Background Dominant mutations in valosin-containing protein (VCP) gene cause an adult onset inclusion body myopathy, Paget’s disease of bone, and frontotemporal dementia also termed multisystem proteinopathy (MSP). The genotype-phenotype relationships in VCP-related MSP are still being defined; in order to understand this better, we investigated the phenotypic diversity and patterns of weakness in the Cure VCP Disease Patient Registry. Methods Cure VCP Disease, Inc. was founded in 2018 for the purpose of connecting patients with VCP gene mutations and researchers to help advance treatments and cures. Cure VCP Disease Patient Registry is maintained by Coordination of Rare Diseases at Sanford. The results of two questionnaires with a 5-point Likert scale questions regarding to patients’ disease onset, symptoms, and daily life were obtained from 59 participants (28 males and 31 females) between June 2018 and May 2020. Independent of the registry, 22 patients were examined at the Cure VCP Disease annual patient conference in 2019. Results In the questionnaires of the registry, fifty-three patients (90%) reported that they were with inclusion body myopathy, 17 patients (29%) with Paget’s disease of bone, eight patients (14%) with dementia, two patients (3%) with amyotrophic lateral sclerosis, and a patient with parkinsonism. Thirteen patients (22%) reported dysphagia and 25 patients (42%) reported dyspnea on exertion. A self-reported functional rating scale for motor function identified challenges with sit to stand (72%), walking (67%), and climbing stairs (85%). Thirty-five (59%) patients in the registry answered that their quality of life is more than good. As for the weakness pattern of the 22 patients who were evaluated at the Cure VCP Disease annual conference, 50% of patients had facial weakness, 55% had scapular winging, 68% had upper proximal weakness, 41% had upper distal weakness, 77% had lower proximal, and 64% had lower distal weakness. Conclusions The Cure VCP Disease Patient Registry is useful for deepening the understanding of patient daily life, which would be a basis to develop appropriate clinical outcome measures. The registry data is consistent with previous studies evaluating VCP patients in the clinical setting. Patient advocacy groups are essential in developing and maintaining disease registries.

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Objective To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). Methods We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross‐sectional observational study using previously validated patient‐reported outcome assessments (ACTIVLIM, PROMIS‐57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. Results A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5‐1 lb/year). Cross‐sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. Interpretation This study is the largest description of LGMDD1 patients to date and highlights potential genotype‐dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients.

LGMDD2 is due to a transportin-3 defect, involved in HIV nuclear inport, the pathogenetic link is unknown. We determined cytokines by Luminex analysis in plasma from 4 patients carrying mutations of LGMDD2. Two patients are part of an Italian-Spanish family (mutation c.2771delA QVTSAEECKQ VCWALRDFT R LFRCSHSCTV PVTQECLF * ) two are from a family of Hungarian origin, carrying the TPNO3 mutation c.2767delC; each family included an elderly patient and one descendant. Plasma from 4 LGMDD2 patients and 4 health donors were measured in duplicate, using a 1/1 or 1/20 sample dilution. The expression levels of TNFRSF8, IFN-, IL-8/CXCL8 and S100A9 were measured by Multiplex Luminex Assay using two custom-made plates (R&D Systems). Analysis was performed on a Bio-Plex 200 System (Bio-Rad). Statistical analysis was performed with the nonparametric test Mann-Whitney test using GraphPad Prism v9software.Observed concentration was calculated for the cytokines mentioned thorough Bio-Plex 200 system software or by manual interpolation of concentration in the curve. The expression levels of IFNβ were reduced 25 fold (p < 0.005) in patients, while IFN-α increased 2.05 fold. The level of GRO-β was increased 1.65 fold (p < 0.05), in LGMDD2 patients, TNFRSF8 and ICAM-1 were 1.58 fold and 2.15 fold (p < 0.001) enhanced. The levels of S100A8 (p < 0.001) and S100A9 (p < 0.005) were reduced 6 fold and 25-34 fold respectively in LGMDD2 patients compared to control. Expression of IL-1 RI was 2-fold reduced(p < 0.05) in LGMDD2. Age influences expression levels of IL-1 α, MMP10, MMP8 and CXCL5 that gathered in youngest or older patients, independently from family. The genetic mutation that causes the disease makes patients immune to AIDS by unknown mechanism(s), holding promise for research in this field, reassuring patients regarding possible HIV infection. The mutation could block the activity of the HIV-1 intasome, CD3, CD28 peripheral blood cells from transportinopathy patients show lower production of viral proteins in patients than control. The present data demonstrate that the cytokine profile is significantly differentially affected in 4 patients from 2 independent TPNO3 families.

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