Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia

Christelle Tesson, Magdalena Nawara, Mustafa A M Salih, Rodrigue Rossignol, Maha S. Zaki, Mohammed Al Balwi, Rebecca Schule, Cyril Mignot, Emilie Obre, Ahmed Bouhouche, Filippo M. Santorelli, Christelle M. Durand, Andrés Caballero Oteyza, Khalid H. El-Hachimi, Abdulmajeed Al Drees, Naima Bouslam, Foudil Lamari, Salah A. Elmalik, Mohammad M. Kabiraj, Mohammed Z. SeidahmedTyphaine Esteves, Marion Gaussen, Marie Lorraine Monin, Gabor Gyapay, Doris Lechner, Michael Gonzalez, Christel Depienne, Fanny Mochel, Julie Lavie, Ludger Schols, Didier Lacombe, Mohamed Yahyaoui, Ibrahim Al Abdulkareem, Stephan Zuchner, Atsushi Yamashita, Ali Benomar, Cyril Goizet, Alexandra Durr, Joseph G. Gleeson, Frederic Darios, Alexis Brice, Giovanni Stevanin

Research output: Contribution to journalArticlepeer-review


Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function.

Original languageEnglish
Pages (from-to)1051-1064
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Dec 7 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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