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Frontotemporal dementia, ubiquitin-positive(HDDD)

MedGen UID:
375285
Concept ID:
C1843792
Disease or Syndrome
Synonyms: Dementia, hereditary dysphasic disinhibition; FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, GRN-RELATED; FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATED; FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS; FTLD-TDP, GRN-RELATED; GRN-Related Frontotemporal Dementia; HDDD
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): GRN (17q21.31)
OMIM®: 607485

Definition

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. [from GTR]

Additional descriptions

From GeneReviews
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.  https://www.ncbi.nlm.nih.gov/books/NBK1371
From OMIM
Clinically, FTLD-TDP is a type of frontotemporal dementia (see FTD; 600274) which shows variable phenotypic expression, but most commonly presents with social, behavioral, or language deterioration, rather than memory or motor deficits. Other variations of the phenotype have been referred to as 'dysphasic disinhibition dementia' and 'primary progressive aphasia' (PPA) (Huey et al., 2006; Mukherjee et al., 2006; Mesulam et al., 2007). Some patients may present with a clinical diagnosis of Alzheimer disease (AD; 104300) or Parkinson disease (PD; 168600), which are part of the phenotypic spectrum of this disorder (Brouwers et al., 2007). Genetic Heterogeneity of FTLD-TDP The specific presence of TDP43 (TARDBP; 605078)-positive inclusions on neuropathologic examination defines a genetically heterogeneous group of dementias known collectively as 'FTLD-TDP.' FTLD-TDP is a neuropathologic diagnosis; only about 20% of patients with this neuropathologic diagnosis have GRN mutations (review by Van Deerlin et al., 2010). TDP43-positive inclusions also occur in ALS10 (612069), caused by mutation in the TARDBP gene (605078); IBMPFD (167320), caused by mutation in the VCP gene (601023); and FTDALS (105550), caused by mutation in the C9ORF72 gene (614260). Mackenzie and Rademakers (2007) provided a detailed review of the molecular genetics of FTLD, with special emphasis on FTLDU. Cairns and Ghoshal (2010) reviewed the molecular pathology and genetic heterogeneity of FTLD, including FTLD-TDP, and also noted that FTLDU is now referred to as FTLD-TDP.  http://www.omim.org/entry/607485
From GHR
GRN-related frontotemporal dementia 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 6 to 7 years after the appearance of symptoms. However, 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 dementia. 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 dementia 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.Some people with GRN-related frontotemporal dementia also develop movement disorders, such as parkinsonism and corticobasal syndrome. The signs and symptoms of these disorders include tremors, rigidity, unusually slow movement (bradykinesia), involuntary muscle spasms (myoclonus), uncontrolled muscle tensing (dystonia), and an inability to carry out purposeful movements (apraxia).  https://ghr.nlm.nih.gov/condition/grn-related-frontotemporal-dementia

Clinical features

Aphasia
MedGen UID:
8159
Concept ID:
C0003537
Mental or Behavioral Dysfunction
A cognitive disorder marked by an impaired ability to comprehend or express language in its written or spoken form. This condition is caused by diseases which affect the language areas of the dominant hemisphere. Clinical features are used to classify the various subtypes of this condition. General categories include receptive, expressive, and mixed forms of aphasia.
Apraxia
MedGen UID:
8166
Concept ID:
C0003635
Mental or Behavioral Dysfunction
A defect in the understanding of complex motor commands and in the execution of certain learned movements, i.e., deficits in the cognitive components of learned movements.
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
Gliosis is the focal proliferation of glial cells in the central nervous system.
Polyphagia
MedGen UID:
9369
Concept ID:
C0020505
Finding
A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.
Mutism
MedGen UID:
6476
Concept ID:
C0026884
Disease or Syndrome
The inability to generate oral-verbal expression, despite normal comprehension of speech. This may be associated with BRAIN DISEASES or MENTAL DISORDERS. Organic mutism may be associated with damage to the FRONTAL LOBE; BRAIN STEM; THALAMUS; and CEREBELLUM. Selective mutism is a psychological condition that usually affects children characterized by continuous refusal to speak in social situations by a child who is able and willing to speak to selected persons. Kussmal aphasia refers to mutism in psychosis. (From Fortschr Neurol Psychiatr 1994; 62(9):337-44)
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of restlessness associated with unpleasant feelings of irritability and tension. Causes include pain, stress, fever, alcohol and nicotine withdrawal, cocaine and hallucinogenic drugs use, depression, bipolar disorders, and schizophrenia.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
An emotional state of indifference characterized by a lack of interest or concern.
Perseveration
MedGen UID:
66686
Concept ID:
C0233651
Mental or Behavioral Dysfunction
Perseveration can be defined as the contextually inappropriate and unintentional repetition of a response or behavioral unit. In other words, the observed repetitiveness does not meet the demands of the situation, is not the product of deliberation, and may even unfold despite counterintention. Perseveration can therefore be differentiated from goal-directed and intentional forms of repetition, such as linguistic redundancies designed to enhance communicative or poetic impact.
Memory impairment
MedGen UID:
68579
Concept ID:
C0233794
Mental or Behavioral Dysfunction
An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
Sensory hallucination
MedGen UID:
115982
Concept ID:
C0235153
Sign or Symptom
Perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid, substantial, and located in external objective space.
Brain atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Personality changes
MedGen UID:
66817
Concept ID:
C0240735
Sign or Symptom
A noticeable change in a person's behavior and thinking. Causes include depression, drug or alcohol abuse, brain injuries, brain tumors, and Alzheimer's disease.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
A group of disorders which feature impaired motor control characterized by bradykinesia, MUSCLE RIGIDITY; TREMOR; and postural instability. Parkinsonian diseases are generally divided into primary parkinsonism (see PARKINSON DISEASE), secondary parkinsonism (see PARKINSON DISEASE, SECONDARY) and inherited forms. These conditions are associated with dysfunction of dopaminergic or closely related motor integration neuronal pathways in the BASAL GANGLIA.
Hypersexuality
MedGen UID:
137208
Concept ID:
C0312420
Mental or Behavioral Dysfunction
Pathological persistent sexual disinhibiting behavior, directed at oneself or to others.
Frontotemporal dementia
MedGen UID:
83266
Concept ID:
C0338451
Disease or Syndrome
The clinical manifestations of MAPT-related disorders (MAPT-related tauopathies) are most typically those of frontotemporal dementia (FTDP-17), but also include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), mild late-onset parkinsonism, and dementia with epilepsy. Clinical presentation of frontotemporal dementia (FTD) is variable: some present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs, whereas others present with rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders. Onset is usually between ages 40 and 60 years, but may be earlier or later. The disease progresses over a few years into profound dementia with mutism. PSP is characterized by progressive vertical gaze palsy in combination with a prominent loss of balance at early stages of the disease. With progression, axial rigidity, dysarthria, and dysphagia become prominent, often in combination with a frontal dysexecutive syndrome. CBD is a progressive neurodegenerative disorder which affects both the frontoparietal cortex and the basal ganglia, resulting in a mild to moderate dementia in combination with asymmetric parkinsonism, ideomotor apraxia, aphasia, and an alien-hand syndrome.
Disinhibition
MedGen UID:
140859
Concept ID:
C0424296
Mental or Behavioral Dysfunction
A lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment.
Dysphasia
MedGen UID:
242346
Concept ID:
C0973461
Mental or Behavioral Dysfunction
Impairment of verbal communication skills, often resulting from brain damage.
Hyperorality
MedGen UID:
325386
Concept ID:
C1838320
Finding
A tendency or compulsion to examine objects by mouth.
Progressive language deterioration
MedGen UID:
334494
Concept ID:
C1843793
Finding
Progressive loss of previously present language abilities.
Neuronal loss in central nervous system
MedGen UID:
342515
Concept ID:
C1850496
Finding
Dilation of lateral ventricles
MedGen UID:
383904
Concept ID:
C1856409
Finding
Repetitive compulsive behavior
MedGen UID:
409891
Concept ID:
C1969697
Mental or Behavioral Dysfunction

Professional guidelines

PubMed

Burgunder JM, Finsterer J, Szolnoki Z, Fontaine B, Baets J, Van Broeckhoven C, Di Donato S, De Jonghe P, Lynch T, Mariotti C, Schöls L, Spinazzola A, Tabrizi SJ, Tallaksen C, Zeviani M, Harbo HF, Gasser T; EFNS.
Eur J Neurol 2010 May;17(5):641-8. Epub 2010 Mar 9 doi: 10.1111/j.1468-1331.2010.02985.x. PMID: 20298421

Recent clinical studies

Etiology

Léger GC, Banks SJ
Dement Geriatr Cogn Disord 2014;37(1-2):104-12. Epub 2013 Oct 10 doi: 10.1159/000354368. PMID: 24135712Free PMC Article
Baborie A, Griffiths TD, Jaros E, Momeni P, McKeith IG, Burn DJ, Keir G, Larner AJ, Mann DM, Perry R
Arch Neurol 2012 Aug;69(8):1052-60. doi: 10.1001/archneurol.2011.3323. PMID: 22529248
Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR Jr, Parisi JE, Lucas JA, Petersen RC, Rademakers R
Brain 2012 Mar;135(Pt 3):765-83. doi: 10.1093/brain/aws004. PMID: 22366793Free PMC Article
Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC
J Neurol Neurosurg Psychiatry 2011 May;82(5):476-86. Epub 2010 Oct 22 doi: 10.1136/jnnp.2010.212225. PMID: 20971753
Mitsuyama Y, Inoue T
Neuropathology 2009 Dec;29(6):649-54. Epub 2009 Sep 22 doi: 10.1111/j.1440-1789.2009.01059.x. PMID: 19780984

Diagnosis

Perry DC, Brown JA, Possin KL, Datta S, Trujillo A, Radke A, Karydas A, Kornak J, Sias AC, Rabinovici GD, Gorno-Tempini ML, Boxer AL, De May M, Rankin KP, Sturm VE, Lee SE, Matthews BR, Kao AW, Vossel KA, Tartaglia MC, Miller ZA, Seo SW, Sidhu M, Gaus SE, Nana AL, Vargas JNS, Hwang JL, Ossenkoppele R, Brown AB, Huang EJ, Coppola G, Rosen HJ, Geschwind D, Trojanowski JQ, Grinberg LT, Kramer JH, Miller BL, Seeley WW
Brain 2017 Dec 1;140(12):3329-3345. doi: 10.1093/brain/awx254. PMID: 29053860
Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR Jr, Parisi JE, Lucas JA, Petersen RC, Rademakers R
Brain 2012 Mar;135(Pt 3):765-83. doi: 10.1093/brain/aws004. PMID: 22366793Free PMC Article
Hsiung GY, DeJesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E, Butler R, Leung B, Fok A, Rutherford NJ, Baker M, Rademakers R, Mackenzie IR
Brain 2012 Mar;135(Pt 3):709-22. Epub 2012 Feb 17 doi: 10.1093/brain/awr354. PMID: 22344582Free PMC Article
Nalbandian A, Donkervoort S, Dec E, Badadani M, Katheria V, Rana P, Nguyen C, Mukherjee J, Caiozzo V, Martin B, Watts GD, Vesa J, Smith C, Kimonis VE
J Mol Neurosci 2011 Nov;45(3):522-31. Epub 2011 Sep 3 doi: 10.1007/s12031-011-9627-y. PMID: 21892620
Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC
J Neurol Neurosurg Psychiatry 2011 May;82(5):476-86. Epub 2010 Oct 22 doi: 10.1136/jnnp.2010.212225. PMID: 20971753

Therapy

She A, Kurtser I, Reis SA, Hennig K, Lai J, Lang A, Zhao WN, Mazitschek R, Dickerson BC, Herz J, Haggarty SJ
Cell Chem Biol 2017 Jul 20;24(7):892-906.e5. Epub 2017 Jul 14 doi: 10.1016/j.chembiol.2017.06.010. PMID: 28712747Free PMC Article
Tsai RM, Boxer AL
J Neurochem 2016 Aug;138 Suppl 1:211-21. Epub 2016 Jun 15 doi: 10.1111/jnc.13640. PMID: 27306957Free PMC Article
Burrell JR, Halliday GM, Kril JJ, Ittner LM, Götz J, Kiernan MC, Hodges JR
Lancet 2016 Aug 27;388(10047):919-31. Epub 2016 Mar 14 doi: 10.1016/S0140-6736(16)00737-6. PMID: 26987909
Hughes LE, Rittman T, Regenthal R, Robbins TW, Rowe JB
Brain 2015 Jul;138(Pt 7):1961-75. Epub 2015 May 21 doi: 10.1093/brain/awv133. PMID: 26001387Free PMC Article
Arvanitakis Z
Neurologist 2010 Jan;16(1):16-22. doi: 10.1097/NRL.0b013e3181b1d5c6. PMID: 20065792Free PMC Article

Prognosis

Perry DC, Brown JA, Possin KL, Datta S, Trujillo A, Radke A, Karydas A, Kornak J, Sias AC, Rabinovici GD, Gorno-Tempini ML, Boxer AL, De May M, Rankin KP, Sturm VE, Lee SE, Matthews BR, Kao AW, Vossel KA, Tartaglia MC, Miller ZA, Seo SW, Sidhu M, Gaus SE, Nana AL, Vargas JNS, Hwang JL, Ossenkoppele R, Brown AB, Huang EJ, Coppola G, Rosen HJ, Geschwind D, Trojanowski JQ, Grinberg LT, Kramer JH, Miller BL, Seeley WW
Brain 2017 Dec 1;140(12):3329-3345. doi: 10.1093/brain/awx254. PMID: 29053860
Léger GC, Banks SJ
Dement Geriatr Cogn Disord 2014;37(1-2):104-12. Epub 2013 Oct 10 doi: 10.1159/000354368. PMID: 24135712Free PMC Article
Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC
J Neurol Neurosurg Psychiatry 2011 May;82(5):476-86. Epub 2010 Oct 22 doi: 10.1136/jnnp.2010.212225. PMID: 20971753
Borroni B, Bonvicini C, Alberici A, Buratti E, Agosti C, Archetti S, Papetti A, Stuani C, Di Luca M, Gennarelli M, Padovani A
Hum Mutat 2009 Nov;30(11):E974-83. doi: 10.1002/humu.21100. PMID: 19655382
Velakoulis D, Walterfang M, Mocellin R, Pantelis C, McLean C
Br J Psychiatry 2009 Apr;194(4):298-305. doi: 10.1192/bjp.bp.108.057034. PMID: 19336778

Clinical prediction guides

Perry DC, Brown JA, Possin KL, Datta S, Trujillo A, Radke A, Karydas A, Kornak J, Sias AC, Rabinovici GD, Gorno-Tempini ML, Boxer AL, De May M, Rankin KP, Sturm VE, Lee SE, Matthews BR, Kao AW, Vossel KA, Tartaglia MC, Miller ZA, Seo SW, Sidhu M, Gaus SE, Nana AL, Vargas JNS, Hwang JL, Ossenkoppele R, Brown AB, Huang EJ, Coppola G, Rosen HJ, Geschwind D, Trojanowski JQ, Grinberg LT, Kramer JH, Miller BL, Seeley WW
Brain 2017 Dec 1;140(12):3329-3345. doi: 10.1093/brain/awx254. PMID: 29053860
Léger GC, Banks SJ
Dement Geriatr Cogn Disord 2014;37(1-2):104-12. Epub 2013 Oct 10 doi: 10.1159/000354368. PMID: 24135712Free PMC Article
Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC
J Neurol Neurosurg Psychiatry 2011 May;82(5):476-86. Epub 2010 Oct 22 doi: 10.1136/jnnp.2010.212225. PMID: 20971753
Borroni B, Bonvicini C, Alberici A, Buratti E, Agosti C, Archetti S, Papetti A, Stuani C, Di Luca M, Gennarelli M, Padovani A
Hum Mutat 2009 Nov;30(11):E974-83. doi: 10.1002/humu.21100. PMID: 19655382
Sakurai Y, Tsuchiya K, Oda T, Hori K, Tominaga I, Akiyama H, Bando M, Haga C, Iwata M, Mannen T
J Neurol Sci 2006 Dec 1;250(1-2):3-9. Epub 2006 Oct 11 doi: 10.1016/j.jns.2006.05.067. PMID: 17045299

Recent systematic reviews

Mishra A, Ferrari R, Heutink P, Hardy J, Pijnenburg Y, Posthuma D; International FTD-Genomics Consortium.
Brain 2017 May 1;140(5):1437-1446. doi: 10.1093/brain/awx066. PMID: 28387812
Pievani M, Pini L, Ferrari C, Pizzini FB, Boscolo Galazzo I, Cobelli C, Cotelli M, Manenti R, Frisoni GB
J Alzheimers Dis 2017;57(3):825-843. doi: 10.3233/JAD-161105. PMID: 28304293
DeLozier SJ, Davalos D
Am J Alzheimers Dis Other Demen 2016 Aug;31(5):381-8. Epub 2015 Dec 24 doi: 10.1177/1533317515618899. PMID: 26705377
Caceres BA, Frank MO, Jun J, Martelly MT, Sadarangani T, de Sales PC
Int J Nurs Stud 2016 Mar;55:71-84. Epub 2015 Oct 31 doi: 10.1016/j.ijnurstu.2015.10.016. PMID: 26612696
van Swieten JC, Heutink P
Lancet Neurol 2008 Oct;7(10):965-74. Epub 2008 Sep 2 doi: 10.1016/S1474-4422(08)70194-7. PMID: 18771956

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