GRN-related frontotemporal lobar degeneration is a progressive brain disorder that can affect behavior, language, and movement. The symptoms of this disorder usually become noticeable in a person's fifties or sixties, and affected people typically survive 7 to 13 years after the appearance of symptoms. However, symptoms can begin as early as a person's thirties or as late as a person's eighties. The features of this condition vary significantly, even among affected members of the same family.

Behavioral changes are the most common early signs of GRN-related frontotemporal lobar degeneration. These include marked changes in personality, judgment, and insight. It may become difficult for affected individuals to interact with others in a socially appropriate manner. Affected people may also become easily distracted and unable to complete tasks. They increasingly require help with personal care and other activities of daily living.

Many people with GRN-related frontotemporal lobar degeneration develop progressive problems with speech and language (aphasia). Affected individuals may have trouble speaking, remembering words and names (dysnomia), and understanding speech. Over time, they may completely lose the ability to communicate (mutism). People with this condition also experience a decline in intellectual function (dementia).

Some people with GRN-related frontotemporal lobar degeneration also develop movement disorders, such as parkinsonism and corticobasal syndrome. The signs and symptoms of these disorders include tremors, muscle stiffness (rigidity), unusually slow movement (bradykinesia), walking problems (gait disturbance), involuntary muscle spasms (myoclonus), uncontrolled muscle tensing (dystonia), and an inability to carry out purposeful movements (apraxia).

The prevalence of GRN-related frontotemporal lobar degeneration varies worldwide. It affects an estimated 3 to 15 per 100,000 people aged 45 to 64.

GRN-related frontotemporal lobar degeneration results from mutations (pathogenic variants) in the GRN gene. This gene provides instructions for making a protein called progranulin. Progranulin is active in many different tissues in the body, where it helps control the growth, division, and survival of cells. Progranulin's function in the brain is not well understood, although it appears to play an important role in the survival of nerve cells (neurons).

Most mutations in the GRN gene prevent any progranulin from being produced from one copy of the gene in each cell. As a result, cells make only half the usual amount of progranulin. It is unclear how a shortage of this protein leads to the features of GRN-related frontotemporal lobar degeneration. However, studies have shown that the disorder is characterized by the buildup of a protein called TAR DNA-binding protein 43 (TDP-43) in certain brain cells. The TDP-43 protein forms clumps (aggregates) that may interfere with cell functions and ultimately lead to cell death. Researchers are working to determine how mutations in the GRN gene, and the resulting loss of progranulin, are related to a buildup of TDP-43 in the brain.

The features of GRN-related frontotemporal lobar degeneration result from the gradual loss of neurons in regions near the front of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. The death of neurons in these areas causes problems with many critical brain functions. However, it is unclear why the loss of neurons occurs in the frontal and temporal lobes more often than other brain regions in people with GRN-related frontotemporal lobar degeneration.

Genetic Testing Information

• Genetic Testing Registry: Grn-related frontotemporal lobar degeneration with Tdp43 inclusions

Genetic and Rare Diseases Information Center

• Frontotemporal dementia

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• FRONTOTEMPORAL DEMENTIA 2; FTD2

Scientific Articles on PubMed

• PubMed

• Chen Q, Boeve BF, Senjem M, Tosakulwong N, Lesnick T, Brushaber D, Dheel C, Fields J, Forsberg L, Gavrilova R, Gearhart D, Graff-Radford J, Graff-Radford N, Jack CR Jr, Jones D, Knopman D, Kremers WK, Lapid M, Rademakers R, Ramos EM, Syrjanen J, Boxer AL, Rosen H, Wszolek ZK, Kantarci K. Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study. Neurobiol Aging. 2020 Apr;88:42-50. doi: 10.1016/j.neurobiolaging.2019.12.004. Epub 2019 Dec 12. Citation on PubMed
• Hsiung GYR, Feldman HH. GRN Frontotemporal Dementia. 2007 Sep 7 [updated 2020 Feb 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1371/ Citation on PubMed
• Le Ber I, Camuzat A, Hannequin D, Pasquier F, Guedj E, Rovelet-Lecrux A, Hahn-Barma V, van der Zee J, Clot F, Bakchine S, Puel M, Ghanim M, Lacomblez L, Mikol J, Deramecourt V, Lejeune P, de la Sayette V, Belliard S, Vercelletto M, Meyrignac C, Van Broeckhoven C, Lambert JC, Verpillat P, Campion D, Habert MO, Dubois B, Brice A; French research network on FTD/FTD-MND. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain. 2008 Mar;131(Pt 3):732-46. doi: 10.1093/brain/awn012. Epub 2008 Feb 1. Citation on PubMed
• Rabins PV, Rovner BW, Rummans T, Schneider LS, Tariot PN. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Focus (Am Psychiatr Publ). 2017 Jan;15(1):110-128. doi: 10.1176/appi.focus.15106. Epub 2017 Jan 11. Citation on PubMed or Free article on PubMed Central
• Ramos EM, Dokuru DR, Van Berlo V, Wojta K, Wang Q, Huang AY, Deverasetty S, Qin Y, van Blitterswijk M, Jackson J, Appleby B, Bordelon Y, Brannelly P, Brushaber DE, Dickerson B, Dickinson S, Domoto-Reilly K, Faber K, Fields J, Fong J, Foroud T, Forsberg LK, Gavrilova R, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grant I, Grossman M, Heuer HW, Hsiung GR, Huey E, Irwin D, Kantarci K, Karydas A, Kaufer D, Kerwin D, Knopman D, Kornak J, Kramer JH, Kremers W, Kukull W, Litvan I, Ljubenkov P, Lungu C, Mackenzie I, Mendez MF, Miller BL, Onyike C, Pantelyat A, Pearlman R, Petrucelli L, Potter M, Rankin KP, Rascovsky K, Roberson ED, Rogalski E, Shaw L, Syrjanen J, Tartaglia MC, Tatton N, Taylor J, Toga A, Trojanowski JQ, Weintraub S, Wong B, Wszolek Z, Rademakers R, Boeve BF, Rosen HJ, Boxer AL; ARTFL/LEFFTDS consortium; Coppola G. Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases. Alzheimers Dement. 2020 Jan;16(1):118-130. doi: 10.1002/alz.12011. Citation on PubMed
• Staffaroni AM, Bajorek L, Casaletto KB, Cobigo Y, Goh SM, Wolf A, Heuer HW, Elahi FM, Ljubenkov PA, Dever R, Kornak J, Appleby B, Bove J, Bordelon Y, Brannelly P, Brushaber D, Caso C, Coppola G, Dheel C, Dickerson BC, Dickinson S, Dominguez S, Domoto-Reilly K, Faber K, Ferrall J, Fields JA, Fishman A, Fong J, Foroud T, Forsberg LK, Gavrilova R, Gearhart D, Ghazanfari B, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grant I, Grossman M, Haley D, Hsiung GY, Huey ED, Irwin DJ, Jones DT, Jones L, Kantarci K, Karydas A, Kaufer DI, Kerwin DR, Knopman DS, Kraft R, Kremers WK, Kukull WA, Litvan I, Lucente D, Lungu C, Mackenzie IR, Maldonado M, Manoochehri M, McGinnis SM, McKinley E, Mendez MF, Miller BL, Multani N, Onyike C, Padmanabhan J, Pantelyat A, Pearlman R, Petrucelli L, Potter M, Rademakers R, Ramos EM, Rankin KP, Rascovsky K, Roberson ED, Rogalski E, Sengdy P, Shaw LM, Syrjanen J, Tartaglia MC, Tatton N, Taylor J, Toga A, Trojanowski JQ, Weintraub S, Wang P, Wong B, Wszolek Z, Boxer AL, Boeve BF, Kramer JH, Rosen HJ; ARTFL/LEFFTDS consortium. Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint. Alzheimers Dement. 2020 Jan;16(1):11-21. doi: 10.1016/j.jalz.2019.01.012. Citation on PubMed or Free article on PubMed Central
• Van Deerlin VM, Wood EM, Moore P, Yuan W, Forman MS, Clark CM, Neumann M, Kwong LK, Trojanowski JQ, Lee VM, Grossman M. Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations. Arch Neurol. 2007 Aug;64(8):1148-53. doi: 10.1001/archneur.64.8.1148. Citation on PubMed
• van Swieten JC, Heutink P. Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia. Lancet Neurol. 2008 Oct;7(10):965-74. doi: 10.1016/S1474-4422(08)70194-7. Epub 2008 Sep 2. Citation on PubMed
• Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, Galloway NM, Feldman H, Woltjer R, Miller CA, Wood EM, Grossman M, McCluskey L, Clark CM, Neumann M, Danek A, Galasko DR, Arnold SE, Chen-Plotkin A, Karydas A, Miller BL, Trojanowski JQ, Lee VM, Schellenberg GD, Van Deerlin VM. The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol. 2010 Feb;67(2):161-70. doi: 10.1001/archneurol.2009.328. Citation on PubMed or Free article on PubMed Central