SPG9 HSP: dominant and recessive inheritance

Both pure and complicated forms of HSP

 

Assoc Prof Marina Kennerson
Assoc Prof Marina Kennerson

The finding of both dominant and recessive inheritance patterns, and both pure and complicated forms of SPG9 HSP can easily lead to misdiagnosis. This multinational study included researchers from France, Canada, USA, Portugal and Germany, and from Australia, Marina Kennerson of the ANZAC Research Institute in Sydney.

 

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.

 

SOURCE: Brain. 2015 Aug;138(Pt 8):2191-205. doi: 10.1093/brain/awv143. Epub 2015 May 29. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. PMID: 26026163 [PubMed – in process]

 

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

 

Coutelier M1, Goizet C2, Durr A3, Habarou F4, Morais S5, Dionne-Laporte A6, Tao F7, Konop J8, Stoll M9, Charles P10, Jacoupy M11, Matusiak R11, Alonso I12,Tallaksen C11, Mairey M8, Kennerson M9, Gaussen M8, Schule R13, Janin M4, Morice-Picard F2, Durand CM14, Depienne C3, Calvas P15, Coutinho P16,Saudubray JM10, Rouleau G17, Brice A3, Nicholson G9, Darios F11, Loureiro JL18, Zuchner S7, Ottolenghi C4, Mochel F3, Stevanin G19.

  • 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 [email protected].

 

Your email address will not be published. Required fields are marked *