Genotype–phenotype correlations in valosin-containing protein disease: a retrospective muticentre study

Abstract

BackgroundValosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget’s disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype–phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype–phenotype correlations.MethodsDescriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene.ResultsTwo hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death.ConclusionThis study expands the knowledge on the phenotypic presentation, natural history, genotype–phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

Multisystem proteinopathies (MSPs) and MSP‐like disorders: Clinical‐pathological‐molecular spectrum

“…The progression of limb weakness, either from myopathy or MND, was relatively slow with most IBM patients (84%) still ambulating 10 years after symptom onset, more than half without a cane or walker. Loss of ambulation exclusively occurred in VCP ‐MSP patients, 29% at a median of 12 years follow‐up, in keeping with the recently reported data of 23% at 8.5 years 45 . Supportive care, including physical and occupational therapy, and prompt access to gait aids to improve functionality, was crucial.…”

“…Reports on small number of cases have linked specific VCP mutations exclusively to Charcot–Marie‐Tooth 43 or dementia 44 . A large multicenter study associated VCP c.463C > T (p.Arg155Cys) with earlier disease onset (30 s‐40 s), higher frequency of axial‐upper limb weakness, and cognitive impairment 45 . Recently, HNRNPA2B1 heterozygous frameshift variants were discovered in early‐onset myopathy with ophthalmoparesis without cognitive or bone involvement, but the oldest patient was in his early 40s 46 .…”

“… 44 A large multicenter study associated VCP c.463C > T (p.Arg155Cys) with earlier disease onset (30 s‐40 s), higher frequency of axial‐upper limb weakness, and cognitive impairment. 45 Recently, HNRNPA2B1 heterozygous frameshift variants were discovered in early‐onset myopathy with ophthalmoparesis without cognitive or bone involvement, but the oldest patient was in his early 40s. 46 The understanding of these disorders phenotypic variability is limited.…”

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

“…Multisystem proteinopathy 1, or inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia, is a rare autosomal dominant disease caused by mutations in the VCP gene [ 1 , 2 ]. It manifests clinically as myopathy and/or Paget’s associated bone pain that starts in the mid-thirties and dementia in the late fifties [ 3 , 4 ]. Proximal muscle weakness progresses to involve limbs and respiratory muscles [ 5 ].…”

“…Currently, there are over 65 heterozygous missense variants known to cause MSP1. The most common VCP /p97 mutations include R155H, R155C, R159H, and R93C [ 4 ]. To date, additional VCP variants have been reported, a few of which were classified as variants of unknown significance that were not previously associated with human disease [ 3 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”