Reply: ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism.

Abstract

Sir, In their Letter to the Editor, Panza et al. (2015) share their results following our recent description of mutations in ALDH18A1 in autosomal dominant and recessive hereditary spastic paraplegia (HSP) (Coutelier et al. , 2015). In our report (Coutelier et al. , 2015), we used a combination of whole genome mapping, exome sequencing and candidate gene screening, to demonstrate multiple inheritance modes associated with mutations in ALDH18A1 in patients from seven families. Mutations segregating in the autosomal recessive mode had previously been shown to cause De Barsy syndrome (MIM#219150) (Baumgartner et al. , 2005). We extended the clinical spectrum to patients with primary HSP, without any cutaneous alterations. In addition, we described, for the first time, monoallelic ALDH18A1 mutations segregating in an autosomal dominant way in HSP patients with low levels of plasma ornithine, citrulline, arginine and proline as biological trait biomarkers; this suggests that the pathway involving the enzyme encoded by ALDH18A1 (Δ1-pyrroline-5-carboxylate synthase, P5CS) is deficient. Furthermore, we showed that the enzymatic activity linked to one of the dominant mutations …