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GRN-related frontotemporal lobar degeneration with Tdp43 inclusions(FTD2)

MedGen UID:
375285
Concept ID:
C1843792
Disease or Syndrome
Synonyms: Dementia, hereditary dysphasic disinhibition; FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, GRN-RELATED; Frontotemporal dementia, ubiquitin-positive; FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS; FTD2; FTLD-TDP, GRN-RELATED; GRN-Related Frontotemporal Dementia
 
Gene (location): GRN (17q21.31)
 
Monarch Initiative: MONDO:0011842
OMIM®: 607485

Disease characteristics

Excerpted from the GeneReview: GRN Frontotemporal Dementia
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. [from GeneReviews]
Authors:
Ging-Yuek Robin Hsiung  |  Howard H Feldman   view full author information

Additional descriptions

From OMIM
Frontotemporal dementia-2 (FTD2) is a neurodegenerative disorder characterized by adult onset of progressive cognitive decline which shows variable phenotypic expression but most commonly presents as behavioral changes with executive dysfunction (bvFTD) and/or language deterioration. The age at onset for individuals with heterozygous GRN mutations ranges from 40 to 85 years. Gestural apraxia, parkinsonism, visual loss, and visual hallucinations are present in 25 to 40% of patients. Other variations of the phenotype have been referred to as 'dysphasic disinhibition dementia,' 'primary progressive aphasia' (PPA), or 'corticobasal degeneration.' Some patients may present with a clinical diagnosis of Alzheimer disease (AD; 104300) or Parkinson disease (PD; 168600), features of which are part of the phenotypic spectrum of this disorder. Most GRN mutations are null and lead to haploinsufficiency. Rare individuals with biallelic, likely hypomorphic mutations have been reported (Brouwers et al., 2007; Huey et al., 2006; Mukherjee et al., 2006; Mesulam et al., 2007; Huin et al., 2020). See also FTD1 (600274), caused by mutation in the MAPT gene (157140), which is also on chromosome 17q21. 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 MedlinePlus Genetics
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).  https://medlineplus.gov/genetics/condition/grn-related-frontotemporal-lobar-degeneration

Clinical features

From HPO
Aphasia
MedGen UID:
8159
Concept ID:
C0003537
Mental or Behavioral Dysfunction
An acquired language impairment of some or all of the abilities to produce or comprehend speech and to read or write.
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.
Hallucinations
MedGen UID:
6709
Concept ID:
C0018524
Mental or Behavioral Dysfunction
Perceptions in a conscious and awake state that, in the absence of external stimuli, have qualities of real perception. These perceptions are vivid, substantial, and located in external objective space.
Polyphagia
MedGen UID:
9369
Concept ID:
C0020505
Finding
A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.
Impulse control disorder
MedGen UID:
5769
Concept ID:
C0021122
Mental or Behavioral Dysfunction
Reduced ability to control, or a failure to resist a temptation, urge, or impulse. Examples include disregard for social conventions, general impulsivity, and poor risk assessment.
Mutism
MedGen UID:
6476
Concept ID:
C0026884
Disease or Syndrome
Complete lack of speech or verbal communication in a person despite attempts to engage in conversation. Mutism as a phenomena assumes the individual has previous capacity for speech and in the pediatric population it assumes that the person is past the age of typical language development.
Lewy bodies
MedGen UID:
43126
Concept ID:
C0085200
Cell Component
Intracytoplasmic, eosinophilic, round to elongated inclusions found in vacuoles of injured or fragmented neurons. The presence of Lewy bodies is the histological marker of the degenerative changes in LEWY BODY DISEASE and PARKINSON DISEASE but they may be seen in other neurological conditions. They are typically found in the substantia nigra and locus coeruleus but they are also seen in the basal forebrain, hypothalamic nuclei, and neocortex.
Neurofibrillary tangles
MedGen UID:
39273
Concept ID:
C0085400
Finding
Pathological protein aggregates formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form.
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of excessive motor activity that is associated with mental distress or a feeling of substantial unease or inner tension. Distinguished from restlessness by the increased level of emotional distress and negative intensity of the experience. Agitation has a significant level of physical activity that is typically threatening to the self or others.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
Apathy is a quantitative reduction of interest, motivation and the initiation and persistence of goal-directed behavior, where often the accompanying emotions, thoughts, and social interactions are also diminished. The individual is typically non-reactive to provocations, positive or negative, and appears to not care. Distinguished from lethargy which involves lack of physical or mental energy.
Perseverative thought
MedGen UID:
66686
Concept ID:
C0233651
Mental or Behavioral Dysfunction
The repetitive production of the same response to different commands.
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.
Personality changes
MedGen UID:
66817
Concept ID:
C0240735
Mental or Behavioral Dysfunction
An abnormal shift in patterns of thinking, acting, or feeling.
Parkinsonian disorder
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Frontotemporal dementia
MedGen UID:
83266
Concept ID:
C0338451
Disease or Syndrome
In general, frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative disorders associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104). Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also collectively been termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTD2 (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTDALS7 (600795), caused by mutation in the CHMP2B gene (609512) on chromosome 3p11; inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS1 (105550), caused by mutation in the C9ORF72 gene (614260) on 9p21. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Hyperorality
MedGen UID:
325386
Concept ID:
C1838320
Finding
Hyperorality is a condition characterized by an excessive preoccupation with oral sensations and behaviors, such as chewing, sucking, biting, swallowing, and excessive mouthing of objects.
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
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
Repetitive compulsive behavior
MedGen UID:
409891
Concept ID:
C1969697
Mental or Behavioral Dysfunction
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Amplification of sexual behavior
MedGen UID:
1853285
Concept ID:
C5873000
Individual Behavior
An abnormal increase of libido (sexual desire), typically accompanied by a higher frequency of sexual activity compared to from a person's previous norm.

Professional guidelines

PubMed

Chitramuthu BP, Bennett HPJ, Bateman A
Brain 2017 Dec 1;140(12):3081-3104. doi: 10.1093/brain/awx198. PMID: 29053785

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