Pain, pain genetics, and 'next‐generation’ pain genetics
This commentary starts by looking at those very rare children with either a complete inability to sense pain, or who suffer intermittent severe pain, who usually have Mendelian single gene disorders.
Abstract
Children who suffer pain are frequently seen in clinical practice and unsurprisingly, analgesics are amongst the most common drugs prescribed to these children. This commentary starts by looking at those very rare children with either a complete inability to sense pain, or who suffer intermittent severe pain. These individuals usually have Mendelian single gene disorders. However, it is becoming clear that changes (polymorphisms) in these same genes can affect pain tolerance ⁄ pain threshold in the general population. Furthermore, research dissection of the function of these genes ⁄ proteins is producing new analgesics for widespread use. This process of mainstreaming ‘pain genetics’ has become possible through the availability of high quality, rapid, and cheap DNA sequencing using the next generation technologies, detailed in the first commentary of this series. Mendelian disorders of pain sensing can be broadly classified as deficiencies of pain sensing, of sensory nerve formation and preservation, and as complex. In this latter group pain sensing is rarely the predominant feature (e.g. Navajo Hepatocerebral syndrome [OMIM 256810] due to MPV17 mutations) so these are not the focus of this review. In the first category, deficiencies of pain sensing, are, so far, just two genes, SCN9A and TRPA1. SCN9A encodes for a membrane protein (called Nav1.7) present in pain-sensing neurons. Recessive, bi-allelic inactivating mutations of SCN9A lead to congenital insensitivity to pain (OMIM 243000). Affected individuals feel no pain at any time, anywhere in their body. All are anosmic, but rarely complain of this. The males often die young from reckless injuries, but all suffer repeated painless injuries including early self-mutilation of lips and tongue, and later burns and fractures. Intelligence is normal (as evidenced by pain behaviors being learnt). Conversely, dominant activating mutations in SCN9A give rise to a spectrum of disorders from paroxysmal extreme pain disorder (OMIM 167400) where stabbing pain is felt on defecation throughout life, and from the adolescent years onwards similar pain occurs elsewhere, especially the face, to congenital primary erythermalgia (OMIM 133020) where pain progressively develops after the first decade in the lower then upper limbs, followed by erythema). A family with a dominant activating mutation in TRPA1 has been described in a new episodic pain syndrome rather like abdominal migraine – how common this condition is awaits further study. In general, unless there is a family history these conditions are difficult to diagnose initially, because of their rarity and the fact that extensive neurological evaluation maybe normal, including nerve biopsy. The diagnosis can only be confirmed at present by DNA sequencing. The hereditary sensory and autonomic neuropathies (HSANs) are an incompletely catalogued group of conditions where pain-sensing neurons either fail to develop or rapidly degenerate. HSAN1 is dominant; the others are recessive with HSAN4 and HSAN5 being more common in Pakistani populations, HSAN3 (familial dysautonomia) is almost only found in Ashkenazi Jews, and HSAN2 is rare but seen in Caucasians. All can be clinically suspected, have distinct nerve biopsy findings, and confirmed by DNA sequencing of the relevant genes. Of note: HSAN3 is caused by bi-allelic mutations in the gene IKBKAP and autonomic features predominate; HSAN4 and HSAN5 are caused by mutations in either NTRK1 or NGF and constitute a clinical spectrum from insensitivity to pain and temperature, through to those also with intellectual disability, an inability to sweat and an immune deficiency with propensity to osteomyelitis and septic arthritis. However, further Mendelian pain disorders await discovery and next generation exome sequencing (where almost all of an individual’s genes exons are read in a single experiment) will surely hasten this process of genetic dissection of pain phenotypes. However, the impact of next generation is going to be far greater in general paediatric pain management. Individualized medicine is now a specific aim in the NHS, but in pain it is an imperative; does each child feel similar amounts of pain, do some children need more analgesics than others, and why are responses to analgesics sometimes idiosyncratic? In this context recent pain gene findings are exciting – e.g. polymorphisms in COMT, KCNS1, SLC6A4, and SCN9A have been identified that each affect a person’s pain thresholds for common painful conditions, Furthermore, changes in a number of genes have been reported to underlie the degree of response to various analgesics. An almost complete unresponsiveness to local anesthetics is a rare but real phenomenon and is likely to be a Mendelian trait. The speed that large amounts of DNA can be read by next generation sequencing will allow the identification of these ‘pain response’ gene changes. With these discoveries comes the realistic prospect of a single DNA test available rapidly for any child giving a ‘genetic pain response profile’ (c.f. antibiotics sensitivities for treating infections)!