A number sign (#) is used with this entry because frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6) is caused by heterozygous mutation in the VCP gene (601023) on chromosome 9p13.

Heterozygous mutation in the VCP gene can also cause inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), which shows some overlapping features. In some families with a VCP mutation, family members may have ALS, FTD, or IBMPFD.

Frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6) is an autosomal dominant neurodegenerative disorder with highly variable manifestations. Some patients present in adulthood with progressive FTD, often classified as the 'behavioral variant,' which is characterized by reduced empathy, impulsive behavior, personality changes, and reduced verbal output. Other patients present with features of amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disease characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. The pathologic hallmarks of this disease include pallor of the corticospinal tract due to loss of motor neurons (in ALS). In both ALS and FTD, there are ubiquitin-positive inclusions within surviving neurons as well as deposition of pathologic TDP43 (TARDBP; 605078) or p62 (SQSTM1; 601530) aggregates. Patients with a D395G mutation (601023.0014) have been shown to develop pathologic tau (MAPT; 157140) aggregates. Some patients with the disorder may have features of both diseases, and there is significant interfamilial and intrafamilial phenotypic variability (summary by Johnson et al., 2010; Wong et al., 2018; Al-Obeidi et al., 2018; Darwich et al., 2020).

For a general phenotypic description and a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).

Johnson et al. (2010) reported an Italian family in which 4 affected members had ALS. Affected individuals presented in adulthood (range, 37-53 years) with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classic ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations. In another family, 2 patients had ALS with frontotemporal dementia, and a third had Paget disease followed by ALS, suggesting an overlap with IBMPFD.

Johnson et al. (2010) reported a patient with classic ALS confirmed by postmortem studies, who was a member of a large family with IBMPFD previously reported by Watts et al. (2004). However, the family member reported by Johnson et al. (2010) had rapidly progressive ALS without evidence of Paget disease, myopathy, or FTD. Postmortem examination of this patient showed loss of brainstem and spinal cord motor neurons with Bunina bodies in surviving neurons, TDP43-positive immunostaining, and mild pallor of the lateral corticospinal tracts, all features consistent with a diagnosis of ALS. The patient carried the same heterozygous mutation as his family members with IBMPFD (R155H; 601023.0001), indicating an expanded phenotype associated with this mutation.

Wong et al. (2018) reported 3 unrelated Dutch patients who presented with the behavioral variant of FTD between 41 and 60 years of age. Clinical features included reduced empathy, loss of interest in grooming, personality changes, aggressive and obsessive behavior, and word-finding and semantic difficulties. Brain imaging showed cortical atrophy. None had signs of a myopathy, motor neuron disease, or bone disease. The patients died between 46 and 67 years of age. Postmortem examination of 2 patients (patients 2 and 3) showed prominent frontal atrophy with neuronal loss and gliosis, as well as neuronal intranuclear inclusions (NII), short dystrophic neurites (DN), and positive immunostaining for TDP43 and p62 (SQSTM1; 601530). A few hyperphosphorylated tau (MAPT; 157140) deposits without amyloid plaques were observed in 1 patient, and several amyloid plaques were observed in the other patient. Rare NII showed VCP-positive immunostaining. The pathologic findings were consistent with FTLD-TDP subtype D, although the severity and distribution of the pathologic findings varied somewhat.

Darwich et al. (2020) reported 4 patients from 2 unrelated families with the behavioral variant of FTD associated with VCP mutations. Three sibs (family A) from the US presented between 40 and 50 years of age with progressive behavioral changes, poor judgment, and loss of language. One died at age 55. The proband in the other family (family B), of Greek descent, presented with a similar phenotype at age 35. Both families had similarly affected individuals in the older generations.

Clinical Variability

Abrahao et al. (2016) reported a Brazilian family in which 2 brothers and their father had different clinical manifestations of VCP-related neurologic disease. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of IBMPFD1, but without Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant ALS without signs of frontotemporal dementia or Paget disease, and their father presented at age 66 with behavioral variant frontotemporal dementia without signs of myopathy, Paget disease, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family.

The transmission pattern of FTDALS6 in the families reported by Johnson et al. (2010) was consistent with autosomal dominant inheritance with variable expressivity.

The transmission pattern of FTDALS6 in the families reported by Darwich et al. (2020) was consistent with autosomal dominant inheritance.

Using exome sequencing, Johnson et al. (2010) identified a heterozygous mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of an Italian family with ALS with or without FTD. Screening of the VCP gene in 210 familial ALS cases and 78 autopsy-proven ALS cases identified 3 additional pathogenic VCP mutations (601023.0001; 601023.0008, and 601023.0009) in 4 patients. The findings expanded the phenotype associated with VCP mutations to include classic ALS.

In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous missense mutation in exon 3 of the VCP gene (N91Y; 601023.0012). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband had features of IBMPFD1 without Paget disease or FTD, his brother had features of ALS without Paget disease or FTD, and their father had isolated behavioral variant FTD without features of myopathy, Paget disease, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family.

In 3 unrelated adult Dutch patients with the behavioral variant of FTD without signs of myopathy or motor neuron disease, Wong et al. (2018) identified heterozygous missense mutations in the VCP gene (T262S, M158V, and R159S; 601023.0013). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. Functional studies of the variants were not performed.

In 4 adult patients from 2 unrelated families with the behavioral variant of FTD without signs of myopathy, bone disease, or motor neuron disease, Darwich et al. (2020) identified a heterozygous missense mutation in the VCP gene (D395G; 601023.0014). The substitution occurred at a conserved residue in the lid subdomain of the D1 ATPase domain. The mutation, which was found by targeted, whole-exome, or whole-genome sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Neuropathologic examination of 1 patient showed frontal atrophy, neuronal vacuolization, and abundant phosphorylated tau (MAPT; 157140) aggregates identical to neurofibrillary tangles (NFT) observed in patients with Alzheimer disease (see, e.g., AD, 104300). MAPT mutations were absent in both families. The distribution of the vacuoles and NFTs were inversely related: vacuoles were more prominent in the occipital cortex, which showed minimal neurodegeneration, whereas NFTs were more prominent in frontal regions and other areas that showed cerebral atrophy, neuronal loss, and reactive gliosis. TDP43 (605078), beta-amyloid (APP; 104760), SNCA (163890), and prion protein (PRNP; 176640) aggregates were not observed. The pathologic tau distribution was confirmed by brain imaging studies. In vitro functional expression studies showed that the D395G mutation resulted in decreased ATPase activity with a 30% reduction in maximum enzyme velocity compared to controls, which was consistent with a hypomorphic mutation. Additional in vitro studies showed that VCP normally acts as a disaggregase for polyubiquitinated phosphorylated pathologic tau fibrils derived from brains of patients with Alzheimer disease. Cells with the D395G mutation had increased intracellular tau aggregates, suggesting that this specific mutation impairs the turnover of pathologic tau aggregates, resulting in neurodegeneration. Transgenic mice expressing this mutation showed similar pathologic tau accumulation when seeded with AD-derived tau (see ANIMAL MODEL). Darwich et al. (2020) emphasized the distinct pathogenetic mechanism associated with this mutation, and named this disease 'vacuolar tauopathy' (VT).

Tyzack et al. (2019) examined motor neurons derived from 2 human induced pluripotent stem cell (iPSC) lines with different heterozygous VCP mutations (R155C, 601023.0002 and R191Q, 601023.0006) and identified a decrease in the nuclear to cytoplasmic localization of the FUS (137070) protein during motor neuron differentiation compared to controls. Tyzack et al. (2019) also identified evidence for nuclear to cytoplasmic FUS mislocalization in postmortem spinal cord tissue from individuals with sporadic ALS compared to controls.

Al-Obeidi et al. (2018) studied 231 individuals from 36 families carrying 15 different heterozygous VCP mutations. Of these individuals, 187 were clinically symptomatic and 44 were presymptomatic carriers. The cohort of patients were of various ethnicities, including European, Brazilian, Hispanic/Apache, and an African-American. Most (90%) of symptomatic patients presented with myopathy at a mean age of 43 years (range, 20-70 years). Paget disease of bone was identified in 42% of patients with a mean age at onset of 41 years (range, 23-65 years), and dementia was diagnosed in 29.4% of patients at a mean age of 55.9 years (range, 30-80 years). When possible to ascertain, the dementia included sociobehavioral and language changes, as well as loss of executive function. Sixteen (8.6%) of patients were diagnosed with ALS associated with upper and lower motor neuron degeneration. Some patients were diagnosed with Parkinson disease (3.8%) or Alzheimer disease (2.1%). Although VCP mutations are associated with a triad of symptoms, only 10% of patients had all 3 features of myopathy, bone disease, and dementia. After stratification by mutation type, there were no apparent genotype/phenotype correlations, although the R159C mutation was associated with a slightly later age at onset of myopathy (57 years) compared to other mutations. Functional studies of the variants were not performed. The authors emphasized the enormous phenotypic heterogeneity both between and within families.

Darwich et al. (2020) found that transgenic mice expressing the VCP D395G mutation (601023.0014) did not spontaneously develop a neurodegenerative phenotype and their brains did not show abnormal tau (MAPT; 157140) accumulation. However, when stimulated with pathologic tau derived from patients with Alzheimer disease (see, e.g., 104300), transgenic mice developed pathologic tau aggregation in several brain regions. The findings suggested that neurons with this VCP mutation have increased susceptibility to pathologic tau aggregation under certain circumstances, resulting in downstream neurodegeneration.