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 (or likely 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.

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 (or likely pathogenic) variant in CHMP2B by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of a heterozygous CHMP2B variant of uncertain significance does not establish or rule out the diagnosis.

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).

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].

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.

Mode of Inheritance

CHMP2B frontotemporal dementia (CHMP2B-FTD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• To date, almost all individuals diagnosed with CHMP2B-FTD have an affected parent.
• One individual with FTD and no clear family history of neurodegenerative disease was reported to have a CHMP2B variant [Skibinski et al 2005].
• Molecular genetic testing and neurologic examination are recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the CHMP2B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.* Though theoretically possible, no instances of a proband inheriting a pathogenic variant from a parent with germline mosaicism have been reported.
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals diagnosed with CHMP2B-FTD may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

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 and/or is known to have the CHMP2B pathogenic variant, the risk that sibs will be heterozygous for the pathogenic variant is 50%.
• If the CHMP2B pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the CHMP2B pathogenic variant but are clinically unaffected on neurologic examination, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CHMP2B-FTD because of the possibility of a late onset of the disease in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with CHMP2B-FTD has a 50% chance of inheriting the CHM2B pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CHMP2B pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the CHMP2B pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of CHMP2B-FTD, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the CHMP2B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CHMP2B encodes CHMP2B (charged multivesicular body protein 2B or chromatin modifying protein 2B), which belongs to the multiprotein endosomal sorting complex required for transport-III (ESCRT-III). In combination with the related complexes ESCRT-0, ESCRT-I, and ESCRT-II, ESCRTs function sequentially in the sorting of endocytosed transmembrane proteins into multivesicular bodies (MVBs), also known as late endosomes. MVBs subsequently fuse with lysosomes to enable degradation of their contents.

Mechanism of disease causation. CHMP2B-FTD occurs through a gain-of-function mechanism. C-terminally truncated CHMP2B protein impairs trafficking in the MVB and autophagy pathways [Filimonenko et al 2007, Lee et al 2007, Urwin et al 2010, Ghazi-Noori et al 2012]. The altered protein accumulates on the endosomal membrane. This gain-of-function effect impairs fusion of endosomes with lysosomes, resulting in lysosomal pathology [Urwin et al 2010, Nielsen et al 2012, Clayton et al 2015].

The c.532-1G>C splice site pathogenic variant leads to the formation of two aberrant transcripts that code for proteins lacking the C terminus of the protein [Skibinski et al 2005] (see Table 3). A nonsense variant, c.493C>T (p.Gln165Ter), also predicted to lead to a protein lacking the C terminus, was subsequently identified in a Belgian individual with familial frontotemporal lobar degeneration [van der Zee et al 2008].

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

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

• 2 July 2020 (sw) Comprehensive update posted live
• 4 October 2012 (me) Comprehensive update posted live
• 23 August 2007 (me) Review posted live
• 11 July 2007 (ih) Original submission

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