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Case Report/Case Series
December 2014

Extensive White Matter Involvement in Patients With Frontotemporal Lobar Degeneration: Think Progranulin

Author Affiliations
  • 1Institut du Cerveau et de la Moelle Épinière (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM), U 1127, Paris, France
  • 2University Pierre and Marie Curie, UMR S975, F-75013, Paris, France
  • 3Centre National de la Recherche Scientifique, UMR 7225, ICM, Paris, France
  • 4Institut du Cerveau et de la Moelle Épinière, Paris, France
  • 5Centre de Référence des Démences Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris (AP-HP), Paris, France
  • 6Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
  • 7Département de Neurophysiologie Clinique, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
  • 8Laboratoire de biochimie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
  • 9Service de Neuroradiologie Diagnostique et Fonctionnelle, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
  • 10Institut National de la Recherche en Informatique, Automatique et Mathématiques Appliquées, Centre Paris-Rocquencourt, Rocquencourt, France
  • 11Centre Mémoire de Ressource et de Recherche, Service de Neurologie, Centre Hospitalier Universitaire Pontchaillou, Rennes, France
  • 12Université de Caen/Basse-Normandie, École Pratique des Hautes Études, INSERM, Unité U1077, Groupement d’Intérêt Public, Cyceron, Caen, France
  • 13Service de Neurologie et Centres Mémoire de Ressources et de Recherche, Centre Hospitalier Universitaire, Rouen, France
  • 14Département de Génétique et Cytogénétique, Unité Fonctionnelle de Génétique Clinique, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France
JAMA Neurol. 2014;71(12):1562-1566. doi:10.1001/jamaneurol.2014.1316

Importance  Mutations in the progranulin (GRN) gene are responsible for 20% of familial cases of frontotemporal dementias. All cause haploinsufficiency of progranulin, a protein involved in inflammation, tissue repair, and cancer. Carriers of the GRN mutation are characterized by a variable degree of asymmetric brain atrophy, predominantly in the frontal, temporal, and parietal lobes. We describe 4 GRN mutation carriers with remarkable widespread white matter lesions (WML) associated with lobar atrophy shown on magnetic resonance imaging.

Observations  Four GRN mutation carriers (age at onset, 56-65 years) presenting with severe WML were selected from 31 GRN mutation carriers who were followed up in our dementia centers. The WML were predominantly in the frontal and parietal lobes and were mostly confluent, affecting the periventricular subcortical white matter and U-fibers. In all patients, common vascular, metabolic, inflammatory, dysimmune, and mitochondrial disorders were excluded and none had severe vascular risk factors.

Conclusions and Relevance  Our data suggest that white matter involvement may be linked to progranulin pathological processes in a subset of GRN mutation carriers. The plasma progranulin measurement, which is predictive of GRN mutations, and GRN sequencing should thus be included in investigations of patients with frontotemporal lobar degenerations who show unusual white matter hyperintensities and atrophy on magnetic resonance imaging.