Clinical characteristics.

CHMP2B-related frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) is characterized most frequently by FTD with subtle personality changes and slowly progressive behavioral changes, dysexecutive syndrome, and language disturbances. Disinhibition or loss of initiative is the most common presenting symptom. Individuals can also have features of ALS, a combined phenotype of FTD-ALS, or atypical phenotypes. Onset is typically between ages 46 and 65 years. Additional features of asymmetric akinetic rigid syndrome with arm and gait dystonia and pyramidal signs may be related to treatment with neuroleptic drugs. Clinical manifestations 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-ALS is established in a proband with suggestive findings and a heterozygous pathogenic variant in CHMP2B identified by molecular genetic testing.

Management.

Treatment of manifestations: Environmental, behavioral, and physical interventions to minimize undesired behaviors; counseling for affective disorders; selective serotonin reuptake inhibitors for affective disorders or disinhibition; serotonin and noradrenaline reuptake inhibitors for prominent apathy; atypical antipsychotics may improve physical aggressiveness. Administered antipsychotics should be reevaluated at short intervals with the goal of discontinuation as soon as feasible. Cognitive rehabilitation; management of motor neuron involvement per physical medicine and rehabilitation, occupational therapy, and physical therapy; spasmolytics for severe spasticity; psychosocial support, education, and discussion of advanced care planning.

Surveillance: At least annual neurologic examination with evaluation for behavioral and psychiatric manifestations; screening evaluation for cognitive function; physical medicine and rehabilitation and physical therapy evaluation of mobility; physical and occupational therapy evaluation of activities of daily living; assessment of caregiver and social work needs; EEG if seizures are suspected.

Genetic counseling.

CHMP2B-FTD-ALS is inherited in an autosomal dominant manner. Penetrance is age dependent and appears to be nearly complete. Almost all individuals diagnosed with CHMP2B-FTD-ALS have an affected parent. Each child of an individual with CHMP2B-FTD-ALS has a 50% chance of inheriting the pathogenic variant. Once the CHMP2B pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

CHMP2B-related frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) should be suspected in individuals with the following clinical, neuroimaging, and neuropathology findings and family history.

Clinical findings

• FTD. Early-onset dementia with progressive behavioral and personality changes or language disturbances, with a neuropsychological profile of dysexecutive syndrome. Common features include impaired emotion recognition, apathy, and stereotyped behavioral routines.
• ALS. Weakness, atrophy, fasciculations, spasticity, and hyperreflexia with coexistence of upper and lower motor neuron signs in the same region, progressing over time. Cognitive or behavioral changes may indicate FTD-ALS overlap.
• Atypical presentations mimicking other neurodegenerative disorders. Motor signs such as dystonia, pyramidal features, or myoclonus resembling parkinsonian syndromes (e.g., corticobasal syndrome, progressive supranuclear palsy), memory impairment and global cognitive decline mimicking Alzheimer disease, or behavioral and personality changes mimicking primary psychiatric disorders, particularly in younger individuals.

Neuroimaging findings

• Brain CT or MRI show generalized cortical and central atrophy and ventricular enlargement [Gydesen et al 2002]. Parietal and posterior central regions are involved [Häkkinen et al 2020].
• Cerebral blood flow (CBF)-positron emission tomography (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].

Neuropathology findings. 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]. P62-positive, ubiquitin-positive inclusions have also been found in spinal cord tissue [IE Holm, unpublished data].

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CHMP2B-FTD-ALS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in CHMP2B identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology 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 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). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

CHMP2B-related frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) is characterized most frequently as an early-onset dementia affecting primarily frontal lobe functions. Individuals can also have features of ALS, a combined phenotype of FTD-ALS, or atypical phenotypes. CHMP2B-FTD-ALS typically starts with subtle personality changes, behavioral changes with disinhibition, and language disturbances. Apathy and lack of empathy can mimic depression. Stereotyped behavior can occur. Upon testing, a dysexecutive syndrome is found, and it may include dyscalculia [Stokholm et al 2013]. Reduced emotional recognition and semantic association is often present. With progression, a global dementia develops. Later stages of the disease are characterized by dystonia, myoclonus, and parkinsonism, ultimately leading to immobilization, bed confinement, and death [Roos et al 2022].

To date, CHMP2B-FTD has been described in 44 affected individuals in one large Danish family [Roos et al 2022], several additional individuals/families with FTD [Skibinski et al 2005, van der Zee et al 2008, Li et al 2023, Rubio-Guerra et al 2025], and a small number of individuals with ALS [van Blitterswijk et al 2012, Narain et al 2018, Bartoletti-Stella et al 2021].

Onset. Symptoms usually start between ages 46 and 70 years, with an average age at onset of 58 years. No reliable predictor of age at onset has been identified, including parental disease course or lifestyle factors [Roos et all 2022].

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, although not commonly. Lack of insight into illness is an early feature. Stereotypic speech, pacing activity, and stereotypic behavioral routines are frequent with progression [Gydesen et al 2002, Brown et al 2004, Roos et al 2022].

Psychiatric symptoms. Psychotic symptoms are uncommon, although 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. Persecutory delusions and auditory hallucinations have been reported in one individual [Li et al 2023].

Cognitive decline. Loss of executive function is a common early feature, as is lack of emotional recognition 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. 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. Spasticity in upper and lower extremities leaves the affected individual bedridden.

Prognosis. Disease progression is heterogeneous. Duration is from three to more than 20 years. Mean age at institutionalization is 65, with early onset correlated to an earlier institutionalization [Roos et al 2022]. The disease progresses over a few years into profound dementia with mutism and spasticity [Gydesen et al 2002, Brown et al 2004]. Mean age at death is 68, but with huge variability [Roos et al 2022].

Neuropathology. Macroscopic examinations find severe generalized atrophy with an asymmetric and frontal preponderance; brain weight is below 1,000 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 clinically relevant genotype-phenotype correlations have been identified.

Penetrance

Penetrance is age dependent and appears to be nearly complete in the largest family reported to date [Gydesen et al 2002, Skibinski et al 2005]. The Danish CHMP2B pedigree now comprises 528 individuals across six generations; 44 individuals with the familial CHMP2B pathogenic variant have been described in this family [Roos et al 2022].

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, mediated, or related frontotemporal dementia (FTD).

When motor neuron symptoms are the primary feature, the term CHMP2B-related amyotrophic lateral sclerosis (ALS) or CHMP2B-ALS-FTD can be applied.

Prevalence

CHMP2B-FTD has been described in 44 affected individuals in one large Danish family [Roos et al 2022] and several additional individuals/families [Skibinski et al 2005, van der Zee et al 2008, Li et al 2023, Rubio-Guerra et al 2025]. A CHMP2B pathogenic variant has been identified in a small number of individuals with ALS [van Blitterswijk et al 2012, Narain et al 2018, Bartoletti-Stella et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CHMP2B-FTD-ALS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CHMP2B-FTD-ALS. Individuals with CHMP2B-FTD-ALS benefit from supportive care to improve quality of life, maximize function, and reduce complications. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, see Table 6 for recommended evaluations. Note: Members of the Danish family with CHMP2B-FTD-ALS are followed at the Copenhagen Memory Disorders Clinic, the Danish Dementia Research Centre, a multidisciplinary clinic involving neurologic and psychiatric services, genetic counseling, molecular genetic testing, and clinical diagnostic and follow-up medical service [Hasselbalch et al 2025].

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-related frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• To date, almost all individuals diagnosed with CHMP2B-FTD-ALS have an affected parent.
• One individual with FTD and no clear family history of neurodegenerative disease was reported to have a CHMP2B pathogenic variant [Skibinski et al 2005].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing and neurologic examination are recommended for the parents of the proband to evaluate their clinical/genetic status and inform recurrence risk assessment.
• Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members because of a milder phenotypic presentation, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of a CHMP2B pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the CHMP2B pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/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 identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The penetrance of CHMP2B-FTD-ALS in heterozygous individuals is age dependent and appears to be nearly complete (see Penetrance).
• If the CHMP2B pathogenic variant identified in the proband is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal 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-ALS because of the possibility of late onset of the disease in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with CHMP2B-FTD-ALS has a 50% chance of inheriting the CHMP2B 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 typically adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern, and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of CHMP2B-FTD-ALS, 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic 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-related frontotemporal dementia-amyotrophic lateral sclerosis 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 found in the large Danish family leads to the formation of two aberrant transcripts that code for proteins lacking the C terminus of the protein [Skibinski et al 2005]. 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]. The c.532-2A>T splice site pathogenic variant leads to retainment of the entire intron 5 in mRNA, resulting in a truncated protein with loss of effect in the C-terminal domain [Li et al 2023]. The c.35-1G>A pathogenic variant in the canonical splice acceptor site of intron 1 causes a premature stop codon, predicting a C-truncated protein composed of only the first 16 amino acids [Rubio-Guerra et al 2025].

Author Notes

Dr Jørgen Erik Nielsen (kd.hnoiger@10.neslein.kire.negreoj) and Dr Peter Roos (kd.hnoiger@soor.retep) are actively involved in clinical research regarding individuals with CHMP2B-related frontotemporal dementia (FTD). They would be happy to communicate with persons who have any questions regarding diagnosis of CHMP2B-FTD or other considerations.

Contact Dr Nielsen (kd.hnoiger@10.neslein.kire.negreoj) or Dr Adrian Isaacs (ku.ca.lcu@scaasi.a) to inquire about review of CHMP2B variants of uncertain significance.

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

Troels T Nielsen, MSc, PhD
Neurogenetics Clinic & Research Lab
Danish Dementia Research Center
Rigshospitalet
Copenhagen, Denmark

Peter Johannsen, MD, PhD
Danish Dementia Research Center
Rigshospitalet
Copenhagen, Denmark

Jeremy M Brown, MD, PhD
Department of Neurology
Addenbrooke's Hospital
Cambridge, United Kingdom

Author History

Jeremy M Brown, MD, PhD; Addenbrooke's Hospital (2007-2026)
Patrick Ejlerskov, MSc, PhD (2026-present)
Ida E Holm, MD, DMSc (2007-present)
Adrian M Isaacs, DPhil (2007-present)
Peter Johannsen, MD, PhD; Rigshospitalet (2012-2026)
Jørgen E Nielsen, MD, PhD (2012-present)
Troels T Nielsen, MSc, PhD; Rigshospitalet (2020-2026)
Peter Roos, MD, PhD (2020-present)
Anders Toft, MD, PhD (2026-present)

Revision History

• 25 March 2026 (sw) Comprehensive update posted live
• 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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