Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia
Marie Coutelier
(1, 2, 3)
,
Cyril Goizet
(4, 5)
,
Alexandra Durr
(3)
,
Florence Habarou
(6)
,
Sara Morais
(2, 7, 8, 3)
,
Alexandre Dionne-Laporte
(9)
,
Feifei Tao
(10, 11, 12)
,
Juliette Konop
(2, 3)
,
Marion Stoll
(13)
,
Perrine Charles
,
Maxime Jacoupy
(3)
,
Raphaël Matusiak
(3)
,
Isabel Alonso
(8, 14, 7)
,
Chantal Tallaksen
(3)
,
Mathilde Mairey
(2, 3)
,
Marina Kennerson
(13)
,
Marion Gaussen
(2, 3)
,
Rebecca Schule
(10, 11, 12, 15)
,
Maxime Janin
(6)
,
Fanny Morice-Picard
(4, 5)
,
Christelle Durand
(5)
,
Christel Depienne
(3)
,
Patrick Calvas
(16, 17)
,
Paula Coutinho
(8, 14, 18)
,
Jean-Marie Saudubray
,
Guy Rouleau
(9, 19)
,
Alexis Brice
(3)
,
Garth Nicholson
(13)
,
Frédéric Darios
(3)
,
José Loureiro
(8, 18)
,
Stephan Zuchner
(10, 11, 12)
,
Chris Ottolenghi
(6, 20)
,
Fanny Mochel
(3)
,
Giovanni Stevanin
(2, 3)
1
UCL -
Université Catholique de Louvain = Catholic University of Louvain
2 EPHE - École Pratique des Hautes Études
3 ICM - Institut du Cerveau = Paris Brain Institute
4 CHU de Bordeaux Pellegrin [Bordeaux]
5 UB - Université de Bordeaux
6 Hôpital Necker - Enfants Malades [AP-HP]
7 ICBAS - Instituto de Ciências Biomédicas de Abel Salazar
8 IBMC - Instituto de Biologia Molecular e Celular - institute for molecular and cell biology [Porto, Portugal]
9 Montreal Neurological Institute and Hospital
10 Department of Human Genetics - Dr. John T. Macdonald Foundation [Miami, FL, USA]
11 John P. Hussman Institute for Human Genomics
12 UMMSM - University of Miami Leonard M. Miller School of Medicine
13 Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
14 I3S - Instituto de Investigação e Inovação em Saúde
15 Eberhard Karls University
16 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
17 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
18 Centro Hospitalar de Entre o Douro e Vouga
19 Hospital, McGill University
20 Service de biochimie métabolique [CHU Necker]
2 EPHE - École Pratique des Hautes Études
3 ICM - Institut du Cerveau = Paris Brain Institute
4 CHU de Bordeaux Pellegrin [Bordeaux]
5 UB - Université de Bordeaux
6 Hôpital Necker - Enfants Malades [AP-HP]
7 ICBAS - Instituto de Ciências Biomédicas de Abel Salazar
8 IBMC - Instituto de Biologia Molecular e Celular - institute for molecular and cell biology [Porto, Portugal]
9 Montreal Neurological Institute and Hospital
10 Department of Human Genetics - Dr. John T. Macdonald Foundation [Miami, FL, USA]
11 John P. Hussman Institute for Human Genomics
12 UMMSM - University of Miami Leonard M. Miller School of Medicine
13 Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia
14 I3S - Instituto de Investigação e Inovação em Saúde
15 Eberhard Karls University
16 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
17 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde
18 Centro Hospitalar de Entre o Douro e Vouga
19 Hospital, McGill University
20 Service de biochimie métabolique [CHU Necker]
Cyril Goizet
- Fonction : Auteur
- PersonId : 925163
Alexandra Durr
- Fonction : Auteur
- PersonId : 758970
- ORCID : 0000-0002-8921-7104
- IdRef : 148675018
Perrine Charles
- Fonction : Auteur
Maxime Janin
- Fonction : Auteur
- PersonId : 775827
- IdRef : 189671920
Christelle Durand
- Fonction : Auteur
- PersonId : 772439
- ORCID : 0000-0002-3890-0632
Christel Depienne
- Fonction : Auteur
- PersonId : 757923
- ORCID : 0000-0002-7212-9554
- IdRef : 150923163
Patrick Calvas
- Fonction : Auteur
- PersonId : 853869
Jean-Marie Saudubray
- Fonction : Auteur
Guy Rouleau
- Fonction : Auteur
- PersonId : 764544
- ORCID : 0000-0001-8403-1418
Stephan Zuchner
- Fonction : Auteur
- PersonId : 806121
- ORCID : 0000-0002-8498-5235
Chris Ottolenghi
- Fonction : Auteur
- PersonId : 917454
- ORCID : 0000-0002-0734-344X
- IdRef : 069528403
Giovanni Stevanin
- Fonction : Auteur
- PersonId : 758031
- ORCID : 0000-0001-9368-8657
- IdRef : 119149982
Résumé
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.