Brown-Vialetto-Van Laere syndrome (BVVLS) represents a phenotypic spectrum of motor, sensory, and... more Brown-Vialetto-Van Laere syndrome (BVVLS) represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter (RFVT) genes, SLC52A2 and SLC52A3, have recently been linked to BVVLS. However, the genetic frequency, neuropathology and downstream consequences of RFVT mutations have previously been undefined. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between RFVT mutations and BVVLS, identifying twenty-two pathogenic mutations in SLC52A2 and SLC52A3, fourteen of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nu...
Coenzyme Q10 (CoQ10) is essential for mitochondrial aerobic production of ATP via oxidative phosp... more Coenzyme Q10 (CoQ10) is essential for mitochondrial aerobic production of ATP via oxidative phosphorylation, but has had little study in horses. Its biologically active form is ubiquinol. We evaluated the effects of daily supplementation with ubiquinol on gluteal muscle CoQ10 concentrations and an indicator of phosphorylation status, citrate synthase (CS), in fit Thoroughbreds. Six horses received either 1 g ubiquinol daily for 3 weeks followed by 21 days without supplement, or had a 3 week unsupplemented period followed by 3 weeks of supplementation. A seventh horse received the same diet as the other horses, but no supplement, and served as a negative control. Middle gluteal muscle biopsies were obtained before feeding at day 0 (baseline), and after 10 and 21 days of each period. Muscle CoQ10 concentration was determined by HPLC with UV detection at 275 nm. CS was measured spectrophotometrically at 37 °C and related to mitochondrial CoQ10 concentration. Results (mean ± standard de...
Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a ... more Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, c...
Journal of pediatric gastroenterology and nutrition, Dec 30, 2016
Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome... more Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an important cause of acute liver failure (ALF) in infancy. Early and accurate diagnosis is important since liver transplantation (LT) is often contraindicated. It is unclear which methods are the best to diagnose MLD in the setting of ALF. To determine the incidence of MLD in children under two with ALF and the utility of routine investigations to detect MLD. Thirty-nine consecutive infants with ALF were admitted to a single unit from 2009-11. All were extensively investigated using an established protocol. Genes implicated in MDS were sequenced in all cases and tissue mtDNA copy number measured where available. Five infants (17%) had genetically proven MLD: DGUOK (n = 2), POLG (n = 2) and MPV17 (1). Four of these died whilst one recovered. Two had normal muscle mtDNA copy number and 3 had normal muscle respiratory chain enzymes. An additional 8 children had low hepatic mtDNA ...
Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysio... more Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysiological mechanisms are poorly understood. We present a child of Pakistani consanguineous parents, diagnosed with late-onset PA at 18months of age. He presented a mild phenotype, showed no severe further decompensations, normal growth and psychomotor development on a low protein diet and carnitine supplementation. At 15years, a mildly dilated left ventricle was noticed. At 17years he presented after a 2-3month history of lethargy and weight loss with severe decompensated dilated cardiomyopathy. He was stabilised on inotropic support and continuous haemofiltration; a Berlin Heart biventricular assist device was implanted. He received d,l-hydroxybutyrate 200mg/kg/day, riboflavin and thiamine 200mg/day each and coenzyme Q10 (CoQ10). Myocardial biopsy showed endocardial fibrosis, enlarged mitochondria, with atypical cristae and slightly low respiratory chain (RC) complex IV activity relative ...
Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a va... more Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a variety of disease mechanisms. Defects of mitochondrial protein synthesis account for the largest subgroup of disorders manifesting with impaired respiratory chain capacity; yet, only a few have been linked to dysfunction in the protein components of the mitochondrial ribosomes. Here, we report a subject presenting with dyskinetic cerebral palsy and partial agenesis of the corpus callosum, while histochemical and biochemical analyses of skeletal muscle revealed signs of mitochondrial myopathy. Using exome sequencing, we identified a homozygous variant c.215C>T in MRPS25, which encodes for a structural component of the 28S small subunit of the mitochondrial ribosome (mS25). The variant segregated with the disease and substitutes a highly conserved proline residue with leucine (p.P72L) that, based on the high-resolution structure of the 28S ribosome, is predicted to compromise inter-prote...
There is a growing interest in coenzyme Q10 (CoQ10) and its involvement in many aspects of daily ... more There is a growing interest in coenzyme Q10 (CoQ10) and its involvement in many aspects of daily living including physical and mental health, energy, aging, stress, skin care and exercise. This book aims to highlight our current understanding of CoQ10 in each of these areas by presenting a selection of topics that clearly illustrates its role in both health and disease. Each chapter provides a specialist’s insight into the subject whilst being written in a manner that is accessible to the non-CoQ10 expert. Is CoQ10 deficiency a contributor to heart disease, depression or migraines? Can taking CoQ10 supplements reduce symptoms of menopause, increase exercise tolerance or make our skin look younger? What is known about the genetics of CoQ10 biosynthesis? These are just some of the questions addressed in this book: which of them is fact and which is fiction?
Brown-Vialetto-Van Laere syndrome (BVVLS) represents a phenotypic spectrum of motor, sensory, and... more Brown-Vialetto-Van Laere syndrome (BVVLS) represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter (RFVT) genes, SLC52A2 and SLC52A3, have recently been linked to BVVLS. However, the genetic frequency, neuropathology and downstream consequences of RFVT mutations have previously been undefined. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between RFVT mutations and BVVLS, identifying twenty-two pathogenic mutations in SLC52A2 and SLC52A3, fourteen of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nu...
Coenzyme Q10 (CoQ10) is essential for mitochondrial aerobic production of ATP via oxidative phosp... more Coenzyme Q10 (CoQ10) is essential for mitochondrial aerobic production of ATP via oxidative phosphorylation, but has had little study in horses. Its biologically active form is ubiquinol. We evaluated the effects of daily supplementation with ubiquinol on gluteal muscle CoQ10 concentrations and an indicator of phosphorylation status, citrate synthase (CS), in fit Thoroughbreds. Six horses received either 1 g ubiquinol daily for 3 weeks followed by 21 days without supplement, or had a 3 week unsupplemented period followed by 3 weeks of supplementation. A seventh horse received the same diet as the other horses, but no supplement, and served as a negative control. Middle gluteal muscle biopsies were obtained before feeding at day 0 (baseline), and after 10 and 21 days of each period. Muscle CoQ10 concentration was determined by HPLC with UV detection at 275 nm. CS was measured spectrophotometrically at 37 °C and related to mitochondrial CoQ10 concentration. Results (mean ± standard de...
Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a ... more Friedreich’s ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, c...
Journal of pediatric gastroenterology and nutrition, Dec 30, 2016
Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome... more Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an important cause of acute liver failure (ALF) in infancy. Early and accurate diagnosis is important since liver transplantation (LT) is often contraindicated. It is unclear which methods are the best to diagnose MLD in the setting of ALF. To determine the incidence of MLD in children under two with ALF and the utility of routine investigations to detect MLD. Thirty-nine consecutive infants with ALF were admitted to a single unit from 2009-11. All were extensively investigated using an established protocol. Genes implicated in MDS were sequenced in all cases and tissue mtDNA copy number measured where available. Five infants (17%) had genetically proven MLD: DGUOK (n = 2), POLG (n = 2) and MPV17 (1). Four of these died whilst one recovered. Two had normal muscle mtDNA copy number and 3 had normal muscle respiratory chain enzymes. An additional 8 children had low hepatic mtDNA ...
Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysio... more Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysiological mechanisms are poorly understood. We present a child of Pakistani consanguineous parents, diagnosed with late-onset PA at 18months of age. He presented a mild phenotype, showed no severe further decompensations, normal growth and psychomotor development on a low protein diet and carnitine supplementation. At 15years, a mildly dilated left ventricle was noticed. At 17years he presented after a 2-3month history of lethargy and weight loss with severe decompensated dilated cardiomyopathy. He was stabilised on inotropic support and continuous haemofiltration; a Berlin Heart biventricular assist device was implanted. He received d,l-hydroxybutyrate 200mg/kg/day, riboflavin and thiamine 200mg/day each and coenzyme Q10 (CoQ10). Myocardial biopsy showed endocardial fibrosis, enlarged mitochondria, with atypical cristae and slightly low respiratory chain (RC) complex IV activity relative ...
Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a va... more Mitochondrial disorders are clinically and genetically heterogeneous and are associated with a variety of disease mechanisms. Defects of mitochondrial protein synthesis account for the largest subgroup of disorders manifesting with impaired respiratory chain capacity; yet, only a few have been linked to dysfunction in the protein components of the mitochondrial ribosomes. Here, we report a subject presenting with dyskinetic cerebral palsy and partial agenesis of the corpus callosum, while histochemical and biochemical analyses of skeletal muscle revealed signs of mitochondrial myopathy. Using exome sequencing, we identified a homozygous variant c.215C>T in MRPS25, which encodes for a structural component of the 28S small subunit of the mitochondrial ribosome (mS25). The variant segregated with the disease and substitutes a highly conserved proline residue with leucine (p.P72L) that, based on the high-resolution structure of the 28S ribosome, is predicted to compromise inter-prote...
There is a growing interest in coenzyme Q10 (CoQ10) and its involvement in many aspects of daily ... more There is a growing interest in coenzyme Q10 (CoQ10) and its involvement in many aspects of daily living including physical and mental health, energy, aging, stress, skin care and exercise. This book aims to highlight our current understanding of CoQ10 in each of these areas by presenting a selection of topics that clearly illustrates its role in both health and disease. Each chapter provides a specialist’s insight into the subject whilst being written in a manner that is accessible to the non-CoQ10 expert. Is CoQ10 deficiency a contributor to heart disease, depression or migraines? Can taking CoQ10 supplements reduce symptoms of menopause, increase exercise tolerance or make our skin look younger? What is known about the genetics of CoQ10 biosynthesis? These are just some of the questions addressed in this book: which of them is fact and which is fiction?
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