The Curious Case Files: Congenital Insensitivity to Pain with Anhidrosis (CIPA)

Dear Prospective Medical Students, it's time to scrub in.

In this case series, join me to explore some of the incredibly terrifying conditions manufactured by mutations. Today's take is on Congenital Insensitivity to Pain with Anhidrosis (CIPA)

Overview

Can you imagine what it would feel like to have a tapeworm in your stomach, a fracture in your arm, a gash on your cheek and not even know it? You would feel nothing, no pain, no feeling. That is the case for CIPA patients; is it a curse or a blessing? 

Congenital Insensitivity to Pain with Anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by a mutation in the NTRK1 gene, which encodes a receptor essential for the development of pain-sensing neurones, leading to an inability to feel pain or regulate temperature. [NIH] It is a rare subtype of the hereditary sensory and autonomic neuropathy (HSAN) quartet, classified as the fourth type, known as the HSAN4 phenotype. [WebMD] The likelihood of being born with this condition are about 1 in 125 million. [NIH] Though ‘pain’ may seem like an inconvenience to most, it is actually a vital alert system that keeps you aware of changes in your body's health or internal conditions. Patients with CIPA lack this safety net. 

Several doctors and scientists explored the condition’s nature; however, the groundbreaking discovery linking the condition to the mutation of the NTRK1 gene was accredited to Dr Yasuhiro Indo, a Japanese geneticist, in 1996. He showed that the mutations disrupted the TrkA receptor necessary for nerve growth factor signalling, altering perception of pain and temperature. Let’s explore that today!

Causation

[JBC]

In a unmutated body, this is what happens. The NTRK1 gene codes for the receptor, Tropomyosin Receptor Kinase A; it is located on the surface of sensory neurons, which detect pain and temperature, and the autonomic neurons, which control involuntary processes like sweating, primarily on the axon terminals. The TrkA is a transmembrane receptor protein, having an intracellular and extracellular domain, signalling for nerves to survive and grow by binding to the NGF. [ScienceDirect] The nerve growth factor (NGF) is a soluble protein secreted into the extracellular space. These NGF proteins are essentially ‘grabbed’ by the TrkA’s extracellular domain due to highly specific complementary binding. This triggers the intracellular binding pathways and retrograde signalling. In neurons, signals generally travel from the soma to the axon terminal; however, in retrograde signalling, this order is reversed. The TrkA-NGF complex is internalised, forming a vesicle which carries the signal from the terminal to the soma, instructing the neurone to survive, connect to target tissues and grow more axons so that nervous communication can continue. The activated intracellular pathways switch off apoptosis genes and promote growth genes in the neurons. [PubMed]

In the case of CIPA patients, the TrkA receptor is mutated, and so the extracellular domain changes from the original highly specific shape; it is no longer complementary to the NGF protein, and so it cannot bind. The internal domain may also face some mutation, preventing downstream signalling even if NGF binding occurs. Nociceptive sensory neurons (control pain and temperature) and autonomic neurons (control sweating) no longer receive the survival signals, and so these neurons die, as the lack of activated pathways reverts the neuron to following the default pathway of apoptosis (programmed cell death).  [ScienceDirect] Pain and temperature signalling, thus, comes to a stop, resulting in this lack of alerts about temperature/pain.

Symptoms

1. Loss of nociceptive neurons:

   - Analgesia (loss of pain) >  fractures and internal problems often go unnoticed

   - Loss of temperature > risk of hypothermia or skin burns

2. Autonomic symptoms:

   - Anhidrosis (inability to sweat) > risk of hyperthermia/dry skin [VeryWellHealth]

3. Secondary complications:

   - Self-mutilation> biting of the tongue, lips or fingers can become severe wounds due to a lack of pain feedback indicating to stop biting.

   - Recurrent injuries or infections due to untreated wounds

   - Corneal ulcers and injuries and eye dryness due to a lack of sensation of needing to blink or protect the eyes. [Neurology]

4. Mild intellectual disabilities

   - The NGF and TrkA are also present within the CNS during development, playing a crucial role in the survival and growth of certain basal forebrain cholinergic neurons (BFCNs).  [ScienceDirect] These neurons release acetylcholine; reduced cholinergic signalling is important for cognitive function, and the apoptosis of certain neurons during brain development will result in incomplete neural circuits. 

To Identify and Diagnose...

• Clinical History of previous recurrent injuries and hyperthermia episodes due to inability to sweat was discovered.

• Patient will be examined physically to test pain perception (possibly through pinprick experiments), looking for reduced or delayed response to pain.

• Pilocarpine tests are taken to check sweating

• Genetic diagnosis through molecular testing (checking for mutations in the NTRK1 gene)

Management & Treatment

As of now, there is no cure for CIPA, simply just injury prevention and support techniques. 

• Protective gear for hands, feet, sensitive, injury-prone areas etc.

• Avoiding high-risk activities

• Regular check-ups and inspections for injuries

• Remaining in generally cool environments, avoiding hot ones and staying hydrated

• Prompt care of wounds/infections

• Eye care to prevent corneal ulcers

• Watching out for self-mutilation

• Physiotherapy to maintain mobility 

[NIH]

Future treatment prospects…

• Gene therapy targeting NTRK1 mutations

• Theoretically, CRISPR technology should be able to cut out the faulty sequence of genes and insert the correct DNA sequence to restore functional TrkA receptors; however, there are currently challenges of getting the CRISPR safely into the correct cells and ensuring that the correct areas of the genome are targeted. [NIH]