title: Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.
abstract: Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs. Some limited pyramidal involvement also occurs in patients with an autosomal recessive neurocutaneous syndrome due to ALDH18A1 mutations. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), an enzyme that catalyses the first and common step of proline and ornithine biosynthesis from glutamate. Through exome sequencing and candidate gene screening, we report two families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality. More interestingly, we also identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency. Glutamine loading tests in two fibroblast cultures from two related affected subjects confirmed a metabolic block at the level of P5CS in vivo. Besides expanding the clinical spectrum of ALDH18A1-related pathology, we describe mutations segregating in an autosomal dominant pattern. The latter are associated with a potential trait biomarker; we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes.
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 5 Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, B-1200, Brussels, Belgium 6 Ecole Pratique des Hautes Etudes, F-75014, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Coutelier
authors.affiliation: 7 Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, EA4576, F-33000, Bordeaux, France 8 CHU Pellegrin, Service de Génétique Médicale, F-33000, Bordeaux, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: 10 Metabolic Biochemistry Lab, Necker-Enfants Malades Hospital, APHP, F-75015; and University Paris Descartes, F-75006, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Habarou
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 6 Ecole Pratique des Hautes Etudes, F-75014, Paris, France 11 UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, P-4150, Porto, Portugal 12 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, P-4150, Porto, Portugal 13 Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, P-4150, Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Morais
authors.affiliation: 14 Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.affiliation: 15 Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Feifei
authors.initials: F
authors.lastname: Tao
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 6 Ecole Pratique des Hautes Etudes, F-75014, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Konop
authors.affiliation: 16 Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2138, Sydney, Australia.
authors.forename: Marion
authors.initials: M
authors.lastname: Stoll
authors.affiliation: 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Jacoupy
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Matusiak
authors.affiliation: 11 UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, P-4150, Porto, Portugal 12 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, P-4150, Porto, Portugal 13 Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, P-4150, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Alonso
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Tallaksen
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 6 Ecole Pratique des Hautes Etudes, F-75014, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Mairey
authors.affiliation: 16 Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2138, Sydney, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Kennerson
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 6 Ecole Pratique des Hautes Etudes, F-75014, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gaussen
authors.affiliation: 15 Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA 17 Centre for Neurology and Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, G-72074, Tübingen, Germany 18 German Centre of Neurodegenerative Diseases (DZNE), Eberhard-Karls-University, G-72074, Tübingen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schule
authors.affiliation: 10 Metabolic Biochemistry Lab, Necker-Enfants Malades Hospital, APHP, F-75015; and University Paris Descartes, F-75006, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Janin
authors.affiliation: 7 Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, EA4576, F-33000, Bordeaux, France 8 CHU Pellegrin, Service de Génétique Médicale, F-33000, Bordeaux, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Morice-Picard
authors.affiliation: 7 Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, EA4576, F-33000, Bordeaux, France.
authors.forename: Christelle M
authors.initials: CM
authors.lastname: Durand
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.affiliation: 19 Fédération de Neurologie et Service de Génétique Médicale, CHU de Toulouse, Hôpital Purpan, F-31059, Toulouse, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.affiliation: 11 UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, P-4150, Porto, Portugal 12 Instituto de Investigação e Inovação em Saúde, Universidade do Porto, P-4150, Porto, Portugal 20 Serviço de Neurologia, Centro Hospitalar de Entre o Douro e Vouga, P-4520-211, Santa Maria da Feira, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho
authors.affiliation: 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Saudubray
authors.affiliation: 14 Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada 21 Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Rouleau
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: 16 Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2138, Sydney, Australia.
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Darios
authors.affiliation: 11 UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, P-4150, Porto, Portugal 20 Serviço de Neurologia, Centro Hospitalar de Entre o Douro e Vouga, P-4520-211, Santa Maria da Feira, Portugal.
authors.forename: José L
authors.initials: JL
authors.lastname: Loureiro
authors.affiliation: 15 Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: 10 Metabolic Biochemistry Lab, Necker-Enfants Malades Hospital, APHP, F-75015; and University Paris Descartes, F-75006, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.affiliation: 1 INSERM, U 1127, F-75013, Paris, France 2 CNRS, UMR 7225, F-75013, Paris, France 3 Sorbonne Universités, UPMC Univ Paris 06, UMRS_1127, F-75013, Paris, France 4 Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France 6 Ecole Pratique des Hautes Etudes, F-75014, Paris, France 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France giovanni.stevanin@upmc.fr.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D001120:Arginine / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009952:Ornithine / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018698:Glutamic Acid; D001120:Arginine; D009952:Ornithine; C000596432:ALDH18A1 protein, human; D000444:Aldehyde Dehydrogenase
keywords: ALDH18A1; citrulline; delta-1-pyrroline-5-carboxylate synthase; hereditary spastic paraplegia; ornithine