ArticleBrain : a journal of neurology2015
Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.
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Article in Brain : a journal of neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53citing papers in PubMed
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53 citing papers in PubMed, 103 citations in OpenAlex.
- Novel mutations in the ALDH18A1 gene in complicated hereditary spastic paraplegia with cerebellar ataxia and cognitive impairment.Journal of human genetics · 2018Trial
- Hereditary Congenital Cataract With Spastic Paraplegia Associated With a Missense PAX6 Variant (p.Arg26Trp).Cureus · 2026Article
- Genetic variants among patients with motor neuron disease in Lithuania - a retrospective single-center study.Neurogenetics · 2026Article
- Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics.Annals of clinical and translational neurology · 2026Article
- Missense variant in TTBK2 kinase domain causes loss of function and impaired protein phosphorylation.Scientific reports · 2025Article
- Novel missense ALDH18A1 variant in a family with autosomal dominant spastic paraplegia.Journal of neurology · 2025Article
- From Overgrowth to Complex Malformations: A NovelChildren (Basel, Switzerland) · 2025Article
- Biomarkers in Hereditary Spastic Paraplegias.International journal of molecular sciences · 2025Review
- Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants in a series of Italian patients, shedding light upon genetic and phenotypic variability.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Autosomal Dominant Spastic Paraplegia With Dysregulation of Bowel Function Associated With Heterozygous AP4S1 Gene Mutation: Case Report.Neurology. Genetics · 2024Article
- Article
- Multiomic analysis in fibroblasts of patients with inborn errors of cobalamin metabolism reveals concordance with clinical and metabolic variability.EBioMedicine · 2024Article
- Hereditary spastic paraplegia: Novel insights into the pathogenesis and management.SAGE open medicine · 2024Review
- Enhanced oxidative phosphorylation, re-organized intracellular signaling, and epigenetic de-silencing as revealed by oligodendrocyte translatome analysis after contusive spinal cord injury.Scientific reports · 2023Article
- Molecular Mimicry between Meningococcal B Factor H-Binding Protein and Human Proteins.Global medical genetics · 2023Article
- Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review.Genes · 2023Article
- Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism.Human molecular genetics · 2023Article
- The role and control of arginine levels in arginase 1 deficiency.Journal of inherited metabolic disease · 2023Review
- The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia.Frontiers in neurology · 2023Article
- Lipodystrophy-associated progeroid syndromes.Hormones (Athens, Greece) · 2022Review
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Authors and funding
34 authors at 18 institutions in 7 countries.
Marie Coutelier1 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.
Cyril Goizet7 Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, EA4576, F-33000, Bordeaux, France 8 CHU Pellegrin, Service de Génétique Médicale, F-33000, Bordeaux, France.
Alexandra Durr1 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.
Florence Habarou10 Metabolic Biochemistry Lab, Necker-Enfants Malades Hospital, APHP, F-75015; and University Paris Descartes, F-75006, Paris, France.
Sara Morais1 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.
Alexandre Dionne-Laporte14 Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada.
Feifei Tao15 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.
Juliette Konop1 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.
Marion Stoll16 Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2138, Sydney, Australia.
Perrine Charles9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
Maxime Jacoupy1 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.
Raphaël Matusiak1 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.
Isabel Alonso11 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.
Chantal Tallaksen1 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.
Mathilde Mairey1 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.
Marina Kennerson16 Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2138, Sydney, Australia.
Marion Gaussen1 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.
Rebecca Schule15 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.
Maxime Janin10 Metabolic Biochemistry Lab, Necker-Enfants Malades Hospital, APHP, F-75015; and University Paris Descartes, F-75006, Paris, France.
Fanny Morice-Picard7 Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, EA4576, F-33000, Bordeaux, France 8 CHU Pellegrin, Service de Génétique Médicale, F-33000, Bordeaux, France.
Christelle M Durand7 Univ. Bordeaux, Laboratoire Maladies Rares: Génétique et Métabolisme, EA4576, F-33000, Bordeaux, France.
Christel Depienne1 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.
Patrick Calvas19 Fédération de Neurologie et Service de Génétique Médicale, CHU de Toulouse, Hôpital Purpan, F-31059, Toulouse, France.
Paula Coutinho11 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.
Jean-Marie Saudubray9 APHP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, F-75013, Paris, France.
Guy Rouleau14 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.
Alexis Brice1 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.
Garth Nicholson16 Northcott Neuroscience Laboratory, ANZAC Research Institute; Molecular Medicine Laboratory, Concord Hospital; Sydney Medical School University of Sydney, NSW 2138, Sydney, Australia.
Frédéric Darios1 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.
José L Loureiro11 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.
Stephan Zuchner15 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.
Chris Ottolenghi10 Metabolic Biochemistry Lab, Necker-Enfants Malades Hospital, APHP, F-75015; and University Paris Descartes, F-75006, Paris, France.
Fanny Mochel1 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.
Giovanni Stevanin1 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.
Centre National de la Recherche Scientifique · FRInstitut du Cerveau · FRUniversité de Bordeaux · FRUniversité Paris Cité · FRUniversity of Miami · USAnzac Research Institute · AUÉcole Pratique des Hautes Études · FRHôpital Necker-Enfants Malades · FRInserm · FRMontreal Neurological Institute and Hospital · CASorbonne Université · FRAssistance Publique – Hôpitaux de Paris · FRCentro Hospitalar de Entre o Douro e Vouga E.P.E. · PTConcord Hospital · USHôpital Purpan · FRi3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto · PTPitié-Salpêtrière Hospital · FRUniversidade do Porto · PT
Funding
trainingU54NS065712 · NINDS · WAYNE STATE UNIVERSITY · PI SHY, MICHAEL E. · 2009 to 2023
$19.6MGENOME STUDIES IN HEREDITARY SPASTIC PARAPLEGIA - beyond the exomeR01NS072248 · NINDS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Stephan Zuchner · 2011 to 2026
$9.2MGenomic Studies in Charcot-Marie-Tooth DiseaseR01NS075764 · NINDS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI SHY, MICHAEL E., ZUCHNER, STEPHAN · 2012 to 2016
$3.0MNINDS NIH HHS 5R01NS072248NINDS NIH HHS R01NS075764NINDS NIH HHS U54NS065712
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.
Indexed as
AdolescentAdultAldehyde DehydrogenaseArginineFemaleGlutamic AcidHumansMaleMiddle AgedMutationOrnithinePedigreePhenotypeSpastic Paraplegia, HereditaryYoung AdultAldehyde DehydrogenaseALDH18A1 protein, humanArginineGlutamic AcidOrnithineALDH18A1citrullinedelta-1-pyrroline-5-carboxylate synthasehereditary spastic paraplegiaornithine
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