A substantial minority of degenerative dementias, perhaps 10%, lack the distinctive pathologic features that allow subclassification as Alzheimer disease (see 104300) or other forms of dementia. In perhaps half of these cases of nonspecific dementia, there is a ... A substantial minority of degenerative dementias, perhaps 10%, lack the distinctive pathologic features that allow subclassification as Alzheimer disease (see 104300) or other forms of dementia. In perhaps half of these cases of nonspecific dementia, there is a positive family history of dementia, with an apparent autosomal dominant mode of inheritance. See also frontotemporal lobe dementia (FLDEM; 600274), which maps to chromosome 17 and is caused by mutation in the microtubule-associated protein tau gene (MAPT; 157140).
Brown et al. (1995) studied a large kindred from the Jutland region of Denmark, constituting the largest published pedigree with multiple members affected by dementia unassociated with distinctive histopathologic features. The family had previously been described by Gydesen ... Brown et al. (1995) studied a large kindred from the Jutland region of Denmark, constituting the largest published pedigree with multiple members affected by dementia unassociated with distinctive histopathologic features. The family had previously been described by Gydesen et al. (1987). Gydesen et al. (2002) provided additional clinical information on 22 affected individuals spanning 3 generations of this Danish kindred. The disease presented at an average age of 57 years with an insidious change in personality and behavior, including memory loss, cognitive decline, apathy, aggressiveness, stereotyped behavior, and disinhibition. Later in the illness, most patients developed a motor syndrome with abnormal gait, rigidity, hyperreflexia, and pyramidal signs. PET scan of 2 affected individuals revealed a global reduction in cerebral blood flow, and pathologic examination of several individuals showed generalized cerebral atrophy most prominent in the frontal and parietal lobes. Microscopic examination revealed cortical neuronal loss, astrocytosis, and white matter changes due to loss of myelin, but no plaques, fibrillary tangles, or inclusions. The authors termed the disorder FTD3 (chromosome 3-linked frontotemporal dementia). Gydesen et al. (2002) noted that the family reported by Kim et al. (1981) showed similarities to FTD3. Poduslo et al. (1999) described a patient with a family history of dementia who presented with the clinical signs of Alzheimer disease which lasted for 13 years. At autopsy, brain tissue had amyloid-containing neuritic plaques, but no fibrillary tangles (i.e., the tissue was negative for staining with tau antibody). Furthermore, genetic analysis of DNA from family members revealed no linkage with chromosome 17 markers, where another form of frontotemporal dementia (FLDEM; 600274) had been mapped. Linkage was found with chromosome 3 markers, located, however, somewhat 'downstream' from those linked in the Danish family reported by Brown et al. (1995) and Brown (1998) (see MAPPING). Poduslo et al. (1999) may thus have described a distinct entity; see 604154. Van der Zee et al. (2008) reported a Belgian woman with onset of frontotemporal dementia at age 58 years. Initial symptoms included progressive dysgraphia, memory loss, and mild disinhibition. Two years later, she had a light disorientation in space and time, severe dysgraphia, confabulation, dyspraxia, and dyscalculia. Brain CT scan showed mild frontal cortical atrophy. At the age of 64, she was clearly disoriented in space and time, her handwriting had become unreadable, and she was dyslexic with logorrhoea and perseveration. Repeat CT scan showed generalized cortical atrophy. Her mother and maternal aunt were reportedly similarly affected.
In 11 affected members of a large Danish family with frontotemporal dementia reported by Brown et al. (1995) and Gydesen et al. (2002), Skibinski et al. (2005) identified a heterozygous mutation in the CHMPB2 gene (609512.0001). The authors ... In 11 affected members of a large Danish family with frontotemporal dementia reported by Brown et al. (1995) and Gydesen et al. (2002), Skibinski et al. (2005) identified a heterozygous mutation in the CHMPB2 gene (609512.0001). The authors identified a different CHMPB2 mutation (609512.0002) in a single unrelated patient with nonspecific dementia. Momeni et al. (2006) did not identify pathogenic mutations in the CHMPB2 gene in 128 probands with frontotemporal dementia in whom MAPT mutations had been excluded. A truncating mutation in the CHMPB2 gene was identified in 2 middle-aged unaffected Afrikaner individuals from a large affected family; however, their affected father and 5 affected paternal relatives did not have the mutation. The maternal side of the family had no reported dementia. Momeni et al. (2006) noted that the large Danish family reported by Skibinski et al. (2005) had a similar truncating mutation in the CHMPB2 gene, which resulted from a different nucleotide change. The findings raised questions about the pathogenicity of the CHMPB2 mutation identified by Skibinski et al. (2005) and suggested that CHMPB2 mutations are not a common cause of frontotemporal dementia. Cannon et al. (2006) did not identify pathogenic CHMPB2 mutations in 141 familial frontotemporal probands from the U.S. and U.K. In addition, the splice site mutation reported by Skibinski et al. (2005) was not found in 450 control individuals. Van der Zee et al. (2008) identified a truncating mutation in the CHMPB2 gene (609512.0004) in a Belgian patient with autosomal dominant frontotemporal lobar degeneration.
The diagnosis of chromosome 3-linked frontotemporal dementia (FTD3) is supported by the following findings:...
DiagnosisClinical DiagnosisThe diagnosis of chromosome 3-linked frontotemporal dementia (FTD3) is supported by the following findings:Frontotemporal dementia Generalized atrophy on neuroimaging: Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical and central atrophy and ventricular enlargement [Gydesen et al 2002]. PET-CBF scanning shows a global reduction in cortical cerebral blood flow with sparing of the visual cortex and basal ganglia [Gydesen et al 2002]. Family history of frontotemporal dementia in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance Neuropathology showing ubiquitin-positive, TDP-43-negative, and FUS-negative cytoplasmic intraneuronal inclusions in the hippocampal dentate granule cells and in neurons in the frontal and temporal cortex [Holm et al 2007, Holm et al 2009]The definitive diagnosis of FTD3 relies on demonstration of a disease-causing mutation in CHMP2B [Skibinski et al 2005, Lindquist et al 2008]. Molecular Genetic TestingGene. CHMP2B is the only gene in which mutations are known to cause FTD3. Clinical testing Table 1. Summary of Molecular Genetic Testing Used in Frontotemporal Dementia, Chromosome 3-LinkedView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1 Test AvailabilityCHMP2BSequence analysis Sequence variants, including c.532-1G>C 2, 3Unknown 4Clinical1. 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. The c.532-1G>C mutation in CHMP2B, a change in the acceptor site of exon 6, has only been identified in one large Danish kindred with frontotemporal dementia [Gydesen et al 2002, Skibinski et al 2005, Lindquist et al 2008]. 4. A number of other simplex cases (i.e., a single occurrence in a family) and familial cases of FTD have been screened for mutations in CHMP2B [Cannon et al 2006, Momeni et al 2006a, Rizzu et al 2006, Ghanim et al 2010]. Individuals with ALS, as well as controls, have likewise been screened for mutations in CHMP2B [Parkinson et al 2006, Blair et al 2008, Cox et al 2010]. These studies have only revealed cases with missense mutations of currently unknown significance [Isaacs et al 2011].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 Strategy To confirm/establish the diagnosis in a proband. The definitive diagnosis of FTD3 relies on demonstration of a disease-causing mutation in CHMP2B. 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 other phenotypes are known to be associated with mutation of CHMP2B.
Chromosome 3-linked frontotemporal dementia (FTD3) is an early onset dementia affecting primarily frontal functions. The disease typically starts with subtle personality changes and slowly progressive behavioral changes, dyscalculia, and language disturbances. The disease has so far been described in a family which originates and resides in western Jutland, Denmark as well as in an affected individual with familial FTD3 from Belgium. The first description of this family was by Gydesen et al [1987]....
Natural HistoryChromosome 3-linked frontotemporal dementia (FTD3) is an early onset dementia affecting primarily frontal functions. The disease typically starts with subtle personality changes and slowly progressive behavioral changes, dyscalculia, and language disturbances. The disease has so far been described in a family which originates and resides in western Jutland, Denmark as well as in an affected individual with familial FTD3 from Belgium. The first description of this family was by Gydesen et al [1987].Symptoms usually start between ages 46 and 65 years, with an average age of onset of 57 years. Disease duration is from three to more than 20 years. The disease progresses over a few years into profound dementia with mutism [Gydesen et al 2002, Brown et al 2004].Behavioral changes. Disinhibition or loss of initiative is the most common presenting symptom. Affected individuals lose interest in their environment and neglect personal hygiene. The manifestations may vary from very disinhibited to very apathetic. Affected individuals may show inappropriate emotional responses. Hyperorality is common including overeating sweet foods and chain smoking. Restlessness, disinhibition, and lack of insight into their illness are common features. Stereotyped behavioral routines are frequent [Gydesen et al 2002, Brown et al 2004]. Psychiatric symptoms. Psychotic symptoms are probably unusual, but it is difficult to determine if a very disinhibited person is psychotic. Some individuals develop depressive symptoms early in the illness; they are typically mild. Cognitive decline. Dyscalculia can be an early feature. Spontaneous speech declines, although repetition and reading from a text is relatively preserved. Perseveration, repetitive utterances, and echolalia are common. Affected individuals develop a non-fluent aphasia and then often become mute. Route-finding problems or visuospatial problems are unusual. Mini-Mental Status Examination (MMSE) scores are relatively preserved early in the disease, followed by a sharp decline with worsening aphasia [Gydesen et al 2002, Brown et al 2004]. Extrapyramidal signs. Four years into the illness, several individuals have developed a striking motor syndrome that develops into an asymmetric akinetic rigid syndrome with arm and gait dystonia and pyramidal signs. This syndrome may be related to treatment with neuroleptic drugs [Gydesen et al 2002, Brown et al 2004]. Epilepsy. Generalized tonic-clonic epileptic seizures seem uncommon in individuals with FTD3. Motor neuron disease. Severe motor neuron disease has not been described in individuals with FTD3; however, some signs of motor neuron involvement (e.g., fasciculations) can be seen. Neuropathology. Severe generalized atrophy (predominantly in the frontotemporal region) is seen; brain weight is below 1000 g. Microscopic analysis reveals neuronal loss, gliosis, and spongiosis in the superficial cortical layers.Immunohistochemical analysis shows pathologic accumulation of ubiquitin-positive, TDP-43-negative and FUS-negative cytoplasmic inclusions in the hippocampal dentate granule cells and in a few cortical neurons [Holm et al 2007, Holm et al 2009]. The neuropathology is currently classified as FTLD-UPS [Mackenzie et al 2010].
Mutation in CHMP2B has only been identified in one large Danish kindred with frontotemporal dementia [Gydesen et al 2002, Skibinski et al 2005, Lindquist et al 2008], and an affected individual with familial FTD3 from Belgium [van der Zee et al 2008]. ...
Differential DiagnosisMutation in CHMP2B has only been identified in one large Danish kindred with frontotemporal dementia [Gydesen et al 2002, Skibinski et al 2005, Lindquist et al 2008], and an affected individual with familial FTD3 from Belgium [van der Zee et al 2008]. Mutations in CHMP2B are considered to be a much rarer cause of frontotemporal dementia than mutations in MAPT (encoding tau), GRN (encoding progranulin), or C9orf72.Frontotemporal dementia with parkinsonism-17 (FTDP-17). Mutations in MAPT (encoding tau) are causative. The resulting frontotemporal dementia can be associated with extrapyramidal signs (rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders) [Foster et al 1997, Bird et al 1999, van Swieten et al 2010]. Symptoms usually start 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 may be up to 20 to 30 years. Inheritance is autosomal dominant. GRN-related frontotemporal dementia (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]. The age of onset of FTD-GRN ranges from 48 to 83 years with a mean of 59±7 years. Inheritance is autosomal dominant. Inclusion body myopathy associated with Paget disease of bone (PDB) and/or 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; pathologic fractures occur on occasion. 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. Inheritance is autosomal dominant. C9orf72-related frontotemporal dementia is characterized by adult-onset rapidly progressive features of frontotemporal dementia, amyotrophic lateral sclerosis, or a combination of both in one individual. This condition demonstrates significant intrafamilial variability. It is caused by an expanded hexanucleotide repeat in the noncoding region of the open reading frame 72 gene on chromosome 9 [DeJesus-Hernandez et al 2011, Renton et al 2011]. The above differential diagnoses can be ruled out by neuropathologic examination (as each entity shows distinct characteristics [Cairns et al 2007]) or by molecular genetic testing.Other considerations. Structural imaging may show a frontal preponderance of the generalized atrophy and may exclude other causes of dementia (e.g., frontal meningeoma, chronic subdural hematoma). The diagnosis of Alzheimer disease should be considered in individuals with mild behavioral changes, prominent memory disturbance and loss of initiative, or word-finding problems in the absence of evident frontotemporal atrophy on neuroimaging (see Alzheimer Disease Overview). Other familial neurologic diseases associated with dementia such as Huntington disease and dementia with Lewy bodies also need to be considered. Non-genetic acquired causes of dementia should always be considered. 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 in an individual diagnosed with chromosome 3-linked frontotemporal dementia (FTD3), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with chromosome 3-linked frontotemporal dementia (FTD3), the following evaluations are recommended:A general medical history and family history Physical and neurologic examination Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination Genetic counseling Treatment of ManifestationsBehavioral changes and the loss of insight and judgment in individuals with FTD3 often present a considerable burden for caregivers. Information about the disease and psychological support for partners or other caregivers is essential.The behavioral and psychological symptoms (BPSD) should be treated as in other types of FTD. There is no consensus treatment guideline for FTD3. In clinical practice those affected individuals who present with very aggressive symptoms have proven quite difficult to treat and have in some cases required high doses of antipsychotics and/or antidepressants in order to relieve the physical aggressiveness.SurveillanceMembers of the Danish family with FTD3 are followed in the Copenhagen Memory Disorders Clinic, a multidisciplinary clinic involving neurologic and psychiatric services, genetic counseling, molecular genetic testing, and clinical diagnostic and follow-up medical service. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationExperimental studies with gene therapy are ongoing [Nielsen et al 2012].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. Frontotemporal Dementia, Chromosome 3-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCHMP2B3p11.2Charged multivesicular body protein 2bAlzheimer Disease & Frontotemporal Dementia Mutation Database alsod/CHMP2B genetic mutations ALS mutation database CHMP2B homepage - Mendelian genesCHMP2BData 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 Frontotemporal Dementia, Chromosome 3-Linked (View All in OMIM) View in own window 600795FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED; FTD3 609512CHMP FAMILY, MEMBER 2B; CHMP2BNormal allelic variants. CHMP2B comprises six exons. While no normal allelic variants are known, there are missense mutations of unknown clinical significance, some of which may in future be demonstrated to be normal variants. Pathologic allelic variants. The c.532-1G>C mutation is a splice site mutation leading to the formation of two aberrant transcripts that code for proteins lacking the C terminus of the protein [Skibinski et al 2005] (Table 2). A c.493C>T nonsense mutation also predicted to lead to a protein lacking the C terminus was subsequently identified in a Belgian individual with familial frontotemporal lobar degeneration (FTLD) [van der Zee et al 2008].Table 2. Selected CHMP2B Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencec.532-1G>C--NM_014043.3c.493C>Tp.Gln165*See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Allelic variants of unknown clinical significance. The following variants have been identified in a few cases; their clinical significance has yet to be demonstrated (Table 3).Table 3. Selected CHMP2B Allelic Variants of Unknown Clinical SignificanceView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences 1 Referencec.85A>Gp.Ile29Val 2 NM_014043.3 NP_054762.2Cannon et al [2006] Parkinson et al [2006] Rizzu et al [2006] Cox et al [2010] c.311C>Ap.Thr104Asn 3 Cox et al [2010]c.442G>Tp.Asp148Tyr 4 Skibinski et al [2005] 556C>Tp.Arg186* 5 Momeni et al [2006b] 618A>Cp.Gln206His 6 Parkinson et al [2006] See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Reference sequence (www.ncbi.nlm.nih.gov/Genbank)2. Cases identified: 2 frontotemporal dementia, 1 frontotemporal dementia-amyotrophic lateral sclerosis, 2 primary muscular atrophy, 1 control3. Cases identified: 1 primary muscular atrophy4. Cases identified: 1 frontotemporal dementia5. Cases identified: 1 control6. Cases identified: 1 primary muscular atrophyNormal gene product. The CHMP2B protein appears to be part of the ESCRT-III complex, which is required for formation of the multivesicular body. CHMP2B is an abbreviation of charged multivesicular body protein 2B (also known as chromatin modifying protein 2B). Human CHMP2B belongs to a set of class E Vps proteins that form three separate heteromeric protein complexes: ESCRT-I, ESCRT-II, and ESCRT-III. These protein complexes are transiently recruited from the cytoplasm to the endosomal membrane where they function sequentially in the sorting of the transmembrane proteins into the multivesicular bodies (MVB) pathway. Abnormal gene product. C-terminally truncated mutant CHMP2B protein impairs trafficking in the MVB and autophagy pathways [Filimonenko et al 2007, Lee et al 2007, Urwin et al 2010]. Expression of a C-terminally truncated mutant CHMP2B in transgenic mice recapitulates aspects of the neuropathology observed in the brains of individuals with FTD3 including p62- and ubiquitin-positive, TDP-43 and FUS-negative inclusions [Ghazi-Noori et al 2012]. This suggests that the C-terminal truncation drives the neuropathologic changes observed in FTD3, but loss of function of CHMP2B could still contribute to other aspects on the disease phenotype.