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Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia
- Source :
- Brain 138(8), 2191-2205 (2015). doi:10.1093/brain/awv143, Brain-A Journal of Neurology, Brain-A Journal of Neurology, Oxford University Press (OUP), 2015, 138 (8), pp.2191-2205. ⟨10.1093/brain/awv143⟩, Brain-A Journal of Neurology, 2015, 138 (8), pp.2191-2205. ⟨10.1093/brain/awv143⟩
- Publication Year :
- 2015
- Publisher :
- Oxford Univ. Press, 2015.
-
Abstract
- International audience; 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.
- Subjects :
- Male
Ornithine
Candidate gene
Arginine
medicine.disease_cause
chemistry.chemical_compound
0302 clinical medicine
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Citrulline
Exome sequencing
Genetics
0303 health sciences
Mutation
ALDH18A1
MESH: Middle Aged
delta-1-pyrroline-5-carboxylate synthase
genetics [Aldehyde Dehydrogenase]
Middle Aged
Phenotype
3. Good health
Pedigree
delta1-pyrroline-5-carboxylate synthase, human
MESH: Spastic Paraplegia, Hereditary / genetics
MESH: Young Adult
[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Female
metabolism [Ornithine]
Adult
Adolescent
Hereditary spastic paraplegia
MESH: Pedigree
metabolism [Arginine]
Glutamic Acid
MESH: Ornithine / genetics
genetics [Mutation]
MESH: Spastic Paraplegia, Hereditary / metabolism
Biology
MESH: Phenotype
MESH: Aldehyde Dehydrogenase / genetics
03 medical and health sciences
Young Adult
genetics [Spastic Paraplegia, Hereditary]
MESH: Arginine / metabolism
medicine
Humans
ddc:610
hereditary spastic paraplegia
030304 developmental biology
MESH: Adolescent
genetics [Ornithine]
MESH: Humans
Spastic Paraplegia, Hereditary
MESH: Mutation / genetics
MESH: Glutamic Acid / metabolism
metabolism [Glutamic Acid]
MESH: Ornithine / metabolism
MESH: Adult
Original Articles
Aldehyde Dehydrogenase
medicine.disease
MESH: Male
chemistry
metabolism [Spastic Paraplegia, Hereditary]
citrulline
ornithine
Neurology (clinical)
MESH: Female
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 00068950 and 14602156
- Database :
- OpenAIRE
- Journal :
- Brain 138(8), 2191-2205 (2015). doi:10.1093/brain/awv143, Brain-A Journal of Neurology, Brain-A Journal of Neurology, Oxford University Press (OUP), 2015, 138 (8), pp.2191-2205. ⟨10.1093/brain/awv143⟩, Brain-A Journal of Neurology, 2015, 138 (8), pp.2191-2205. ⟨10.1093/brain/awv143⟩
- Accession number :
- edsair.doi.dedup.....65824196cff904a241c2d95a0e9d0d03