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GRN-Related Frontotemporal Dementia.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2007 Sep 7 [updated 2013 Mar 14].



The spectrum of frontotemporal dementia associated with GRN (also known as PGRN) mutation (FTD-GRN or FTD-PGRN) includes the behavioral variant (FTD-bv), primary progressive aphasia (PPA; further sub-categorized as progressive non-fluent aphasia [PNFA] and semantic dementia [SD]), and movement disorders with extrapyramidal features such as parkinsonism and corticobasal syndrome. A broad range of clinical features both within and across families is observed. The age of onset ranges from 35 to 87 years. Behavioral disturbances are the most common early feature, followed by progressive aphasia. Impairment in executive function manifests as loss of judgment and insight. In early stages, PPA often manifests as deficits in naming, word finding, or word comprehension. In late stages, affected individuals often become mute and lose their ability to communicate. Early findings of parkinsonism include rigidity, bradykinesia or akinesia (slowing or absence of movements), limb dystonia, apraxia (loss of ability to carry out learned purposeful movements), and disequilibrium. Late motor findings may include myoclonus, dysarthria, and dysphagia. Most affected individuals eventually lose the ability to walk. Disease duration is three to 12 years.


Diagnosis is based on clinical features, characteristic neuropathologic findings of TDP-43 inclusions, and molecular genetic testing of GRN, the only gene in which mutation is known to cause FTD-GRN.


Treatment of manifestations: Behavioral symptoms such as apathy, impulsivity, and compulsiveness may respond to selective serotonin reuptake inhibitors. Roaming, delusions, and hallucinations may respond to antipsychotic medications. Reports have suggested potential benefits with certain pharmacotherapy on management of FTD; however, evidence from randomized controlled trials is limited. Small-scale studies have suggested that trazodone may be helpful for treating irritability, agitation, depression, and eating disorders; methylphenidate and dextro-amphetamine may help minimize risk-taking behavior. Cholinesterase inhibitors examined in clinical trials were generally well-tolerated: galantamine was used to treat primary progressive aphasia with stabilization of symptoms; rivastigmine was used to treat behavior symptoms and appeared to decrease caregiver burden. Two open-label studies of memantine, an NMDA partial agonist-antagonist, demonstrated some efficacy on frontal behavior in those with FTD-bv and improvement in cognitive performance in those with PPA-PNFA. Therapies under investigation: Clinical trials are investigating efficacy of a variety of medications for treatment of FTD in general.


FTD-GRN is inherited in an autosomal dominant manner. About 95% of individuals diagnosed with FTD-GRN have an affected parent. The proportion of cases caused by de novo mutation is unknown but would be estimated at 5% or less. Each child of an individual with FTD-GRN has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in a family is known.

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