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GRN-Related Frontotemporal Dementia

Synonyms: FTDU-17, Hereditary Dysphasic Disinhibition Dementia

, MD, MHSc, FRCPC and , MD, CM, FRCPC.

Author Information

Initial Posting: ; Last Update: March 14, 2013.

Estimated reading time: 28 minutes


Clinical characteristics.

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 subcategorized 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 pathogenic variants are 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.

Genetic counseling.

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 a de novo pathogenic variant 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.


Clinical Diagnosis

The spectrum of frontotemporal dementia associated with mutation of GRN (also known as PGRN) (FTD-GRN or FTD-PGRN) includes the behavioral variant (FTD-bv), primary progressive aphasia (PPA), and movement disorders with extrapyramidal features including parkinsonism and corticobasal syndrome.

FTD-Behavioral Variant (FTD-bv)

The most recent diagnostic criteria for the frontotemporal dementia behavioral variant (FTD-bv) improved diagnostic accuracy over previous criteria and incorporated structural or functional brain imaging [Rascovsky et al 2011]. According to this new set of criteria, the following symptoms must be present for diagnosis of FTD-bv, with progressive deterioration of behavior and/or cognition by observation or by history as provided by a knowledgeable informant.

For the diagnosis of possible FTD-bv, three of the following six behavioral/cognitive symptoms must be present. Ascertainment requires that symptoms be persistent or recurrent, rather than single or rare events:

  • Early behavioral disinhibition (one of the following must be present):
    • Socially inappropriate behavior
    • Loss of manners or decorum
    • Impulsive, rash, or careless actions
  • Early apathy or inertia (one of the following must be present):
    • Apathy
    • Inertia
  • Early loss of sympathy or empathy (one of the following must be present):
    • Diminished response to other people's needs and feelings
    • Diminished social interest, interrelatedness, or personal warmth
  • Early perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following must be present):
    • Simple repetitive movements
    • Complex, compulsive, or ritualistic behaviors
    • Stereotypy of speech
  • Hyperorality and dietary changes (one of the following must be present):
    • Altered food preferences
    • Binge eating, increased consumption of alcohol or cigarettes
    • Oral exploration or consumption of inedible objects
  • Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (all of the following must be present):
    • Deficits in executive tasks
    • Relative sparing of episodic memory
    • Relative sparing of visuospatial skills

For the diagnosis of probable FTD-bv, all of the following must be present:

  • Meets criteria for possible FTD-bv as above
  • Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or other functional activities assessments)
  • Imaging results consistent with FTD-bv (one of the following must be present):
    • Frontal and/or anterior temporal atrophy on head MRI or CT
    • Frontal and/or anterior temporal hypoperfusion or hypometabolism on positron emission tomography (PET) or single-photon emission computed tomography (SPECT)

Primary Progressive Aphasia (PPA)

PPA has been further classified into three subtypes: progressive non-fluent aphasia (PNFA, also known as non-fluent or agrammatic subtype of PPA); semantic dementia (SD); and the newly recognized logopenic variant (logopenic PPA) [Gorno-Tempini et al 2011]. The majority of the literature describes PNFA to be the predominant form of PPA in FTD-GRN, although there are a few reports of the SD phenotype as well. To date there have not been any reports of the logopenic variant of PPA being associated with FTD-GRN.

The currently proposed diagnostic algorithm for PNFA requires a two-step process. First, individuals must meet the criteria for PPA, and after the diagnosis of PPA is established, the main features of the speech and language abnormalities may be considered to subcategorize into each of the PPA variants.

Based on the criteria by Mesulam, the diagnosis of PPA must fulfill the following inclusion and exclusion criteria [Mesulam 2001]:

  • Inclusion. All of the following must be answered positively:
    • Most prominent clinical feature is difficulty with language.
    • These deficits are the principal cause of impaired daily living activities.
    • Aphasia is the most prominent deficit at symptom onset and for the initial phases of the disease.
  • Exclusion. All of the following must be answered negatively:
    • Pattern of deficits is better accounted for by other nondegenerative nervous system or medical disorders.
    • Cognitive disturbance is better accounted for by a psychiatric diagnosis.
    • Prominent initial episodic memory, visual memory, and visuoperceptual impairments are present.
    • Prominent initial behavioral disturbance is present.

Progressive Nonfluent Aphasia (PNFA) Variant of PPA (PPA-PNFA)

For the nonfluent/agrammatic variant PPA (PPA-PNFA), the diagnostic criteria include the following [Gorno-Tempini et al 2011].

Clinical presentation of aphasia must include both of the following:

  • At least one of the following core features:
    • Agrammatism in language production
    • Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech)
  • At least two of the three following supportive features:
    • Impaired comprehension of syntactically complex sentences
    • Spared single-word comprehension
    • Spared object knowledge

For an imaging-supported nonfluent/agrammatic variant (PPA-PNFA) diagnosis, both of the following criteria must be present:

  • Clinical diagnosis of nonfluent/agrammatic variant PPA
  • Imaging that shows one or both of the following results:
    • Predominant left posterior fronto-insular atrophy on MRI
    • Predominant left posterior fronto-insular hypoperfusion or hypometabolism on PET or SPECT

Semantic Dementia (SD) Variant of PPA (PPA-SD)

By contrast, the diagnostic criteria of PPA-SD require the presence of:

  • Both of the following core features:
    • Impaired confrontation naming
    • Impaired single-word comprehension
  • At least three of the following four additional diagnostic features:
    • Impaired object knowledge, particularly for low frequency or low-familiarity items
    • Surface dyslexia or dysgraphia
    • Spared repetition
    • Spared speech production (grammar and motor speech)

For imaging-supported PPA-SD diagnosis, both of the following criteria must be present:

  • Clinical diagnosis of PPA-SD
  • Imaging that shows one or both of the following results:
    • Predominant anterior temporal lobe atrophy
    • Predominant anterior temporal hypoperfusion or hypometabolism on PET or SPECT

GRN-Related Movement Disorders with Extrapyramidal Features: Parkinsonism

Clinical diagnostic features include the following:

  • Bradykinesia
  • Rigidity
  • Gait instability
  • Resting tremor

GRN-Related Movement Disorders with Extrapyramidal Features: Corticobasal Syndrome

Clinical diagnostic features include the following [Boeve et al 2003]:

  • Progressive asymmetric rigidity
  • Apraxia
  • Alien-limb phenomenon
  • Cortical sensory loss
  • Focal dystonia
  • Myoclonus
  • Dementia



  • Computed tomography (CT) or magnetic resonance imaging (MRI) may show focal, often asymmetric atrophy in the frontal and/or temporal regions. A study comparing the pattern of cerebral atrophy in persons with FTD using voxel-based morphometry suggests that those with GRN pathogenic variants have a more widespread and severe pattern of gray matter loss in the frontal, temporal, and parietal lobes than those who do not have a GRN pathogenic variant [Whitwell et al 2007]. Volumetric studies comparing the rate of brain atrophy between FTD-GRN and FTD caused by mutation of MAPT (FTD-MAPT) showed that individuals with pathogenic variants in GRN have a higher rate of whole-brain atrophy (3.5% per year) than those with MAPT-related FTD [Whitwell et al 2011].
  • Single photon emission computed tomography (SPECT) may reveal decreased perfusion in the frontal and temporal lobes [Pasquier et al 2003]. There is also evidence of poor cerebral perfusion in both anterior parietal lobes, predominantly on the left hemisphere and on the right inferior parietal cortex [Snowden et al 2006, Le Ber et al 2008].
  • Positron emission tomography (PET) may also demonstrate decreased glucose metabolism in the frontotemporal region, often before structural changes can be appreciated [Pasquier et al 2003].

Neuropathology. The neuropathology of FTD-GRN is characterized by the following [Mackenzie et al 2006]:

  • Tau-negative alpha-synuclein-negative ubiquitin-positive "cat-eye" or lentiform-shaped neuronal intranuclear inclusions (NII), often found in the neocortex and striatum
  • Superficial laminar spongiosis with ubiquitin-positive neurites and neuronal cytoplasmic inclusions (NCI) in the neocortex
  • Granular appearance of the ubiquitin-immunoreactive (ub-ir) neurites in the striatum and the NCI in the hippocampus
  • Phosphorylation of S409/410 of TDP-43 (see following) in pathologic inclusions [Neumann et al 2009]

The major protein component of these ubiquitin inclusions is a TAR DNA-binding protein of 43 kd (TDP 43). TDP-43 is a nuclear factor involved in regulating transcription and alternative splicing [Arai et al 2006, Neumann et al 2006]. It is mostly a nuclear protein, although recent studies have shown that it shuttles between the nucleus and cytoplasm in normal conditions [Ayala et al 2008]. While its physiologic function remains unclear, it has been demonstrated to bind to a large number of RNA targets with a preference for UG-rich intronic regions and is important in many vital cellular processes [Sendtner 2011].

It is now recognized that pathologically, FTD-GRN is a major subtype of frontotemporal lobar degeneration (FTLD). The neuropathologic diagnostic criteria for FTLD have recently been updated based on current molecular understanding of the disease [Mackenzie et al 2011].

Molecular Genetic Testing

Gene. GRN, encoding the protein granulin, is the only gene in which mutation is known to cause frontotemporal dementia with ub-ir NII pathology [Baker et al 2006, Cruts et al 2006a]. GRN is also known as PGRN, encoding progranulin.

Table 1.

Molecular Genetic Testing Used in GRN-Related Frontotemporal Dementia

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
GRNSequence analysis 4Sequence variants 55% 6
Deletion/duplication analysis 7(Multi)exon or whole-gene deletion/duplication 8Unknown

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


In a series of 378 individuals with frontotemporal lobar degeneration, 23% of those with a positive family history had a GRN pathogenic variant identified by sequence analysis of the entire gene including the promoter region, whereas 4.8% of simplex cases (i.e., a single occurrence in a family) had an identifiable GRN pathogenic variant [Gass et al 2006].


In a series of 167 individuals with FTLD referred to Alzheimer Disease Research Centers (ADRC) (population sample), 5% were found to have GRN pathogenic variants. The GRN pathogenic variants were as common as pathogenic variants in the tau gene (MAPT), associated with frontotemporal dementia with parkinsonism-17 (FTDP-17) [Gass et al 2006].


Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Deletion of one or more exons and of the whole gene have been reported.

Testing Strategy

To confirm/establish the diagnosis in a proband. The algorithm for diagnosis of FTD begins with detailed clinical assessment and consideration of the consensus clinical criteria. Because FTD-GRN has distinct neuropathologic findings, one approach is to first determine if other relatives with dementia had an autopsy demonstrating the characteristic neuropathologic findings [Mackenzie et al 2006].

For those individuals with a family history of FTD and at least one relative with the characteristic NII pathologic findings, the following molecular genetic testing is warranted:


Sequence analysis of GRN


If no pathogenic variant is identified, deletion/duplication analysis

Note: Several studies have found that a low serum or plasma progranulin level is predictive of the presence of a GRN pathogenic variant, although its use in a clinical setting has not been endorsed [Ghidoni et al 2008, Carecchio et al 2009, Schofield et al 2010, Hsiung et al 2011].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

Frontotemporal dementia associated with mutation of GRN (FTD-GRN) generally affects the frontal and temporal cortex leading to behavioral changes, executive dysfunction, and language disturbances. In FTD-GRN, the parietal cortex and basal ganglia may be affected as well, resulting in parkinsonism, cortical basal syndrome, and memory impairment [Baker et al 2006, Masellis et al 2006, Mukherjee et al 2006, Behrens et al 2007, Josephs et al 2007, Mesulam et al 2007, Spina et al 2007].

Age of onset. The age of onset of FTD-GRN ranges from 35 to 87 years with a mean of 64.9 ± 11.3 years [Bruni et al 2007]. Comparison studies demonstrate that the age of onset in individuals with an identified GRN pathogenic variant do not differ significantly from individuals without an identified GRN pathogenic variant (non-GRN FTD) [Beck et al 2008, Pickering-Brown et al 2008], while some studies suggested a younger age of onset in individuals with a GRN pathogenic variant than in those without one (non-GRN FTD) [Huey et al 2006, Davion et al 2007]. The majority of individuals develop the disease at approximately age 60 years [Le Ber et al 2007, Rademakers et al 2007].

Neurocognitive symptoms. Neuropsychological testing may demonstrate early symptoms of impairment on frontal lobe tasks or specific language dysfunction prior to the onset of frank dementia.

Behavioral disturbances are the most common early feature, followed by progressive aphasia [Gass et al 2006, Josephs et al 2007]. This is usually an insidious but profound change in personality and conduct, characterized by distractibility, loss of initiative, apathy, and loss of interest in their environment, often accompanied by neglect in personal hygiene and social disinhibition. Some affected individuals demonstrate impulsiveness or compulsiveness and may alter their eating habits with food fads and food craving.

With impairment in executive function, there is loss of judgment and insight, which may manifest early in the disease as making poor financial decisions, quitting jobs abruptly, or becoming unduly forward or rude to strangers. Alternatively, persons with predominant apathy symptoms may lose all interest and initiative with usual activities, appear socially withdrawn, ignore all previous interests and hobbies, and be unable to complete tasks due to lack of persistence. Early in the course of the illness, affected individuals may be misdiagnosed as having psychiatric conditions such as depression, mania, or psychosis because of the unusual and bizarre nature of their behavior. Psychometric testing may demonstrate impairment on frontal executive tasks including the Trail-Making Test, proverb interpretation, descriptions of similarities, categorical naming, and abstract pattern recognition (e.g., Wisconsin Card Sort Test).

Language deficits. Primary progressive aphasia (PPA), particularly the progressive non-fluent aphasia (PNFA) variant, can be another presentation of FTD-GRN [Mesulam et al 2007]. In early stages, PPA-PNFA often manifests as deficits in naming, word finding, or word comprehension. Although behavioral manifestations tend to be more common than language deficits as the initial presentation of FTD-GRN, in one series 82% of affected individuals eventually developed language problems [Josephs et al 2007, Caso et al 2012].

In contrast with PPA-PNFA, semantic dementia is characterized by impaired naming and comprehension, semantic paraphasias, and impaired recognition of familiar faces or objects. Although the pure semantic dementia (PPA-SD) is rare in FTD-GRN, it has been described in a few studies [Whitwell et al 2007, Beck et al 2008]. In late stages, affected individuals with PPA-SD may develop impaired face recognition and behavioral changes including disinhibition and compulsion [Seeley et al 2005].

A number of recent studies have reported individuals with FTD-GRN who have presented with amnestic mild cognitive impairment, which may be mistaken for Alzheimer disease [Carecchio et al 2009, Kelley et al 2010].

Movement disorders. In several families with FTD-GRN parkinsonism is prominent, and in some the initial clinical diagnosis was corticobasal syndrome [Gass et al 2006, Masellis et al 2006, Benussi et al 2009, Moreno et al 2009]. Early findings 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.

Motor neuron disease. Although the histopathologic findings of ubiquitin-positive inclusions were initially associated with motor neuron disease, it appears to occur only rarely (if at all) in families with GRN pathogenic variants [Schymick et al 2007].

Disease course. The mean age at death is 65±8 years. The disease duration ranges from three to 12 years [Gass et al 2006].

Genotype-Phenotype Correlations

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

If the final cellular effect of all pathogenic variants is the same (i.e., haploinsufficiency for granulin) one could anticipate some uniformity of clinical features. However, a broad range of clinical features both within and across families is observed. The heterogeneity in clinical presentation likely reflects individual differences in the anatomic distribution of the lesions, while the variation in age of onset and disease duration suggests that other modifying genetic or environmental factors are involved.


Penetrance is about 90% by age 75 years, but apparent incomplete penetrance has also been observed in a few cases [Cruts et al 2006a, Gass et al 2006]. More reports will be needed before the penetrance can be more accurately established.

A study of the common p.Arg493Ter 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 [Rademakers et al 2007].

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 incomplete penetrance [Le Ber et al 2007].


No clear evidence of genetic anticipation has been found for FTD-GRN.


The term FTD is used in this GeneReview to designate the clinical presentation of the dementing illness, while frontotemporal lobar degeneration (FTLD) is used to denote the pathologic diagnosis of the disease.

FTDP-17 has been used to denote individuals with FTD with or without parkinsonism associated with mutation of MAPT, the gene encoding the tau protein. This syndrome includes persons diagnosed with Pick's disease.

The term FTD-GRN is used in this GeneReview to designate FTD associated with mutation of GRN. Note that the alternative term FTD-PGRN (caused by mutation of PGRN) is often used in the literature as well.

Prior to the identification of GRN as the gene in which a pathogenic variant is responsible for this form of FTD, a number of terms were used to describe this disorder.

  • FTDU-17. Analogous to FTDP-17, the term FTDU-17 has been used because the pathologic characteristics of this condition are associated with ubiquitinated inclusions and the genetic locus was also located on chromosome 17.
  • HDDD1 and HDDD2. Other kindreds with familial dementia with similar clinical presentations were descriptively named as hereditary dysphasic disinhibition dementia (HDDD1 and HDDD2). It has now been shown that pathogenic variants in GRN (PGRN) are also responsible for these families, and therefore these are basically the same disease [Mukherjee et al 2006, Behrens et al 2007].


FTD is a progressive neurodegenerative disease accounting for 5%-10% of all individuals with dementia and 10%-20% of individuals with dementia with onset before age 65 years [Bird et al 2003].

FTD-GRN represents about 5% of all FTD, and 20% of FTD in which the family history is positive. FTD-GRN is at least as common as FTDP-17.

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 FTD associated with mutation of GRN (FTD-GRN) significantly overlap with those of other inherited conditions including FTDP-17, familial Parkinson disease and Alzheimer disease, as well as sporadically occurring disorders such as Pick's disease, frontotemporal dementia, corticobasal degeneration, other parkinsonian syndromes, and Creutzfeldt-Jacob disease. 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 [Chow et al 1999, Rosso et al 2003].

Frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). Expanded hexanucleotide GGGGCC repeat pathogenic variants in C9ORF72 have been found to be responsible for FTD associated with amyotrophic lateral sclerosis (FTD-ALS) [DeJesus-Hernandez et al 2011, Renton et al 2011]. There is wide variation in age of onset (mean = 54.3 years, range = 34-74 years) and disease duration (mean = 5.3 years, range = 1-16 years) [Boeve et al 2012, Hsiung et al 2012]. This condition may be misdiagnosed as FTD-bv, PPA-PNFA, or ALS (see Amyotrophic Lateral Sclerosis Overview). Heterogeneity in clinical presentation is also common within families. There is a tendency for the phenotypes to converge with disease progression. TDP-43 pathology in FTD-ALS is found in a wide neuroanatomic distribution, with particular involvement in the extramotor neocortex and hippocampus as well as in the lower motor neurons.

Frontotemporal dementia with parkinsonism-17 (FTDP-17) is a presenile dementia affecting the frontal and temporal cortex and some subcortical nuclei. Clinical presentation is variable. Individuals may present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs. Onset is usually between ages 40 and 60 years, but may occur earlier or later. The disease progresses over a few years into profound dementia with mutism. Disease duration is usually between five and ten years, but occasionally may be up to 20-30 years. MAPT, the gene encoding microtubule-associated protein tau, is the only gene associated with FTDP-17. Between 25% and 40% of families with autosomal dominant frontotemporal dementia show mutation of MAPT.

At autopsy, all persons with FTDP-17 consistently show tau-positive inclusion pathology, whereas all persons with FTD-GRN show ub-ir neuronal intranuclear inclusions [Ghetti et al 2003, Mackenzie 2007].

Inclusion body myopathy with Paget disease of the bone (PDB) and frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. Cardiac failure and cardiomyopathy have been observed in later stages. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, and relative preservation of memory, and later stages by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 55 years. VCP is the only gene known to be associated with IBMPFD.

Other. Pathogenic variants in CHMP2B, the gene encoding the chromatin-modifying protein 2B, have been identified in individuals with autosomal dominant FTD [Skibinski et al 2005, Momeni et al 2006, Parkinson et al 2006] (see CHMP2B-Related Frontotemporal Dementia).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRN-related frontotemporal dementia (FTD-GRN), the following evaluations are recommended:

  • Detailed general, neurologic, and family history
  • Physical, neurologic, and cognitive examination
  • Consultation with a clinical geneticist and/or genetic counselor

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 the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, gender, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.

Treatment of Manifestations

There is currently no known treatment for FTD-GRN or FTD in general. However, some behavioral symptoms such as apathy, impulsivity, and compulsiveness may respond to selective serotonin reuptake inhibitors.

Symptoms of roaming, delusions, and hallucinations may respond to antipsychotic medications.

Although reports have suggested potential benefits with certain pharmacotherapy on management of FTD in general, evidence from randomized controlled trials is limited [Freedman 2007]. All of the following findings require confirmation with larger clinical trials.

  • One double-blind placebo-controlled crossover trial suggests that trazodone, a serotonergic agent, may be beneficial in treating the symptoms of irritability, agitation, depression, and eating disorders in FTD [Lebert et al 2004].
  • While an open-label study suggested some benefits on behavioral symptoms with paroxetine, a double-blind placebo-controlled trial of ten subjects found worsening of performance on paired associates learning, reversal learning, and delayed pattern recognition [Moretti et al 2003, Deakin et al 2004].
  • A study of galantamine in FTD-bv and primary progressive aphasia (PPA) found significant benefits in subjects with PPA but not in those with FTD-bv [Kertesz et al 2005]. A follow-up study of 36 individuals who were on galantamine therapy for 18 weeks revealed stabilization but not improvement on language scores in the PPA group [Kertesz et al 2008].
  • A 12-month open-label rivastigmine trial showed improvement of behavioral symptoms and decreased caregiver burden in individuals with FTD but the treatment did not prevent cognitive decline [Moretti et al 2004].
  • A double-blind placebo-controlled crossover study of methylphenidate found attenuation of risk-taking behavior but worsening of spatial span [Rahman et al 2006].
  • A small clinical trial of dextroamphetamine treatment on eight individuals with FTD-bv revealed improvement of behavioral symptoms [Huey et al 2008].
  • A few open-label studies of memantine, a partial NMDA agonist, demonstrated an improvement on the frontal battery inventory (FBI) in individuals with FTD-bv after a six-month trial, but a decline in other cognitive performance was observed [Diehl-Schmid et al 2008]. Among the three subtypes of FTD, PPA-PNFA remained stable on cognitive and functional measurements when treated with memantine [Boxer et al 2009]. A study using [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) as a surrogate outcome in individuals with semantic dementia found that cortical metabolic activity in salience network hubs were sustained when treated with memantine over a six-month period [Chow et al 2013].

Note: Donepezil treatment has been associated with exacerbation of disinhibition and compulsion symptoms [Mendez et al 2007].

Agents/Circumstances to Avoid

Limited epidemiologic studies suggest that head injury may be a risk factor for FTD in general, although this finding requires confirmation [Rosso et al 2003].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A clinical trial on a formulation of methothioninium (TRx0237), a compound that has been shown to inhibit tau aggregation in preclinical studies and may also have effect on TDP-43, is currently underway for individuals with FTD-bv.

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Frontotemporal dementia caused by pathogenic variants in GRN (FTD-GRN) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most (95%) individuals diagnosed with FTD-GRN have an affected parent [Gass et al 2006].
  • A proband with FTD-GRN may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown but would be estimated at 5% or less.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include a neurologic assessment and molecular genetic testing of GRN. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with FTD-GRN have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents.

Offspring of a proband. Each child of an individual with FTD-GRN has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may also be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the variant occurred de novo in the proband. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GRN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for GRN-related frontotemporal dementia are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

GRN-Related Frontotemporal Dementia: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for GRN-Related Frontotemporal Dementia (View All in OMIM)


Molecular Genetic Pathogenesis

To date, evidence suggests that all GRN pathogenic variants exert their pathogenic effect through reduced progranulin protein levels by (1) loss of transcript (pathogenic nonsense or frameshift variants), (2) reduced transcription (promoter variants), (3) loss of translation (mutation of initiating methionine), or (4) loss of protein function (pathogenic missense variants) [Baker et al 2006, Cruts et al 2006a, Gass et al 2006, van der Zee et al 2007].

Benign variants. A number of normal variants as well as other variants of unknown significance in GRN have been identified.

Pathogenic variants. More than 200 genetic variations in GRN have now been identified, of which 68 have been shown to be pathogenic. The Flanders Interuniversity Institute for Biotechnology in Belgium keeps an up-to-date tally of all pathogenic variants associated with FTD (see Alzheimer Disease & Frontotemporal Dementia Mutation Database).

To date, the most frequently found pathogenic variant is g.3240C>T (p.Arg493Ter). Haplotype analyses suggest that it may result from a founder effect [Gass et al 2006, Bronner et al 2007, van der Zee et al 2007].

The majority of the pathogenic variants are nonsense, frameshift, and splice-site variants that cause premature termination of the coding sequence and degradation of the mutated RNA by nonsense-mediated decay [Baker et al 2006, Gass et al 2006]. Another study has shown that deletion of the progranulin locus can also lead to the same clinical presentation of FTD as a result of haploinsufficiency [Gijselinck et al 2008].

Other unusual pathogenic variants include the following [Gass et al 2006, Bronner et al 2007, van der Zee et al 2007]:

  • A 5' splice site in exon 1 that leads to loss of the Kozac sequence
  • A missense variant in the hydrophobic core of the granulin signal peptide
  • Missense variants predicted in silico to affect protein folding
  • Sequence variations in the 5' regulatory region that may affect GRN transcriptional activity

All of these pathogenic variants are expected to result in loss of a functional GRN transcript and consequent haploinsufficiency.

Table 2.

Selected GRN Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. The granulins are a family of cysteine-rich polypeptides, some of which have growth-modulating activity. All four known human granulin-like peptides are encoded in a single precursor, progranulin, a 593-amino-acid glycoprotein with a highly conserved 12-cysteine backbone defining a consensus sequence that is repeated seven times [Bateman & Bennett 1998].

Progranulin, also known as PC-cell-derived growth factor, proepithelin, granulin-epithelin, or acrogranin, is a high molecular weight secreted mitogen. Progranulin mRNA is widely expressed in rapidly cycling epithelial cells, in the immune system, and in neurons such as cerebellar Purkinje cells, suggesting an important function in these tissues. Progranulin is involved in multiple physiologic processes such as cellular proliferation and survival as well as tissue repair, and pathologic processes including tumorigenesis [He & Bateman 2003]. Transcriptome analyses show that the progranulin gene is induced in numerous situations varying from obesity to the transcriptional response of cells to antineoplastic drugs [Ong & Bateman 2003]. The full-length form of the progranulin protein has trophic and anti-inflammatory activity, while the cleaved granulin peptides promote inflammatory activity. In the periphery, progranulin is involved in wound healing responses and modulates inflammatory events. In the central nervous system, progranulin is expressed by neurons and microglia [Eriksen & Mackenzie 2008].

The progranulin gene comprises a total of 13 exons, including a non-coding exon 0 and 12 protein-coding exons covering about 3,700 bp [Cruts et al 2006a]. Each tandem granulin repeat is encoded by two nonequivalent exons, a configuration unique to the granulins that would permit the formation of hybrid granulin-like proteins by alternate splicing [Bateman & Bennett 2009].

Abnormal gene product. Although pathogenic variants of GRN have been identified as a cause of autosomal dominant FTD, the ubiquitin-positive inclusions are not stained by progranulin immunostaining, suggesting that most pathogenic variants do not result in production of abnormal progranulin. In fact, most pathogenic variants lead to abnormal mRNAs that are degraded by nonsense-mediated decay (i.e., null variants). This progranulin haploinsufficiency likely leads to neurodegeneration from reduced progranulin-mediated neuronal survival [Baker et al 2006, Cruts et al 2006b, Chiang et al 2008]. Several recent reports suggest that the risk of developing GRN-related FTD may be modified by other genetic factors, including the APOE genotype, rs5848 polymorphism, and polymorphisms on another gene, TMEM106B [Beck et al 2008, Rademakers et al 2008, Van Deerlin et al 2010, Hsiung et al 2011]. These genetic modifiers and their role in pathogenesis of FTD are currently under further investigation.


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Chapter Notes


The authors gratefully acknowledge the funding received from the Canadian Institutes of Health Research operating grant #74580 and #179009 in support of their research on FTD as well as the collaborations of the investigators of the UBC FTD research team including Drs I Mackenzie, B Hallam, C Jacova, E Dwosh, and AD Sadovnick. Dr GYR Hsiung is supported by a CIHR Clinical Genetics Investigatorship.

Revision History

  • 14 March 2013 (me) Comprehensive update posted live
  • 7 September 2007 (me) Review posted live
  • 1 June 2007 (gyrh) Original submission
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