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 ... 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 FLTD-TDP, and also noted the FTLDU is now referred to as FTLD-TDP.
Finch et al. (2009) used ELISA analysis to measure plasma GRN levels in a consecutive series of 207 patients with FTLD, 70 control individuals, 72 early-onset probable Alzheimer disease patients, and 9 symptomatic and 18 asymptomatic relatives of ... Finch et al. (2009) used ELISA analysis to measure plasma GRN levels in a consecutive series of 207 patients with FTLD, 70 control individuals, 72 early-onset probable Alzheimer disease patients, and 9 symptomatic and 18 asymptomatic relatives of GRN mutation carriers. All 8 FTLD patients with GRN loss-of-function mutations showed significantly reduced plasma GRN levels of about one-third of the levels found in non-GRN carriers and controls individuals (p less than 0.001). There was no overlap in the distribution of plasma GRN levels between the 8 GRN mutation carriers (range, 53-94 ng/ml) and 191 non-GRN mutation carriers (range, 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. ELISA analysis also identified 1 (1.4%) probable AD patient who carried a GRN mutation. The ELISA technique only identified full-length GRN, but not GRN fragments. The study demonstrated that ELISA analysis of plasma GRN can detect asymptomatic carriers of pathogenic GRN mutations.
In an Ohio family of Bavarian origin, Morris et al. (1984) described a distinct disease entity, which they termed 'hereditary dysphasic dementia,' in 10 of 16 members who lived past the age of 60. Over 3 generations, the ... In an Ohio family of Bavarian origin, Morris et al. (1984) described a distinct disease entity, which they termed 'hereditary dysphasic dementia,' in 10 of 16 members who lived past the age of 60. Over 3 generations, the disease was inherited as an autosomal dominant trait; male-to-male transmission was observed. The clinical characteristics included progressive cognitive deficits with memory loss and personality changes, severe dysphasic disturbances leading to mutism, and hyperphagia. Morris et al. (1984) suggested that the kindred reported by Kim et al. (1981) had the same disorder. This was a family of Italian extraction in which 4 of 10 members of a single generation developed dementia, dysphasia, and, in some cases, parkinsonian signs and bulimia. Froelich et al. (1997) and Basun et al. (1997) reported a large Swedish family with rapidly progressive FTD inherited in an autosomal dominant pattern. The mean age at onset was 51 years, and mean disease duration was 3 years. Four patients were described in detail. Two patients presented with speech disturbances leading to a progressive, nonfluent aphasia, 1 patient had onset symptoms of leg apraxia with akinesia and muscular rigidity, and 1 patient developed reckless driving and personality changes. All developed loss of spontaneous speech, and 3 had emotional bluntness. Cerebral perfusion was decreased in the frontal areas in all patients. Postmortem examination showed frontal lobe degeneration with spongy changes and gliosis. Skoglund et al. (2009) reported follow-up of the Swedish family reported by Froelich et al. (1997) and Basun et al. (1997) and added 6 additional affected individuals. These additional patients presented with personality and behavioral changes (2), language impairment (2), and memory impairment (2). Although there was a large variation of the initial symptoms in this family, the common pattern of clinical features included rapid disease progression and ultimately nonfluent aphasia with loss of spontaneous speech patients. Limb ataxia and parkinsonism were uncommon symptoms, and there was no motor neuron disease, although dysphagia was seen in 3 patients. Neuropathologic examination revealed frontotemporal neurodegeneration with ubiquitin and TDP43 immunoreactive intraneuronal inclusions. Molecular analysis identified a frameshift mutation in the GRN gene (138945.0016) that resulted in functional haploinsufficiency. Lendon et al. (1998) studied a kindred with the same manifestations as those in the kindred reported by Morris et al. (1984) and renamed the disorder hereditary dysphasic disinhibition dementia (HDDD). For both kindreds, the mean age of disease onset was approximately 60 years. The range of duration of disease was 5 to 11 years in the kindred reported by Lendon et al. (1998) and 4 to 22 years in the kindred reported by Morris et al. (1984). Early manifestations included gradual onset with progressive memory loss and other cognitive deficits. There were more abnormalities of language earlier in the course of disease, frequently as the initial symptom, than are typically seen in the dementia of Alzheimer disease (AD; 104300). These included hesitancy of speech, reduction in spontaneous output, diminished fluency, and dysnomia progressing to auditory and reading-comprehension deficits, and eventual mutism. Behavioral and personality changes were occasional in the kindred reported by Morris et al. (1984) and more notable in the kindred reported by Lendon et al. (1998), sometimes occurring as the initial symptoms. Disinhibition, hypersexuality, bulimia, inappropriate behavior, and unaccustomed excessive alcohol consumption was present in some patients in both kindreds. Also in both families, parkinsonian features frequently developed, usually at a later stage of the disease. Kertesz et al. (2000) reported a family with a highly penetrant form of autosomal dominant frontotemporal dementia, or 'clinical Pick disease.' Age at onset ranged from 38 to 44 years, with a rapid progression. Affected members had similar clinical features characterized by social withdrawal, lack of motivation, inappropriate behavior, disinhibition, and perseveration. Strikingly similar features were hyperorality and stealing. Kertesz et al. (2000) noted the similarities to Kluver-Bucy syndrome. Neuropsychologic examination indicated inattention, word-finding difficulties, and disorganization of memories. Rosso et al. (2001) reported a large Dutch family, previously reported by Heutink et al. (1997) with autosomal dominant frontotemporal dementia (FTD) linked to chromosome 17q21-q22 (lod score of 3.46), but without mutations in the tau gene (MAPT; 157140). Mean age at onset was 61 years, with loss of initiative and decreased spontaneous speech as the most predominant presenting symptoms. Other features included agitation and restlessness, language difficulties, and hyperorality. Krefft et al. (2003) reported 3 sibs with classic primary progressive aphasia, defined as an isolated progressive language dysfunction. Onset of word-finding and naming difficulties occurred at ages 60, 61, and 65 years, respectively. All showed left frontotemporal atrophy. The eldest sib had mild right motor impairment, including hemiparesis and mild tremor, and died mute and bedridden 12 years after onset. A younger brother had behavioral changes, and a younger sister had significant parkinsonism, cortical release signs, and dementia. She died 4 years after onset, and postmortem neuropathologic examination showed marked cortical thinning with neuronal loss, gliosis, spongiosis, and ubiquitin-positive inclusions within cortical neurons. Other features included hippocampal sclerosis and Lewy bodies in the substantia nigra, which may have represented a concurrent pathologic process. Genetic analysis excluded common mutations in the MAPT gene. Mesulam et al. (2007) reported 2 sisters with a typical presentation of primary progressive aphasia. The phenotype was an isolated aphasia beginning at ages 65 and 62 years, respectively, without other features. There was rapid progression of aphasia to complete mutism within 2 to 3 years. One sister developed a right-sided tremor, clumsiness, rigidity, and impaired motor function. Genetic analysis identified a heterozygous mutation in the GRN gene (R493X; 138945.0009) in both sisters. Gliebus et al. (2010) reported neuropathologic findings of 1 of the sisters with PPA reported by Mesulam et al. (2007). She died at the age of 67 years, 5 years after onset. She had significantly more neuronal intranuclear and cytoplasmic TDP43-positive inclusions and dystrophic neurites in the left inferior parietal lobule and superior temporal gyrus compared to the right, consistent with involvement of language areas of the brain. The findings illustrated a concordance between the aphasic phenotype in this patient and pathologic involvement of the language-related regions of the brain rather than memory-related regions. In a retrospective study, Van Deerlin et al. (2007) compared the clinical features of 9 patients with FTLDU and GRN mutations to 19 patients with the same pathologic diagnosis of FTLDU but without GRN mutations. Family history was significantly more common in those with mutations. Although both patient groups had social and personality deficits, neuropsychologic testing showed that those with a GRN mutation had a significant recognition memory deficit, whereas those without a GRN mutation had a significant language deficit. Van Deerlin et al. (2007) concluded that patients with a GRN mutation differ clinically from those with the same pathologic diagnosis but no GRN mutation. Rogalski et al. (2008) observed a significantly higher frequency of self-reported learning disabilities among 108 PPA probands (14.8%) and their first-degree relatives (29.6%) compared to 84 individuals with the behavioral variant of FTD (7.1%) and their relatives (14.3%), 154 individuals with AD (4.5%) and their relatives (10.4%), and 353 controls (1.4%) and their relatives (6.8%). PPA patients and PPA family members reported deficits specifically in the area of language, suggesting that individuals who develop PPA may have an antecedent selective vulnerability in the anatomic brain regions that underlie language. Rohrer et al. (2008) reported a large British kindred with FTLDU associated with a mutation in the GRN gene (138945.0005). The average age at disease onset was 57.8 years. All patients had clinical and radiographic features of frontotemporal lobar degeneration with behavioral changes and language deficits. Nonfluent aphasia was present in 2 patients, and 3 became mute several years into the illness. Most also had features suggestive of parietal lobe involvement, including dyscalculia, visuoperceptual/visuospatial dysfunction, and limb apraxia. Brain imaging showed extension of the atrophy to the parietal lobe. Moreno et al. (2009) reported the clinical features of 21 patients of Basque origin with FTD caused by the same heterozygous mutation in the GRN gene (138945.0019). The mean age at onset was 59.2 years (range, 42 to 71 years), and 4 of 21 patients died after a mean duration of 4.75 years. Overall, 14 (66.7%) had a diagnosis of behavioral variant FTD, 10 (47.6%) had a diagnosis of corticobasal degeneration, and 7 (33.3%) had a diagnosis of progressive nonfluent aphasia. None developed signs of motor neuron disease/ALS, but 8 with corticobasal degeneration had motor signs, including limb rigidity or apraxia and myoclonus. The most prominent behavioral symptoms were apathy, impulsivity, disinhibition, and bulimia, suggesting involvement of the medial frontal and orbitofrontal cortex. Dysgraphia, dyscalculia, apraxia, and hemineglect suggested parietal dysfunction. Kelley et al. (2010) reported a large family with autosomal dominant inheritance of FTLD associated with a heterozygous mutation in the GRN gene (154delA; 138945.0017). Of 10 affected individuals, 6 presented with early amnestic symptoms resulting in initial clinical diagnoses of Alzheimer disease or amnestic mild cognitive impairment, and 3 with frontotemporal dementia; 1 had nonspecific dementia. Neuropathologic examination of 6 individuals showed FTLD with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions, even in those with an AD diagnosis. The mean age at onset was younger in the third generation (60.7 years) than in the second generation (75.8 years). Kelley et al. (2010) noted that the presentation in some individuals with GRN-related FTLD may include Alzheimer disease-like clinical features, particularly anterograde amnesia. In an international collaborative study comparing clinical features of 97 unrelated patients with FTLD due to GRN mutations and 453 patients with FTLD who did not have GRN mutations, Chen-Plotkin et al. (2011) found clinical differences between the 2 groups. Those with GRN mutations had a younger age at disease onset (median age 58.0 vs 61.0 years), younger age at death (median age 65.5 vs 69.0 years), and less motor neuron disease (5.4% vs 26.3%). Clinical diagnoses of Parkinson disease, corticobasal syndrome, and progressive supranuclear palsy were more common in GRN mutation carriers (5.3% vs 1.3%), and more patients with GRN mutations presented with aphasia. Fifty different mutations were identified, with the most common being R493X (138945.0009), found in 18.6% of GRN cases. The A9D mutation (138945.0008) was found in 6.2% of cases and associated with an even younger age at onset (51.0 years) and more parkinsonian features compared to those with other GRN mutations. - Neuropathologic Findings Morris et al. (1984) reported that complete neuropathologic examination of 4 of their patients showed asymmetric focal cerebral atrophy (characteristic of Pick disease), neuritic plaques (characteristic of Alzheimer disease), and depletion of neurons in the pigmented nuclei of the brainstem (characteristic of paralysis agitans). There was also cortical neuronal loss, nonspecific spongiform degeneration of the external layers of cerebral cortex, and reactive gliosis. Pick cells and Pick bodies were absent, and in 1 patient, Lewy bodies were present in nigral neurons. Transmissibility studies were negative. Morris et al. (1984) concluded that this is a distinct entity but 'may be best considered as part of a Pick-Alzheimer spectrum of cortical neuronal degenerations.' Behrens et al. (2007) provided neuropathologic analysis of another member of the family reported by Morris et al. (1984). She had a disease course similar to that of other family members, with onset at age 62 years of personality changes and disinhibition, followed by nonfluent dysphasia and memory loss that progressed to mutism and total dependence, with death at age 84. There was severe generalized brain atrophy. Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in the frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and neurofibrillary tangles in the parietal and occipital cortices. The case met neuropathologic criteria for both FTLD-U and Alzheimer disease. No Pick bodies were present. Neuropathologic examination of affected members of a family by Kertesz et al. (2000) showed severe hippocampal atrophy, frontal lobe atrophy, loss of pigmented neurons in the substantia nigra, and ubiquitin-positive inclusions that were not immunoreactive to tau or alpha-synuclein (SNCA; 163890). The authors referred to these inclusions as ITSNU. No mutations in the MAPT gene were detected. Neuropathologic examination of affected members of a family by Rosso et al. (2001) also showed ubiquitin-positive inclusions that were not immunoreactive to tau or alpha-synuclein. There were no abnormalities in tau isoform distribution. Four affected members of the large Canadian family reported by Mackenzie et al. (2006) had undergone postmortem examination. In all cases cerebral atrophy was moderate to severe and was largely restricted to the frontal lobe. There was often mild atrophy at the head of the caudate nucleus and some loss of pigmentation of the substantia nigra. Microscopic examination of the neocortex showed nonspecific chronic degenerative changes including neuronal loss and gliosis with an anterior-to-posterior anatomic gradient of severity. Apart from a small number of neurofibrillary tangles identified in 1 family member, no other pathology was identified with silver stains, or immunohistochemistry for tau, alpha-synuclein, or nonphosphorylated or phosphorylated neurofilament; specifically, there were no senile plaques, Pick bodies, Lewy bodies, glial inclusions, or achromatic neurons. In contrast, ubiquitin-immunoreactive neurites and neuronal cytoplasmic inclusions were present in the superficial laminae of the frontal and temporal neocortex in all cases. Discrete dense ubiquitin-immunoreactive neuronal intranuclear inclusions were identified in all 4 cases and had a similar anatomic distribution to the dense neuronal cytoplasmic inclusions, being most numerous in the frontal neocortex and striatum and less common in the dentate granule cells, globus pallidus, and thalamus. The number of neuronal intranuclear inclusions varied between the anatomic regions, and they were always much less numerous than the neuronal cytoplasmic inclusions. All neuronal intranuclear inclusions were reactive to SUMO1 in addition to ubiquitin, and a proportion was positive for PML, suggesting to Mackenzie et al. (2006) that these inclusions form in the nuclear body and providing a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21. Neumann et al. (2006) identified TDP43 (605078) as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal lobar degeneration and amyotrophic lateral sclerosis (see 105400). Pathologic TDP43 is hyperphosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. Neumann et al. (2006) concluded that TDP43 represents the common pathologic substrate linking these neurodegenerative disorders. Mukherjee et al. (2006) described additional neuropathologic findings of 8 affected individuals from the family reported by Lendon et al. (1998). Atrophy varied from moderate to severe and was most pronounced in the frontal lobe, with lesser degrees of atrophy in the temporal and parietal lobes. All cases had severe cortical neuronal loss, status spongiosus, and reactive astrocytosis. The hippocampus was less atrophied and showed less neuronal loss than is usually seen in Alzheimer disease. Immunohistochemical analysis showed ubiquitin-positive, tau-negative, neuronal cytoplasmic inclusions; dystrophic neurites; and neuronal intranuclear inclusions in 7 of 8 cases. Further studies showed that progranulin was not a component of any of the pathologic inclusions. Forman et al. (2006) performed a clinicopathologic assessment of 124 patients with either a clinical or pathologic diagnosis of frontotemporal dementia. Neuropathologic examination showed that 46% had a tauopathy, 29% had FTLD with ubiquitin inclusions, and 17% had findings consistent with Alzheimer disease. Patients with FTLD with ubiquitin inclusions were more likely to present with social and language dysfunction; tauopathies were more commonly associated with an extrapyramidal disorder; and AD was associated with greater deficits in memory and executive function. Davion et al. (2007) found that 4 of 9 patients with a pathologic diagnosis of FTLDU had mutations in the GRN gene (138945.0009; 138945.0012; 138945.0013). Two presented with frontotemporal dementia and 2 with primary progressive aphasia. Neuropathologic examination of all 9 cases showed that those with the GRN mutations had more frequent ubiquitinated neuronal cytoplasmic and intranuclear inclusions in the frontal lobe, temporal lobe, and striatum than those without GRN mutations, who had more neurocytoplasmic inclusions in the dentate gyrus. Grossman et al. (2007) noted that several subtypes of FTLDU had been characterized based on neuropathologic localization of TDP43-positive ubiquitin inclusions. In a retrospective review of 23 patients, the authors found notable clinical differences between the subtypes. Only 4 of the 23 patients had mutations in the GRN gene; this was a pathologic study. Patients with numerous TDP43-positive neuronal intracytoplasmic inclusions had shorter survival; patients with numerous TDP43-positive neurites had difficulty with object naming; and patients with TDP43-positive neuronal intranuclear inclusions had substantial executive deficits. Different anatomical distributions of ubiquitin pathologic features in FTLDU subgroups were consistent with their cognitive deficits.
Zhukareva et al. (2001) stated that no tau gene mutation had been detected in the family reported by Lendon et al. (1998) in which linkage to 17q21-q22 had been established. However, they identified a loss of tau protein ... Zhukareva et al. (2001) stated that no tau gene mutation had been detected in the family reported by Lendon et al. (1998) in which linkage to 17q21-q22 had been established. However, they identified a loss of tau protein by Western blot analysis of protein extracts from brain regions both with and without neuronal degeneration, and concluded that, functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene. In a series of 98 genealogically unrelated Belgian patients with frontotemporal lobar degeneration (FTLD), van der Zee et al. (2006) identified an ancestral 8-cM MAPT-containing haplotype in 2 patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 (maximum summed lod score of 5.28 at D17S931). Interestingly, the same DR2/DR8 ancestral haplotype was observed in 5 additional familial FTLD patients, indicating a founder effect. In the FTLD series, the DR2/DR8 ancestral haplotype explained 7% (7 of 98) of FTLD and 17% (7 of 42) of familial FTLD and was 7 times more frequent than MAPT mutations (1 of 98, or 1%). Clinically, DR2/DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in 1 carrier the neuropathologic diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, van der Zee et al. (2006) concluded that their results strongly suggested that the DR2/DR8 founder haplotype in 17q21 harbors a tau-negative FTLD-causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations. Baker et al. (2006) identified a frameshift mutation in exon 1 of the progranulin gene (138945.0005) in family UBC17 reported by Mackenzie et al. (2006). Baker et al. (2006) then sequenced GRN in affected individuals from an additional 41 families with clinical and pathologic features consistent with tau-negative FTD. This analysis identified an additional 7 GRN mutations in 8 families, each predicted to cause premature termination of the coding sequence. The mutations included 4 nonsense mutations, 2 frameshift mutations, and a mutation at the 5-prime site of exon 8. Cruts et al. (2006) independently found mutation in progranulin in a Belgian founder family reported by van der Zee et al. (2006): a mutation in the splice donor site of intron 0, indicating loss of mutant transcript by nuclear degradation (138945.0001). Cruts et al. (2006) also found a mutation of the initiating methionine and found that GRN haploinsufficiency leads to neurodegeneration because of reduced GRN-mediated neuronal survival. Furthermore, in a Belgian series of familial FTD patients, GRN mutations were 3.5 times more frequent than mutations in MAPT, underscoring a principal involvement of GRN in FTD pathogenesis. Both Baker et al. (2006) and Cruts et al. (2006) found a premature termination mutation in the Dutch family reported by Rademakers et al. (2002) (138945.0002). In affected members of the family with HDDD originally reported by Lendon et al. (1998), Mukherjee et al. (2006) identified a heterozygous mutation in the GRN gene (A9D; 138945.0008). Huey et al. (2006) identified a nonsense mutation in the GRN gene (R493X; 138945.0009) in 3 unrelated patients with rapidly progressive frontotemporal dementia. All had predominantly behavioral symptoms, and 2 families showed mild parkinsonism. Brain imaging of 2 patients showed frontotemporal atrophy and hypometabolism with a right-sided predominance. In the patients with primary progressive aphasia reported by Krefft et al. (2003), Mesulam et al. (2007) identified a heterozygous R493X mutation in the GRN gene. Le Ber et al. (2007) identified 9 novel null mutations in the GRN gene in 10 (4.8%) of 210 unrelated patients with frontotemporal dementia. The frequency was 12.8% (5 of 39) in familial cases and 3.2% (5 of 158) in sporadic cases. The phenotype was heterogeneous with age at onset ranging from 45 to 74 years and frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%). No GRN mutations were identified in 43 patients with a dementia and motor neuron disease. Le Ber et al. (2007) stated that 31 GRN mutations had been identified in patients worldwide. In affected members of the family originally reported by Morris et al. (1984), Mukherjee et al. (2008) identified a heterozygous mutation in the GRN gene (138945.0014). Affected members of another family with the disorder were found to carry the same mutation, and haplotype analysis indicated a founder effect. Western blot analysis showed a 50% reduction in GRN protein compared to controls, suggesting haploinsufficiency. Borroni et al. (2008) identified a pathogenic mutation in the GRN gene (138945.0015) in 4 (1.64%) of 243 unrelated Italian patients with a clinical diagnosis of FTLD. Two female patients were diagnosed with the behavioral variant of frontotemporal dementia, and 2 males with progressive nonfluent aphasia. The estimated age at onset ranged from 53 to 64 years, and all showed evidence of hypoperfusion of the frontotemporal brain regions. Three of the 4 had a family history of the disorder. Considering all patients in the study with a well-known family history for dementia, the frequency of this mutation was 6% (4 of 84). Haplotype analysis indicated a founder effect. Gijselinck et al. (2008) provided a detailed review of granulin mutations associated with frontotemporal lobar degeneration. They noted that 63 heterozygous loss-of-function mutations had been identified in 163 families worldwide, representing about 5 to 10% of FTLD. Seelaar et al. (2008) found a family history consistent with autosomal dominant inheritance in 98 (27%) of 364 probands with frontotemporal dementia. Among the familial cases, mutations in the GRN and MAPT gene were identified in 6% and 11%, respectively. Those with GRN mutations had a higher mean age at onset (61.8 years) compared to those with MAPT mutations (52.4). Neuropathologic findings, when available, were consistent with genetic analysis. In a population-based study of 59 patients with pathologically confirmed FTLDU and 433 controls, Rademakers et al. (2008) identified a C-to-T SNP (dbSNP rs5848; 138945.0018) in the 3-prime untranslated region of the GRN gene that conferred increased risk for the development of FTLDU when present in the homozygous state. Functional studies showed that the minor T allele increased binding of MIR659, a translation suppressor, providing a novel mechanism for loss of GRN function. Among 225 patients with a diagnosis of FTLD, Rohrer et al. (2009) found that 41.8% had some family history of the disorder, although only 10.2% had a clear autosomal dominant history. Those with the behavioral variant of the disorder were more likely to have a positive family history than those with the language syndromes. Mutations in the MAPT and GRN genes were found in 8.9% and 8.4% of the cohort, respectively. Yu et al. (2010) reported the results of a large collaborative study of GRN mutations involving 8 academic centers. Twenty-four pathogenic GRN mutations, including 8 novel mutations, were found among 434 patients with various forms of cognitive neurodegenerative diseases. Approximately 55% of the patients with FTD for whom information was available had a family history of the disorder. Overall, the frequency of GRN mutations was 6.9% (30 of 434) of all FTD-spectrum cases. The frequency was 21.4% (9 of 42) in those with a pathologically confirmed diagnosis of FTLD-U; 16.0% (28 of 175) of FTD-spectrum cases with a family history; and 56.2% (9 of 16) of FTLD-U with a family history. The authors noted that GRN mutations were found only in FTD-spectrum cases and not in other related neurodegenerative diseases, such as Pick disease (172700) or progressive supranuclear palsy (PSNP1; 601104). In addition, GRN mutations were not found in patients with ALS (105400) or multiple system atrophy (MSA; 146500) in whom TDP43 deposits were a neuropathologic feature. Yu et al. (2010) concluded that haploinsufficiency of GRN is the predominant mechanism leading to FTD. - Genetic Modifiers Van Deerlin et al. (2010) performed a genomewide association study of 515 individuals with FTLD-TDP and 2,509 controls from 45 clinical centers representing 11 countries. Eighty-nine (17.7%) of the patients had mutations in the GRN gene, and 23% had accompanying motor neuron disease. A significant association was found between FTLD-TDP and 12 SNPs in strong linkage disequilibrium (LD) within a 68-kb interval spanning the TMEM106B gene (613413) on chromosome 7p21.3. The most significant association was with a T-to-C transition (dbSNP rs1990662) located 6.9-kb downstream of TMEM106B (odds ratio of 0.61; p = 1.08 x 10(-11)). The findings were replicated in a cohort of 89 patients, including 10 (13.5%) with GRN mutations. When stratified by GRN mutation status, dbSNP rs1990662 still showed a significant association with FTLD-TDP, both in those with and without GRN mutations (p = 1.34 x 10(-9) and 6.90 x 10(-7), respectively). Further studies showed the T risk allele of dbSNP rs1990662 was significantly correlated with increased TMEM106B protein and mRNA expression in lymphoblastoid cell lines. Brain tissue from 18 patients with FTLD-TDP showed increased TMEM106B expression compared to controls, and this expression correlated with presence of the T risk allele; these results were found in both GRN-positive and GRN-negative individuals. The results were compatible with a model in which mutations in GRN may act upstream of TMEM106B expression in increasing the risk for FTLD-TDP. Van Deerlin et al. (2010) concluded that a locus on chromosome 7p21.3, most likely reflecting variants affecting expression of the TMEM106B gene, represents a genetic risk factor for the development of FTLD-TDP, both in patients with and without GRN mutations. Finch et al. (2011) found a significant association between SNPs in the TMEM106B gene and disease penetrance in patients with FTLD due to GRN mutations. In a group of 78 GRN mutation-positive patients, there was a highly significant decrease in the frequency of homozygous carriers of the minor alleles of 3 SNPs, with the strongest results for dbSNP rs1990662 (CC genotype frequency of 2.6% in patients vs 19.1% in controls, p = 0.009). Only 2 patients were homozygous for these SNPs, and both showed later disease onset compared to other patients. There was also a significant association between the minor alleles of these SNPs and increased plasma GRN protein levels in controls and increased GRN mRNA levels in patients and controls. There was an inverse correlation between TMEM106B levels and GRN levels. Sequencing of the TMEM106B gene identified a coding variant (thr185-to-ser, T185S, dbSNP rs3173615) that was in linkage disequilibrium with 2 of the other SNPs. Finch et al. (2011) noted that haploinsufficiency for GRN is associated with disease development, and postulated that variation in TMEM106B may alter GRN levels, thus influencing disease penetrance in mutation carriers. In a study of 50 GRN mutation carriers from 4 families with FTLD, Cruchaga et al. (2011) found a significant association between the A risk allele of dbSNP rs1990662 and earlier age at onset: those homozygous for the risk A allele had a median onset 13 years earlier than those heterozygous and homozygous for the minor G allele (p = 9.9 x 10(-7)). There was also an association between the risk allele and decreased GRN plasma levels in both mutation carriers and healthy older adults. However, unlike the findings of Van Deerlin et al. (2010), Cruchaga et al. (2011) found no association between the SNP and TMEM106B or GRN mRNA levels in frontal cortex from individuals without dementia, suggesting that the association of dbSNP rs1990662 with GRN plasma levels is not driven by changes in gene expression. The T185S variant was in perfect linkage disequilibrium with dbSNP rs1990662.
The spectrum of frontotemporal dementia associated with GRN (also known as PGRN) mutations (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. ...
DiagnosisClinical DiagnosisThe spectrum of frontotemporal dementia associated with GRN (also known as PGRN) mutations (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 behaviorLoss of manners or decorumImpulsive, rash, or careless actionsEarly apathy or inertia (one of the following must be present):ApathyInertiaEarly loss of sympathy or empathy (one of the following must be present):Diminished response to other people’s needs and feelingsDiminished social interest, interrelatedness, or personal warmthEarly perseverative, stereotyped, or compulsive/ritualistic behavior (one of the following must be present):Simple repetitive movementsComplex, compulsive, or ritualistic behaviorsStereotypy of speechHyperorality and dietary changes (one of the following must be present):Altered food preferencesBinge eating, increased consumption of alcohol or cigarettesOral exploration or consumption of inedible objectsNeuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions (all of the following must be present):Deficits in executive tasksRelative sparing of episodic memoryRelative sparing of visuospatial skillsFor the diagnosis of probable FTD-bv, all of the following must be present:Meets criteria for possible FTD-bv as aboveExhibits 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 CTFrontal 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 sub-categorize 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 have:At least one of the following core features:Agrammatism in language productionEffortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech) ANDAt least two of the three following supportive features:Impaired comprehension of syntactically complex sentencesSpared single-word comprehensionSpared object knowledgeFor an imaging-supported nonfluent/agrammatic variant (PPA-PNFA) diagnosis, both of the following criteria must be present:Clinical diagnosis of nonfluent/agrammatic variant PPAImaging that shows one or both of the following results:Predominant left posterior fronto-insular atrophy on MRIPredominant left posterior fronto-insular hypoperfusion or hypometabolism on PET or SPECTSemantic 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 namingImpaired single-word comprehension ANDAt least three of the following four additional diagnostic features:Impaired object knowledge, particularly for low frequency or low-familiarity itemsSurface dyslexia or dysgraphiaSpared repetitionSpared speech production (grammar and motor speech)For Imaging-supported PPA-SD diagnosis, both of the following criteria must be present:Clinical diagnosis of PPA-SDImaging that shows one or both of the following results:Predominant anterior temporal lobe atrophyPredominant anterior temporal hypoperfusion or hypometabolism on PET or SPECTGRN-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 TestingNeuroimaging 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 mutations 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 mutation [Whitwell et al 2007]. Volumetric studies comparing the rate of brain atrophy between FTD-GRN and FTD caused by mutations in MAPT (FTD-MAPT) showed that individuals with mutations in GRN have a higher rate of whole-brain atrophy (3.5% per year) than those with mutations in MAPT [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 TestingGene. GRN, encoding the protein granulin, is the only gene in which mutations are 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. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in GRN-Related Frontotemporal DementiaView in own windowGeneTest MethodMutations DetectedMutation Detection Frequency 1 Test AvailabilityGRNSequence analysis Sequence variants 2, 3 5% 4 Clinical Deletion / duplication analysis 5Exonic, multiexonic, or whole-gene deletion / duplication 6Unknown 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. In a series of 378 individuals with frontotemporal lobar degeneration, 23% of those with a positive family history had a GRN mutation 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 mutation [Gass et al 2006].4. In a series of 167 individuals with FTLD referred to Alzheimer Disease Research Centers (ADRC) (population sample), 5% were found to have GRN mutations. The GRN mutations were as common as mutations in the tau gene (MAPT), associated with frontotemporal dementia with parkinsonism-17 (FTDP-17) [Gass et al 2006].5. Testing that identifies 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.6. Deletion of one or more exons and of the whole gene have been reported.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo 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:1.Sequence analysis of GRN2.If no mutation is identified, deletion/duplication analysisNote: Several studies have found that a low serum or plasma progranulin level is predictive of the presence of a GRN mutation, although its use in a clinical setting has not been endorsed [Carecchio et al 2009, Ghidoni et al 2008, Schofield et al 2010, Hsiung et al 2011]. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than FTD-GRN are associated with mutations in GRN.
Frontotemporal dementia associated with GRN mutations (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]....
Natural HistoryFrontotemporal dementia associated with GRN mutations (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 mutation do not differ significantly from individuals without an identified GRN mutation (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 mutation 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 seems to occur only rarely if at all in families with GRN mutations [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].
No obvious correlations between age of onset, disease duration, or clinical phenotype and specific GRN mutations have been identified. Variability is high among persons who have the same mutation....
Genotype-Phenotype CorrelationsNo obvious correlations between age of onset, disease duration, or clinical phenotype and specific GRN mutations have been identified. Variability is high among persons who have the same mutation.If the final cellular effect of all mutations 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.
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)....
Differential DiagnosisNeuroimaging 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 GRN mutations (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 mutation 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 mutations 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. 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 mutations in 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. Mutations 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). Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with GRN-related frontotemporal dementia (FTD-GRN), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 Medical genetics consultationWhen 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 ManifestationsThere 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 cross-over 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 cross-over 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 AvoidLimited 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationA 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 ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGRN17q21.31GranulinsAlzheimer Disease & Frontotemporal Dementia Mutation Database alsod/PGRN genetic mutations GRN homepage - Mendelian genesGRNData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for GRN-Related Frontotemporal Dementia (View All in OMIM) View in own window 138945GRANULIN PRECURSOR; GRN 607485FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATEDMolecular Genetic PathogenesisTo date, evidence suggests that all GRN mutations exert their pathogenic effect through reduced progranulin protein levels by (1) loss of transcript (nonsense or frameshift mutations), (2) reduced transcription (promoter mutations), (3) loss of translation (mutation of initiating methionine), or (4) loss of protein function (missense mutations) [Baker et al 2006, Cruts et al 2006a, Gass et al 2006, van der Zee et al 2007].Normal allelic variants. A number of normal variants as well as other variants of unknown significance in GRN have been identified. Pathologic allelic variants. Over 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 mutations associated with FTD (see Alzheimer Disease & Frontotemporal Dementia Mutation Database).To date, the most frequently found mutation is g.3240C>T (p.Arg493*). 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 mutations are nonsense, frameshift, and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant 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 mutations 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 mutation in the hydrophobic core of the granulin signal peptide Missense mutations predicted in silico to affect protein folding Sequence variations in the 5' regulatory region that may affect GRN transcriptional activity All of these mutations are expected to result in loss of a functional GRN transcript and consequent haploinsufficiency.Table 2. Selected GRN Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1 )Protein Amino Acid ChangeReference Sequences c.1477C>T (g.3240C>T)p.Arg493*NM_002087 NP_002078See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal 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 GRN mutations have been identified as a cause of autosomal dominant FTD, the ubiquitin-positive inclusions are not stained by progranulin immunostaining, suggesting that most mutations do not result in production of abnormal progranulin. In fact, most mutations lead to abnormal mRNAs that are degraded by nonsense-mediated decay (i.e., null mutations). 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 FTD with GRN mutations 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.