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Case Reports
. 2022 Dec;188(12):3531-3534.
doi: 10.1002/ajmg.a.62953. Epub 2022 Aug 17.

Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants

Dustin L Gable  1   2   3 , Alisa Mo  1   3 , Elicia Estrella  3   4 , Afshin Saffari  3 , Partha S Ghosh  3   4 , Darius Ebrahimi-Fakhari  3   5   6
Affiliations
Case Reports

Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants

Dustin L Gable et al. Am J Med Genet A. 2022 Dec.

Abstract

Bi-allelic loss-of-function variants in Von Willebrand factor type A (VWA1) were recently discovered to lead to an early onset motor neuropathy or neuromyopathy. What makes this discovery particularly notable is the high frequency of one of the VWA1 (NM_022834.5) founder variants, c.62_71dup (p.Gly25ArgfsTer74), which nears 0.01% in European populations, and suggests that there may be a wide spectrum of disease features and severity. Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1. We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum.

Keywords: Von Willebrand factor a domain containing 1; foot deformities; neuropathy; pyramidal signs; spasticity.

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References

REFERENCES

    1. Allen, J. M., Bateman, J. F., Hansen, U., Wilson, R., Bruckner, P., Owens, R. T., Sasaki, T., Timpl, R., & Fitzgerald, J. (2006). WARP is a novel multimeric component of the chondrocyte pericellular matrix that interacts with perlecan. The Journal of Biological Chemistry, 281(11), 7341-7349. https://doi.org/10.1074/jbc.M513746200
    1. Allen, J. M., Zamurs, L., Brachvogel, B., Schlotzer-Schrehardt, U., Hansen, U., Lamande, S. R., Rowley, L., Fitzgerald, J., & Bateman, J. F. (2009). Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function. The Journal of Biological Chemistry, 284(18), 12020-12030. https://doi.org/10.1074/jbc.M806968200
    1. Arribat, Y. (2021). Genetic alterations of VWA1: A new link between extracellular matrix and neuromuscular diseases. Brain, 144(2), 362-365. https://doi.org/10.1093/brain/awaa464
    1. Deschauer, M., Hengel, H., Rupprich, K., Kreiss, M., Schlotter-Weigel, B., Grimmel, M., Admard, J., Schneider, I., Alhaddad, B., Gazou, A., Sturm, M., Vorgerd, M., Balousha, G., Balousha, O., Falna, M., Kirschke, J. S., Kornblum, C., Jordan, B., Kraya, T., … Haack, T. B. (2021). Bi-allelic truncating mutations in VWA1 cause neuromyopathy. Brain, 144(2), 574-583. https://doi.org/10.1093/brain/awaa418
    1. Fitzgerald, J. (2020). WARP: A unique extracellular matrix component of cartilage, muscle, and endothelial cell basement membranes. Anatomical Record (Hoboken), 303(6), 1619-1623. https://doi.org/10.1002/ar.24087

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