Microneurographic Assessment of Peripheral Nerves in Healthy Volunteers and Individuals With Sensory Dysfunction Caused by Inherited Mutations in the PIEZO2 Gene

Обзор

Background: PIEZO2 Deficiency Syndrome (PDS) is a genetic disorder that affects a person s ability to feel touches and pain. Researchers want to know more about how PDS changes nerve function. Objective: To compare nerve function in people with PDS to that in people without PDS. Eligibility: People aged 18 years and older with PDS enrolled in protocol 16-AT-0077. Healthy volunteers are also needed. Design: Participants will have at least 1 clinic visit. They will undergo a test that measures activity in the nerves. For the test: Participants will place their arm or leg in a comfortable position. Ultrasound will be used to locate nerves. A smooth wand will be slid over the skin to capture images of the structures below. Two thin needles will be inserted through the skin. These needles are much smaller than the kind used to draw blood. The needles will record nerve activity as different sensations are applied to the skin. These include mild electrical pulses; heat and cold; bending of the knee or elbow; vibration; air puffs; pulling a hair; and tapping, stroking (brushing), stretching, pinching, and pushing on the skin at different levels of force. Each test takes 5 to 10 minutes. Participants will describe the sensations they feel. Participants may opt for an additional test that measures how nerves respond after heat pulses are used to create mild redness on the skin. Researchers would like at least 2 tests from each person. Participants may return for up to 3 additional visits, if desired, to complete all the testing.

Подробное описание

Study Description:

The study aims to characterize peripheral nerve function and physiology in healthy participants and participants with inherited mutations in the PIEZO2 gene (otherwise known as PIEZO2- Deficiency Syndrome \[PDS\]). PIEZO2 encodes a stretch-gated ion channel whose function has been shown to be essential for aspects of gentle touch sensation, vibration detection, mechanical allodynia and proprioception in humans. The physiological effects of PIEZO2 mutations on sensory neurons in humans are unknown. The study will improve our understanding of the molecular mechanisms for touch and mechanical pain sensation and determine if the peripheral neurons remain otherwise healthy in the absence of a functioning PIEZO2 channel.

Objectives:

Primary Objective:

To determine whether peripheral neurons have a blunted response to gentle mechanical stimulation (e.g., soft brushing) in PDS patients compared to healthy participants using direct electrical recording from peripheral nerves.

Secondary Objectives:

To examine the physiological properties of different types of mechanically sensitive sensory neurons in response to innocuous and noxious stimuli in PDS patients and healthy participants. We expect the loss of PIEZO2 to have greater impact on the responsiveness of certain types mechano-receptor subtypes over others.

Endpoints:

Primary Endpoint:

Our primary endpoint is evidence of reduced responsiveness (i.e., firing rate \[Hz\]) of peripheral neurons to gentle mechanical (brushing) stimulation in PDS patients compared to controls. We expect a reduction of at least 50% in firing rate (Hz).

Secondary Endpoints:

Our secondary endpoint is the emergence of a differential effect of the loss of PIEZO2 on mechanoreceptor subclasses. Mechanoreceptor subclasses will be identified using established criteria (e.g., stimulus sensitivity, receptive field size, spike morphology and axon conduction velocity). The effect of the loss of PIEZO2 on the responsiveness of single-unit subclasses will be quantified by firing rate measures on single-unit data. In addition, the percept evoked to intraneural electrical stimulation of single-unit subclasses will be noted.

Первичные конечные точки

• Firing rate (Hz) in response to fast and slow brushing. [Срок оценки: At each visit (max of 4 visits) during microneurography procedure.]

Вторичные конечные точки (1)

• Firing rate (Hz) in response to other sensory modalities, e.g., thermal, and other mechanical stimuli. [Срок оценки: At each visit (max of 4 visits) during microneurography procedure.]

Критерии участия

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

All Participants

• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female, aged 18 years and over.
• The ability to provide written informed consent.
• Enrolled in 16-AT-0077, "Clinical and Scientific Assessment of Pain and Painful Disorders".

PDS Patients

-Clinical and genetic diagnosis of PIEZO2-LOF.

Healthy participants

-In good general health as evidenced by medical evaluation under 16-AT-0077.

Критерии исключения

All Participants:

• Difficulties with communication that make subjective innocuous and pain assessments impossible or unreliable.
• Unable to comply with study procedures or visits.
• Has a dermatological condition that might influence cutaneous sensitivity.
• Congenital limb deficiency or amputation of any limb.
• Prior history of syncope.
• Peripheral neuropathy or current chronic pain condition or has had chronic pain in the past year (painful condition lasting more than six months), including ongoing treatment with medications for neuropathic pain (e.g. gabapentin, tricyclic antidepressants, pregabalin, tramadol).
• Has a major medical condition, such as kidney, liver, cardiovascular, autonomic, pulmonary, or neurological problems (e.g., epilepsy) or a chronic systemic disease (e.g., diabetes), or Raynaud's Disease.
• Current and untreated diagnosis of depression, post-traumatic stress, syndrome, bipolar disorder, psychosis, anxiety or panic disorder, alcohol or substance use disorders.
• Pregnant (verbal confirmation) or breastfeeding.
• Are participating in other ongoing research protocols involving interventions that would interfere with somatosensation.
• Employees or staff that work at NCCIH.
• Adults who are unable to provide their own consent.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

США · 1 центр

• National Institutes of Health Clinical Center — Bethesda

Публикации

• Chesler AT, Szczot M, Bharucha-Goebel D, Ceko M, Donkervoort S, Laubacher C, Hayes LH, Alter K, Zampieri C, Stanley C, Innes AM, Mah JK, Grosmann CM, Bradley N, Nguyen D, Foley AR, Le Pichon CE, Bonnemann CG. The Role of PIEZO2 in Human Mechanosensation. N Engl J Med. 2016 Oct 6;375(14):1355-1364. doi: 10.1056/NEJMoa1602812. Epub 2016 Sep 21. PMID 27653382
• Case LK, Liljencrantz J, Madian N, Necaise A, Tubbs J, McCall M, Bradson ML, Szczot M, Pitcher MH, Ghitani N, Frangos E, Cole J, Bharucha-Goebel D, Saade D, Ogata T, Donkervoort S, Foley AR, Bonnemann CG, Olausson H, Bushnell MC, Chesler AT. Innocuous pressure sensation requires A-type afferents but not functional RhoIotaEpsilonZetaOmicron2 channels in humans. Nat Commun. 2021 Jan 28;12(1):657. do PMID 33510158
• Nagi SS, Marshall AG, Makdani A, Jarocka E, Liljencrantz J, Ridderstrom M, Shaikh S, O'Neill F, Saade D, Donkervoort S, Foley AR, Minde J, Trulsson M, Cole J, Bonnemann CG, Chesler AT, Bushnell MC, McGlone F, Olausson H. An ultrafast system for signaling mechanical pain in human skin. Sci Adv. 2019 Jul 3;5(7):eaaw1297. doi: 10.1126/sciadv.aaw1297. eCollection 2019 Jul. PMID 31281886
• Curry TB, Charkoudian N. The use of real-time ultrasound in microneurography. Auton Neurosci. 2011 Jul 5;162(1-2):89-93. doi: 10.1016/j.autneu.2011.03.007. Epub 2011 Apr 22. PMID 21514900
• Delle Vedove A, Storbeck M, Heller R, Holker I, Hebbar M, Shukla A, Magnusson O, Cirak S, Girisha KM, O'Driscoll M, Loeys B, Wirth B. Biallelic Loss of Proprioception-Related PIEZO2 Causes Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis, and Scoliosis. Am J Hum Genet. 2016 Nov 3;99(5):1206-1216. doi: 10.1016/j.ajhg.2016.09.019. Epub 2016 Oct 27. PMID 27843126
• Dunham JP, Sales AC, Pickering AE. Ultrasound-guided, open-source microneurography: Approaches to improve recordings from peripheral nerves in man. Clin Neurophysiol. 2018 Nov;129(11):2475-2481. doi: 10.1016/j.clinph.2018.07.011. Epub 2018 Jul 29. PMID 30107982
• Eckberg DL, Wallin BG, Fagius J, Lundberg L, Torebjork HE. Prospective study of symptoms after human microneurography. Acta Physiol Scand. 1989 Dec;137(4):567-9. doi: 10.1111/j.1748-1716.1989.tb08804.x. No abstract available. PMID 2690582
• Edin BB, Abbs JH. Finger movement responses of cutaneous mechanoreceptors in the dorsal skin of the human hand. J Neurophysiol. 1991 Mar;65(3):657-70. doi: 10.1152/jn.1991.65.3.657. PMID 2051199

Идентификаторы

NCT: NCT06052631 · 10001678 · 001678-AT

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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