Chmp2b Frontotemporal Dementia
Summary
Clinical characteristics.
CHMP2B frontotemporal dementia (CHMP2B-FTD) has been described in a single family from Denmark, in one individual with familial FTD from Belgium, and in one individual with FTD and no family history. It typically starts between ages 46 and 65 years with subtle personality changes and slowly progressive behavioral changes, dysexecutive syndrome, 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 extrapyramidal symptoms and 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. Symptoms and disease course are highly variable. Disease duration may be as short as three years or longer than 20 years.
Diagnosis/testing.
The diagnosis of CHMP2B-FTD is established in a proband by identification of a heterozygous pathogenic variant in CHMP2B by molecular genetic testing.
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. Psychosocial support is essential and should include occupational therapy and environmental and physical interventions. Antipsychotics and/or antidepressants may improve physical aggressiveness. Administered antipsychotics should be reevaluated at short intervals with the goal of discontinuation as soon as feasible.
Genetic counseling.
CHMP2B-FTD is inherited in an autosomal dominant manner. Penetrance is age dependent and appears to be nearly complete; most individuals with CHMP2B-FTD have an affected parent. To date, de novo CHMP2B pathogenic variants have not been reported. Each child of an individual with CHMP2B-FTD has a 50% chance of inheriting the pathogenic variant. Once a CHMP2B pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CHMP2B-FTD are possible.
Diagnosis
Suggestive Findings
CHMP2B frontotemporal dementia (CHMP2B-FTD) should be suspected in individuals with the following:
- Frontotemporal dementia
- A neuropsychological profile of a dysexecutive syndrome, behavioral changes, lack of emotional recognition, and dyscalculia
- 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].
- Cerebral blood flow-positron emission tomography (CBF-PET) shows a global reduction in cortical CBF with sparing of the visual cortex and basal ganglia [Gydesen et al 2002].
- CBF-MRI shows a decreased CBF in occipital and parietal lobes in presymptomatic CHMP2B-FTD heterozygotes [Lunau et al 2012].
- Fluorodeoxyglucose (FDG)-PET shows globalized hypometabolism [Johannsen et al 2016].
- Family history of frontotemporal dementia in two or more first-degree relatives consistent with an autosomal dominant mode of inheritance
- Neuropathology showing p62-positive, 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]
Establishing the Diagnosis
The diagnosis of CHMP2B-FTD is established in a proband by identification of a heterozygous pathogenic variant in CHMP2B by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CHMP2B-FTD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype of familial FTD without neuropathology suggestive of CHMP2B-FTD are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and imaging findings suggest the diagnosis of CHMP2B-FTD, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of CHMP2B to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.Note: Targeted analysis for CHMP2B pathogenic variant c.532-1G>C can be performed first in individuals of Danish ancestry [Skibinski et al 2005].
- A multigene panel that includes CHMP2B and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) Given the rarity of CHMP2B-FTD some panels for dementia may not include this gene. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by frontotemporal dementia, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in CHMP2B Frontotemporal Dementia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| CHMP2B | Targeted analysis for c.532-1G>C | See footnote 3. |
| Sequence analysis 4 | All reported 3, 5 | |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
The c.532-1G>C pathogenic variant in CHMP2B, a change in the acceptor site of exon 6, has been identified in a single large Danish kindred with frontotemporal dementia [Gydesen et al 2002, Skibinski et al 2005, Lindquist et al 2008].
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
C-terminal truncations of CHMP2B appear to cause FTD [Skibinski et al 2005, Momeni et al 2006a, van der Zee et al 2008, Clayton et al 2015]. In one simplex case (i.e., a single occurrence in a family) a C-terminal truncation was reported [van der Zee et al 2008], while CHMP2B analysis in additional simplex cases and families with FTD evaluated for pathogenic variants [Cannon et al 2006, Rizzu et al 2006, Ghanim et al 2010] have only identified missense variants of uncertain significance [Isaacs et al 2011]. An apparently benign nonsense variant was identified in two unaffected members, but not identified in affected members of the same FTD family [Momeni et al 2006b].
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
Clinical Description
CHMP2B frontotemporal dementia (CHMP2B-FTD) is an early-onset dementia affecting primarily frontal lobe functions. CHMP2B-FTD typically starts with subtle personality changes, behavioral changes, dyscalculia, and a dysexecutive syndrome [Stokholm et al 2013].
To date, CHMP2B-FTD has been described in a family that originates and resides in western Jutland, Denmark. The first description of this family was by Gydesen et al [1987]. CHMP2B-FTD has also been described in an affected individual with familial FTD from Belgium [van der Zee et al 2008]. In addition, one individual from the United Kingdom with FTD and no clear family history was reported to have a CHMP2B missense variant [Skibinski et al 2005].
Symptoms usually start between ages 46 and 70 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 and a lack of empathy. Hyperorality is common including overeating sweet foods and chain smoking. Restlessness is common. Aggressiveness and hypersexuality have been described. Lack of insight into illness is common. Stereotypic speech, pacing activity, and stereotypic behavioral routines are frequent [Gydesen et al 2002, Brown et al 2004].
Psychiatric symptoms. Psychotic symptoms are 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. Manic syndromes have been observed in a few individuals.
Cognitive decline. Loss of executive function is a common early feature, as is dyscalculia and language impairment. Spontaneous speech declines, although repetition and reading from a text is relatively preserved. Perseveration, repetitive utterances, and echolalia are common. Affected individuals develop a nonfluent aphasia and then often become mute. Memory can be spared until late in the illness. Route finding and other 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, Stokholm et al 2013].
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]. Akinetic mutism has been observed in late stages of disease.
Epilepsy. Generalized tonic-clonic epileptic seizures are rare in individuals with CHMP2B-FTD.
Motor neuron disease. Severe motor neuron disease has not been described in individuals with CHMP2B-FTD; however, signs of lower motor neuron dysfunction (e.g., fasciculations) can be seen in the tongue or thigh muscles.
Neuropathology. Macroscopic examinations find severe generalized atrophy with an asymmetric and frontal preponderance; brain weight is below 1000 g [Holm et al 2007].
Microscopic analysis reveals neuronal loss, gliosis, and spongiosis in the superficial cortical layers.
Immunohistochemical analysis shows pathologic accumulation of p62-positive, 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]. Consequently, the neuropathology is currently classified as frontotemporal lobar degeneration with inclusions positive for ubiquitin proteasome system markers [Mackenzie et al 2010, Mackenzie & Neumann 2016].
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Penetrance
Penetrance is age dependent and appears to be nearly complete in the Danish family.
Nomenclature
CHMP2B-FTD was originally described as familial nonspecific dementia. Molecular genetic studies published by Brown et al [1995] demonstrated linkage of the disease-associated gene in the Danish family to the pericentromeric region of chromosome 3, leading to the designation chromosome 3-linked frontotemporal dementia (FTD3 or FTD-3).
Following identification of a causative pathogenic variant in CHMP2B [Skibinski et al 2005], FTD3 is referred to as CHMP2B-associated frontotemporal dementia, CHMP2B-mediated frontotemporal dementia, or now CHMP2B-FTD.
Prevalence
CHMP2B-FTD has been described in one large Danish family [Gydesen et al 2002, Skibinski et al 2005], in one affected individual with familial FTD from Belgium [van der Zee et al 2008], and in one individual with FTD and no family history [Skibinski et al 2005].
Differential Diagnosis
Pathogenic variants in CHMP2B have been identified in one large Danish family with frontotemporal dementia [Gydesen et al 2002, Skibinski et al 2005, Lindquist et al 2008] and in an affected individual with familial frontotemporal dementia (FTD) from Belgium [van der Zee et al 2008]. (A CHMP2B missense variant in one individual from the United Kingdom with FTD and no clear family history was also reported [Skibinski et al 2005]).
Pathogenic variants in CHMP2B are considered to be a much rarer cause of frontotemporal dementia than pathogenic variants in MAPT (encoding tau), GRN (encoding progranulin), or C9orf72.
Table 2.
Genes of Interest in the Differential Diagnosis of CHMP2B Frontotemporal Dementia (CHMP2B-FTD)
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/CHMP2B-FTD | Distinguishing from CHMP2B-FTD | |||
| APP PSEN1 PSEN2 1 | Early-onset familial Alzheimer disease (EOFAD) | AD |
| Absence of focal frontotemporal atrophy on neuroimaging |
| C9orf72 | C9orf72-ALS/FTD | AD | Adult-onset rapidly progressive features of FTD, ALS, or a combination of both |
|
| FUS | ALS 6 w/or w/o FTD | AD | MND w/FTD |
|
| GBA SNCA SNCB | Lewy body dementia (OMIM 127750) | AD |
|
|
| GRN | GRN-FTD | AD |
|
|
| HTT | Huntington disease | AD |
|
|
| MAPT | FTD w/parkinsonism-17 (OMIM 600274) | AD |
|
|
| TARDBP | TARDBP frontotemporal lobar degeneration (OMIM 612069) | AD |
|
|
| TBK1 | FTD &/or ALS 4 (OMIM 616439) | AD |
|
|
| UBQLN2 | ALS 15 w/or w/o FTD (OMIM 300857) | XL |
|
|
| VCP | Inclusion body myopathy with Paget disease of bone &/or FTD | AD |
|
|
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; FDG-PET = fluorodeoxyglucose-positron emission tomography; FTD = frontotemporal dementia; MND = motor neuron disease; MOI = mode of inheritance; PDB = Paget disease of bone; XL = X-linked
- 1.
It is likely that pathogenic variants in other genes causative of EOFAD will be identified because families with autosomal dominant FAD with no known pathogenic variants in PSEN1, PSEN2, or APP have been described [Pasanen et al 2018].
- 2.
Adult-onset proximal and distal muscle weakness in inclusion body myopathy associated w/Paget disease of bone and/or FTD clinically resembles a limb-girdle muscular dystrophy syndrome.
- 3.
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.
Other considerations
- Structural imaging may show a frontal preponderance of the generalized atrophy and will exclude other treatable causes of dementia (e.g., frontal meningioma, chronic subdural hematoma).
- Nongenetic acquired causes of dementia should always be considered.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with CHMP2B frontotemporal dementia (CHMP2B-FTD), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) 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
- Discussion of capabilities for job and for driving
- Consultation with a clinical geneticist and/or genetic counselor
- Discussion of advanced care planning
Treatment of Manifestations
Behavioral changes and the loss of insight and judgment in individuals with CHMP2B-FTD often present a considerable burden for caregivers. Information about the disease and psychological support for partners or other caregivers is essential. Caregiver support groups are valuable.
Psychosocial support is essential in the management of FTD and should include occupational therapy and environmental and physical interventions.
The behavioral and psychological symptoms should be treated as in other types of FTD. There is no consensus treatment guideline for CHMP2B-FTD. In clinical practice those affected individuals who present with very aggressive symptoms have proven quite difficult to treat and in some instances have been treated with high doses of antipsychotics and/or antidepressants in order to relieve the physical aggressiveness. Administered antipsychotics should be reevaluated at short intervals with the goal of discontinuation as soon as feasible.
Surveillance
Members of the Danish family with CHMP2B-FTD 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
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.