1. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia
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Marie Coutelier, Alexandre Dionne-Laporte, Marion Stoll, Alexandra Durr, Perrine Charles, Isabel Alonso, Maxime Jacoupy, Marion Gaussen, Paula Coutinho, Fanny Mochel, Garth A. Nicholson, Fanny Morice-Picard, Stephan Züchner, Giovanni Stevanin, Juliette Konop, Rebecca Schüle, Chris Ottolenghi, Florence Habarou, José Leal Loureiro, Cyril Goizet, Raphaël Matusiak, Alexis Brice, Maxime Janin, S. Sara Morais, Christel Depienne, Guy A. Rouleau, Marina L. Kennerson, Frédéric Darios, Mathilde Mairey, Chantal M. E. Tallaksen, Jean-Marie Saudubray, Feifei Tao, Christelle M. Durand, Patrick Calvas, Université Catholique de Louvain = Catholic University of Louvain (UCL), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU de Bordeaux Pellegrin [Bordeaux], Université de Bordeaux (UB), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto, Instituto de Biologia Molecular e Celular - institute for molecular and cell biology [Porto, Portugal] (IBMC), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), University of Miami [Coral Gables], John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia, Instituto de Investigação e Inovação em Saúde (I3S), Eberhard Karls University, CHU Toulouse [Toulouse], Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro Hospitalar de Entre o Douro e Vouga, Hospital, McGill University, Centre d'infectiologie Necker-Pasteur [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], CARBILLET, Véronique, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade do Porto = University of Porto, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de biochimie métabolique [CHU Necker], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
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Male ,Ornithine ,Candidate gene ,Arginine ,medicine.disease_cause ,chemistry.chemical_compound ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Citrulline ,Exome sequencing ,Genetics ,0303 health sciences ,Mutation ,ALDH18A1 ,MESH: Middle Aged ,delta-1-pyrroline-5-carboxylate synthase ,genetics [Aldehyde Dehydrogenase] ,Middle Aged ,Phenotype ,3. Good health ,Pedigree ,delta1-pyrroline-5-carboxylate synthase, human ,MESH: Spastic Paraplegia, Hereditary / genetics ,MESH: Young Adult ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Female ,metabolism [Ornithine] ,Adult ,Adolescent ,Hereditary spastic paraplegia ,MESH: Pedigree ,metabolism [Arginine] ,Glutamic Acid ,MESH: Ornithine / genetics ,genetics [Mutation] ,MESH: Spastic Paraplegia, Hereditary / metabolism ,Biology ,MESH: Phenotype ,MESH: Aldehyde Dehydrogenase / genetics ,03 medical and health sciences ,Young Adult ,genetics [Spastic Paraplegia, Hereditary] ,MESH: Arginine / metabolism ,medicine ,Humans ,ddc:610 ,hereditary spastic paraplegia ,030304 developmental biology ,MESH: Adolescent ,genetics [Ornithine] ,MESH: Humans ,Spastic Paraplegia, Hereditary ,MESH: Mutation / genetics ,MESH: Glutamic Acid / metabolism ,metabolism [Glutamic Acid] ,MESH: Ornithine / metabolism ,MESH: Adult ,Original Articles ,Aldehyde Dehydrogenase ,medicine.disease ,MESH: Male ,chemistry ,metabolism [Spastic Paraplegia, Hereditary] ,citrulline ,ornithine ,Neurology (clinical) ,MESH: Female ,030217 neurology & neurosurgery - Abstract
International audience; 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.
- Published
- 2015
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