Clinical Guidance

No obvious correlations between age of onset, disease duration, or clinical phenotype and specific GRN pathogenic variants have been identified. Clinical variability is high among individuals with the same GRN pathogenic variant.

Source: GeneReviews — "GRN Frontotemporal Dementia"

Penetrance

Penetrance of GRN-FTD is about 90% by age 75 years, but apparent reduced penetrance has also been observed on occasion . A study of the common pathogenic variant showed that 60% of individuals with this variant were affected by age 60 years, and more than 95% were affected by age 70 years . Age at onset of frontotemporal lobar degeneration (FTLD) was younger in individuals with a GRN pathogenic variant vs those without one (median: 58.0 vs 61.0 years), as was age at death (median: 65.5 vs 69.0 years) . In a large series in France, 3.2% of simplex cases (i.e., only one affected individual in a family) with FTD were found to have a GRN pathogenic variant, suggesting possible de novo variant or reduced penetrance .

Source: GeneReviews — "GRN Frontotemporal Dementia"

Diagnostic Criteria

Suggestive Findings

GRN frontotemporal dementia (GRN-FTD) should be suspected in individuals with the following clinical presentations and neuroimaging findings.

Clinical Presentations

Clinical presentations of GRN-FTD vary widely both among and within families and may resemble behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), atypical parkinsonism, or corticobasal syndrome. Behavioral variant FTD

Source: GeneReviews — "GRN Frontotemporal Dementia"

Differential Diagnosis

Neuroimaging can evaluate for other conditions that mimic frontotemporal dementia (FTD) (e.g., white matter diseases, frontotemporal focal lesions, frontal lobe tumors, and cerebrovascular disease). The clinical manifestations of GRN-FTD significantly overlap with those of other conditions including FTD with or without parkinsonism associated with pathogenic variants in MAPT, Parkinson disease, Alzheimer disease, Pick disease (OMIM 172700), other inherited FTD disorders, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jacob disease (OMIM 123400). This clinical overlap makes it difficult to predict which family has a GRN pathogenic variant by clinical presentation alone. Up to 50% of individuals with FTD have a positive family history of dementia, usually with autosomal dominant inheritance. below lists the most common genes associated with familial FTD. Table 2. Genes in the Differential Diagnosis of GRN Frontotemporal Dementia

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRN frontotemporal dementia (GRN-FTD), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Detailed general, neurologic, and family history

• Physical examination

• Neurologic examination

• Cognitive examination. When clinical cognitive assessments are not informative enough, a neuropsychological assessment may be performed to provide a more comprehensive and objective view of a patient's cognitive function. Formal neuropsychological assessment requires comparison of the patient's raw score on a specific test to a large general population normative sample which is usually drawn from a population comparable to that of the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, sex, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.

• Discussion of capabilities for job and for driving

• Discussion of advanced care planning

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

There is currently no known treatment for GRN-FTD or FTD in general. Psychosocial support is essential in the management of FTD and should include occupational therapy and environmental and physical interventions.

Source: GeneReviews — "GRN Frontotemporal Dementia"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "GRN Frontotemporal Dementia"

Surveillance Guidelines

Patients are often followed in a memory disorder clinic or a similar multidisciplinary clinic involving neurologic and psychiatric services and follow-up medical care.

Source: GeneReviews — "GRN Frontotemporal Dementia"