrial disorder in adult patients. The clinical outcome is characterized by a rapid progression to dilation and failure. A mitochondrial etiology in these cases is not obvious at clinical investigation and may represent an unexpected finding at autopsy or after cardiac transplant. We describe the morphologic, biochemical, and molecular features of hearts from 3 transplanted patients with isolated mitochondrial cardiomyopathy caused by homoplasmic mutations in the MTTI gene, coding for mitochondrial isoleucine tRNA (mt-tRNA(Ile)). On gross examination, the 3 hearts showed a symmetric pattern of hypertrophy. At histology, cardiomyocytes were hypertrophic and showed sarcoplasmic vacuoles filled with granules that stain with antimitochondrial antibodies. On frozen sections, the combined cytochrome c oxidase (COX)/succinate dehydrogenase stain showed a large prevalence of COX-deficient cardiomyocytes. Mitochondrially encoded COX subunit I was almost absent on immunohistochemistry, whereas the nuclear-encoded COX subunit IV was normally expressed. Ultrastructural analysis confirmed the marked mitochondrial proliferation. Biochemical studies of cardiac homogenates revealed a combined respiratory chain defect. Quantitative restriction fragment length polymorphism analysis of DNA from cardiac homogenate confirmed that the mt-tRNA mutations were also detected in the patient's blood. High-resolution Northern blot analysis showed a marked decrease in the steady-state level of mt-tRNA(Ile), confirming pathogenicity. In conclusion, pathologists play a major role in unraveling the mitochondrial etiology of isolated hypertrophic cardiomyopathies, provided that a detailed diagnostic flowchart is followed. Once the mitochondrial etiology is clearly defined, molecular analyses on the heart are an invaluable tool to assign mutation pathogenicity.
  Human pathology 01/2013; · 3.03 Impact Factor
• Article: The m.3291T>C mt-tRNA(Leu(UUR)) mutation is definitely pathogenic and causes multisystem mitochondrial disease.

  John W Yarham, Emma L Blakely, Charlotte L Alston, Mark E Roberts, John Ealing, Piyali Pal, Douglass M Turnbull, Robert McFarland, Robert W Taylor
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  ABSTRACT: Mitochondrial tRNA point mutations are important causes of human disease, and have been associated with a diverse range of clinical phenotypes. Definitively proving the pathogenicity of any given mt-tRNA mutation requires combined molecular, genetic and functional studies. Subsequent evaluation of the mutation using a pathogenicity scoring system is often very helpful in concluding whether or not the mutation is causing disease. Despite several independent reports linking the m.3291T>C mutation to disease in humans, albeit in association with several different phenotypes, its pathogenicity remains controversial. A lack of conclusive functional evidence and an over-emphasis on the poor evolutionary conservation of the affected nucleotide have contributed to this controversy. Here we describe an adult patient who presented with deafness and lipomas and evidence of mitochondrial abnormalities in his muscle biopsy, who harbours the m.3291T>C mutation, providing conclusive evidence of pathogenicity through analysis of mutation segregation with cytochrome c oxidase (COX) deficiency in single muscle fibres, underlining the importance of performing functional studies when assessing pathogenicity.
  Journal of the neurological sciences 12/2012; · 2.32 Impact Factor
• Article: What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?

  Vivienne C M Neeve, David C Samuels, Laurence A Bindoff, Bianca van den Bosch, Gert Van Goethem, Hubert Smeets, Anne Lombès, Claude Jardel, Michio Hirano, Salvatore Dimauro, [......], Birgit Czermin, Angela Abicht, Hanns Lochmüller, Gavin Hudson, Grainne G Gorman, Doug M Turnbull, Robert W Taylor, Elke Holinski-Feder, Patrick F Chinnery, Rita Horvath
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  ABSTRACT: Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported significantly more frequently in females than in males, and also showed an association with one of the chromosomal markers defining the POLG haplotype. In conclusion, our clinical results show that the homozygous p.Ala467Thr POLG mutation does not cause discrete phenotypes, as previously suggested, but rather there is a continuum of clinical symptoms. Our results suggest that the mitochondrial DNA background plays an important role in modifying the disease phenotype but nuclear modifiers, epigenetic and environmental factors may also influence the severity of disease.
  Brain 12/2012; 135(Pt 12):3614-26. · 9.46 Impact Factor
• Source

  Available from: David A Young

  Article: Mitochondrial dysfunction in osteoarthritis is associated with a down-regulation of superoxide dismutase 2.

  Christos Gavriilidis, Satomi Miwa, Thomas von Zglinicki, Robert W Taylor, David A Young
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  ABSTRACT: OBJECTIVE: Superoxide dismutase 2 (SOD2) is downregulated in osteoarthritis (OA). Here we investigated the functional effects of this downregulation in the context of oxidative damage and mitochondrial dysfunction. METHODS: Lipid peroxidation in OA and healthy control neck of femur fracture (NOF) cartilage was assessed by measuring malondialdehyde levels using the thiobarbituric acid reactive substances assay. Long-range PCR amplification and a mitochondrial DNA (mtDNA) strand break assays were used to investigate the presence of somatic large-scale mtDNA rearrangements in cartilage. Microscale oxygraphy was used to explore possible changes in mitochondrial respiratory activity between OA and NOF chondrocytes. RNA interference was used to determine the consequence of SOD2 depletion on lipid peroxidation, mtDNA damage and mitochondrial respiration. RESULTS: OA cartilage had higher levels of lipid peroxidation compared to NOF and similar to SOD2 depleted chondrocytes. SOD2 depletion led to a significant increase in mtDNA strand breaks in chondrocytes but, with no difference detected in OA compared to NOF mtDNA. Furthermore, only very low levels of somatic, large-scale mtDNA rearrangements were identified in OA cartilage. OA chondrocytes showed less spare respiratory capacity (SRC) and higher proton leak compared to NOF. SOD2-depleted chondrocytes also showed a lower SRC and higher proton leak. CONCLUSION: This is the first study to analyse the effects of SOD2 depletion in HAC in terms of oxidative damage and mitochondrial function. These findings suggest that SOD2 depletion in chondrocytes leads to oxidative damage and mitochondrial dysfunction potentially contributing to OA. © 2012 American College of Rheumatology.
  Arthritis & Rheumatism 11/2012; · 7.87 Impact Factor
• Article: Concentric hypertrophic remodelling and subendocardial dysfunction in mitochondrial DNA point mutation carriers.

  Matthew G D Bates, Kieren G Hollingsworth, Jane H Newman, Djordje G Jakovljevic, Andrew M Blamire, Guy A Macgowan, Bernard D Keavney, Patrick F Chinnery, Douglass M Turnbull, Robert W Taylor, Michael I Trenell, Grainne S Gorman
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  ABSTRACT: AIMS: Hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Screening strategies for cardiac disease are unclear. We investigated whether myocardial abnormalities could be identified in mitochondrial DNA mutation carriers without clinical cardiac involvement. METHODS AND RESULTS: Cardiac magnetic resonance imaging was performed in 22 adult patients with mitochondrial disease due to the m.3243A>G mutation, but no known cardiac involvement, and 22 age- and gender-matched control subjects: (i) Phosphorus-31- magnetic resonance spectroscopy, (ii) cine imaging (iii), cardiac tagging and (iv) late gadolinium enhancement (LGE) imaging. Disease burden was determined using the Newcastle Mitochondrial Disease Adult Scale (NMDAS) and urinary mutation load. Compared with control subjects, patients had an increased left ventricular mass index (LVMI), LV mass to end-diastolic volume (M/V) ratio, wall thicknesses (all P < 0.01), torsion and torsion to endocardial strain ratio (both P < 0.05). Longitudinal shortening was decreased in patients (P < 0.0001) and correlated with an increased LVMI (r = -0.52, P < 0.03), but there were no differences in the diastolic function. Among patients there was no correlation of LVMI or the M/V ratio with diabetic or hypertensive status, but the mutation load and NMDAS correlated with the LVMI (r = 0.71 and r = 0.79, respectively, both P < 0.001). The phosphocreatine/adenosine triphosphate ratio was decreased in patients (P < 0.001) but did not correlate with other parameters. No patients displayed focal LGE. CONCLUSION: Concentric remodelling and subendocardial dysfunction occur in patients carrying m.3243A>G mutation without clinical cardiac disease. Patients with higher mutation loads and disease burden may be at increased risk of cardiac involvement.
  European heart journal cardiovascular Imaging. 11/2012;
• Article: Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations.

  Laura C Greaves, Joanna L Elson, Marco Nooteboom, John P Grady, Geoffrey A Taylor, Robert W Taylor, John C Mathers, Thomas B L Kirkwood, Doug M Turnbull
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  ABSTRACT: Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selective constraints, which have been shown to occur in the germline, on the occurrence and expansion of these mtDNA mutations within individual somatic cells. Here we compared the pattern and spectrum of mutations observed in ageing human colon to those observed in the general population (germline variants) and those associated with primary mtDNA disease. The pathogenicity of the protein encoding mutations was predicted using a computational programme, MutPred, and the scores obtained for the three groups compared. We show that the mutations associated with ageing are randomly distributed throughout the genome, are more frequently non-synonymous or frameshift mutations than the general population, and are significantly more pathogenic than population variants. Mutations associated with primary mtDNA disease were significantly more pathogenic than ageing or population mutations. These data provide little evidence for any selective constraints on the occurrence and expansion of mtDNA mutations in somatic cells of the human colon during human ageing in contrast to germline mutations seen in the general population.
  PLoS Genetics 11/2012; 8(11):e1003082. · 8.69 Impact Factor
• Article: Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics.

  Robert D S Pitceathly, Conrad Smith, Carl Fratter, Charlotte L Alston, Langping He, Kate Craig, Emma L Blakely, Julie C Evans, John Taylor, Zarfishan Shabbir, [......], Peter W Lunt, Michael G Hanna, Andrew M Schaefer, Robert McFarland, Rita Horvath, Patrick F Chinnery, Douglass M Turnbull, Joanna Poulton, Robert W Taylor, Gráinne S Gorman
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  ABSTRACT: Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico-pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy.
  Brain 10/2012; · 9.46 Impact Factor
• Article: Universal heteroplasmy of human mitochondrial DNA.

  Brendan A I Payne, Ian J Wilson, Patrick Yu-Wai-Man, Jonathan Coxhead, David Deehan, Rita Horvath, Robert W Taylor, David C Samuels, Mauro Santibanez-Koref, Patrick F Chinnery
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  ABSTRACT: Mammalian cells contain thousands of copies of mitochondrial DNA (mtDNA). At birth, these are thought to be identical in most humans. Here, we use long read length ultra-deep resequencing-by-synthesis to interrogate regions of the mtDNA genome from related and unrelated individuals at unprecedented resolution. We show that very low-level heteroplasmic variance is present in all tested healthy individuals, and is likely to be due to both inherited and somatic single base substitutions. Using this approach, we demonstrate an increase in mtDNA mutations in the skeletal muscle of patients with a proofreading-deficient mtDNA polymerase γ due to POLG mutations. In contrast, we show that OPA1 mutations, which indirectly affect mtDNA maintenance, do not increase point mutation load. The demonstration of universal mtDNA heteroplasmy has fundamental implications for our understanding of mtDNA inheritance and evolution. Ostensibly de novo somatic mtDNA mutations, seen in mtDNA maintenance disorders and neurodegenerative disease and aging, will partly be due to the clonal expansion of low-level inherited variants.
  Human Molecular Genetics 10/2012; · 7.64 Impact Factor
• Article: Diagnostic investigations of patients with chronic progressive external ophthalmoplegia.

  Patrick Yu-Wai-Man, Grainne S Gorman, Robert W Taylor, Douglass M Turnbull
  The British journal of ophthalmology 09/2012; · 2.92 Impact Factor
• Article: OPA1 mutations induce mtDNA proliferation in leukocytes of patients with dominant optic atrophy.

  Kamil S Sitarz, Gitte J Almind, Rita Horvath, Birgit Czermin, Karen Grønskov, Angela Pyle, Robert W Taylor, Michael Larsen, Patrick F Chinnery, Patrick Yu-Wai-Man
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  ABSTRACT: OPA1 mutations cause autosomal dominant optic atrophy (DOA), a debilitating mitochondrial optic neuropathy characterized by irreversible loss of retinal ganglion cells (RGCs) and progressive visual failure starting in early childhood.(1) Interestingly, ∼20% of OPA1 carriers will develop a more severe form of the disease, DOA+, where the optic atrophy is compounded by additional neurologic features.(1) OPA1 is a multifunctional mitochondrial inner membrane protein, and rather unexpectedly, high levels of cytochrome c oxidase (COX)-negative muscle fibers were recently identified in biopsy specimens from patients manifesting both the pure and syndromal phenotypes.(2,3) These COX-negative muscle fibers harbored high levels of somatically acquired mitochondrial DNA (mtDNA) deletions and marked mtDNA proliferation was also observed, clearly revealing OPA1 to be a novel disorder of mtDNA maintenance.(4) To further investigate this key pathologic mechanism, mtDNA copy number was quantified in blood leukocytes from 3 independent patient cohorts with molecularly confirmed OPA1 mutations.
  Neurology 09/2012; 79(14):1515-1517. · 8.31 Impact Factor
• Article: Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.

  Charlotte L Alston, James E Davison, Francesca Meloni, Francois H van der Westhuizen, Langping He, Hue-Tran Hornig-Do, Andrew C Peet, Paul Gissen, Paola Goffrini, Ileana Ferrero, Evangeline Wassmer, Robert McFarland, Robert W Taylor
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  ABSTRACT: Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency.
  Journal of Medical Genetics 09/2012; 49(9):569-77. · 6.36 Impact Factor
• Source

  Available from: Giulia d'Amati

  Article: Cardiac involvement in mitochondrial DNA disease: clinical spectrum, diagnosis, and management.

  Matthew G D Bates, John P Bourke, Carla Giordano, Giulia d'Amati, Douglass M Turnbull, Robert W Taylor
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  ABSTRACT: Mitochondrial disease refers to a heterogenous group of genetic disorders that result from dysfunction of the final common pathway of energy metabolism. Mitochondrial DNA mutations affect key components of the respiratory chain and account for the majority of mitochondrial disease in adults. Owing to critical dependence of the heart on oxidative metabolism, cardiac involvement in mitochondrial disease is common and may occur as the principal clinical manifestation or part of multisystem disease. Recent advances in our understanding of the clinical spectrum and genetic aetiology of cardiac involvement in mitochondrial DNA disease have important implications for cardiologists in terms of the investigation and multi-disciplinary management of patients.
  European Heart Journal 08/2012; · 10.48 Impact Factor
• Article: Mutations in the mitochondrial tRNA(Ser(AGY)) gene are associated with deafness, retinal degeneration, myopathy and epilepsy.

  Helen Al Tuppen, Karin Naess, Nancy G Kennaway, Mazhor Al-Dosary, Nicole Lesko, John W Yarham, Helene Bruhn, Rolf Wibom, Inger Nennesmo, Richard G Weleber, Emma L Blakely, Robert W Taylor, Robert McFarland
  European journal of human genetics: EJHG 08/2012; 20(8):910. · 3.56 Impact Factor
• Article: A proposed consensus panel of organisms for determining evolutionary conservation of mt-tRNA point mutations.

  John W Yarham, Robert McFarland, Robert W Taylor, Joanna L Elson
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  ABSTRACT: Assigning pathogenicity to mt-tRNA variants requires multiple strands of evidence. Evolutionary conservation is often considered mandatory, but lack of a standard panel of organisms to assess conservation complicates comparison between reports and undermines the value of conservation-based evidence. We demonstrate that intra-species MTT sequence variation is sufficiently low for sequence data from a single organism to adequately represent a species. On this basis, we propose a standardised panel of organisms for conservation assessment and describe integration of this conservation panel into a pathogenicity scoring system designed to assess mt-tRNA variation associated with mitochondrial disease.
  Mitochondrion 07/2012; 12(5):533-8. · 3.62 Impact Factor
• Article: Cytochrome c oxidase-intermediate fibres: importance in understanding the pathogenesis and treatment of mitochondrial myopathy.

  Julie L Murphy, Thiloka E Ratnaike, Ersong Shang, Gavin Falkous, Emma L Blakely, Charlotte L Alston, Tanja Taivassalo, Ronald G Haller, Robert W Taylor, Doug M Turnbull
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  ABSTRACT: An important diagnostic muscle biopsy finding in patients with mitochondrial DNA disease is the presence of respiratory-chain deficient fibres. These fibres are detected as cytochrome c oxidase-deficient following a sequential cytochrome c oxidase-succinate dehydrogenase reaction, often in a mosaic pattern within a population of cytochrome c oxidase-normal fibres. Detailed analysis of muscle biopsies from patients with various mitochondrial DNA defects shows that a spectrum of deficiency exists, as there are a large number of fibres which do not correspond to being either completely cytochrome c oxidase-normal (brown staining) or cytochrome c oxidase-deficient (blue staining). We have used a combination of histochemical and immunocytochemical techniques to show that a population of cytochrome c oxidase-intermediate reacting fibres are a gradation between normal and deficient fibres. We show that cytochrome c oxidase-intermediate fibres also have different genetic characteristics in terms of amount of mutated and wild-type mtDNA, and as such, may represent an important transition between respiratory normal and deficient fibres. Assessing changes in intermediate fibres will be crucial to evaluating the responses to treatment and in particular to exercise training regimes in patients with mitochondrial DNA disease.
  Neuromuscular Disorders 05/2012; 22(8):690-8. · 2.80 Impact Factor
• Article: Toward a mtDNA locus-specific mutation database using the LOVD platform.

  Joanna L Elson, Mary G Sweeney, Vincent Procaccio, John W Yarham, Antonio Salas, Qing-Peng Kong, Francois H van der Westhuizen, Robert D S Pitceathly, David R Thorburn, Marie T Lott, Douglas C Wallace, Robert W Taylor, Robert McFarland
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  ABSTRACT: The Human Variome Project (HVP) is a global effort to collect and curate all human genetic variation affecting health. Mutations of mitochondrial DNA (mtDNA) are an important cause of neurogenetic disease in humans; however, identification of the pathogenic mutations responsible can be problematic. In this article, we provide explanations as to why and suggest how such difficulties might be overcome. We put forward a case in support of a new Locus Specific Mutation Database (LSDB) implemented using the Leiden Open-source Variation Database (LOVD) system that will not only list primary mutations, but also present the evidence supporting their role in disease. Critically, we feel that this new database should have the capacity to store information on the observed phenotypes alongside the genetic variation, thereby facilitating our understanding of the complex and variable presentation of mtDNA disease. LOVD supports fast queries of both seen and hidden data and allows storage of sequence variants from high-throughput sequence analysis. The LOVD platform will allow construction of a secure mtDNA database; one that can fully utilize currently available data, as well as that being generated by high-throughput sequencing, to link genotype with phenotype enhancing our understanding of mitochondrial disease, with a view to providing better prognostic information.
  Human Mutation 05/2012; 33(9):1352-8. · 5.69 Impact Factor
• Article: Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations.

  Gerald Pfeffer, Emma L Blakely, Charlotte L Alston, Adam Hassani, Mike Boggild, Rita Horvath, David C Samuels, Robert W Taylor, Patrick F Chinnery
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  ABSTRACT: Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ∼50% cases. Mutations in the mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients. Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations. Three pedigrees had mutations in MTATP6, two of which have not been reported previously and are detailed in this report. These families had the m.9185T>C and m.9035T>C mutations, respectively, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were non-specific or normal. MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a mitochondrial DNA disorder.
  Journal of neurology, neurosurgery, and psychiatry 05/2012; 83(9):883-6. · 4.87 Impact Factor