Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.
Brain. 2015-05-29; 138(8): 2191-2205
DOI: 10.1093/brain/awv143
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Coutelier M(1), Goizet C(2), Durr A(3), Habarou F(4), Morais S(5), Dionne-Laporte
A(6), Tao F(7), Konop J(8), Stoll M(9), Charles P(10), Jacoupy M(11), Matusiak
R(11), Alonso I(12), Tallaksen C(11), Mairey M(8), Kennerson M(9), Gaussen M(8),
Schule R(13), Janin M(4), Morice-Picard F(2), Durand CM(14), Depienne C(3),
Calvas P(15), Coutinho P(16), Saudubray JM(10), Rouleau G(17), Brice A(3),
Nicholson G(9), Darios F(11), Loureiro JL(18), Zuchner S(7), Ottolenghi C(4),
Mochel F(3), Stevanin G(19).
Author information:
(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
.
Comment in
Brain. 2016 Jan;139(Pt 1):e4.
Brain. 2016 Jan;139(Pt 1):e3.
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.
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