Institut du Cerveau et de la Moelle Épinière (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM), U 1127, Paris, France2University Pierre and Marie Curie, UMR S975, F-75013, Paris, France3Centre National de la Recherche Scientifique.
Centre de Référence des Démences Rares, Hôpital de la Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris (AP-HP), Paris, France.
JAMA Neurol. 2014 Dec;71(12):1562-6. doi: 10.1001/jamaneurol.2014.1316.
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.
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.
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.
颗粒蛋白前体 (GRN) 基因的突变导致 20% 的额颞叶痴呆家族病例。GRN 基因突变导致颗粒蛋白的单倍体不足，而颗粒蛋白参与炎症、组织修复和癌症。GRN 突变的携带者表现为程度不同的不对称性脑萎缩，主要发生在额、颞和顶叶。我们描述了 4 名 GRN 突变携带者，他们具有显著的广泛的白质病变 (WML)，磁共振成像显示与脑叶萎缩相关。
从我们痴呆症中心随访的 31 名 GRN 突变携带者中选择了 4 名 GRN 突变携带者（发病年龄 56-65 岁），这些携带者具有严重的 WML。WML 主要位于额部和顶叶，且多为融合性的，影响脑室周围皮质下白质和 U 型纤维。在所有患者中，均排除了常见的血管、代谢、炎症、自身免疫和线粒体疾病，且均无严重的血管危险因素。
我们的数据表明，在一部分 GRN 突变携带者中，脑白质的受累可能与颗粒蛋白前体的病理过程有关。因此，对于磁共振成像显示不寻常的白质高信号和脑叶萎缩的额颞叶变性患者，应进行血浆颗粒蛋白前体检测（可预测 GRN 突变）和 GRN 测序。
