2. Academic Validation
  3. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia

Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia

  • Brain. 2015 Aug;138(Pt 8):2191-205. doi: 10.1093/brain/awv143.
Marie Coutelier 1,  Cyril Goizet 2,  Alexandra Durr 3,  Florence Habarou 4,  Sara Morais 5,  Alexandre Dionne-Laporte 6,  Feifei Tao 7,  Juliette Konop 8,  Marion Stoll 9,  Perrine Charles 10,  Maxime Jacoupy 11,  Raphaël Matusiak 11,  Isabel Alonso 12,  Chantal Tallaksen 11,  Mathilde Mairey 8,  Marina Kennerson 9,  Marion Gaussen 8,  Rebecca Schule 13,  Maxime Janin 4,  Fanny Morice-Picard 2,  Christelle M Durand 14,  Christel Depienne 3,  Patrick Calvas 15,  Paula Coutinho 16,  Jean-Marie Saudubray 10,  Guy Rouleau 17,  Alexis Brice 3,  Garth Nicholson 9,  Frédéric Darios 11,  José L Loureiro 18,  Stephan Zuchner 7,  Chris Ottolenghi 4,  Fanny Mochel 3,  Giovanni Stevanin 19
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 10 Metabolic Biochemistry Lab, Necker-Enfants Malades Hospital, APHP, F-75015; and University Paris Descartes, F-75006, Paris, France.
  • 5 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.
  • 6 14 Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada.
  • 7 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.
  • 8 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 16 Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2138, Sydney, Australia.
  • 10 9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
  • 11 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.
  • 12 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.
  • 13 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.
  • 14 7 Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, EA4576, F-33000, Bordeaux, France.
  • 15 19 Fédération de Neurologie et Service de Génétique Médicale, CHU de Toulouse, Hôpital Purpan, F-31059, Toulouse, France.
  • 16 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.
  • 17 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.
  • 18 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.
  • 19 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.
PMID: 26026163 DOI: 10.1093/brain/awv143
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.

Keywords

ALDH18A1; citrulline; delta-1-pyrroline-5-carboxylate synthase; hereditary spastic paraplegia; ornithine.

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