Maria Del Mar Amador1, Benoit Colsch2, Foudil Lamari3,4, Claude Jardel3,4, Farid Ichou5, Agnès Rastetter6, Frédéric Sedel7, Fabien Jourdan8, Clément Frainay8, Ronald A Wevers9, Emmanuel Roze1,4,6, Christel Depienne10, Christophe Junot2, Fanny Mochel11,12,13,14. 1. Assistance Publique-Hôpitaux de Paris, Département de Neurologie, La Pitié-Salpêtrière University Hospital, Paris, France. 2. Service de Pharmacologie et Immuno-Analyse (SPI), Laboratoire d'Etude du Métabolisme des Médicaments, CEA, INRA, Université Paris Saclay, MetaboHUB, F-91191, Gif-sur-Yvette, France. 3. Assistance Publique-Hôpitaux de Paris, Laboratoire de Biochimie Métabolique, La Pitié-Salpêtrière University Hospital, Paris, France. 4. Université Pierre et Marie Curie, Groupe de Recherche Clinique Neurométabolique et Centre de Référence Neurométabolique Adulte, Paris, France. 5. Institute of Cardiometabolism And Nutrition, ICAN, Metabolomics Core Facility, Paris, France. 6. Sorbonne Universités, UPMC-Paris 6, UMR S 1127, and Inserm U 1127, and CNRS UMR 7225, and ICM, F-75013, Paris, France. 7. MedDay Pharmaceuticals, Paris, France. 8. Université de Toulouse, INRA, Université de Toulouse 3 Paul Sabatier, Toulouse, France. 9. Radboud University Medical Centre, Translational Metabolic Laboratory, Department Laboratory Medicine, Nijmegen, the Netherlands. 10. Hôpitaux Universitaires de Strasbourg, Unité de cytogénétique chromosomique et moléculaire, Strasbourg, France. 11. Université Pierre et Marie Curie, Groupe de Recherche Clinique Neurométabolique et Centre de Référence Neurométabolique Adulte, Paris, France. fanny.mochel@upmc.fr. 12. Sorbonne Universités, UPMC-Paris 6, UMR S 1127, and Inserm U 1127, and CNRS UMR 7225, and ICM, F-75013, Paris, France. fanny.mochel@upmc.fr. 13. Assistance Publique-Hôpitaux de Paris, Département de Génétique, La Pitié-Salpêtrière University Hospital, Paris, France. fanny.mochel@upmc.fr. 14. Reference Center for Neurometabolic Diseases, Department of Genetics, La Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France. fanny.mochel@upmc.fr.
Abstract
BACKGROUND: In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. METHODS AND RESULTS: First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. CONCLUSION: Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome.
BACKGROUND: In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. METHODS AND RESULTS: First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. CONCLUSION: Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome.
Authors: Maja Tarailo-Graovac; Casper Shyr; Colin J Ross; Gabriella A Horvath; Ramona Salvarinova; Xin C Ye; Lin-Hua Zhang; Amit P Bhavsar; Jessica J Y Lee; Britt I Drögemöller; Mena Abdelsayed; Majid Alfadhel; Linlea Armstrong; Matthias R Baumgartner; Patricie Burda; Mary B Connolly; Jessie Cameron; Michelle Demos; Tammie Dewan; Janis Dionne; A Mark Evans; Jan M Friedman; Ian Garber; Suzanne Lewis; Jiqiang Ling; Rupasri Mandal; Andre Mattman; Margaret McKinnon; Aspasia Michoulas; Daniel Metzger; Oluseye A Ogunbayo; Bojana Rakic; Jacob Rozmus; Peter Ruben; Bryan Sayson; Saikat Santra; Kirk R Schultz; Kathryn Selby; Paul Shekel; Sandra Sirrs; Cristina Skrypnyk; Andrea Superti-Furga; Stuart E Turvey; Margot I Van Allen; David Wishart; Jiang Wu; John Wu; Dimitrios Zafeiriou; Leo Kluijtmans; Ron A Wevers; Patrice Eydoux; Anna M Lehman; Hilary Vallance; Sylvia Stockler-Ipsiroglu; Graham Sinclair; Wyeth W Wasserman; Clara D van Karnebeek Journal: N Engl J Med Date: 2016-05-25 Impact factor: 91.245
Authors: Maria van der Ham; Berthil H C M T Prinsen; Jan G M Huijmans; Nicolaas G G M Abeling; Bert Dorland; Ruud Berger; Tom J de Koning; Monique G M de Sain-van der Velden Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2006-11-22 Impact factor: 3.205
Authors: Ines Thiele; Neil Swainston; Ronan M T Fleming; Andreas Hoppe; Swagatika Sahoo; Maike K Aurich; Hulda Haraldsdottir; Monica L Mo; Ottar Rolfsson; Miranda D Stobbe; Stefan G Thorleifsson; Rasmus Agren; Christian Bölling; Sergio Bordel; Arvind K Chavali; Paul Dobson; Warwick B Dunn; Lukas Endler; David Hala; Michael Hucka; Duncan Hull; Daniel Jameson; Neema Jamshidi; Jon J Jonsson; Nick Juty; Sarah Keating; Intawat Nookaew; Nicolas Le Novère; Naglis Malys; Alexander Mazein; Jason A Papin; Nathan D Price; Evgeni Selkov; Martin I Sigurdsson; Evangelos Simeonidis; Nikolaus Sonnenschein; Kieran Smallbone; Anatoly Sorokin; Johannes H G M van Beek; Dieter Weichart; Igor Goryanin; Jens Nielsen; Hans V Westerhoff; Douglas B Kell; Pedro Mendes; Bernhard Ø Palsson Journal: Nat Biotechnol Date: 2013-03-03 Impact factor: 54.908
Authors: F Mochel; F Sedel; A Vanderver; U F H Engelke; J Barritault; B Z Yang; B Kulkarni; D R Adams; F Clot; J H Ding; C R Kaneski; F W Verheijen; B W Smits; F Seguin; A Brice; M T Vanier; M Huizing; R Schiffmann; A Durr; R A Wevers Journal: Brain Date: 2009-01-19 Impact factor: 13.501
Authors: Pilar Quijada-Fraile; Mar O'Callaghan; Elena Martín-Hernández; Raquel Montero; Àngels Garcia-Cazorla; Ana Martínez de Aragón; Jordi Muchart; Ignacio Málaga; Rafael Pardo; Pedro García-Gonzalez; Cristina Jou; Julio Montoya; Sonia Emperador; Eduardo Ruiz-Pesini; Joaquín Arenas; Miguel Angel Martin; Aida Ormazabal; Mercè Pineda; María T García-Silva; Rafael Artuch Journal: Orphanet J Rare Dis Date: 2014-12-24 Impact factor: 4.123
Authors: Adam Amara; Clément Frainay; Fabien Jourdan; Thomas Naake; Steffen Neumann; Elva María Novoa-Del-Toro; Reza M Salek; Liesa Salzer; Sarah Scharfenberg; Michael Witting Journal: Front Mol Biosci Date: 2022-03-08