Blog 13 - CIPA - Congenital Insensitivity to Pain and Anhidrosis

- Unravelling the Mind-Blowing Mystery Behind People Who Can’t Feel Pain!

by Nahin Siara Prova

T.Y.B.Sc Department of Biotechnology DES Fergusson College, Pune. For BTH3507

Blog Category: Nervous System/ Neural Pathways

Growing up we marveled at the idea of living a life devoid of pain, sort of like a super hero who can endure immense pain without a flinch. Scientifically speaking is that anything more than a vain thought? Doubt as you may but interestingly there are indeed people who can never sense pain and temperature. To add more, they cannot even sweat! And no, this is not their heroic act of pain endurance rather it is incapability of their sensory or afferent neuron to get stimulated by tissue damaging stimuli or pain stimuli that leaves them insensitive to pain. Also lack of innervation in eccrine sweat glands causes anhidrosis. This is an extremely rare autosomal recessive disorder termed as Congenital insensitivity to pain and anhidrosis (CIPA) or hereditary sensory autonomic neuropathy type IV (HSAN IV). There are only a handful of cases worldwide and mostly observable in consanguineous marriage as it’s a genetic disorder.

Fig 1. Clinical features of CIPA patients. (A) In a 9-year-old child loss of fingertips due to trauma, poor wound healing, and chronic Staphylococcal aureus infections (B) Loss of a portion of lower lip due to self-biting as a toddler in a 7-year old child (C) Charcot’s joint (nerves in lower leg and feet damaged causing loss of sensation in feet) in a CIPA patient. The affected individual had chronic elbow dislocation, which became permanent and resulted in significantly reduced arm movement. (D) Method for applying pressure to the proximal nail bed to test pain sensitivity. Credit: GeneReviews, © University of Washington.

Fig 2. Binding of NGF to NGF/TRKA receptor. NGF dimer binding to TRKA receptor results in homodimer formation and phosphorylation of TRKA i.e. intracellular signal transduction. TRKA protein domain structure: SP signal peptide, CC1 and CC2 first and second cysteine clusters, LRMs leucine rich motives, Ig-1 and Ig-2 first and second immunoglobulin like motifs, TM transmembrane, JX juxta membrane, TK tyrosine kinase. Extracellular domain important for NGF binding while intracellular domain for downstream signaling domain.

For the survival and growth of sympathetic neurons and nociceptive sensory neurons as well as cholinergic neurons of basal forebrain, nerve growth factor (NGF) plays a crucial role (Indo 2002). Sympathetic neurons deliver information about stress or imminent danger to the body while nociceptive sensory neurons provide tissue damaging stimuli like extreme temperature or pressure also cholinergic neurons are required for attentive functions. On chromosome 1(1q21-q22) of human genome TRKA(NTRK1) gene encodes for receptor tyrosine kinase which gets phosphorylated in response to NGF which in turn activates various intracellular signaling pathways (Indo 2002). As TRKA acts as the receptor of NGF so neurons dependent upon NGF cannot be maintained and often lost by apoptosis during development in TRKA mutation. In CIPA, defect in pain and temperature sensation as well as anhidrosis is due to loss of function mutation in TRKA gene as afferent neurons or sensory neurons which usually are activated by tissue damaging stimuli are lost. Also, in spite of having normal sweat glands loss of sympathetic innervation leaves it non-functional which explains episodic fever as body loses homeostasis to control body temperature by sweating. Moreover, their inability to perceive pain leaves them highly vulnerable to injuries be it external or self-inflicted.

Diagnosis, Treatment and Social Awareness of CIPA

Initial diagnosis is based upon clinical features and physical diagnosis followed by histamine and sweating test (Mardy, Miura, Endo, Mastuda 1999; Indo 2002). Later skin and sural nerve (at calf of leg a sensory nerve) biopsy is commonly performed. For specific diagnosis molecular genetic testing is performed. As CIPA is an autosomal recessive disorder so children born from consanguineous marriage are more at risk of inheriting this disorder. So, it is of utmost importance that we stay aware of consanguineous marriage drawbacks. Unfortunately, there are no specific treatment available for CIPA but palliative care is important. Parents who are carriers or affected or at risk of being carriers requires to have genetic counselling and also prenatal testing (to check if a fetus is affected by CIPA). Often society treats CIPA patients as clumsy as they are more prone to injuries than most other people. Nevertheless, CIPA patients are in greatest need of an understanding society as these patients are often mentally retarded and incapable to take care of themselves. Multidisciplinary approach is the only way to care for CIPA patients as they suffer from varied conditions and which requires constant attention from healthcare providers.

However, there are a lot of answered questions that CIPA gave rise to:

- How can a CIPA patient has same behavioral or emotional stability as most others except for pain perception?

- Can NTRK1 gene manipulation be the future target for pain management?

References:

• Ravichandra KS, Kandregula CR, Koya S, and Lakhotia D. Congenital Insensitivity to Pain and Anhydrosis: Diagnostic and Therapeutic Dilemmas revisited Int J Clin Pediatr Dent. 2015;10.5005

• Indo Y. Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor Clin Auton Res. 2002; 10.1007/s102860200016

• Mardy S, Miura Y, Endo F, Matsuda I, Sztriha L, Frossard P, Moosa A, Ismail E A, Macaya A, Andria G, Toscano E, Gibson W, Graham G E, Indo Y. Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. Am J Hum Genet. 1999; 10.1086/302422

• Indo Y, Tsuruta M, Hayashida Y, Karim M A, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya H, Matsuda I. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996; 10.1038/ng0896-485

• National Library of Medicine (US). Genetics Home Reference [ Internet]. The Library; 2020 Aug 17. [Illustration] Congenital Insensitivity to pain with anhidrosis overview; [Reviewed May 2011; cited 2020 Aug 30]; Available from:https://ghr.nlm.nih.gov/primer/illustrations/therapyvector (http://www.genereviews.org/) and copyright (© 1993-2020 University of Washington)

• Daneshjou K, MD, Jafarieh H, Raaeskarami S R. Congenital Insensitivity to Pain and Anhydrosis (CIPA) Syndrome; A Report of 4 Cases. Iran J Pediatr. 2012; 22(3): 412–416.