C5 Molecular Genetics of frontotemporal lobar neurodegeneration

Abstract

Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically and genetically highly complex disorder. Up to 50% of FTLD patients have a positive family history of dementia and in the majority of these families the disease is inherited as an autosomal dominant trait. Mutations have been identified in the microtubule associated protein tau ( MAPT, 17q21.1), the progranulin (PGRN, 17q21.31), and more rarely in the charged multivesicular body protein 2B ( CHMP2B, 3p11.2) and the valosin containing protein ( VCP, 9p13.3) genes. In VCP carriers the disease is associated with inclusion body myopathy, Paget disease of the bone, and frontotemporal lobar degeneration (FTLD), referred to as IBMPFD. FTLD patients are characterized by progressive deterioration in behavior, personality and language with initial relative preservation of memory. In addition, FTLD patients may develop movement abnormalities such as parkinsonism and motor neuron disease. At autopsy MAPT mutation carriers consistently show tau pathology. In contrast, mutations in PGRN, CHMP2B and VCP lead to FTD with ubiquitin-immunoreactive (ub-ir) inclusions (FTDU) with as main component the TAR-DNA-binding protein (TDP-43). Mutations were not identified in the TARDBP gene at 1p36 in FTLD patients but in amyotrophic lateral sclerosis (ALS) patients. The similar ub-ir pathology suggests that these genes may be connected trough a common disease pathway leading to neurodegeneration and the formation of these pathognomic inclusions. However, functional data has not yet been able to provide evidence for a direct biological between both.