## 3 VCP and Genotype-Phenotype Correlations  
Mutations in _VCP_ cause a spectrum of phenotypes presenting in adulthood, which may coexist with each other in the same patient. We summarize the different clinical featureswhich may appear as manifestations of \(VCP\) mutations in Table 1. Myopathy is the most common feature and is present in approximately 90% of patients [42]. This most frequently manifests as proximal weakness but variations in the phenotype are described. PDB is present in up to 50% of patients [43] and is caused by altered bone turnover, resulting in bone deformities and pathological fractures. FTD develops in 30% of cases, characterized by early onset and rapidly progressive cognitive syndrome with early behavioral and language deficits [42]. Approximately 10% of patients develop ALS [42], in which there is multifocal degeneration of motor neurons in the brain and spinal cord causing progressive weakness. Other rare and atypical phenotypes have also been described including Charcot-Marie-Tooth disease type 2Y [44; 45], hereditary spastic paraplegia [46], and variations on the myopathy phenotype resembling facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, scapulohumeral muscular dystrophy, octulopharyngeal muscular dystrophy, and distal myopathy [12; 47]. Other neurodegenerative conditions may be more common in patients with \(VCP\) mutations, including Parkinson disease and Alzheimer disease [42]. Cardiomyopathy is described as an important feature in case series [48] but the prevalence of cardiac dysfunction is unknown. Expert opinion also cites respiratory muscle weakness as an important consideration for screening and management [49; 50]. This broad clinical heterogeneity means that VCP-MSP should be considered in numerous different clinical presentations. Genotype-phenotype correlation remains a major challenge. There have been major efforts to compile clinical and genetic information from large cohorts of patients, but one of the major limitations is that nearly three-quarters of reported cases are caused by mutations at a single codon for the arginine residue at position 155 [42]. So, although there is much variability for these mutations at position 155, with larger numbers, it may become evident that there is a clear phenotypic correlation for mutations at other residues. Thus far, clear genotype-phenotype correlations appear to be limited. The mutations associated with Charcot-Marie-Tooth disease type 2Y appear to cause restricted phenotypes that differ substantially from classical multisystem involvement of multisystem proteinopathy [44; 45; 51]. Extended follow-up of these patients may still identify some of the classical VCP-MSP manifestations over time. Two mutations at position 395 also appear to be strongly associated with dementia as a single system disorder [52; 53], although again this is based on small case numbers and extended follow-up may identify other associations. We have provided a summary of previously reported pathogenic variants in \(VCP\) with their genotype-phenotype-mechanistic correlations, organized by their VCP domain in Table 2. These different mutations are also pictorially represented showing their positions in the postulated three-dimensional conformation of the VCP hexamer in Figure 1. \begin{table}
\begin{tabular}{c c c} \hline \hline
**Localization** & **Phenotype or Disease** & **Frequency in VCP-MSP** \\ \hline Central nervous system & **Frontotemporal dementia** & 30\% \\ \hline  & Alzheimer disease & 2\% \\ \hline  & Parkinson disease & 4\% \\ \hline  & Spastic paraplegia & Case reports \\ \hline Peripheral nervous system & **Inclusion body myopathy** & 90\% \\ \hline  & Amyotrophic lateral sclerosis & 10\% \\ \hline  & Charcot-Marie-Tooth disease & Case reports \\ \hline  & Sensory polneuropathy & Case reports \\ \hline Non-neurological & **Paget disease of bone** & 40\% \\ \hline  & Cardiomyopathy & Uncertain \\ \hline \hline \end{tabular}
\end{table}