engleski

ALS and FTLD: two faces of TDP-43 proteinopathy

Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD): Recently, TAR DNA-binding protein 43 (TDP-43) was identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. The majority of familial cases of FTLD-U are now known to have mutations in the granulin (GRN) gene. In the light of these important discoveries, we describe two kindreds with FTLD-U with GRN gene mutations: Hereditary Dysphasic Disinhibition Dementia Family 1 and 2 (HDDD1 and 2) characterized by changes in behavior and language deficits. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B (CHMP2B) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders including: FTLD-U, FTLD-U with ALS and ALS. For the practicing neurologist, knowledge of these recent discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, facilitate clinicopathological studies, and advance the quest for biomarkers and rational therapeutics.

frontotemporal lobar degeneration; TDP-43; ubiquitin; frontotemporal dementia; motor neuron disease; amyotrophic lateral sclerosis; granulin (GRN)

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