Clinical characteristics: The spectrum of GRN frontotemporal dementia (GRN-FTD) includes the behavioral variant (bvFTD), primary progressive aphasia (PPA; further subcategorized as progressive nonfluent aphasia [PNFA] and semantic dementia [SD]), and movement disorders with extrapyramidal features such as parkinsonism and corticobasal syndrome (CBS). A broad range of clinical features both within and between 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/testing: The diagnosis of GRN-FTD is established in a proband with suggestive findings and a heterozygous pathogenic variant in GRN identified by molecular genetic testing.

Management: Treatment of manifestations: Behavioral manifestations 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 PPA with stabilization of symptoms; rivastigmine was used to treat behavioral manifestations 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 bvFTD and improvement in cognitive performance in those with PPA-PNFA.

Genetic counseling: GRN-FTD is inherited in an autosomal dominant manner. About 95% of individuals diagnosed with GRN-FTD have an affected parent. The proportion of affected individuals with a de novo GRN pathogenic variant is unknown but is estimated to be 5% or fewer. Each child of an individual with GRN-FTD has a 50% chance of inheriting the pathogenic variant. Once a GRN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.