Congenial Insensitivity to Pain with Anhidrosis
From Science Online
Contents |
Structure
This is the structure of the Tyroinse Kinase protein. It contains 11 alpha helices and 4 beta sheets. All beta sheets are anti parallel. Two contain 5 strains within the beta sheets and the others hold 3 and 2 strains. It has over 3900 atoms and is held together by hydrogen bonding.
Introduction
Congenial Insensitivity to pain with anhidrosis is a recessive disorder that is characterized by the absence of pain and the inability to sweat. CIPA is also known as hereditary sensory and autonomic neuropathy type IV. The first case of CIPA was reported in 1951. CIPA is caused by mutations in the Neurotrophic Tyrosine Kinase, receptor, type 1. Also known as the TRKA or NTRKA genes. Though CIPA is considered a very rare disorder, over 300 cases have been found in Japan and around 60 in the United States. Cipa usually manifests in childhood with repeated unrecognized trauma and self-mutilation. The diagnosing of CIPA is very very important at an early age. For a period of time CIPA was also known as the "mystery of broken bones." However, it is not the broken bones that have led to most of the deaths of patients diagnosed with CIPA, but it is the overheating that has been described as killing more than half of CIPA patients before the age of 3. A person with CIPA cannot feel pain or differentiate between temperatures. "Anhidrosis" means the body does not sweat and "congenial" means that the disease is present from birth.
What is CIPA
Congenial Insensitivity to pain with anhidrosis, also known as CIPA, is an autosomal recessive hereditary disorder characterized by the absence of pain and temperature sensation and the lack of sweating. The absence of feeling pain and temperature sensation in CIPA are caused by the lack of afferent neurons caused by tissue damaging stimuli. The nerve growth factor, NGF, allows survival of sympathetic neurons from the neural crest and sensory neurons from the forebrain. Sensory neurons that respond to tissue damage are NGF dependent for development, survival, and maintenence. The human TRKA gene encodes the receptor the tyrosine kinase nerve growth factor. It is believed that mutations in the Tyrosine kinase domain is the main cause for CIPA. The TRKA gene plays an important role in the formation of autonomic neurons and small sensory neurons through the tyrosine kinase domain. Mutations are changes in the sequence of the nucleotides. The mutations in the tyrosine kinase is the main cuase of CIPA and to this day is untreatable. The genetic mutation that cuases CIPA disrupts the development of the small nerve fibers that carry sensations of cold, heat, and cold to the brain.
People with CIPA are very likely to injure themselves in ways that would normally be prevented by feeling pain. Congenial insensitivity to pain is a very rare disorder. There are only 60 cases documented in the United States, however more than 300 in Japan. It is the lack of pain sensation, painless injuries of the extremeties, and oral structures with self mutilation. Infection and scarring of the tongue,lips and gums occurs frequently.
In Fiction
1. In an episode of HOUSE, "Insensitive", House treats a young girl that can't feel pain.
2. In an episode of GREYS ANATOMY, "Sometimes a Fantasy", a girl has undiagnosed CIPA and has a long strain of broken limbs and traumas.
3. "Ingenious Pain", by Andrew Miller. The main character was born unable to feel pain.
Symptoms
Congenial Insensitivity to pain with Andhidrosis is characterized by recurrent fevers, inability to sweat, self-mutilating behavior, and mental retardation. The cardinal feature of CIPA is extreme hyperpyrexia which is usually the earliest sign of the disorder. Anhidrosis contributes to to the thick appearance of skin with a leathery hardening texture, nails with adequite nutritional development, and a less than normal amount of hair on the scalp or the body. Emotional tearing is also normal among the symptoms of CIPA patients. The insensitivity to pain can lead to auto-amputation and corneal scarring. Small fractures repair slowly and damaged joints are suceptible to repeated trauma.
Diagnosis and Treatments
To establish this disorder the following need to be met:
1.The absence of pain and temperature sensation
2.Lack of sweating of the entire body
3. Mental retardation
4. Self-mutilation
A physical form of diagnosing a patient with CIPA is through oral manifestations. The typical and common feature among patients is the occurence of a decubital ulcer. A decubital ulcer occurs when a bony part of the body rests for a long period of time against a hard surface restricting blood flow to the area. Patients bite their tongues without pain and suffer through frequent accidental injuries. Lip wounds are noticed on the lower lip becuase the lower lip is more likely to be self-mutilated than the upper lip.
Confirmed diagnosis of CIPA consists of a nerve biopsy after infancy when self-mutilation is apparent. Nerve biosy is a very invasive techinique and using the galvanic test by needle electrode is more difficutlt when the child is an infant. Therefore tests are usually put on hold till later in their childhood. Motor nerve conducting velocity is of little help becuase the velocity in CIPA patients is normal. Becuase confirming CIPA is such a lengthy processe the patient has already suffered from joint destruction and bit off their tongue. However, you can obtain an early diagnosis occasionally with sympathetic skin response test (SSR). This test measures the change in voltage that originates from the surface of the skin after electrical stimulation. This test is easy and represents the sudomotor fibers and is therefore very reliable to diagnosing. Especially those CIPA patients whose sympathetic fibers are defective or completely destroyed.
The main treatment of CIPA is prevention of injury and symptomatic therapy becuase radical treatment of this disease is unknown at present. Most patients dont live past the age of 25. For this reason, it is hard for scientist to get closer to understanding the human body with CIPA.
Biochemistry of the Tyrosine Kinase Protein
The TRKA gene, also known as the Tyrosine Kinase protein, located on chromosome 1 has an alpha receptor that is autophosphorylated in response to NGF and is the genetic basis of CIPA. It was identified when loss-of-function mutations in TRKA were found in patients. Microneurology shows neural activity from A-beta sensory fibers connected to low threshold mechanoreceptors where skin sympathetic C-fiber nerve activity is not present. Most of the mutations in the TRKA gene are heterogenous, meaning the gene has many variants or differnt forms. TRKA mutations can include a deletion, splicing, and a missense mutation. It has also been identified that polymorphisms and pathogenic mutations can be found among CIPA patients. Mutations are located in both extracellular and intracellular domains. Human TRKA maps to many chromosomes and is divided into 17 exons and 16 introns. The entire sequence is estimated to code for 790 or 796 amino acids. 6 amino acides found in exon 9 are in the extracellular domain of the neuronal specific TRKA receptor. The 2 isoforms differ by 6 ammino acids (VSFSPV) found in the extracellular domain. The 796 long isoform is found in neronal cells, whereas the 790 amino acid sequence is found in cells of nonneuronal areas.
Due to extensive research and experiments, it has been shown that eight unrelated families with CIPA showed some sign of the transformation of Glycine 571 to Arginine (G571R) and Arginine 774 to Proline (R774P) which lead to the inactivation of the TRKA receptor. They interfere with the autphosphorylation process. Because the TRKA protein contains an extracellular area with Ig-like and cystein rich domains, as well as transmembrane region, a juxtamembrane region, the tyrosine kinase domain and a c-terminal tail, the Arginine 85 to Serine (R85S) located on the extracellular domain is leucine rich not cystein rich. On the same allel Leucine 213 to Proline (L213P) occurs in the Ig-like domain causing a frameshift and premature termination of the allele. However there is also evidence to suggests the Histidine 598 to Tyrosine (H598Y) and Glycine 607 to Valine (G607V), both on the tyrosine kinase domain are associated on the same chromosome with a mutation creating a stop codon. The wild type of the TRKA receptor in the presence of NGF leads to cellular transformation. The L213P mutation produces only 110-KDA, a partially glycosylated TRKA protein, proving the mutation intereferes with the receptor process.
Based on another study of another set of unrelated families showed another mutation can occur. It suggested that another mutating affect of CIPA contained the Glycine 708, which leads a critical role in the inactivation effect of the mutation. It is located within an alpha helix of the C-terminal domain of the kinase where it is substituted for serine. It is not proven but possible that the serine side chain in a hydrophobic environment confuses the conformation, destablazing the structure and its active site.
Based on research of 9 unrelated CIPA families were found to have a Cystein (C) to Threonine (T) transition at nucleotide 610 in exon 5, which changes Glycine to a termination codon at amino acid 176. Not only do the mutations, as stated earlier, have a substituted amino acid but also a truncation after amino acids such as Val505, Ser131, and Arg502. Truncation or deletion of certain amino acids can be the primary cause for frameshift and premature termination being the apparent cause for CIPA. Also found in this study was the summary of mutations that can occur. It contained two missense mutations, (Val709Ala) and (Arg755Trp), and two nonsense mutations, (Gln176Ter) and (Tyr751Ter). It is suggested that the two missense mutations are the primary cuase for CIPA. The Val709Ala is located in the intracellular tyrosine kinase domain and reserved among receptor tyrosine kinases. Val709Ala could also possibly affect autophosphorylation of the TRKA protein. The two nonsense mutations are located on the second cystein cluster of the extracellular domain. The Glycine 176 to a termination codon (Gln176Ter) results in truncation of the TRKA polypeptide in the extracellular domain, causing defect in the function of the receptor tyrosine kinase for the NGF.
The absence of pain and temperature sensation is caused by the lack of afferent neurons activation by tissue-damaging stimuli and the anhidrosis is the result of loss of inervation of exocrine sweat glands.
