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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of FTD-CHMP2B is supported by the findings of frontotemporal dementia, frontal and/or temporal atrophy on neuroimaging, family history consistent with autosomal dominant inheritance, and neuropathology showing ubiquitin-positive and TDP-43-negative cytoplasmic intraneuronal inclusions in the hippocampal dentate granule cells and in neurons in the frontal and temporal cortex. CHMP2B is the only gene known to be associated with frontotemporal dementia linked to chromosome 3. The definitive diagnosis of FTD-CHMP2B relies upon demonstration in a reserch study of either a disease-causing mutation in the CHMP2B gene or linkage to the pericentromeric region of chromosome 3.
Management. Treatment of manifestations: Partners or other caregivers need information and psychological support to manage the behavioral changes and the loss of insight and judgment in affected individuals. Agents/circumstances to avoid: The risk of motor and cognitive decline with neuroleptic drugs is considerable. Other: The selective serotonin reuptake inhibitor (SSRI) paroxetine may cause an increase in cognitive impairment; however, another SSRI, trazodone, showed a favorable effect on behavioral disturbances and agitation without cognitive decline. Thus, further studies are needed to clarify the risks/benefits of SSRI use.
Genetic counseling. FTD-CHMP2B is inherited in an autosomal dominant manner. Most individuals with FTD-CHMP2B would be expected to have an affected parent. To date, no cases resulting from de novo mutations have been identified. Each child of an individual with FTD-CHMP2B has a 50% chance of inheriting the mutation. No laboratories offering molecular genetic testing for prenatal diagnosis for FTD-CHMP2B are listed in the GeneTests Laboratory Directory; however, prenatal testing may be available for families in which the disease-causing mutation has been identified through a laboratory offering custom prenatal testing. Requests for prenatal testing for adult-onset conditions such as FTD-CHMP2B are not common.
The diagnosis of CHMP2B-related frontotemporal dementia (FTD-CHMP2B) is supported by the following findings:
Frontotemporal dementia
Frontal and/or temporal atrophy on neuroimaging:
Computed tomography (CT) or magnetic resonance imaging (MRI) show generalized cortical atrophy and ventricular enlargement [Gydesen et al 2002].
PET-CBF scanning shows a global reduction in cerebral blood flow [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 and TDP-43-negative cytoplasmic intraneuronal inclusions in the hippocampal dentate granule cells and in neurons in the frontal and temporal cortex [Holm et al, in press].
The definitive diagnosis of FTD-CHMP2B relies upon demonstration in a research study of either a disease-causing mutation in the CHMP2B gene or linkage to the pericentromeric region of chromosome 3 [Skibinski et al 2005].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. CHMP2B is the only gene known to be associated with frontotemporal dementia linked to chromosome 3.
Research testing
| Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|
| Sequence analysis | c.532-1G>A | Unknown | Research only 2 |
1. Proportion of affected individuals with a mutation(s) as classified by test method
2. No laboratories offering clinical molecular genetic testing for this disorder are listed in the GeneTests Laboratory Directory. However, clinical confirmation of mutations identified in research laboratories may be available for families in which a disease-causing mutation has been identified in a research laboratory. For laboratories offering such testing, see
.
No other phenotypes are known to be associated with mutations in CHMP2B.
CHMP2B-related frontotemporal dementia (FTD-CHMP2B) is a presenile dementia affecting the frontal and temporal cortex. The disease typically starts with subtle personality changes and slowly progressive behavioral changes, dyscalculia, and language disturbances. The disease has so far only been described in a single family which originates and resides in western Jutland, Denmark. 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 between three and 21 years. The disease progresses over a few years into profound dementia with mutism [Gydesen et al 2002, Brown et al 2004].
Behavioral changes. Disinhibition and loss of initiative are the most common presenting symptoms. Affected individuals lose interest in their environment and neglect their personal hygiene. They 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. Psychiatric features are unusual, although some individuals become depressed early in the illness.
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 State Examination (MMSE) scores are relatively good 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. Epileptic seizures have not been described in individuals with FTD-CHMP2B.
Motor neuron disease. Motor neuron disease has not been described in individuals with FTD-CHMP2B. Two different missense mutations have been found in one individual with FTD associated with amyotrophic lateral sclerosis (FTD-ALS) and one individual with ALS; however, the pathogenicity of these changes is presently unclear (see Molecular Genetics).
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 and TDP-43-negative cytoplasmic inclusions in the hippocampal dentate granule cells and in a few cortical neurons [Holm et al, in press].
Clinical presentation and neuropathologic changes vary very little in the Danish family, but the number of autopsied cases is limited to seven and tissue is only available for examination in four cases.
Penetrance appears to be nearly complete in the Danish pedigree.
There is no evidence for anticipation in FTD-CHMP2B.
CHMP2B-related frontotemporal dementia 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 frontotemporal dementia linked to chromosome 3 (FTD-3).
Subsequent extensive sequencing of candidate genes in the region resulted in identification of a mutation in the CHMP2B gene [Skibinski et al 2005] and the current designation.
FTD-CHMP2B has only been described in one large Danish kindred [Gydesen et al 2002, Skibinski et al 2005].
Following the establishment of the causative mutation in the CHMP2B gene, a number of other simplex cases (i.e., a single occurrence in a family) and familial cases of FTD have been screened for mutations [Cannon et al 2006; Momeni, Bell et al 2006; Rizzu et al 2006; Schumacher et al 2006]. Individuals with familial ALS, as well as controls, have likewise been screened for mutations in the CHMP2B gene [Parkinson et al 2006]. These studies have so far failed to reveal any cases other than the Danish family in which mutations in the CHMP2B gene can be established as fcausative.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Mutation in CHMP2B has only been identified in one large Danish kindred with frontotemporal dementia [Gydesen et al 2002, Skibinski et al 2005].
Mutations in CHMP2B are considered to be a rare cause of frontotemporal dementia as compared to mutations in MAPT (tau) and PRGN (progranulin).
Frontotemporal dementia with parkinsonism-17 (FTDP-17). Mutations in the MAPT (tau) gene 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 2007]. 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.
A hereditary form of frontotemporal dementia associated with amyotrophic lateral sclerosis (ALS) has shown linkage to chromosome 9q21-q22 [Hosler et al 2000, Morita et al 2006, Vance et al 2006]; in one family, a mutation in the IFT74 (intraflagellar transport protein 74) gene has been identified, but pathogenicity is unclear [Momeni, Schymick et al 2006].
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 focal 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.
To establish the extent of disease in an individual diagnosed with CHMP2B-related frontotemporal dementia (FTD-CHMP2B), 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
Behavioral changes and the loss of insight and judgment in individuals with FTD-CHMP2B often present a considerable burden for partners or other caregivers. Information about the disease and psychological support for partners or other caregivers is essential.
The risk of motor and cognitive decline with neuroleptic drugs is considerable.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
In persons with FTD in general, one phase II study is investigating the effect of direct current (DC) electrical polarization of the brain on frontal dysfunction; another clinical study is investigating the effects of a stimulant (dextroamphetamine) and an atypical antipsychotic (quetiapine) on behavioral symptoms.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
A recent clinical trial with the selective serotonin reuptake inhibitor (SSRI) paroxetine showed an increase in cognitive impairment in persons treated with this drug [Deakin et al 2004]. In contrast, a previous study with another SSRI, trazodone, showed a favorable effect on behavioral disturbances and agitation without cognitive decline [Lebert et al 2004]. Further studies are needed to clarify the risks/benefits of SSRI use.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
CHMP2B-related frontotemporal dementia (FTD-CHMP2B) is inherited in an autosomal dominant manner.
This section is written from the perspective that molecular genetic testing for this disorder is available on a research basis only and results should not be used for clinical purposes. This perspective may not apply to families using custom mutation analysis. —ED.
Parents of a proband
Most individuals diagnosed with FTD-CHMP2B would be expected to have an affected parent.
A proband with FTD-CHMP2B 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. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or 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 FTD-CHMP2B 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 upon 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 FTD-CHMP2B has a 50% chance of inheriting the mutation.
Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected, his or her family members may be at risk.
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 undisclosed adoption could also be explored.
Family planning. The optimal time for determination of genetic risk 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 at risk.
DNA banking. 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. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.
No laboratories offering molecular genetic testing for prenatal diagnosis of FTD-CHMP2B are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see
.
Requests for prenatal testing for adult-onset conditions such as FTD-CHMP2B 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, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| CHMP2B | 3p11.2 | Charged multivesicular body protein 2b | Alzheimer Disease & Frontotemporal Dementia Mutation Database | CHMP2B |
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence 1 |
|---|---|---|
| c.532-1G>A | -- | NM_014043.2 |
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)
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence 1 | Reference |
|---|---|---|---|
| c.85A>G | p.Ile29Val 2 | NM_014043.2 NP_054762.2 | Cannon et al 2006, Parkinson et al 2006, Rizzu et al 2006 |
| c.442G>T | p.Asp148Tyr 3 | Skibinski et al 2005 | |
| 556C>T | p.Arg186X 4 | Momeni, Rogaeva et al 2006 | |
| 618A>C | p.Gln206His 5 | 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: 3 frontotemporal dementia, 1 control
3. Cases identified: 1 frontotemporal dementia
4. Cases identified: 1 control
5. Cases identified: 1 amyotrophic lateral sclerosis
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: It is not clear at this point whether the mutation has a gain- or loss-of-function effect. Abnormal enlarged endosomal structures have been observed on overexpression of mutant CHMP2B in cell culture [Skibinski et al 2005].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
The Danish family was 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, Denmark
Peter Johansen, MD, PhD and Jørgen Nielsen, MD, PhD
Memory Disorders Research Group
Department of Neurology
Copenhagen University Hospital, Denmark
Susanne Gydesen, MD
Distriktspsykiatrien Ballerup, Denmark
Tove Thusgaard, RN
Distrikt Parkvej
Holstebro, Denmark
Elisabet Englund, MD, PhD
Department of Pathology
University Hospital of Lund, Sweden
John Collinge, MD
MRC Prion Unit
Department of Neurodegenerative Diseases
Institute of Neurology
University College London, UK
Martin Rossor, MD and Elizabeth MC Fisher, PhD
Department of Neurodegenerative Diseases
Institute of Neurology
University College London, UK
23 August 2007 (me) Review posted to live Web site
11 July 2007 (ih) Original submission
