From the Guidelines
VCP mutations are a significant genetic cause of frontotemporal dementia (FTD), and identifying these mutations is crucial for accurate diagnosis and management, as they can increase confidence in the etiology of the disease 1. The presence of a VCP mutation can lead to a rare condition called Inclusion Body Myopathy with Paget's Disease of Bone and Frontotemporal Dementia (IBMPFD), which typically manifests in middle age. Currently, there is no specific treatment targeting VCP mutations directly, and management focuses on symptom control with medications like selective serotonin reuptake inhibitors (SSRIs) for behavioral symptoms, starting at low doses (e.g., sertraline 25mg daily, gradually increasing as needed) and antipsychotics for severe agitation (e.g., quetiapine 25mg as needed) 1. Non-pharmacological approaches include establishing routine, providing environmental cues, and caregiver education. VCP mutations disrupt normal protein degradation pathways in cells, causing toxic protein accumulation that leads to neuronal death. The disease is inherited in an autosomal dominant pattern, meaning children of affected individuals have a 50% chance of inheriting the mutation. Genetic counseling is recommended for family members, and patients should be monitored for associated conditions like muscle weakness and bone abnormalities that often accompany the dementia symptoms. It is essential to distinguish patients with bvFTD from patients with primary psychiatric disorders (PPD) due to the drastically different prognosis and management, and the identification of a VCP mutation can aid in this distinction 1. In terms of diagnosis, the presence of predominant frontal and/or anterior temporal atrophy on structural imaging has good diagnostic specificity, but the sensitivity of standard MRI is insufficient, and the specificity of 18F-fluorodeoxyglucose-PET (FDG-PET) is low due to frequent non-specific abnormal findings in patients with PPD 1. Therefore, a comprehensive diagnostic approach, including clinical assessment, imaging, and genetic testing, is necessary to accurately diagnose and manage patients with VCP mutations and FTD.
From the Research
VCP Mutation in Dementia
- VCP mutations are a rare cause of autosomal dominant frontotemporal dementias, associated with Paget's disease of bone, inclusion body myopathy, and amyotrophic lateral sclerosis 2.
- A study of 199 patients with frontotemporal dementia identified 7 heterozygous VCP mutations, including 3 novel mutations segregating with dementia, expanding the VCP mutation spectrum 2.
- Another study screened a cohort of 48 patients with familial frontotemporal dementia and identified two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD 3.
- The clinical presentation of VCP mutations can be heterogeneous, even in patients carrying the same mutation, and may include behavioral changes, semantic deficits, and other symptoms 3.
- Pathological examination of patients with VCP mutations has shown numerous TDP-43 immunoreactive neuronal intranuclear inclusions and dystrophic neurites, consistent with FTLD-TDP subtype D 3.
- Diagnosis of dementia, including frontotemporal dementia caused by VCP mutations, requires a comprehensive evaluation, including medical history, cognitive and physical examination, laboratory testing, and brain imaging 4.
- Management of dementia should include both nonpharmacologic and pharmacologic approaches, although the efficacy of available treatments remains limited 4.
- VCP mutations are not directly mentioned in studies 5 and 6, which focus on frontotemporal dementia treatment and clinical review, respectively.
- Study 5 discusses the use of serotonin selective reuptake inhibitors (SSRIs) in treating behavioral symptoms of frontotemporal dementia, while study 6 provides a clinical review of frontotemporal dementias, including their diagnosis and management.