Publications by authors named "Angela Pyle"

93 Publications

Metabolic shift underlies recovery in reversible infantile respiratory chain deficiency.

EMBO J 2020 12 31;39(23):e105364. Epub 2020 Oct 31.

Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6-months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt-tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
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http://dx.doi.org/10.15252/embj.2020105364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705457PMC
December 2020

Age-associated mitochondrial DNA mutations cause metabolic remodelling that contributes to accelerated intestinal tumorigenesis.

Nat Cancer 2020 Oct 21;1(10):976-989. Epub 2020 Sep 21.

Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.
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http://dx.doi.org/10.1038/s43018-020-00112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116185PMC
October 2020

The Human Coronavirus Receptor ANPEP (CD13) Is Overexpressed in Parkinson's Disease.

Mov Disord 2020 12 3;35(12):2134-2136. Epub 2020 Nov 3.

Wellcome Trust Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1002/mds.28354DOI Listing
December 2020

Post-mortem ventricular cerebrospinal fluid cell-free-mtDNA in neurodegenerative disease.

Sci Rep 2020 09 17;10(1):15253. Epub 2020 Sep 17.

Biosciences Institute, 4th Floor Cookson Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Cell-free mitochondrial DNA (cfmtDNA) is detectable in almost all human body fluids and has been associated with the onset and progression of several complex traits. In-life assessments indicate that reduced cfmtDNA is a feature of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and multiple sclerosis. However, whether this feature is conserved across all neurodegenerative diseases and how it relates to the neurodegenerative processes remains unclear. In this study, we assessed the levels of ventricular cerebrospinal fluid-cfmtDNA (vCSF-cfmtDNA) in a diverse group of neurodegenerative diseases (NDDs) to determine if the in-life observations of reduced cfmtDNA seen in lumbar CSF translated to the post-mortem ventricular CSF. To investigate further, we compared vCSF-cfmtDNA levels to known protein markers of neurodegeneration, synaptic vesicles and mitochondrial integrity. Our data indicate that reduced vCSF-cfmtDNA is a feature specific to Parkinson's and appears consistent throughout the disease course. Interestingly, we observed increased vCSF-cfmtDNA in the more neuropathologically severe NDD cases, but no association to protein markers of neurodegeneration, suggesting that vCSF-cfmtDNA release is more complex than mere cellular debris produced following neuronal death. We conclude that vCSF-cfmtDNA is reduced in PD, but not other NDDs, and appears to correlate to pathology. Although its utility as a prognostic biomarker is limited, our data indicate that higher levels of vCSF-cfmtDNA is associated with more severe clinical presentations; suggesting that it is associated with the neurodegenerative process. However, as vCSF-cfmtDNA does not appear to correlate to established indicators of neurodegeneration or indeed indicators of mitochondrial mass, further work to elucidate its exact role is needed.
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http://dx.doi.org/10.1038/s41598-020-72190-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499424PMC
September 2020

Homozygous TAF1C variants are associated with a novel childhood-onset neurological phenotype.

Clin Genet 2020 Nov 25;98(5):493-498. Epub 2020 Aug 25.

PEDEGO Research Unit, University of Oulu, Oulu, Finland.

TATA-box binding protein associated factor, RNA polymerase I subunit C (TAF1C) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygous TAF1C missense variants and an early onset neurological phenotype with severe global developmental delay. Clinical features included lack of speech and ambulation and epilepsy. MRI of the brain demonstrated widespread cerebral atrophy and frontal periventricular white matter hyperintensity. The phenotype resembled that of a previously described variant of UBTF, which encodes another transcription factor of Pol I. TAF1C variants were located in two conserved amino acid positions and were predicted to be deleterious. In patient-derived fibroblasts, TAF1C mRNA and protein expression levels were substantially reduced compared with healthy controls. We propose that the variants impairing TAF1C expression are likely pathogenic and relate to a novel neurological disease. This study expands the disease spectrum related to Pol I transcription machinery, associating the TAF1C missense variants with a severe neurological phenotype for the first time.
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http://dx.doi.org/10.1111/cge.13827DOI Listing
November 2020

Mitochondrial DNA damage and brain ageing in HIV.

Clin Infect Dis 2020 Jul 28. Epub 2020 Jul 28.

Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, UK.

Background: Neurocognitive impairment (NCI) remains common in people living with HIV (PLWH), despite suppressive anti-retroviral therapy (ART), but the reasons remain incompletely understood. Mitochondrial dysfunction is a hallmark of ageing and of neurodegenerative diseases. We hypothesised that HIV or ART may lead to mitochondrial abnormalities in brain thus contributing to NCI.

Methods: We studied post-mortem frozen brain samples from 52 PLWH and 40 HIV negative controls. Cellular mitochondrial DNA (mtDNA) content and levels of large-scale mtDNA deletions were measured by real-time PCR. Heteroplasmic mtDNA point mutations were quantified by deep sequencing (Illumina). Neurocognitive data were taken within 6 months antemortem.

Results: We observed a decrease in mtDNA content, an increase in the mtDNA 'common deletion', and an increase in mtDNA point mutations with age (all p <0.05). Each of these changes was exacerbated in HIV positive cases compared with HIV negative controls (all p <0.05). ART exposures, including nucleoside analogue reverse transcriptase inhibitors, were not associated with changes in mtDNA. The number of mtDNA point mutations was associated low CD4/CD8 ratio (p 0.04) and with NCI (Global T-score, p 0.007).

Conclusions: In people with predominantly advanced HIV infection, there is exacerbation of age-associated mtDNA damage. This change is driven by HIV per se rather than by ART toxicity and may contribute to NCI. These data suggest that mitochondrial dysfunction may be a mediator of adverse ageing phenotypes in PLWH.
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http://dx.doi.org/10.1093/cid/ciaa984DOI Listing
July 2020

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion.

J Neurol 2020 Dec 12;267(12):3643-3649. Epub 2020 Jul 12.

Department of Clinical Neurosciences, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.

Background: Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing.

Methods: Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother.

Results: Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30's, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1.

Conclusions: The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.
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http://dx.doi.org/10.1007/s00415-020-10059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674332PMC
December 2020

Metabolic effects of bezafibrate in mitochondrial disease.

EMBO Mol Med 2020 03 28;12(3):e11589. Epub 2020 Feb 28.

Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.

Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae.
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http://dx.doi.org/10.15252/emmm.201911589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059007PMC
March 2020

Circulating cell-free mitochondrial DNA levels in Parkinson's disease are influenced by treatment.

Mol Neurodegener 2020 02 18;15(1):10. Epub 2020 Feb 18.

Wellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.

Several studies have linked circulating cell-free mitochondrial DNA (ccf-mtDNA) to human disease. In particular, reduced ccf-mtDNA levels in the cerebrospinal fluid (CSF) of both Alzheimer's and Parkinson's disease (PD) patients have raised the hypothesis that ccf-mtDNA could be used as a biomarker for neurodegenerative disease onset and progression. However, how a reduction of CSF ccf-mtDNA levels relates to neurodegeneration remains unclear. Many factors are likely to influence ccf-mtDNA levels, such as concomitant therapeutic treatment and comorbidities. In this study we aimed to investigate these factors, quantifying CSF ccf-mtDNA from the Parkinson's Progression Markers Initiative in 372 PD patients and 159 matched controls at two time points. We found that ccf-mtDNA levels appear significantly reduced in PD cases when compared to matched controls and are associated with cognitive impairment. However, our data indicate that this reduction in ccf-mtDNA is also associated with the commencement, type and duration of treatment. Additionally, we found that ccf-mtDNA levels are associated with comorbidities such as depression and insomnia, however this was only significant if measured in the absence of treatment. We conclude that in PD, similar to reports in HIV and sepsis, comorbidities and treatment can both influence ccf-mtDNA homeostasis, raising the possibility that ccf-mtDNA may be useful as a biomarker for treatment response or the development of secondary phenotypes. Given that, clinically, PD manifests often decades after neurodegeneration begins, predicting who will develop disease is important. Also, identifying patients who will respond to existing treatments or develop secondary phenotypes will have increased clinical importance as PD incidence rises.
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http://dx.doi.org/10.1186/s13024-020-00362-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029508PMC
February 2020

Effects of thyroid hormone on mitochondria and metabolism of human preimplantation embryos.

Stem Cells 2020 03 26;38(3):369-381. Epub 2019 Dec 26.

Division of Women's and Children's Health, Faculty of Life Sciences and Medicine, King's College London and Assisted Conception Unit, Guy's Hospital, London, UK.

Thyroid hormones are regarded as the major controllers of metabolic rate and oxygen consumption in mammals. Although it has been demonstrated that thyroid hormone supplementation improves bovine embryo development in vitro, the cellular mechanisms underlying these effects are so far unknown. In this study, we investigated the role of thyroid hormone in development of human preimplantation embryos. Embryos were cultured in the presence or absence of 10  M triiodothyronine (T3) till blastocyst stage. Inner cell mass (ICM) and trophectoderm (TE) were separated mechanically and subjected to RNAseq or quantification of mitochondrial DNA copy number. Analyses were performed using DESeq (v1.16.0 on R v3.1.3), MeV4.9 and MitoMiner 4.0 platforms. We found that the exposure of human preimplantation embryos to T3 had a profound impact on nuclear gene transcription only in the cells of ICM (1178 regulated genes-10.5% of 11 196 expressed genes) and almost no effect on cells of TE (38 regulated genes-0.3% of expressed genes). The analyses suggest that T3 induces in ICM a shift in ribosome and oxidative phosphorylation activity, as the upregulated genes are contributing to the composition and organization of the respiratory chain and associated cofactors involved in mitoribosome assembly and stability. Furthermore, a number of genes affecting the citric acid cycle energy production have reduced expression. Our findings might explain why thyroid disorders in women have been associated with reduced fertility and adverse pregnancy outcome. Our data also raise a possibility that supplementation of culture media with T3 may improve outcomes for women undergoing in vitro fertilization.
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http://dx.doi.org/10.1002/stem.3129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064942PMC
March 2020

Clinical presentation and proteomic signature of patients with TANGO2 mutations.

J Inherit Metab Dis 2020 03 13;43(2):297-308. Epub 2019 Aug 13.

Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q (CoQ ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
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http://dx.doi.org/10.1002/jimd.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078914PMC
March 2020

Recent advances in understanding the molecular genetic basis of mitochondrial disease.

J Inherit Metab Dis 2020 01 10;43(1):36-50. Epub 2019 May 10.

Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

Mitochondrial disease is hugely diverse with respect to associated clinical presentations and underlying genetic causes, with pathogenic variants in over 300 disease genes currently described. Approximately half of these have been discovered in the last decade due to the increasingly widespread application of next generation sequencing technologies, in particular unbiased, whole exome-and latterly, whole genome sequencing. These technologies allow more genetic data to be collected from patients with mitochondrial disorders, continually improving the diagnostic success rate in a clinical setting. Despite these significant advances, some patients still remain without a definitive genetic diagnosis. Large datasets containing many variants of unknown significance have become a major challenge with next generation sequencing strategies and these require significant functional validation to confirm pathogenicity. This interface between diagnostics and research is critical in continuing to expand the list of known pathogenic variants and concomitantly enhance our knowledge of mitochondrial biology. The increasing use of whole exome sequencing, whole genome sequencing and other "omics" techniques such as transcriptomics and proteomics will generate even more data and allow further interrogation and validation of genetic causes, including those outside of coding regions. This will improve diagnostic yields still further and emphasizes the integral role that functional assessment of variant causality plays in this process-the overarching focus of this review.
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http://dx.doi.org/10.1002/jimd.12104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041634PMC
January 2020

A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts.

Hum Genomics 2019 01 31;13(1). Epub 2019 Jan 31.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Background: Mitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist. We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16-43 years at mtDNA CN assay) and 1338 UKBS females (17-69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children and UKBS males.

Results: A neutrophil-associated locus approached genome-wide significance (rs709591 [MED24], β (change in SD units of mtDNA CN per allele) [SE] - 0.084 [0.016], p = 1.54e-07) in the main meta-analysis of adult females. This association was concordant in magnitude and direction in UKBS males and ALSPAC neonates. SNPs in and around ABHD8 were associated with mtDNA CN in ALSPAC neonates (rs10424198, β [SE] 0.262 [0.034], p = 1.40e-14), but not other study groups. In a meta-analysis of unrelated individuals (N = 11,253), we replicated a published association in TFAM (β [SE] 0.046 [0.017], p = 0.006), with an effect size much smaller than that observed in the replication analysis of a previous in silico GWAS.

Conclusions: In a hypothesis-generating GWAS, we confirm an association between TFAM and mtDNA CN and present putative loci requiring replication in much larger samples. We discuss the limitations of our work, in terms of measurement error and cellular heterogeneity, and highlight the need for larger studies to better understand nuclear genomic control of mtDNA copy number.
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http://dx.doi.org/10.1186/s40246-018-0190-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357493PMC
January 2019

NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.

Brain 2019 01;142(1):50-58

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA USA.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.
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http://dx.doi.org/10.1093/brain/awy310DOI Listing
January 2019

Exposure of Monocytic Cells to Lipopolysaccharide Induces Coordinated Endotoxin Tolerance, Mitochondrial Biogenesis, Mitophagy, and Antioxidant Defenses.

Front Immunol 2018 27;9:2217. Epub 2018 Sep 27.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

In order to limit the adverse effects of excessive inflammation, anti-inflammatory responses are stimulated at an early stage of an infection, but during sepsis these can lead to deactivation of immune cells including monocytes. In addition, there is emerging evidence that the up-regulation of mitochondrial quality control mechanisms, including mitochondrial biogenesis and mitophagy, is important during the recovery from sepsis and inflammation. We aimed to describe the relationship between the compensatory immune and mitochondrial responses that are triggered following exposure to an inflammatory stimulus in human monocytic cells. Incubation with lipopolysaccharide resulted in a change in the immune phenotype of THP-1 cells consistent with the induction of endotoxin tolerance, similar to that seen in deactivated septic monocytes. After exposure to LPS there was also early evidence of oxidative stress, which resolved in association with the induction of antioxidant defenses and the stimulation of mitochondrial degradation through mitophagy. This was compensated by a parallel up-regulation of mitochondrial biogenesis that resulted in an overall increase in mitochondrial respiratory activity. These observations improve our understanding of the normal homeostatic responses that limit the adverse cellular effects of unregulated inflammation, and which may become ineffective when an infection causes sepsis.
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http://dx.doi.org/10.3389/fimmu.2018.02217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170658PMC
October 2019

Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy.

Hum Mol Genet 2019 01;28(2):258-268

Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

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-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 sequencing, we identified a c.1738C>T (p.Arg580Trp) AARS2 variant shared by both patients that was in trans with a loss-of-function heterozygous AARS2 variant; a c.1008dupT (p.Asp337*) nonsense variant or an intragenic deletion encompassing AARS2 exons 5-7. Interestingly, our patients did not harbour the p.Arg592Trp AARS2 founder mutation. In silico modelling of the p.Arg580Trp substitution suggested a deleterious impact on protein stability and folding. We confirmed markedly decreased mt-AlaRS protein levels in patient fibroblasts, skeletal and cardiac muscle, although mitochondrial protein synthesis defects were confined to skeletal and cardiac muscle. In vitro data showed that the p.Arg580Trp variant had a minimal effect on activation, aminoacylation or misaminoacylation activities relative to wild-type mt-AlaRS, demonstrating that instability of mt-AlaRS is the biological mechanism underlying the fatal cardiomyopathy phenotype in our patients.
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http://dx.doi.org/10.1093/hmg/ddy294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321959PMC
January 2019

Cell-free mitochondrial DNA in progressive multiple sclerosis.

Mitochondrion 2019 05 8;46:307-312. Epub 2018 Aug 8.

Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; The Wellcome Centre for Mitochondrial Research, Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. Electronic address:

Recent studies have linked cell-free mitochondrial DNA (ccf-mtDNA) to neurodegeneration in both Alzheimer's and Parkinson's disease, raising the possibility that the same phenomenon could be seen in other diseases which manifest a neurodegenerative component. Here, we assessed the role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in end-stage progressive multiple sclerosis (PMS), where neurodegeneration is evident, contrasting both ventricular cerebral spinal fluid ccf-mtDNA abundance and integrity between PMS cases and controls, and correlating ccf-mtDNA levels to known protein markers of neurodegeneration and PMS. Our data indicate that reduced ccf-mtDNA is a component of PMS, concluding that it may indeed be a hallmark of broader neurodegeneration.
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http://dx.doi.org/10.1016/j.mito.2018.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509276PMC
May 2019

Clonal expansion of mtDNA deletions: different disease models assessed by digital droplet PCR in single muscle cells.

Sci Rep 2018 08 3;8(1):11682. Epub 2018 Aug 3.

Unit of Neurology Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.

Deletions in mitochondrial DNA (mtDNA) are an important cause of human disease and their accumulation has been implicated in the ageing process. As mtDNA is a high copy number genome, the coexistence of deleted and wild-type mtDNA molecules within a single cell defines heteroplasmy. When deleted mtDNA molecules, driven by intracellular clonal expansion, reach a sufficiently high level, a biochemical defect emerges, contributing to the appearance and progression of clinical pathology. Consequently, it is relevant to determine the heteroplasmy levels within individual cells to understand the mechanism of clonal expansion. Heteroplasmy is reflected in a mosaic distribution of cytochrome c oxidase (COX)-deficient muscle fibers. We applied droplet digital PCR (ddPCR) to single muscle fibers collected by laser-capture microdissection (LCM) from muscle biopsies of patients with different paradigms of mitochondrial disease, characterized by the accumulation of single or multiple mtDNA deletions. By combining these two sensitive approaches, ddPCR and LCM, we document different models of clonal expansion in patients with single and multiple mtDNA deletions, implicating different mechanisms and time points for the development of COX deficiency in these molecularly distinct mitochondrial cytopathies.
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http://dx.doi.org/10.1038/s41598-018-30143-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076247PMC
August 2018

Author Correction: Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos.

Nat Cell Biol 2018 08;20(8):991

MRC-Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.

In the version of this Letter originally published, an author error led to the affiliations for Brendan Payne, Jonathan Coxhead and Gavin Hudson being incorrect. The correct affiliations are: Brendan Payne: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK; this is a new affiliation 6 and subsequent existing affiliations have been renumbered. Jonathan Coxhead: Genomic Core Facility, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; this is a new affiliation 11 and subsequent existing affiliations have been renumbered. Gavin Hudson: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. In addition, in Fig. 2d, the numbers on the x-axis of the left plot were incorrectly labelled as negative; they should have been positive. These errors have now been corrected in all online versions of the Letter.
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http://dx.doi.org/10.1038/s41556-018-0064-9DOI Listing
August 2018

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.

Hum Mol Genet 2018 05;27(10):1743-1753

Wellcome Centre for Mitochondrial Research, Institute for Cell and Molecular Biosciences, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T > C predicting p.(Tyr565His) and c.2197G > A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense [p.(Glu733Lys)] variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild-type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues.
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http://dx.doi.org/10.1093/hmg/ddy080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932559PMC
May 2018

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

Genet Med 2018 10 8;20(10):1224-1235. Epub 2018 Mar 8.

Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Purpose: To understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.

Methods: We identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.

Results: The patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.

Conclusion: Mitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.
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http://dx.doi.org/10.1038/gim.2017.251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004311PMC
October 2018

A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies.

Hum Mol Genet 2018 04;27(7):1186-1195

Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

Mitochondrial dynamics play an important role in cellular homeostasis and a variety of human diseases are linked to its dysregulated function. Here, we describe a 15-year-old boy with a novel disease caused by altered mitochondrial dynamics. The patient was the second child of consanguineous Jewish parents. He developed progressive muscle weakness and exercise intolerance at 6 years of age. His muscle biopsy revealed mitochondrial myopathy with numerous ragged red and cytochrome c oxidase (COX) negative fibers and combined respiratory chain complex I and IV deficiency. MtDNA copy number was elevated and no deletions of the mtDNA were detected in muscle DNA. Whole exome sequencing identified a homozygous nonsense mutation (p.Q92*) in the MIEF2 gene encoding the mitochondrial dynamics protein of 49 kDa (MID49). Immunoblotting revealed increased levels of proteins promoting mitochondrial fusion (MFN2, OPA1) and decreased levels of the fission protein DRP1. Fibroblasts of the patient showed elongated mitochondria, and significantly higher frequency of fusion events, mtDNA abundance and aberrant mitochondrial cristae ultrastructure, compared with controls. Thus, our data suggest that mutations in MIEF2 result in imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy.
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http://dx.doi.org/10.1093/hmg/ddy033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159537PMC
April 2018

Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos.

Nat Cell Biol 2018 02 15;20(2):144-151. Epub 2018 Jan 15.

MRC-Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.

Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
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http://dx.doi.org/10.1038/s41556-017-0017-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551220PMC
February 2018

Opening One's Eyes to Mosaicism in Progressive External Ophthalmoplegia.

Neurol Genet 2017 Dec 15;3(6):e202. Epub 2017 Dec 15.

Wellcome Centre for Mitochondrial Research (E.W.S., R.L.J., S.A.H., E.L.B., A.M.S., D.M.T., G.S.G., R.W.T.), Institute of Neuroscience, The Medical School, Newcastle University, United Kingdom; Department of Molecular and Human Genetics (E.W.S.), Baylor College of Medicine, Houston, TX; NHS Highly Specialised Mitochondrial Diagnostic Laboratory (R.L.J., S.A.H., E.L.B., R.W.T.), Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom; Wellcome Centre for Mitochondrial Research (A.P.), Institute of Genetic Medicine, Newcastle University, United Kingdom; and Department of Clinical Neurosciences (P.F.C.), School of Clinical Medicine, and MRC Mitochondrial Biology Unit (P.F.C.), University of Cambridge, United Kingdom.

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http://dx.doi.org/10.1212/NXG.0000000000000202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732003PMC
December 2017

Mitochondrial DNA changes in pedunculopontine cholinergic neurons in Parkinson disease.

Ann Neurol 2017 Dec 4;82(6):1016-1021. Epub 2017 Dec 4.

Division of Brain Sciences, Faculty of Medicine, Hammersmith Hospital Campus, Imperial College London, London, United Kingdom.

In Parkinson disease (PD), mitochondrial dysfunction associates with nigral dopaminergic neuronal loss. Cholinergic neuronal loss co-occurs, particularly within a brainstem structure, the pedunculopontine nucleus (PPN). We isolated single cholinergic neurons from postmortem PPNs of aged controls and PD patients. Mitochondrial DNA (mtDNA) copy number and mtDNA deletions were increased significantly in PD patients compared to controls. Furthermore, compared to controls the PD patients had significantly more PPN cholinergic neurons containing mtDNA deletion levels exceeding 60%, a level associated with deleterious effects on oxidative phosphorylation. The current results differ from studies reporting mtDNA depletion in nigral dopaminergic neurons of PD patients. Ann Neurol 2017;82:1016-1021.
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http://dx.doi.org/10.1002/ana.25099DOI Listing
December 2017

De novo variant is associated with decreased mitochondrial respiratory chain activities.

Neurol Genet 2017 Oct 22;3(5):e187. Epub 2017 Sep 22.

Wellcome Centre for Mitochondrial Research (E.W.S., C.L.A., L.H., G.F., R.M., R.W.T.), Institute of Neuroscience, Newcastle University, United Kingdom; Department of Molecular and Human Genetics (E.W.S.), Baylor College of Medicine, Houston, TX; Wellcome Centre for Mitochondrial Research (A.P.), Institute of Genetic Medicine, Newcastle University; Armistead Child Development Centre (K.N.), Kings Cross Hospital, Dundee, Scotland; Department of Clinical Neurosciences (P.F.C.), School of Clinical Medicine, University of Cambridge; and MRC Mitochondrial Biology Unit (P.F.C.), University of Cambridge, United Kingdom.

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 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) variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued re-evaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.
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http://dx.doi.org/10.1212/NXG.0000000000000187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610040PMC
October 2017

Mitochondrial DNA depletion induces innate immune dysfunction rescued by IFN-γ.

J Allergy Clin Immunol 2017 11 17;140(5):1461-1464.e8. Epub 2017 Jun 17.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Medical Research Council Mitochondrial Biology Unit, Cambridge Biomedical Campus, Cambridge, United Kingdom; Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.04.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667580PMC
November 2017

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

Brain 2017 06;140(6):1561-1578

Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.
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http://dx.doi.org/10.1093/brain/awx095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402316PMC
June 2017

metabolic profiling of Parkinson's disease and mild cognitive impairment.

Mov Disord 2017 06 10;32(6):927-932. Epub 2017 Apr 10.

Mitochondrial Research Group, Newcastle University, Newcastle Upon Tyne, UK.

Background: Early diagnosis of Parkinson's disease and mild cognitive impairment is important to enable prompt treatment and improve patient welfare, yet no standard diagnostic test is available. Metabolomics is a powerful tool used to elucidate disease mechanisms and identify potential biomarkers.

Objectives: The objective of this study was to use metabolic profiling to understand the pathoetiology of Parkinson's disease and to identify potential disease biomarkers.

Methods: This study compared the serological metabolomic profiles of early-stage Parkinson's patients (diagnosed < 12 months) to asymptomatic matched controls using an established array based detection system (DiscoveryHD4™, Metabolon, UK), correlating metabolite levels to clinical measurements of cognitive impairment.

Results: A total of 1434 serological metabolites were assessed in early-stage Parkinson's disease cases (n = 41) and asymptomatic matched controls (n = 40). Post-quality control, statistical analysis identified n = 20 metabolites, predominantly metabolites of the fatty acid oxidation pathway, associated with Parkinson's disease and mild cognitive impairment. Receiver operator curve assessment confirmed that the nine fatty acid oxidation metabolites had good predictive accuracy (area under curve = 0.857) for early-stage Parkinson's disease and mild cognitive impairment (area under curve = 0.759).

Conclusions: Our study indicates that fatty acid oxidation may be an important component in the pathophysiology of Parkinson's disease and may have potential as a diagnostic biomarker for disease onset and mild cognitive impairment. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.26992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485028PMC
June 2017

Genetic heterogeneity of motor neuropathies.

Neurology 2017 Mar 1;88(13):1226-1234. Epub 2017 Mar 1.

From the MRC Centre for Neuromuscular Diseases and John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine (B.B., H.G., T.E., J.D., A.B., V.B., H.S., E.F., A.P., H.L., P.F.C., R.H.), and Institute of Neuroscience (R.G.W., J.M.), Newcastle University, Newcastle upon Tyne; Bristol Genetics Laboratory (T.A., M.G., N.F.), Pathology Sciences, North Bristol NHS Trust, Southmead Hospital; Medical Genetic Center (S.K.), Munich, Germany; Department of Paediatric Neurology (V.R.), Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust; Nuffield Department of Clinical Neurosciences (E.F.), University of Oxford; and Department of Clinical Neurosciences (P.F.C.), Cambridge Biomedical Campus, University of Cambridge, UK.

Objective: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.

Methods: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).

Results: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy.

Conclusions: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.
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http://dx.doi.org/10.1212/WNL.0000000000003772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373778PMC
March 2017