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.

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.

• 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.

EXCLUSION CRITERIA:

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.

All participants will be screened and selected from an existing NCCIH protocol, 16-AT-0077. PDS participants will be referred to 16-AT-0077 for screening from an existing NINDS protocol, 12-N-0095.