Frontotemporal Dementia

A number sign (#) is used with this entry because this form of frontotemporal dementia (FTD) is caused by mutation in the gene encoding microtubule-associated protein tau (MAPT; 157140) on chromosome 17q21. Most cases are caused by heterozygous mutation, although rare homozygous mutations have been reported.

Description

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 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 been collectively 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 FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLD mapping to chromosome 3 (600795), caused by mutation in the CHMP2B gene (609512); 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 FTDALS (105550), caused by mutation in the C9ORF72 gene (614260) on 9p.

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).

Clinical Features

Schmitt et al. (1984) reported a family in which 10 individuals had amyotrophic lateral sclerosis, parkinsonism-dementia or both. The proband was a 59-year-old man who died after a 14-year course of an illness characterized by progressive dementia, parkinsonism, and ALS. The affected persons were rather widely separated in the family, suggesting to the authors recessive inheritance 'with genetic epistasis.' The pathologic features consisted particularly of Alzheimer neurofibrillary tangles in many areas.

Wszolek et al. (1992) reported a large kindred in which 32 members in 8 generations had a neurodegenerative disorder characterized by progressive parkinsonism with dystonia, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, perseverative vocalizations, and urinary incontinence. The course was exceptionally 'aggressive'; onset of symptoms and death consistently occurred in the fifth decade. In the 4 patients so studied, positron emission tomographic (PET) studies with labeled 6-fluoro-L-DOPA (6FD) demonstrated markedly reduced striatal uptake of the 6FD. Autopsy findings included severe neuronal loss with gliosis in substantia nigra, pontine tegmentum, and globus pallidus, with less involvement of the caudate and the putamen. There were no plaques, tangles, Lewy bodies, or amyloid bodies. The pedigree was entirely consistent with autosomal dominant inheritance. Wszolek et al. (1992) proposed the designation autosomal dominant parkinsonism and dementia with pallidopontonigral degeneration (PPND). Wijker et al. (1996) stated that the kindred described by Wszolek et al. (1992) contained 34 affected individuals over 9 generations. The onset of the disease varied from 32 to 58 years. Wijker et al. (1996) estimated that the disease penetrance was 15% by age 40, 80% by age 45, and more than 90% after 50.

Delisle et al. (1999) reported 2 brothers from a French family who presented early in the fourth decade with a neurodegenerative disorder characterized by an akinetic rigid syndrome and dementia. There was widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brainstem nuclei, and white matter.

Yamaoka et al. (1996) described FLDEM as characterized by behavioral and neuropsychologic features reflecting frontal lobe dysfunction. The changes in behavior and personality that are observed within this clinical category may not present as a distinct phenotype and may even suggest other diagnoses such as schizophrenia, amyotrophy, depression, or dysphasia among various affected members of a family (Lynch et al., 1994).

Lynch et al. (1994) described 13 affected individuals, 6 of whom were living, in family Mo. The mean age of onset was 45 years. Personality and behavioral changes, including the Kluever-Bucy syndrome, were the first symptoms in 12 individuals. All affected individuals demonstrated rigidity, bradykinesia, and postural instability. Mean duration of the disease was 13 years. Genetic etiology was suspected because of the familial clustering in family Mo, despite their wide geographic distribution. Clinical features of individual family members suggested a variety of unrelated clinical diagnoses. Two members who had died before the study was initiated had been institutionalized and carried the diagnosis of schizophrenia. Five family members had depression or alcoholism as young adults. A clinical diagnosis of amyotrophy was made in another. In retrospect, when all the cases were viewed as a group, there was a common theme. Disinhibition occurred early in the disease course. This was manifested by alcoholism, hyperreligiosity, inappropriate sexual behavior, excessive eating, and shoplifting. Curiously, many exhibited a pattern of hoarding and craving of sweets. Eventually, all affected family members developed frontal lobe dementia, affecting behavior and judgment more than language and praxis, and parkinsonism.

Yamaoka et al. (1996) studied a family in which members of 3 generations (and by implication a fourth earlier generation) suffered from FLDEM. Clinical features were summarized for 13 patients; autopsy information was available for 3. The proband had onset of symptoms at age 52 years. Early difficulties included 'depression,' personality changes, and multiple physical complaints, including difficulty with walking. Family members described the patient as severely amotivational, apathetic, and sometimes explosively irritable. He showed impairments in naming, visuoperception, and executive functions, but the rapid forgetting and apraxia typical of AD were not observed. Brain magnetic resonance imaging was normal. Resting-state fluorodeoxyglucose positron-emission tomography showed reduced uptake in the anterior portion of the frontal and temporal lobes but no diffuse hypometabolism and no reduction of the parietotemporal cortices as is typical in AD. The average age of onset of the disorder in this family was 54.9 years, with a range of 45 to 63 years. The average duration of disease in 5 individuals on whom data were available was 9.2 years. Although impaired memory abilities were reported, problems with judgment and problem solving, perseveration, lack of insight, and poor social awareness were more prominent.

Murrell et al. (1997) described an autosomal dominant presenile dementia affecting 39 individuals in 7 generations. In the affected members of the family, clinical symptoms began at an average age of approximately 48 years. The presenting clinical features included disequilibrium, neck stiffness, dysphagia, and memory loss. As the disease progressed, further cognitive decline, superior gaze palsy, and dystaxia were also observed. The average duration from onset of symptoms to death was approximately 10 years.

Iijima et al. (1999) described a family with presenile dementia in a mother and her 2 sons. Mean age of onset was 35 years. All 3 patients presented with personality changes progressing to impaired cognition and memory, as well as disorientation. Later, they became mute and apathetic. Iijima et al. (1999) suggested that the clinicopathologic findings were different from those usually described with FTDP17, even though they found a ser305-to-asn amino acid substitution in the tau gene (157140.0010; see MOLECULAR GENETICS). They thought that the features in their family resembled those found in sporadic corticobasal degeneration. They pointed to the report by Brown et al. (1996) of a case of familial corticobasal degeneration with similarities to their family.

Wilhelmsen et al. (2004) reported a family in which at least 6 members spanning 2 generations had a neurodegenerative illness comprising frontotemporal dementia and features of amyotrophic lateral sclerosis (FTD-ALS). Four other members were reportedly affected. Frank disease onset was in the sixth decade, with a rapid progression to death within a few years; however, some patients showed frontal and anterior temporal lobe dysfunction from earlier in life. Variable clinical features included personality changes, cognitive decline, and variable motor dysfunction characterized by weakness, dysarthria, hyperreflexia, and/or parkinsonism. Wilhelmsen et al. (2004) emphasized the motor abnormalities in this family and noted that the predilection for ALS, not dementia, first brought the family to neurologic attention.

Doran et al. (2007) reported a large family from Liverpool, England, in which 8 individuals had frontotemporal dementia associated with the MAPT intron 10 +16 mutation (157140.0006). All patients were initially diagnosed with Alzheimer disease because of presentation of memory deficits and word-finding difficulties. Prototypic features of frontotemporal dementia, such as disinhibition and personality changes, were not noted initially. Doran et al. (2007) noted the phenotypic variability of this mutation.

Josephs et al. (2009) suggested that there are 2 distinct subtypes of right temporal variant frontotemporal dementia, in which the right temporal lobe is the most atrophic region on brain imaging. Among 20 individuals with these imaging findings, 12 had the behavioral variant of FTD, and 8 had semantic dementia. In the behavioral variant group, the most common features were personality change and inappropriate behavior, whereas in the semantic dementia group, the most common features were prosopagnosia, word-finding difficulties, comprehension problems, and topographagnosia. Brain imaging also showed that the behavioral variant group had greater volume loss in the frontal lobes compared to the semantic group, whereas the semantic group showed greater fusiform loss. All 8 behavioral variant patients with pathologic/genetic studies showed abnormalities in the tau protein, including 7 with MAPT mutations, whereas all 3 with semantic dementia studied showed abnormalities in TDP43. These findings suggested that there may be 2 subtypes of right temporal variant frontotemporal dementia.

Neuropathologic Findings

Neuropathologic examination of 6 affected family members by Lynch et al. (1994) demonstrated frontotemporal atrophy and neuronal loss superficial (layer 2) spongiform change, and neuronal loss with gliosis in the substantia nigra and amygdala. Anterior horn cell loss was found in each of the 2 spinal cords examined. One of these was from a person with signs and symptoms of amyotrophy.

Yamaoka et al. (1996) performed full neuropathologic study of 1 member of a family with FLDEM (subject 37), with onset at age 45. Gross examination of the brain showed mild atrophy of the frontal, parietal, and occipital lobes, with moderate atrophy of the temporal lobe. There was severe ventricular dilatation. On microscopic examination, the distribution of cell loss was moderate to severe in the midbrain, amygdala, and entorhinal cortex, with variable involvement in the neocortex. The substantia nigra showed severe neuronal loss and moderate pigment incontinence. Lewy bodies and other inclusions were absent. Limited pathology reports available on 2 other subjects showed neuronal loss and gliosis most prominent in the temporal lobe, the third nerve nucleus, and the substantia nigra. Senile plaques, tangles, and Pick bodies were not seen.

In 9 affected individuals reported by Murrell et al. (1997), neuropathologic studies showed neuronal loss in several areas of the central nervous system, as well as argentophilic tau-immunopositive inclusions in neurons and in oligodendroglia.

Reed et al. (1998) presented the neuropathologic findings in affected members of the PPND kindred reported by Wszolek et al. (1992). Features included abundant ballooned neurons in neocortical and subcortical regions as well as tau-positive inclusions. Electron microscopy showed that the abnormal tau proteins formed flat twisted ribbons similar to those observed in corticobasal degeneration. Reed et al. (1998) concluded that PPND could be subcategorized into the tauopathy group of chromosome 17-linked neurodegenerative disorders.

Hutton et al. (1998) pointed out that most cases of frontotemporal dementia show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein tau, although the tau pathology varies considerably in both its quantity (or severity) and characteristics. The pathologic heterogeneity among families with FTD was emphasized by McKhann et al. (2001) and by Morris et al. (2001).

Neuropathologic examination of 1 affected family member with FTD-ALS by Wilhelmsen et al. (2004) showed cortical atrophy, atrophy of the hippocampus and amygdala, depigmentation of the substantia nigra and locus ceruleus, and both alpha-synuclein (SNCA; 163890) and tau inclusions. No mutations were identified in the MAPT gene. Protein analysis showed that the insoluble tau consisted predominantly of the 4R/0N isoform. Linkage analysis suggested a disease locus on chromosome 17q between markers D17S1862 and D17S928 (lod score of 2.05), distal to the MAPT gene.

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.

Other Features

Boeve et al. (2006) performed polysomnography on 6 affected and 5 at-risk members of the PPND family originally reported by Wszolek et al. (1992). None of the 11 individuals had a history of dream enactment behavior suggesting rapid eye movement (REM) sleep behavior disorder or electrophysiologic features of REM sleep without atonia. Neuropathologic examination of several family members showed severe neuronal loss in the substantia nigra and locus ceruleus, suggesting that these regions are not involved in REM sleep behavior disorder. REM sleep behavior disorder has been described in some patients with parkinsonism and synucleinopathies. By contrast, Boeve et al. (2006) concluded that REM sleep behavior disorder is rare in tauopathies, suggesting differences in the selective vulnerability of brainstem circuits between the synucleinopathies and tauopathies.

Using fluid attenuation inversion recovery (FLAIR) MRI, Frank et al. (2007) detected increased T2 signal and atrophy of the mesial temporal lobes bilaterally in 3 of 4 unrelated patients with the N279K MAPT mutation (157140.0009) and a family history of PPND. One of 3 patients with MRI changes was asymptomatic, as was the patient without detectable MRI changes.

Diagnosis

McKhann et al. (2001) reported on the deliberations of an international work group on the clinical and pathologic diagnosis of FTD and Pick disease. It was emphasized that the clinical course and treatment of patients with FTD are different from those of patients with AD.

Lantos et al. (2002) characterized the neuropathologic findings of 12 brains with the intronic tau 10 +16 mutation (157140.0006). They found that the lesions varied considerably in type, distribution, and severity, both between and within families, but that the hallmark lesions are tau-positive inclusions in neuronal and glial cells. Due to the variable nature of the pathologic findings, the authors suggested that definitive diagnosis requires clinical symptomatology, family history, and molecular genetics.

Mendez et al. (2007) evaluated the diagnosis and 2-year follow-up of 134 patients with suspected FTD. At 2 years, 63 patients were diagnosed with FTD, and 71 had other conditions. On initial assessment, 17.2% of patients met all 5 core criteria for the diagnosis: insidious onset and gradual progression, decline in social interpersonal conduct, impaired regulation of personal conduct, emotional blunting, and loss of insight. The positive predictive value for these criteria was 100%, but the negative predictive value was only 64% owing to many false-positives. Evidence of frontotemporal changes on neuroimaging, including MRI, SPECT, and PET scans were more sensitive (63.5 to 90.5%), but less specific (70.4 to 74.6%). Significant worsening in naming and executive function on serial neuropsychologic tests supported the diagnosis. Mendez et al. (2007) emphasized the difficulty in early diagnosis of FTD due to the variable presentation, and suggested that neuroimaging studies in addition to consensus criteria be used for more accurate diagnosis.

Cairns et al. (2007) provided a report of the consensus statement for neuropathologic diagnostic and nosologic criteria from the Consortium for Frontotemporal Lobar Degeneration.

Differential Diagnosis

Lynch et al. (1994) commented on personality changes similar to those seen in Pick disease as well as in other types of frontal lobe dementia. However, nigral and anterior horn degeneration distinguished the disorder in the Mo family from classic Pick disease. The pathologic features distinguished disinhibition-dementia-parkinsonism-amyotrophy complex from the ALS-parkinsonism-dementia complex of Guam (105500). The late amyotrophy seen in 2 of the affected individuals and the early personality changes seen in 12 of the 13 affected individuals were thought to distinguish the disorder from parkinsonism-dementia with pallidopontonigral degeneration.

Inheritance

In the pedigree described by Lynch et al. (1994), transmission was from females to either females or males; there was no opportunity for male-to-male transmission. In cases where there is familial aggregation, FLDEM appears to be inherited as an autosomal dominant disorder with age-dependent penetrance (Yamaoka et al., 1996).

Goldman et al. (2005) analyzed the family histories of 269 probands with various forms of frontotemporal dementia. The cohort included 99 patients diagnosed with FTD, 27 with FTD-ALS, 53 with semantic dementia, 29 with progressive nonfluent aphasia, 18 with progressive supranuclear palsy, and 43 with corticobasal degeneration. Those with FTD-ALS showed the highest overall positive family history (59.2%), whereas those with semantic dementia showed the lowest positive family history (17%). The pattern of inheritance in all cases was consistent with autosomal dominant.

Pathogenesis

Several neurodegenerative diseases are characterized by the presence of abundant neurofibrillary lesions within certain regions of the brain. These lesions consist of abnormal filaments that are made of microtubular-associated protein tau (MAPT) in the hyperphosphorylated state. The most common of these disorders is Alzheimer disease, in which tau-positive deposits are found in neurofibrillary tangles, neuropil threads, and neurites of plaques. Lesions made of hyperphosphorylated tau similar to those found in AD are present in Down syndrome (190685), Niemann-Pick disease type C (257220), Gerstmann-Straussler-Scheinker disease (137440), prion protein amyloid angiopathy (see 176640), etc.

Spillantini et al. (1997) described an apparently 'new' familial disease with autosomal dominant inheritance that is characterized by an abundant and widespread tau pathology in both nerve cells and glial cells in the absence of beta-amyloid deposits. They named the condition 'familial multiple system tauopathy with presenile dementia' (MSTD). The tau deposits were in the form of twisted filaments that differed in diameter and periodicity from the paired helical filaments of Alzheimer disease. They stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexisted with heparan sulfate in affected neurons and glial cells. Tau protein extracted from filaments of familial MSTD showed a minor 72-kD band and 2 major bands of 64 and 68 kD that contained mainly hyperphosphorylated 4-repeat tau isoforms of 383 and 412 amino acids. Some clinical overlap was noted with progressive supranuclear palsy (601104) and corticobasal degeneration, both conditions in which tau-positive neurofibrillary lesions are found. However, they considered MSTD to be distinct from either of these disorders.

Van Leeuwen et al. (2006) detected aberrant frameshifted proteins, APP+1 (APP; 104760) and UBB+1 (UBB; 191339), within the neuropathologic hallmarks of Alzheimer disease and other MAPT-related dementias, including Pick disease, progressive supranuclear palsy, and less commonly frontotemporal dementia. Van Leeuwen et al. (2006) postulated that accumulation of APP+1 and UBB+1, which represents defective proteasome function, contributes to various forms of dementia.

Botella-Lopez et al. (2006) found increased levels of a 180-kD reelin (RELN; 600514) fragment in CSF from 19 patients with AD compared to 11 nondemented controls. Western blot and PCR analysis confirmed increased levels of reelin protein and mRNA in tissue samples from the frontal cortex of AD patients. Reelin was not increased in plasma samples, suggesting distinct cellular origins. The reelin 180-kD fragment was also increased in CSF samples of other neurodegenerative disorders, including frontotemporal dementia, PSP, and PD.

Neumann et al. (2006) identified TDP43 as the major disease protein in both ubiquitin-positive, tau-, and alpha-synuclein-negative FTLD 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.

Mackenzie et al. (2009, 2010) provided recommendations for a classification of FTLD subtypes according to the neuropathologic findings. The 2 main neuropathologic subtypes of FTLD are those with tau-positive inclusions (FTLD-tau), caused by MAPT mutations, and those with ubiquitinated inclusions, formerly known as FTLDU. FTLDU has been found to be heterogeneous, with most cases specifically due to TDP43 (TARDBP; 605078)-positive inclusions. Mutations in the TARDBP, GRN, VCP, and TARDBP genes can all result in FTLD with TDP43-positive inclusions. Two further subtypes include FTLD-FUS (608030), characterized by FUS-positive inclusions and FTLD-UPS (600795), characterized by inclusions with immunoreactivity to the ubiquitinated proteasome system. Mackenzie et al. (2010) emphasized that this classification is based on neuropathology and does not necessarily presuppose a primary role of the signature protein in pathogenesis.

Mapping

Lynch et al. (1994) performed linkage analysis in the Mo family with microsatellite polymorphisms associated with HOX2B, giving a maximum lod score of 3.03 at theta = 0.0, and with GP3A, giving a maximum lod score of 3.28 at theta = 0.0. This localized the disorder to chromosome 17q21-q23. By linkage studies, Wilhelmsen et al. (1994) mapped the disinhibition-dementia-parkinsonism-amyotrophy complex locus in this family to a 12-cM (sex averaged) region between D17S800 and D17S787 on 17q21-q22.

In the large kindred with PPND described by Wszolek et al. (1992), Wijker et al. (1996) found linkage to chromosome 17q21 (maximum lod score of 9.08 at marker D17S958). Multilocus analysis positioned the disease gene in a region of approximately 10 cM between D17S250 and D17S943. Wijker et al. (1996) suggested that PPND and DDPAC may originate from mutations in the same gene.

In a family with FLDEM studied at Duke University and referred to as DUK1684, Yamaoka et al. (1996) demonstrated linkage to 17q21 with a multipoint location score of 5.52. Yamaoka et al. (1996) suggested that FLDEM, DDPAC, and PPND are allelic disorders.

In 3 unrelated families with autosomal dominant frontotemporal dementia, Heutink et al. (1997) reported linkage to markers in 17q21-q22, with a maximum lod score of 4.70 at theta = 0.05 with marker D17S932. The disorder in 1 of these families had previously been reported as hereditary Pick disease, inappropriately in the view of the authors, because there was no histologic evidence of Pick bodies. They recommended that the term Pick disease be reserved for those cases of frontotemporal dementia with histologic Pick bodies.

Spillantini et al. (1997) stated that preliminary results of a genomic screen suggested that MSTD is linked to 17q21, the same region where the tau gene localizes. They noted that frontotemporal dementia with parkinsonism had been linked to chromosome 17 in unpublished studies.

In the 7-generation family studied by Murrell et al. (1997), a limited genomic screen by use of DNA samples from 28 family members localized the gene for this disorder to a 3-cM region on chromosome 17, between markers THRA1 (190120) (which maps to 17q11.2) and D17S791. Other disorders that map to the same region include DDPAC/FLDEM, pallidopontonigral degeneration, and familial progressive subcortical gliosis (221820). All of these disorders may be allelic, though they do show some differences in clinical and pathologic features.

According to Hutton et al. (1998), 13 families had been described with autosomal dominant frontotemporal dementia with parkinsonism linked to chromosome 17; they symbolized the disorder FTDP17 and stated that the same disorder has historically been termed Pick disease. In addition to those already mentioned, families were reported by Wilhelmsen et al. (1994), Wijker et al. (1996), Foster et al. (1997), Baker et al. (1997), and Dark (1997).

In a genomewide association study in 1,713 individuals of European ancestry with Parkinson disease and 3,978 controls, followed by replication in 3,361 cases and 4,573 controls, Simon-Sanchez et al. (2009) identified association with the MAPT gene (157140) on 17q21 (rs393152, OR = 0.77, p = 1.95 x 10(-16)).

Molecular Genetics

Mutations in the MAPT Gene

Hutton et al. (1998) sequenced the MAPT gene in 13 families with FTDP17 and identified 3 missense mutations (gly272 to val, 157140.0002; pro301 to leu, 157140.0001; and arg406 to trp, 157140.0003) and 3 mutations in the 5-prime splice site of exon 10. The splice site mutations all destabilized a potential stem-loop structure that is probably involved in regulating the alternative splicing of exon 10. This causes more frequent use of the 5-prime splice site and an increased proportion of tau transcripts that include exon 10. The increase of exon 10+ mRNA was expected to increase the proportion of tau transcripts containing 4 microtubule-binding repeats, which is consistent with the neuropathology described in families with FTDP17. In the kindred studied by Wilhelmsen et al. (1994) and Lynch et al. (1994), Hutton et al. (1998) demonstrated a splice donor site mutation in the MAPT gene (157140.0004).

In affected members of the PPND kindred reported by Wszolek et al. (1992), Clark et al. (1998) identified a heterozygous mutation in the MAPT gene (N279K; 157140.0009). Delisle et al. (1999) identified the N279K mutation in 2 French brothers with parkinsonism and dementia. Tsuboi et al. (2002) compared the clinical phenotypes of the original American family reported by Wszolek et al. (1992) and the French family reported by Delisle et al. (1999). The families shared many features, including autosomal dominant inheritance, age of onset and disease duration, parkinsonism, personality changes, dementia, pyramidal signs, and eye movement abnormalities.

In 1 of the families initially reported by Lanska et al. (1994) as having early-onset progressive frontal lobe dementia associated with prominent subcortical gliosis (221820), Petersen et al. (1995) found linkage to chromosome 17q21-q22. Although Petersen et al. (1995) originally described diffuse prion plaques and protease-resistant prion fragments in members of 1 of the families reported by Lanska et al. (1994), no mutations were identified in the PRNP gene. Gambetti (1997) later excluded prion pathology upon revisiting this family. Goedert et al. (1999) identified a heterozygous mutation in the MAPT gene (157140.0006) in affected members of this family, indicating a diagnosis of tau-related frontotemporal dementia. Neuropathologic examination showed hyperphosphorylated tau in both neurons and glial cells. Ultrastructurally, the tau filaments were characterized by wide twisted ribbons made of 4-repeat tau isoforms. Goedert et al. (1999) noted that phenotypic heterogeneity associated with MAPT mutations has led to classification of related diseases into distinct entities.

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.

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.

Mutation in the PSEN1 Gene

Raux et al. (2000) reported 6 members of a family with early-onset frontotemporal dementia, confirmed by imaging studies, with autosomal dominant inheritance. In 2 patients available for testing, the authors found a novel heterozygous mutation in the presenilin-1 gene (L113P; 104311.0023).

Genetic Modifiers and Susceptibility Alleles

Short et al. (2002) determined the tau haplotype frequencies and APOE (107741) allele frequencies in 63 patients with sporadic disease categorized by clinical subtype of frontotemporal lobar degeneration (FTLD). The clinical subtypes are determined by the distribution of pathologic findings: in the frontal lobe, frontotemporal dementia (FD) and progressive nonfluent aphasia (PA), and in the temporal lobes, anomic aphasia (AA) in the left, and visual aphasia in the right. No tau mutations were found. Short et al. (2002) found that the APOE4 allele and the tau H2 haplotype were more common in patients with AA than FD. The tau H2 haplotype was more common in APOE4-positive patients with AA and less common in APOE4-negative patients with FD. Thus, there are genetic differences between the clinical subtypes of FTLD. In addition, the increase of tau H2 frequency in patients with an APOE4 allele and AA suggested that there may be an interaction between these 2 genes, resulting in a specific clinical phenotype.

Verpillat et al. (2002) found that the H1/H1 tau genotype was significantly overrepresented in 100 patients with frontotemporal dementia compared to controls (odds ratio for H1/H1 = 1.95). In addition, there was a significant negative effect in carriers of both the H1/H1 genotype and the APOE2 allele.

Verpillat et al. (2002) determined the APOE genotype frequencies in 94 unrelated patients with frontotemporal dementia and 392 age- and sex-matched controls without cognitive deficits or behavioral disturbances (after excluding 6 patients with autosomal dominant inheritance and mutation in the MAPT gene). Homozygosity for the E2E2 genotype was significantly associated with frontotemporal dementia (odds ratio = 11.3, P = 0.033, exact test) but based on very few subjects (3 patients and 1 control). The result was even more significant in the group with a positive familial history (odds ratio = 23.8, P = 0.019, exact test). For the metaanalysis of the APOE polymorphism in frontotemporal dementia, Verpillat et al. (2002) pooled 10 case-control studies with available genotype or allele information (total of 364 patients and 2,671 controls), but the E2E2 genotype did not reach statistical significance. Because of heterogeneity, Verpillat et al. (2002) analyzed on one hand the neuropathologically-confirmed studies and on the other hand the clinical-based studies. A significant increase in the E2 allele frequency was found in the neuropathologically-confirmed patients, and heterogeneity disappeared (Mantel-Haenszel statistics). The authors concluded that the APOE E2 allele may be a risk factor for frontotemporal dementia, but that the data should be interpreted with caution due to the rarity of the E2E2 genotype.

Borroni et al. (2005) found no association between FTD and the H1 or H2 MAPT haplotypes among 86 patients with FTD and 50 control individuals. However, the findings suggested an earlier age at onset in patients carrying an H2 allele.

Among 32 patients with a clinical diagnosis of frontotemporal dementia, including 15 patient with primary progressive aphasia, Acciarri et al. (2006) found increased frequency of the APOE E2 and E4 alleles and significantly decreased frequency of the E3 allele compared to 87 control individuals. The E2E4 genotype in particular was significantly associated with primary progressive aphasia.

Genotype/Phenotype Correlations

Among 22 patients with FTLD due to a MAPT mutation, Whitwell et al. (2009) found different patterns of gray matter atrophy using MRI voxel-based morphometry. All patients showed gray matter loss in the anterior temporal lobes, with varying degrees of involvement of the frontal and parietal lobes. Within the temporal lobe, individuals with the IVS10+16 IVS10+16 (157140.0006), IVS10+3, N279K (157140.0009), or S305N (157140.0010) mutations showed gray matter loss particularly affecting the medial temporal lobes, including the hippocampus and amygdala. These mutations are all predicted to influence the alternative splicing of MAPT pre-mRNA, resulting in increased 4R tau isoforms. In contrast, patients with the P301L (157140.0001) or V337M (157140.0008) mutations showed gray matter loss particularly affecting the inferior and lateral temporal lobes, with a relative sparing of the medial temporal lobe. P301L and V337M mutation carriers also showed gray matter loss in the basal ganglia. These mutations are predicted to affect the structure and functional properties of the tau protein, which are more prone to aggregation. The different patterns suggested a potential difference in mutant protein function resulting from different pathogenic mutations.

Animal Model

To model tauopathies, Ishihara et al. (1999) overexpressed the smallest human tau isoform in the central nervous system of transgenic mice. These mice acquired age-dependent central nervous system pathology, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules, and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These transgenic mice recapitulated key features of tauopathies and provided models for elucidating mechanisms underlying diverse tauopathies.

Noting that earlier mouse models had focused on neuronal tau pathology, Higuchi et al. (2002) generated transgenic mice overexpressing human tau in glia as well as in neurons. The animals showed accumulation of abnormal tau aggregates in glial cells with progressing age, loss of neurons and glial cells, disruption of myelin sheaths, and progressive motor disturbances such as weakness and dystonia.