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Frontotemporal Dementia, Chromosome 3-Linked

Synonym: FTD-3

, MD, DMSc, , MD, PhD, , MD, , MD, PhD, and , DPhil.

Author Information
, MD, DMSc
Laboratory for Experimental Neuropathology
Department of Pathology
Randers Hospital
Randers, Denmark
Institute of Clinical Medicine
Aarhus University
Aarhus, Denmark
, MD, PhD
Neurogenetics Clinic
Memory Disorders Research Group
Rigshospitalet
Copenhagen, Denmark
, MD
Department of Neurology
Addenbrooke's Hospital
Cambridge, United Kingdom
, MD, PhD
Memory Disorders Research Group
Rigshospitalet
Copenhagen, Denmark
, DPhil
Department of Neurodegenerative Disease
Institute of Neurology
University College London
London, United Kingdom

Initial Posting: ; Last Update: October 4, 2012.

Summary

Disease characteristics. Chromosome 3-linked frontotemporal dementia (FTD3) has been described in a single family from Denmark and in one individual with familial FTD3 from Belgium. It typically starts between ages 46 and 65 years with subtle personality changes and slowly progressive behavioral changes, dyscalculia, and language disturbances. Disinhibition or loss of initiative is the most common presenting symptom. The disease progresses over a few years into profound dementia with mutism. Several individuals have developed an asymmetric akinetic rigid syndrome with arm and gait dystonia and pyramidal signs that may be related to treatment with neuroleptic drugs. Disease duration may be as short as three years or longer than 20 years.

Diagnosis/testing. The diagnosis of FTD3 is supported by the clinical findings of behavioral-variant frontotemporal dementia with a positive family history consistent with autosomal dominant inheritance. Generalized cortical and central atrophy may be seen on structural neuroimaging. Neuropathology shows 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. CHMP2B is the only gene in which mutations are known to cause FTD3. The definitive diagnosis of FTD3 relies on demonstration of a disease-causing mutation in CHMP2B.

Management. Treatment of manifestations: Caregivers need information and psychological support to manage the behavioral changes and the loss of insight and judgment in affected individuals.

Genetic counseling. FTD3 is inherited in an autosomal dominant manner. The penetrance is considered to be complete; most individuals with FTD3 have an affected parent. To date, no cases resulting from de novo mutations have been identified. Each child of an individual with FTD3 has a 50% chance of inheriting the mutation. If the disease-causing mutation has been identified in the family, prenatal testing is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

The 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 Testing

Gene. 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-Linked

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
CHMP2BSequence analysis Sequence variants, including c.532-1G>C 2, 3Unknown 4

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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.

Clinical Description

Natural History

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].

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].

Genotype-Phenotype Correlations

Three different missense mutations have been found in three individuals with a lower motor neuron-predominant variant of amyotrophic lateral sclerosis termed primary muscular atrophy (PMA) [Cox et al 2010]. However, the pathogenicity of these changes is presently unclear (see Molecular Genetics and Isaacs et al [2011] for a further discussion of these missense mutations.

Penetrance

Penetrance appears to be nearly complete in the Danish family.

Anticipation

There is no evidence for anticipation in FTD3.

Nomenclature

FTD3 was originally described as familial nonspecific dementia. Molecular genetic studies published by Brown et al [1995] demonstrated linkage of the disease-causing gene in the Danish family to the pericentromeric region of chromosome 3, leading to the designation chromosome 3-linked frontotemporal dementia (FTD3).

Following identification of a causative mutation in CHMP2B [Skibinski et al 2005]; FTD3 has sometimes been referred to as CHMP2B-related frontotemporal dementia.

Prevalence

FTD3 has only been described in one large Danish kindred [Gydesen et al 2002, Skibinski et al 2005] and in one affected individual with familial FTD from Belgium [van der Zee et al 2008].

Differential Diagnosis

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].

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.

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 Manifestations

Behavioral 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.

Surveillance

Members 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Experimental 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Chromosome 3-linked frontotemporal dementia (FTD3) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with FTD3 would be expected to have an affected parent.
  • A proband with FTD3 may have the disorder as the result of a new gene mutation. To date, no cases resulting from de novo mutations have been identified.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include neurologic examination and/or molecular genetic testing. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although 100% of individuals diagnosed with FTD3 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with FTD3 has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Requests for prenatal testing for adult-onset conditions such as FTD3 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Frontotemporal Degeneration (AFTD)
    290 King of Prussia Road
    Radnor Station Building #2, Suite 320
    Radnor PA 19087
    Phone: 866-507-7222 (Toll-free Helpline); 267-514-7221
    Email: info@theaftd.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Pick's Disease Support Group
    United Kingdom
    Email: frontotemp@aol.com

Molecular Genetics

Information 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 Databases

Data 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)

600795FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED; FTD3
609512CHMP FAMILY, MEMBER 2B; CHMP2B

Normal 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

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
c.532-1G>C--NM_014043​.3
c.493C>Tp.Gln165*

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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 Significance

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences 1 Reference
c.85A>Gp.Ile29Val 2 NM_014043​.3
NP_054762​.2
Cannon 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]

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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 control

3. Cases identified: 1 primary muscular atrophy

4. Cases identified: 1 frontotemporal dementia

5. Cases identified: 1 control

6. Cases identified: 1 primary muscular atrophy

Normal 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.

References

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Suggested Reading

  1. Isaacs AM, Johannsen P, Holm I, Nielsen JE. FReJA consortium. Frontotemporal dementia caused by CHMP2B mutations. Curr Alzheimer Res. 2011;8:246–51. [PMC free article: PMC3182073] [PubMed: 21222599]

Chapter Notes

Acknowledgments

The Danish family is studied by the FReJA (Frontotemporal dementia Research in Jutland Association) Consortium that includes the authors and the following:

Anders Gade, PhD
Institute of Psychology
Copenhagen University
Copenhagen, Denmark

Jette Stokholm, neuropsychologist
Memory Disorders Research Group
Department of Neurology, Rigshospitalet
Copenhagen University Hospital
Copenhagen, Denmark

Susanne Gydesen, MD
Psychiatric Center Ballerup
Copenhagen University Hospital
Ballerup, Denmark

Troels Tolstrup Nielsen, PhD
Neurogenetics Clinic
Memory Disorders Research Group
Department of Neurology, Rigshospitalet
Copenhagen University Hospital
Copenhagen, Denmark

Tove Thusgaard, RN
Health and Social Services Distrikt Parkvej
Holstebro Municipality
Holstebro, Denmark

Elisabet Englund, MD, PhD
Department of Pathology
University Hospital of Lund
Lund, Sweden

John Collinge, MD
MRC Prion Unit
Department of Neurodegenerative Diseases
Institute of Neurology
University College London
London, UK

Martin Rossor, MD and Elizabeth MC Fisher, PhD
Department of Neurodegenerative Diseases
Institute of Neurology
University College London
London, UK

Revision History

  • 4 October 2012 (me) Comprehensive update posted live
  • 23 August 2007 (me) Review posted to live Web site
  • 11 July 2007 (ih) Original submission
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