491P PIEZO2 loss of function syndrome: a highly specific and recognizable phenotype

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.328
• Main Authors: Bharucha-Goebel, D., Lee, M., Saade, D., Donkervoort, S., Yun, P., Mohassel, P., Neuhaus, S., Ogata, T., Averion, G., Mendoza, C., Alter, K., Matsubara, J., Stanley, C., Zampieri, C., Lehky, T., Nickolls, A., Chesler, A., Foley, A., Bonnemann, C.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.337

PIEZO2 is a large stretch-gated ion channel highly expressed in specific sensory neurons which mediates human mechanosensation. Individuals with biallelic loss of function (LOF) variants in the PIEZO2 gene highlight the impact of the congenital absence of specific mechanotransduction-dependent senses, including proprioception aspects of touch and interception. We report on twelve unrelated individuals (except one sibling pair), ranging in age from 4 years to 42 years old with biallelic PIEZO2 LOF, and report on detailed neurological examination, neurophysiology, and evaluations of pulmonary, gastrointestinal and urinary function. We identified common early neonatal and developmental consequences of PIEZO2 LOF including: reduced fetal movements (n=6), hypotonia (n=12), neonatal respiratory distress (n=9), and feeding difficulty (n=11). The age at achievement of independent ambulation (n=8) was markedly delayed (5-16 years old). Pseudoathetosis was frequently clinically observed. Orthopedic and systemic findings included: congenital hip dysplasia (n=11), arthrogryposis (n=12), early progressive scoliosis (n=12), constipation (n=11), reduced voiding frequency (n=10). The findings in these participants with LOF in PIEZO2 recapitulates what is observed in preclinical models, and highlights the developmental, motor functional, systemic, and orthopedic consequences of absent mechanotransduction and proprioception. Initially slow but improving functional gains over time suggest that these maturational processes may rely on emerging executive and motor planning skills combined with visual compensatory input. This expanded series represents the largest cohort of individuals with PIEZO2 LOF across a wide age range. Recognizing and elucidating this PIEZO2-related phenotype improves our understanding of human sensory perception and allows for development of rehabilitative measures aimed at compensatory recruitment of intact sensory modalities to optimize function.