The distinct clinical phenotype of PIEZO2 loss of function


Clinical Other

Poster Number: 15


Dimah Saade, MD, Diana Bharucha-Goebel, MD, Sandra Donkervoort, A. Reghan Foley, MD, Sarah Neuhaus, DO, Joshua Emrick, Eleni Frangos, NCCIH, Katherine Alter, Cristiane Zampieri, Chris Stanley, Jesse Matsubara, Jean Mah, Baiba Lace, Nicolas Chrestian, Carla Grosmann, Michelle Lee, Tanya Stojkovic, Sarah Leonard-louis, Guilhem Sole, Alexander Chesler, Carsten Bonnemann, MD


1. NINDS, NIH, 2. NINDS, NIH,Neurology & Children's National Health System, , 3. NINDS, NIH , 4. NINDS, NIH , 5. NINDS, NIH , 6. Taste and Smell Section NIDCR, NIH, 9. Rehabilitation Medicine Department, NIH , 10. Rehabilitation Medicine Department, NIH , 11. Rehabilitation Medicine Department, NIH , 21. Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD

PIEZO2 is a widely expressed stretch-gated ion channel known to mediate human mechanosensation. We previously recognized a unique clinical phenotype with selective sensory deficits and systemic manifestations in two individuals with loss of function mutations in PIEZO2. Since then we have gathered detailed phenotypic information from 12 patients aged 3 to 42 years , 4 adults and 8 children, with genetically confirmed biallelic inactivating mutations in PIEZO2. Detailed sensory and enteroceptive assessments, dental evaluation, musculoskeletal, respiratory, gastrointestinal and urological evaluations were conducted.

All 12 patients presented with neonatal hypotonia, hip dislocation, joint hypermobility and contractures. There was transient respiratory distress in the newborn period and feeding difficulties as well as evidence of impaired gastrointestinal transit and bladder function. Motor milestones were delayed with acquisition of independent ambulation in late childhood in the absence of muscle weakness, while there was progressive scoliosis in all. All patients had a striking and ubiquitous absence of joint proprioception and of vibratory sense and touch discrimination on glabrous skin specifically, while other sensory modalities were largely preserved. Pain and temperature sensation were preserved, except for allodynia, which was absent. All patients displayed slow improvement in motor function, culminating in independent ambulation, driving and competitive participation in parasports for some, which suggests a maturational process that recruits and relies on mostly visual compensatory sensory inputs.

The PIEZO2-loss of function phenotype is highly specific and clinically recognizable. While advancing our understanding of human sensory perceptions its diagnosis also allows for the development and implementation of rehabilitative measures aimed at recruiting intact sensory modalities in order to compensate for specific deficits and optimize function.