CHMP2B Frontotemporal Dementia

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.