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

Marie Coutelier, Cyril Goizet, Alexandra Durr, Florence Habarou, Sara Morais, Alexandre Dionne-Laporte, Feifei Tao, Juliette Konop, Marion Stoll, Perrine Charles, Maxime Jacoupy, Raphaël Matusiak, Isabel Alonso, Chantal Tallaksen, Mathilde Mairey, Marina Kennerson, Marion Gaussen, Rebecca Schule, Maxime Janin, Fanny Morice-PicardChristelle M. Durand, Christel Depienne, Patrick Calvas, Paula Coutinho, Jean Marie Saudubray, Guy Rouleau, Alexis Brice, Garth Nicholson, Frédéric Darios, José L. Loureiro, Stephan L Zuchner, Chris Ottolenghi, Fanny Mochel, Giovanni Stevanin

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2191-2205
Number of pages15
JournalBrain
Volume138
Issue number8
DOIs
StatePublished - Aug 1 2015

Fingerprint

Hereditary Spastic Paraplegia
Ornithine
Ornithine-Oxo-Acid Transaminase
Mutation
Proline
Skin Abnormalities
Neurocutaneous Syndromes
Exome
Citrulline
Nervous System Diseases
Glutamine
Genes
Arginine
Chromatography
Glutamic Acid
Lower Extremity
Fibroblasts
Biomarkers
Pathology
Phenotype

Keywords

  • ALDH18A1
  • citrulline
  • delta-1-pyrroline-5-carboxylate synthase
  • hereditary spastic paraplegia
  • ornithine

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Coutelier, M., Goizet, C., Durr, A., Habarou, F., Morais, S., Dionne-Laporte, A., ... Stevanin, G. (2015). Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain, 138(8), 2191-2205. https://doi.org/10.1093/brain/awv143

Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. / Coutelier, Marie; Goizet, Cyril; Durr, Alexandra; Habarou, Florence; Morais, Sara; Dionne-Laporte, Alexandre; Tao, Feifei; Konop, Juliette; Stoll, Marion; Charles, Perrine; Jacoupy, Maxime; Matusiak, Raphaël; Alonso, Isabel; Tallaksen, Chantal; Mairey, Mathilde; Kennerson, Marina; Gaussen, Marion; Schule, Rebecca; Janin, Maxime; Morice-Picard, Fanny; Durand, Christelle M.; Depienne, Christel; Calvas, Patrick; Coutinho, Paula; Saudubray, Jean Marie; Rouleau, Guy; Brice, Alexis; Nicholson, Garth; Darios, Frédéric; Loureiro, José L.; Zuchner, Stephan L; Ottolenghi, Chris; Mochel, Fanny; Stevanin, Giovanni.

In: Brain, Vol. 138, No. 8, 01.08.2015, p. 2191-2205.

Research output: Contribution to journalArticle

Coutelier, M, Goizet, C, Durr, A, Habarou, F, Morais, S, Dionne-Laporte, A, Tao, F, Konop, J, Stoll, M, Charles, P, Jacoupy, M, Matusiak, R, Alonso, I, Tallaksen, C, Mairey, M, Kennerson, M, Gaussen, M, Schule, R, Janin, M, Morice-Picard, F, Durand, CM, Depienne, C, Calvas, P, Coutinho, P, Saudubray, JM, Rouleau, G, Brice, A, Nicholson, G, Darios, F, Loureiro, JL, Zuchner, SL, Ottolenghi, C, Mochel, F & Stevanin, G 2015, 'Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia', Brain, vol. 138, no. 8, pp. 2191-2205. https://doi.org/10.1093/brain/awv143
Coutelier M, Goizet C, Durr A, Habarou F, Morais S, Dionne-Laporte A et al. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain. 2015 Aug 1;138(8):2191-2205. https://doi.org/10.1093/brain/awv143
Coutelier, Marie ; Goizet, Cyril ; Durr, Alexandra ; Habarou, Florence ; Morais, Sara ; Dionne-Laporte, Alexandre ; Tao, Feifei ; Konop, Juliette ; Stoll, Marion ; Charles, Perrine ; Jacoupy, Maxime ; Matusiak, Raphaël ; Alonso, Isabel ; Tallaksen, Chantal ; Mairey, Mathilde ; Kennerson, Marina ; Gaussen, Marion ; Schule, Rebecca ; Janin, Maxime ; Morice-Picard, Fanny ; Durand, Christelle M. ; Depienne, Christel ; Calvas, Patrick ; Coutinho, Paula ; Saudubray, Jean Marie ; Rouleau, Guy ; Brice, Alexis ; Nicholson, Garth ; Darios, Frédéric ; Loureiro, José L. ; Zuchner, Stephan L ; Ottolenghi, Chris ; Mochel, Fanny ; Stevanin, Giovanni. / Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. In: Brain. 2015 ; Vol. 138, No. 8. pp. 2191-2205.
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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.",
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AU - Nicholson, Garth

AU - Darios, Frédéric

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