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

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.

Genetic diagnosis of Mendelian disorders via RNA sequencing

“…Our experimental evidence strongly suggests that the two observed variants are pathogenic. Finally, a recent report48 on ALDH18A1 patients extended the phenotypic spectrum to spastic paraplegia without cutis laxa (OMIM #138250). Spastic paraplegia resembles the symptoms of our patient (Supplementary Note 1), which validates these ALDH18A1 mutations as disease-causing.…”

A novel heterozygous variant in ERLIN2 causes autosomal dominant pure hereditary spastic paraplegia

“…So far, only a few other HSP loci have been reported to be able to cause both AD and AR inheritance patterns: SPG7/SPG7 [27], SPG9/ALDH18A1 [28], SPG30/KIF1A [29], SPG58/KIF1C [30], SPG72/ REEP2 [31] and also SPG3A/ATL1 [32]. The possibility of different modes of inheritance obviously has implications for genetic counselling in these forms of HSP.…”

Amino acid synthesis deficiencies

“…In adults with the dominant spastic paraplegia, an important reduction in plasma citrulline was seen in all (4/4) individuals tested, and this reduction could potentially serve as a diagnostic marker for P5CS-related spastic paraplegia (Coutelier et al 2015). …”

“…Adult spastic paraparesis phenotype Coutelier et al (2015)reportedALDH18A1 mutations in adults with spastic paraparesis. Autosomal recessive mutations were associated with a complex spastic paraplegia combined with cognitive impairment.…”