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

Abstract

Background: Valosin-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.

Methods: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene.

Results: Two 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.

Conclusion: This 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.

Keywords: FRONTOTEMPORAL DEMENTIA; GENETICS; INCL BODY MYOSITIS; MUSCLE DISEASE; MYOPATHY.

Figure 1

Frequency of first symptoms (n=226). PDB the category other combination of weakness patterns includes: distal UL symmetric W, five cases; proximal Ll asymmetric W, five cases; distal UL and Ll W, four cases; distal and proximal UL and Ll W, four cases; distal UL and proximal and distal Ll W, three cases; proximal and distal UL W, three cases; proximal UL asymmetric; W, two cases; distal UL asymmetric W, two cases and proximal UL and proximal and distal Ll W, one case. LL, lower limbs; PDB, Paget’s disease of the bone; UL, upper limbs; w, weakness.

Figure 2

Frequency of signs/symptoms at last assessment. Data in brackets represent the number of patients that reported the sign/symptom at last assessment among those in which the data were reported. FTD, frontotemporal dementia; LMN, lower motor neuron signs; PDB, Paget’s disease of the bone; PNP, polyneuropathy; UMN, upper motor neuron signs.

Figure 3

Time of signs/symptoms development from disease onset (y). The box figures show the time of signs/symptoms development from disease onset in years. The limits of the box are the 25th and 75th percentile. The middle line within the boxes represents the median. The ends of the lines extending from the boxes represent the minimum and maximum values. n=number of patients in which data about the time from disease onset was available among those patients who reported the sign/ symptom at last assessment. FTD, frontotemporal dementia; LMN, lower motor neuron signs; PDB, Paget’s disease of the bone; PNP, polyneuropathy; UMN, upper motor neuron; W, weakness.

Figure 4

Frequency of signs/symptoms between the two most frequent variants. The bar graph shows the percentage of signs/symptoms in which significant differences were found between the two most frequent variants identified in this study. Numbers in brackets above the bars represent: the numerator the frequency of patients in whom the sign/symptom was present and the denominator the number of patients in which the data was available by variant. *P<0.05, χ² test.

Figure 5

Kaplan-Meier estimator for full time wheelchair user/confined to bed and death. (A) Kaplan-Meier estimator for full time wheelchair user/confined to bed by FVC <50%. Mean time to being a full-time wheelchair user/confined to bed for FVC >50% was 22.2 years (SE 1.3, 95% CI 19.6 to 24.8 years) from disease onset and for FVC <50% 12.9 (SE 2.4, 95% CI 8.1 to 17.7). (B) Kaplan-Meier estimator for death by FVC value. Mean time to death from disease onset for FVC <50% 18.9 years (SE 2.4, 95% CI 15.2 to 22.6), FVC 50%–59% 18.2 years (SE1.1, 95% CI 16.0 to 20.4), FVC 60%–69% 23.5 years (SE 2.9, 95% CI 17.7 to 29.2), FVC 70%–79% 23.9 years (SE 2.0, 95% CI 19.8 to 27.8) and for FVC >80% 29 years (SE 0.9, 95% CI 27.1 to 30.9). (C) Kaplan-Meier estimator for death by the presence of FTD. Mean time to death from disease onset for patients with FTD 19.4 years (SE 1.8, 95% CI 15.9 to 22.9) and for patients without FTD 27.8 years (SE 2.7, 95% CI 22.6 to 33.1). All the comparisons were significant by log rank (Mantex-Cox) test as detailed in the figures. FVC, vital force capacity; FTD, frontotemporal dementia.