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date: 14 October 2019

Human Genetics of Pain

Abstract and Keywords

Inherited pain disorders are typically rare in the general population. However, in the postgenomic era, single-gene mutations for numerous human Mendelian pain disorders have been described owing to advances in sequencing technology and improvements in pain phenotyping. This chapter describes the history, phenotype, gene mutations, and molecular/cellular pathology of painless and painful inherited monogenic disorders. The study of these disorders has led to the identification of key genes that are needed for the normal development or function of nociceptive neurons. Genes that are covered include ATL1, ATL3, DNMT1, DST, ELP1, FLVCR1, KIF1A, NGF, NTRK1, PRDM12, RETREG1, SCN9A, SCN10A, SCN11A, SPTLC1, SPTLC2, TRPA1, WNK1, and ZFHX2. The study of some Mendelian disorders of pain sensing has the potential to lead to new classes of analgesic drugs.

Keywords: pain insensitivity, hereditary sensory neuropathy, hereditary autonomic neuropathy, chronic pain, voltage-gated sodium channel, Mendelian genetics, inherited pain disorders, monogenic

Introduction and Scope

This chapter discusses and concentrates on the known Mendelian disorders of pain sensing in humans. That is, human extreme phenotypes caused by one or two mutations, typically single-nucleotide changes, in a single gene. And, these changes (pathogenic mutations) cause a pain phenotype irrespective of other genetic background or mutations in other genes; that is, they are fully penetrant.

For painlessness, these Mendelian disorders can be classified as developmental, where no nociceptors are generated during embryonic development or nociceptors undergo apoptosis during fetal development or degenerate later in life; or as functional, where nociceptors are present but cannot be activated or cannot produce an action potential (Nahorski, Chen, & Woods, 2015). These Mendelian pain insensitivity disorders are summarized in Table 1 and shown schematically in Figure 1.

Table 1. Table of Human Mendelian Pain Insensitivity Disorders

Gene

Protein

Inheritance

IQ

Prevalence

Additional features

ATL1

ATL1

AD

N

Rare

Spasticity

ATL3

ATL3

AD

N

Rare

Spasticity

DNMT1

DNMT1

AD

N/decline

Rare

Deafness, cognitive decline

DST

DST

AR

Reduced?

Extremely rare

Joint contractures

ELP1

ELP1/IKAP

AR

N

Founder mutations in Ashkenazim

Autonomic crisis

FLVCR1

FLVCR1

AR

Reduced

Very rare

Retinal involvement

KIF1A

KIF1A

AR

N/reduced

Rare

Muscle atrophy, Spasticity

NGF

NGFBeta

AR

Reduced

Extremely rare

Early lip, tongue, and digit trauma; absent sweating and tears; Staphylococcus aureus infections

NTRK1

TRKA

AR

Reduced

Rare

Early lip, tongue, and digit trauma; absent sweating and tears; S. aureus infections

PRDM12

PRDM12

AR

N

Very rare

Reduced sweating and tears, corneal abrasions common

RETREG1

RETREG1

AR

N

Rare

Severe osteomyelitis

SCN9A

NaV1.7

AR

N

Rare

Anosmia

SCN11A

NaV1.9

AD

N

Extremely rare

Weakness, dystonia, GIT dysmotility, abnormal temperature sensing

SPTLC1

SPTLC1

AD

N

Rare

Lancinating pain

SPTLC2

SPTLC2

AD

N

Rare

Lancinating pain

WNK1

WNK1

AR

N

Rare

Severe osteomyelitis

ZFHX2

ZFHX2

AD

N

Extremely rare

Abnormal temperature sensing, reduced sweating

AD = autosomal dominant; AR = autosomal recessive; GIT = gastrointestinal tract; N = normal.

Human Genetics of PainClick to view larger

Figure 1. Schematic of a primary sensory neuron showing subcellular location of proteins encoded by pain insensitivity genes. Transcriptional regulators PRDM12, ZFHX2, and DNMT1 localize to the nucleus within the dorsal root ganglion (DRG) soma. RETREG1 (reticulophagy regulator 1) is found within the endoplasmic reticulum (ER) and is also a structural protein of the cis-Golgi body. The serine palmitoyltransferase enzymes SPT1 and SPT2 are involved in sphingolipid biosynthesis and localize to the ER. Atlastin proteins ATL1 and ATL3 regulate ER architecture. Voltage-gated sodium (NaV) channels are expressed at both the peripheral and central terminals and along axons of primary afferents. WNK1 (WNK lysine deficient protein kinase 1) is a regulator of ion channels and also interacts with KIF1A (kinesin family member 1A), a kinesin family motor protein involved in axonal transport of synaptic vesicles. DST (dystonin) is involved in intracellular transport and maintains cytoskeletal integrity. IKAP (elongator complex protein 1) mutations are associated with neuronal migration defects and impaired neurotrophic retrograde transport. Nerve growth factor (NGF) and its receptor, TRKA, are important for neuronal development and survival. DHN = dorsal horn neuron.

For Mendelian disorders of paroxysmal, excess pain, the situation is different. All known conditions are caused by gene mutations causing aberrant overactivity, giving the ability to overwhelm homeostatic or corrective responses in the pain system.

These Mendelian disorders collectively have been of great importance to pain research, particularly human pain research. The function of genes when over- or underactive is exposed, sometimes in marked contrast to predictions from expression and functional studies. The pathways that they participate within can be discovered, leading to potential new analgesic targets (e.g., recent trials with nerve growth factor (NGF)/tropomyosin receptor kinase A (TRKA)) antibodies (Miller, Block, & Malfait, 2018). Differences between humans and other species can be exposed, such as biallelic NTRK1 (neurotrophic tyrosine receptor kinase 1) or SCN9A mutations, which cause painlessness in humans but early lethality in mice (Nassar et al., 2004; Smeyne et al., 1994). Expected side effects can be more reliably predicted (e.g., a molecule yielding total abrogation of NaV1.7 voltage-gated sodium activity would be expected to produce analgesia, with the only side effect being a loss of smell, and both would be reversible).

The role of TRKA in nociceptor development and its subsequent roles in pain perception and immune function are fully covered in other chapters of this book. Similarly, inherited migraine disorders are also described elsewhere.

Mendelian Causes of Painlessness

Three Mendelian human pain insensitivity disorders are reported whereby patients present with a normal intraepidermal nerve fiber density (i.e., nociceptors are present but are nonfunctional). These disorders, congenital insensitivity to pain caused by mutations in SCN9A or SCN11A, and Marsili syndrome caused by a mutation in ZFHX2 (zinc finger homeobox 2), are described in this section.

NaV1.7 Congenital Insensitivity to Pain

In 1932, George Van Ness Dearborn described an “average man” in his 50s who had a long history of painless incidents, including “chopping his knee with a sharp hatchet” and shooting himself with a pistol with “the bullet passing through the left index finger” (Dearborn, 1932, p. 615). This is an early example in the medical literature of a case of “congenital general pure analgesia,” and as Dearborn stated, “In short, we know as yet far too little about the nervous system to warrant a single guess as to the neuropathology of such a case as this.” Seventy-four years later, in 2006, similarly remarkable pain-insensitive patients originating from northern Pakistan were described, with the causative gene, SCN9A, identified (Cox et al., 2006). Since then, significant efforts have been made by the pharmaceutical industry to target the encoded NaV1.7 voltage-gated sodium channel, with the aim of generating new potent analgesics (Sexton, Cox, Zhao, & Wood, 2018).

Phenotype

Individuals with NaV1.7 congenital pain insensitivity have a complete inability to experience pain and are also anosmic (lack a sense of smell) (Cox et al., 2006; Weiss et al., 2011). The disorder is congenital and often presents in early childhood through biting of the lips, tongue, and fingers or by parents observing painless immunizations. With the exception of pain sensation, somatosensory functions are normal, with touch, warm and cold temperatures, proprioception, tickle, and pressure all correctly perceived. Patients have normal intelligence and normal motor development and show no symptoms of autonomic nervous system dysfunction. Multiple burns, bruises, cuts, and bone fractures are frequently reported. Visceral pains are not perceived, including painless labor, although a form of neuropathic pain has been reported in a patient following injuries sustained during painless childbirth (Wheeler, Lee, Harrison, Menon, & Woods, 2014). Still a relatively rare disorder, patients have been identified with NaV1.7 pain insensitivity from multiple human populations (Ahmad et al., 2007; Cox et al., 2006; Goldberg et al., 2007).

Nerve and skin biopsies in NaV1.7 pain-insensitive patients typically show structurally normal sensory nerves (Cox et al., 2006, 2010; Goldberg et al., 2007; Klein et al., 2013; Staud et al., 2011). However, a small subgroup of patients has been described where morphological abnormalities of sensory nerves have been identified; these patients are classified as having hereditary sensory and autonomic neuropathy (HSAN) Type IID (Yuan et al., 2013).

Genotype

NaV1.7 congenital insensitivity to pain is an autosomal recessive disorder and was first reported to map to a region on chromosome 2 by autozygosity mapping in three consanguineous families from northern Pakistan (Cox et al., 2006). The minimum critical homozygous region shared by all affected individuals from the three families contained about 50 genes. Candidate gene analysis identified SCN9A as a lead target, with previous mouse Scn9a conditional knockout studies in sensory neurons showing a significant pain-insensitive phenotype (Nassar et al., 2004). Sanger sequencing identified different biallelic truncating mutations in each of three Pakistani families. Independently, two groups also used a homozygosity mapping approach to identify SCN9A pathogenic mutations in a further 10 families (Ahmad et al., 2007; Goldberg et al., 2007). The loss-of-function mutations in SCN9A are typically nonsense, small out-of-frame deletions or duplications, and splice-site mutations, although missense mutations in critical residues have also been reported (Cox et al., 2010; Emery et al., 2015). Patch-clamping studies are used to determine whether novel missense mutations affect the biophysical properties of the mutant channels in order to prove pathogenicity (Cox et al., 2006; Emery et al., 2015).

Pathogenesis

The SCN9A gene was cloned in 1995 from human neuroendocrine cells and was shown to encode the NaV1.7 voltage-gated sodium channel (Klugbauer, Lacinova, Flockerzi, & Hofmann, 1995). NaV1.7 is tetrodotoxin (TTX) sensitive and is a fast-activating and fast-inactivating channel that recovers slowly from fast inactivation. NaV1.7 also has slow closed-state inactivation properties, allowing the channel to generate a ramp current in response to small, slow depolarizations (Cummins, Howe, & Waxman, 1998; Herzog, Cummins, Ghassemi, Dib-Hajj, & Waxman, 2003). These biophysical properties enable NaV1.7-expressing neurons to amplify slowly developing subthreshold depolarizing inputs, such as generator potentials arising in peripheral terminals of nociceptors. Furthermore, studies of NaV1.7-positive neurons in the mouse hypothalamus have shown that a persistent sodium current mediated by NaV1.7 is critical for synaptic integration (Branco et al., 2016). NaV1.7 is predominantly expressed within dorsal root ganglia (DRG), trigeminal ganglia, sympathetic neurons, and olfactory epithelia (Black, Frezel, Dib-Hajj, & Waxman, 2012; Kanellopoulos et al., 2018; Toledo-Aral et al., 1997; Weiss et al., 2011).

Studies in conditional mouse Scn9a knockouts have helped to explain why null mutations cause anosmia and pain insensitivity. Using olfactory sensory neuron (OSN) conditional Scn9a knockouts, Weiss et al. showed that the OSNs were still electrically active and could generate odor-evoked action potentials but failed to initiate synaptic signaling to the projection neurons in the olfactory bulb (Weiss et al., 2011). NaV1.7 is expressed in the terminals of the OSNs and was shown to be an essential and nonredundant requirement for action potential propagation. NaV1.7 is also expressed in the central terminals of primary sensory neurons, as well as in peripheral terminals and along axons (Black et al., 2012; Kanellopoulos et al., 2018). Studies in DRG conditional Scn9a knockouts showed that TTX-sensitive current densities were reduced in sensory neurons that no longer expressed NaV1.7, and substance P release into the dorsal horn of the spinal cord evoked by electrical stimulation was completely abolished in the absence of NaV1.7 (Minett et al., 2012).

Further insights into the consequences of a loss of NaV1.7 have been revealed using transcriptomic analyses of DRG from Scn9a knockout mice, which showed a significant upregulation of the endogenous opioid preproenkephalin (Penk) (Minett et al., 2015). Furthermore, opioid receptor signaling measured with an assay for protein kinase A has been shown to be greatly potentiated in NaV1.7 null mice (Isensee et al., 2017). Interestingly, the opioid receptor antagonist naloxone can dramatically diminish the level of analgesia found in NaV1.7 null mice and enabled a single human NaV1.7 null to detect noxious stimuli that they normally could not feel (Minett et al., 2015). These links between NaV1.7 loss of function and opioid signaling may be used therapeutically as NaV1.7 blockers combined with low-dose opioids or enkephalinase inhibitors are reported to produce profound analgesia (Deuis et al., 2017).

NaV1.9 Congenital Insensitivity to Pain

The voltage-gated sodium channel NaV1.9, encoded by SCN11A, is predominantly expressed not only in nociceptors, but also in other cells, such as myenteric neurons (Cummins et al., 1999; Dib-Hajj, Cummins, Black, & Waxman, 2010). The channel is composed of four homologous domains (DI–DIV), each organized by six transmembrane segments (S1–S6) and cytoplasmic amino and carboxyl termini. NaV1.9 mediates a tetrodotoxin-resistant (TTX-R) sodium ion current with ultraslow kinetics and additional biophysical properties that are compatible with a role as a threshold channel that contributes to the resting potential of neurons. A crucial role for SCN11A in human pain perception was first demonstrated by a mutation that causes heritable painlessness (Leipold et al., 2013). Later, reports on its role in episodic pain, painful neuropathy, and cold-induced pain corroborated a complex contribution to human pain perception (Huang et al., 2014; Leipold et al., 2015; X. Y. Zhang et al., 2013).

Phenotype

Patients with NaV1.9 congenital pain insensitivity present with a complex phenotype including gastrointestinal motility disturbances (diarrhea or severe constipation), joint hypermobility, decreased muscle tone, intense itch, and increased sweating. Intelligence is normal.

Genotype

All known SCN11A disorders are dominantly inherited. Specific gain-of-function point mutations (missense mutations) in the distal S6 segments of the channel’s DI–DIV domains have been linked to human pain insensitivity (p.L396P, p.L811P, p.L1302F) (King, Leipold, Goehringer, Kurth, & Challman, 2017; Leipold et al., 2013; Phatarakijnirund et al., 2016; Woods, Babiker, Horrocks, Tolmie, & Kurth, 2014). These mutations are characterized by gain-of-function characteristics on a channel level, yet data from a respective mouse model suggested that as a consequence the synaptic neurotransmitter release is impaired, leading to a functional loss (Leipold et al., 2013). Interestingly, NaV1.9 mutations that are associated with familial episodic pain or painful peripheral neuropathy (small-fiber neuropathy, SFN) likewise show gain-of-function channel characteristics. The discrepancy in the phenotypic outcome (i.e., pain vs. no pain) is most likely due to slightly different biophysical properties of the respective mutations (see the section on SFN).

Pathogenesis

Biophysical properties of the pain-insensitivity mutations include a slowdown of the channel deactivation. This effectively increased the channel’s open probability and reduced the voltage dependence of steady-state inactivation, resulting in an increase of the availability of mutant channels and an increase in the resting membrane potential. An excess of sodium ion influx at rest triggers subsequent cell depolarization. Consequently, other ion channels, such as NaV1.7, NaV1.8, and voltage-gated calcium ion channels that form the main constituents of the action potential in sensory neurons (DRG neurons) may undergo progressive inactivation, resulting in a conduction block (Leipold et al., 2013). SFN-associated mutations similarly depolarize the resting membrane potential of DRG, enhance spontaneous firing, and increase evoked firing of these neurons (Huang et al., 2014). However, the opposite clinical outcome seemingly depends on the degree of membrane depolarization. Larger membrane depolarizations result in hypoexcitability and pain insensitivity, and smaller depolarizations result in hyperexcitability and pain (Huang et al., 2017; Leipold et al., 2015).

Marsili Syndrome

The phenotype in the Marsili family, originating from Italy, was first reported in 2008 when several members had hyposensitivity to painful thermal and capsaicin stimulation (Spinsanti et al., 2008). There are six affected members in the family spread across three generations, with each individual having a history of painless injuries from childhood (Habib et al., 2018). Each has had bone fractures of the arms or legs that are associated with an absence of pain or pain present only for a few seconds. Subsequently, broken limbs are used without any painful sensations, which can delay the recognition of an injury. The hypoalgesic phenotype is variable across the family, with individuals also having a low ability to correctly sense temperatures and a variable reduction in sweating. Cognitive and motor abilities are normal. A punch skin biopsy in the proband showed a normal intraepidermal nerve fiber density, indicating that the phenotype is not due to SFN.

Genotype

Marsili syndrome is an autosomal dominant disorder, and exome sequencing in all six affected family members identified a heterozygous point mutation in ZFHX2 that changes a highly conserved arginine residue to a lysine. ZFHX2 encodes a transcriptional regulator that is expressed within damage-sensing primary afferents. The mutated amino acid identified maps to one of the three homeodomains found within the protein.

Pathogenesis

Pain behavioral phenotyping in mice expressing the mutant Zfhx2 gene showed the mice to have delayed withdrawal responses to noxious heat (Habib et al., 2018). Furthermore, calcium imaging of DRG neurons isolated from the transgenic mice showed significantly reduced responses to capsaicin. Transcriptomic analyses of the DRG neurons in naïve mice versus littermate controls identified several genes that were upregulated (e.g., somatostatin) and downregulated (e.g., galanin, prostaglandin I receptor) that may contribute to the pain-insensitive phenotype.

Developmental/Neurodegenerative Pain Insensitivity Disorders

The developmental/neurodegenerative pain insensitivity disorders discussed in this section are as follows: HSAN Types 1–6, FLVCR1-associated pain loss, and HSAN Type 8.

Hereditary Sensory and Autonomic Neuropathy Type 1

The HSANs types HSAN1A and HSAN1C are caused, respectively, by pathogenic variants in SPTLC1 (HSAN1A) (Bejaoui et al., 2001; Dawkins, Hulme, Brahmbhatt, Auer-Grumbach, & Nicholson, 2001) and SPTLC2 (HSAN1C) (Rotthier et al., 2010). The serine palmitoyltransferase (SPT) enzymes encoded by these genes catalyze the de novo synthesis of sphingolipids. HSAN1B has been mapped to 3p24-p22, but to date no causative gene variant has been identified. Pathogenic variants in ATL1, previously associated with spastic paraplegia 3A (SPG3A), have also been identified in individuals with hereditary sensory neuropathy Type 1D (HSN1D) (Guelly et al., 2011). HSN1E with dementia and hearing loss is an adult-onset autosomal dominant condition caused by pathogenic missense variants in DNMT1, encoding DNA methyltransferase 1 (Klein et al., 2011). Affected persons with DNMT1 mutations typically have early mortality and often require total care because of dementia, hearing loss, and loss of ambulation from predominant sensory ataxia. The condition is allelic to heritable narcolepsy. HSN1F is caused by pathogenic missense variants in ATL3 and is clinically similar to HSN1D (Fischer et al., 2014; Kornak et al., 2014). Mutations in RAB7 cause Charcot-Marie-Tooth disease Type 2B (CMT2B), with phenotypic features that overlap with HSAN1 (Vance et al., 1996; Verhoeven et al., 2003).

Phenotype

Sensory loss in these autosomal dominant conditions usually starts in the adult and typically affects both touch and pain perception. In rare cases, early onset of symptoms has been reported. Dysesthesia with characteristic lancinating pain helps in clinical diagnosis (especially in the SPTLC1/2-associated disease) but can be absent. Painless injuries and osteomyelitis requiring amputations are frequent. The disease can be associated with sensorineural deafness (HSN1E). Motor involvement is mild to severe (including wheelchair requirement). Visceral autonomic features appear to be uncommon.

Genotype

Different mutations have been identified in the respective genes, but all subtypes of HSAN1 are inherited in an autosomal dominant fashion.

Pathogenesis

Examples for the pathogenesis of the HS(A)N subtypes are given next. All SPTLC1 mutations are missense variants and result in the accumulation of neurotoxic products (Penno et al., 2010). Mutant forms of SPT enzymes show a shift from their canonical substrate L-serine to the alternative substrate L-alanine, and this shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). An L-serine-enriched diet reduced levels of neurotoxic products (dSLs) in both mice and humans and may offer a potential treatment of the disorder (Garofalo et al., 2011; Scherer, 2011).

DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation and gene regulation. HSN1 mutations cluster within the targeting sequence domain of DNMT1 and cause premature degradation of mutant proteins, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation (Klein et al., 2011).

Atlastin proteins (ATL1, ATL3) regulate the fusion of membranes of the endoplasmic reticulum (ER) and thereby contribute to organelle architecture. ATL3 missense mutations fail to localize to branch points of the ER, but instead disrupt the structure of the tubular ER, suggesting that they exert a dominant-negative effect (Kornak et al., 2014). Furthermore, ATL3 mutants have also been shown to promote aberrant ER tethering and cause excessive liposome tethering, although retaining their dimerization-dependent guanosine triphosphatase (GTPase) activity (Krols et al., 2018).

Hereditary Sensory and Autonomic Neuropathy Type 2

Hereditary sensory and autonomic neuropathy Type 2 is genetically heterogeneous, and currently biallelic mutations in at least four genes are reported in HSAN2 subtypes. The first cases of these autosomal recessive conditions were published in 1946 and 1952, respectively, and termed neurogenic acroosteolysis (Giaccai, 1952; Ogryzlo, 1946).

Phenotype

Hereditary sensory and autonomic neuropathy Type 2 is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal, with the lower limbs more severely affected than the upper limbs. Over time, sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease (Kurth, 1993).

Genotype

Different mutations are described for HSAN2 and represent loss-of-function alleles. Causative genes include WNK1 (previously HSN2) (type HSAN2A), RETREG1 (previously FAM134B, JK1) (type HSAN2B), KIF1A (type HSAN2C), and SCN9A (type HSAN2D).

The previously designated HSN2 was first reported as a single-exon gene located in intron 8 of WNK1, with both genes transcribed from the same strand (Lafreniere et al., 2004). However, HSN2 is an alternatively spliced exon present in a nervous system–specific isoform of WNK1 (Shekarabi et al., 2008).

Pathogenesis

The serine/threonine–protein kinase WNK1 regulates blood pressure via reabsorption of ions in the kidney. An alternatively spliced nervous system–specific WNK1 transcript is expressed in DRGs and their neuronal projections. Pathogenic variants in this nervous system–specific transcript, which includes the “HSN2” exon, encode a WNK1 protein that causes HSAN2A disease. The WNK1 protein from this isoform may be involved in ion fluxes in the periphery of DRG. The presence of the WNK1 protein isoform, which includes amino acids encoded by the HSN2 exon, in satellite and Schwann cells could argue for an influence of these cell types in modulating the disease (Kurth, 1993). The expression of this isoform in fibers of the Lissauer tract (Shekarabi et al., 2008) may also be relevant for the development of clinical symptoms, as these neurons have been reported to be missing in congenital insensitivity to pain with anhidrosis.

A kinesin family motor protein, KIF1A contributes to axonal transport of synaptic vesicles and interacts with the neuron-specific isoform of WNK1. Thus, KIF1A could be responsible for the anterograde transport of WNK1 along axons but should be important for the transport of different classes of molecules along the long nerve processes.

The protein encoded by RETREG1 (previously FAM134B) was detected in the Golgi apparatus and the ER (Khaminets et al., 2015; Kurth et al., 2009). The protein contributes to the structure of the cis-Golgi compartment and was reported as first receptor for selective recycling of the ER, so-called ER-phagy (Khaminets et al., 2015; Mochida et al., 2015).

SCN9A is described previously. Obviously, biallelic mutations may lead to nerve fiber loss in addition to a pure conduction block (Yuan et al., 2013).

Hereditary Sensory and Autonomic Neuropathy Type 3

Familial dysautonomia, HSAN3, or Riley-Day syndrome is caused by pathogenic variants in ELP1 (IKBKAP) and is inherited in an autosomal recessive manner (Anderson et al., 2001; Slaugenhaupt et al., 2001). Prevalence of HSAN3 is high in individuals of Ashkenazi Jewish descent as a result of two founder variants that account for more than 99% of mutated alleles. HSAN3 is a sensory neuropathy characterized by prominent autonomic manifestation. Absence of tears (alacrima) with emotional crying is one of the cardinal features. Affected individuals have gastrointestinal dysfunction, nausea and vomiting crises, recurrent pneumonia, and cardiovascular instability culminating in autonomic crisis. Sensitivity to pain and temperature perception is reduced. The respective IKAP protein is involved in multiple pathways, and failed target innervation or impaired neurotrophic retrograde transport are suggested to be the primary cause of neuronal cell death in HSAN3 (Dietrich & Dragatsis, 2016).

Hereditary Sensory and Autonomic Neuropathy Type 4

The HSAN4 condition is the commonest, and archetypical, cause of developmental congenital insensitivity to pain. It is caused by biallelic mutations in the gene NTRK1.

The gene NTRK1 was first located and its exon–intron structure characterized in 1996 (Greco, Villa, & Pierotti, 1996). In 1999, the team led by Indo was the first to describe individuals with biallelic mutations in NTRK1 that had insensitivity to pain (Mardy et al., 1999). The condition was clinically characterized as an HSAN because of the combination of clinical features and that nerve biopsies consistently showed that a neuropathy was present. With the discovery of the causative gene, the condition became more tightly definable and was classified as hereditary sensory and autonomic neuropathy Type 4 (HSAN4) (Indo, 2001).

Phenotype

The phenotype of the condition was defined by Indo et al., although similar cases had been previously described but without genotyping (Indo, 2001). Subsequently, many articles have confirmed the phenotype (e.g., Huehne et al., 2008; Verpoorten et al., 2006). Males and females have similar features, and affected siblings are also strikingly similar.

The painlessness is congenital but is often unrecognized until the eruption of the first teeth, with the correct diagnosis often made in later childhood. The first symptoms are of biting self-mutilation of the tongue, inner cheeks, lips, fingers, and toes. This can lead to permanent scarring of the lips, loss of the anterior third of the tongue (with no subsequent effect on speech), and occasionally loss of digit tips. This phase of the phenotype is impossible to control without using teeth guards or in some cases removal of teeth of the first dentition. Anhidrosis may become apparent now, or later, depending on circumstances (a holiday in hot climes) and geography (living in countries with hot, dry climates). Anhidrosis is accompanied by an inability to sense temperature, both in the environment and of objects and food. As a young child, the risk is of unnoticed hyperthermia, which can lead to fits and death if untreated. As older individuals, they do not know what type of clothing to wear and do not realize when they are becoming overheated or hypothermic. As a consequence, they are at risk of burns and scalds from everyday events such as bathing, eating, and drinking.

The next phase of the disease is characterized by excess bruising, superficial cuts, scalds and burns, and sometimes fractures. Such fractures often present late, as there is no pain or leg limping or cessation of use of an arm—all of which would alert to the presence of a fracture in a normal child feeling pain. It is during this period that child abuse is considered in up to a third of parents. Many children have been removed from their parents, only to be returned when the injuries continue in foster care and the child is old enough for a clinical history of painlessness to be elicited. Anhidrosis can lead to dry skin and itching, and the scratching often leads to lichenification (rough thickening, which itself is often itchy, see Sayyahfar et al., 2013) of extensor surfaces, hands and feet, and the face.

Later childhood and adolescence are characterized by the additional problem of bone and joint fractures. This is because physical activities are unrestrained by pain; in normal children, pain is essential for learning how to look after one’s body and how much exercise/extremes of movements are possible before damage results. All painless children (regardless of causative gene) are considered clumsy/ataxic and developmentally delayed because of movement and actions unrestrained by previous pain conditioning. They do learn to move more gracefully, and some learn to avoid overt behaviors that exhibit their painlessness. As the child ages into a teenager and beyond, the opportunity and risk for orthopedic injuries increases, proportionate to height, weight, and behaviors. During this phase of the disease, developmental delay and cognitive deficits have become clear. Eventual general intelligence is usually within the mild–moderate range of mental retardation. A few cases have an intelligence quotient within the normal range but will always be delayed compared to the rest of their family.

In adulthood, the orthopedic problems become of greater importance. The individuals do not complain of pain and do not restrain their movements (i.e., jumping off buildings, extreme sports, picking fights) despite underlying bone and joint injuries. This has two unfortunate consequences. First, bony injuries can be overlooked by parents and go unrealized by examining doctors, delaying diagnosis and treatment (Rapp, Spiegler, Hartel, Gillessen-Kaesbach, & Kaiser, 2013). Second, there is no pain to warn that bones and joints have not fully healed, so activity continues; either wound healing is delayed or occurs aberrantly or incompletely. This results in long-bone deformities and joints damaged by crush or direct fractures. These are called Charcot joints and are untreatable; amputation can be the only practical therapy in some cases of particularly severe deformity. (Charcot is credited with describing the effects of tertiary syphilis and leprosy on joints.) As noted, the lack of limp or reduced use of an injured limb gives the false impression of normality, whereas X-rays will almost always reveal irreversible joint damage has begun by the age of 10 years.

There is no suggestion that intellect declines at a greater rate than in the normal population, but this has not been formally assessed.

Since the early descriptions of HSAN4, only one new feature has been recognized, that of an immunodeficiency restricted to Staphylococcus aureus; all other bacterial, fungal, and viral infections recover as expected, including other types of Staphylococcus infections (Hepburn et al., 2014; Shatzky et al., 2000). Staphylococcus aureus infections do not provoke as much inflammation as usual and are never painful (S. aureus infections are often painful, compared to other infections, particularly of skin). By the age of 10 years, all children will have had one episode of significant deep-tissue infection, septic arthritis, or osteomyelitis. These infections need to be sought and considered carefully by physicians and require prolonged treatment to prevent chronic infections and tissue loss. Many HSAN4 children lose digit tips, and while this often begins as a self-inflicted bite or blunt trauma, it is the subsequent S. aureus infections that lead to the tissue loss. This S. aureus–specific immune deficiency is not restricted to HSAN4 but is present in all disorders leading to a loss of peripheral nociceptors, as noted previously in this chapter.

Genotype

The inheritance pattern of HSAN4 is autosomal recessive. There are no definite genotype–phenotype correlations yet discovered, and this also applies for the most variable feature of HSAN5: intellectual disability. A large spectrum of mutations has been found in patients with HSAN4: nonsense mutations, frame-shift mutations, splice site mutations, and missense mutations (Indo, 1993). There are no common mutations. Missense mutations must be assessed carefully before being designated as pathogenic; see ACGS (Association for Clinical Genomic Science) guidelines and a recent report of a completely conserved, extremely rare, amino acid change that could not be shown pathogenic by multiple functional tests (Shaikh et al., 2017). The NTRK1 mutation c.2303C>T (p.Pro768Leu) has been reported to give a mild phenotype, although there have been no functional molecular studies to corroborate this (Jung et al., 2013; Ohto et al., 2004; Tanaka, Satoh, Tanaka, & Yokozeki, 2012).

Splicing mutations can be difficult to assess by bioinformatics alone unless they alter the canonical AG and GT splice acceptor and donor sites. Any nucleotide change that is within 50 nucleotides before and 6 nucleotides after an exon and that has a frequency of less than 1% should be carefully considered as a possible splicing mutation (Jung et al., 2013). This can then be assessed by functional assays, for instance, messenger RNA (mRNA) sequencing or a minigene assay of splicing. Maybe NTRK1 is particularly prone to splicing mutations (Kurth et al., 2016; Liu et al., 2018; Mardy et al., 1999; Nam et al., 2017).

NTRK1 has two splice variants, the rarer has the addition of a small six amino acid in-frame exon. This is exon 9 in the 17 exon NTRK1 transcript NM_002529; there are 16 exons in the commoner NTRK1 transcript NM_001012331. Both of these splice variants are present in adult mouse and human DRG. The NM_002529 exon 9 NTRK1 transcript is not included in all clinical laboratory diagnostic sequencing; however, as no mutations have been yet described in this additional exon, its clinical importance is unclear. The addition of this exon in rodent NTRK1 allows both NGF and NTF-3 to be ligands, whereas its omission allows only NGF (Clary & Reichardt, 1994).

Pathogenesis

NTRK1 encodes for the TRKA protein. It is a tyrosine kinase receptor for two ligands, neurotrophin 3 (NT-3) and NGF-β. It is probable that NTF-3 has an early role in sensory neuron development, but it is unclear whether this is essential for early nociceptor differentiation and persistence in humans (Birren, Lo, & Anderson, 1993). However, NGF has a clear essential role for nociceptor differentiation and is trophic for their persistence.

Hereditary Sensory and Autonomic Neuropathy Type 5

Type 5 HSAN is a very rare cause of developmental insensitivity to pain. NGF was discovered in 1956 by Nobel Prize winners Rita Levi-Montalcini and Stanley Cohen (Hamburger, 1993). The gene was not discovered for another 27 years (in 1983), and 21 years later in 2004, biallelic mutations were discovered as a cause of congenital insensitivity to pain (Einarsdottir et al., 2004; Francke, de Martinville, Coussens, & Ullrich, 1983).

Phenotype

The NGF phenotype is probably the same as the NTRK1 phenotype. Only three affected families have been described, making phenotype–genotype and interfamilial comparisons premature (Minde et al., 2009; Minde, Svensson, Holmberg, Solders, & Toolanen, 2006; C. G. Woods, 2018). A Swedish family was first to be described; the phenotype was fully described in a series of articles (Einarsdottir et al., 2004; Minde et al., 2006, 2009). The phenotype of the Swedish family was not as severe as that of the described Arab family, but both are within the HSAN4 spectrum.

Genotype

Each of the three known HSAN5 families has a different homozygous missense mutation. The three mutations have been shown to be functionally deficient compared to wild-type NGF (Carvalho et al., 2011; Covaceuszach et al., 2010; C. G. Woods, 2018). A child has been described with a heterozygous deletion of chromosome 1p13.2, including the whole NGF gene (Fitzgibbon, Kingston, Needham, & Gaunt, 2009). This child was reported to have significant intellectual deficiency, probably greater than that usually expected in HSAN5, and congenital insensitivity to pain. No second mutation in the trans-NGF gene was found. This case remains unexplained as NGF mutation carriers would be expected to be asymptomatic (as are all carriers of autosomal recessive gene mutations), but also see the work of Minde et al. (2009).

Pathogenesis

The pathogenesis of NGF congenital insensitivity to pain in humans seems identical to that of TRKA, and the similarities of the phenotypes support this.

Hereditary Sensory and Autonomic Neuropathy Type 6

Type 6 HSAN is characterized by dysautonomic symptoms, absent tearing, feeding difficulties, absent deep tendon reflexes, abnormal histamine test with no axon flare, distal contractures, motionless open-mouthed facies, severe psychomotor retardation, and early death (Edvardson et al., 2012; Manganelli et al., 2017). DST is a large protein with several distinct isoforms and is involved in maintaining cytoskeletal integrity and intracellular transport. A respective mouse model demonstrated that impaired autophagy is a main cellular pathway in DST-associated HSAN (Ferrier et al., 2015).

FLVCR1-Associated Pain Loss

Autosomal recessive fatal congenital loss of pain perception can be due to FLVCR1 (feline leukemia virus subgroup C receptor 1) gene mutations (Chiabrando et al., 2016). Mutations in FLVCR1 are also linked to vision impairment and posterior column ataxia in humans (Rajadhyaksha et al., 2010). The gene encodes a broadly expressed heme exporter. FLVCR1 mutations in HSAN reduce heme export activity, enhance oxidative stress, and increase sensitivity to programmed cell death. These findings link heme metabolism to sensory neuron maintenance and suggest that intracellular heme overload causes early-onset degeneration of pain-sensing neurons.

Hereditary Sensory and Autonomic Neuropathy Type 8

In 2015, a new type of developmental congenital insensitivity to pain was described (Chen et al., 2015). At least some of the families in this report had been previously described but without molecular genetic pathogenesis (Donaghy et al., 1987). PRDM12 is the gene name for PR/SET domain protein 12, and it is a transcriptional regulator (Matsukawa, Miwata, Asashima, & Michiue, 2015).

Phenotype

The HSAN8 condition was initially described in 11 families consisting of 21 affected individuals. No parents or carrier had any features of the condition. The phenotype was then confirmed and further expanded (Saini et al., 2017; S. Zhang et al., 2016). The phenotype is similar to HSAN4 and HSAN5, but with the following differences: Intelligence is normal (and normal for the family), some visceral pain and headache are felt, and sweating and tearing can be reduced but not absent (Donaghy et al., 1987; S. Zhang et al., 2016).

Recently, a new phenotype has been described called MiTES, midfacial toddler excoriation syndrome (Srinivas, Gowda, Owen, Moss, & Hiremagalore, 2017). This occurs in young children as an intense itch, leading to scratching and facial injuries. The itchiness is confined to the midface and tends to improve with age. Some cases are reported to have PRDM12 polyalanine tract expansions in the same range as seen in PRDM12-CIP. However, the affected children are not reported, to date, to have generalized insensitivity to pain; the explanation for this conundrum remains unclear.

Genotype

Reported biallelic mutations in PRDM12 have been nonsense, missense, and polyalanine tract expansions. The commonest mutation is the polyalanine tract expansion, from a normal range of 7–14 alanines to 17–18 alanines (Chen et al., 2015). To date, familial intergenerational instability has not been reported. The region of the terminal exon 6 of PRDM12 containing the polyalanine repeat is extremely CG rich and hence is difficult to Sanger sequence and is usually not captured in “exome” analysis. No genotype–phenotype correlations have been reported to date.

Pathogenesis

PRDM12 is expressed in fly, mouse, and human stem cell models of sensory neuron development just before terminal differentiation of nociceptors (Chen et al., 2015; Nagy et al., 2015). The protein contains a SET domain, but unlike other PRDM proteins, it lacks intrinsic histone methyltransferase activity but does recruit the methyltransferase G9a (Ehmt2) to dimethylate histone H3 at lysine 9 (H3K9me2) (Matsukawa et al., 2015). Therefore, PRDM12 is hypothesized to control the expression of critical genes necessary for nociceptor development. However, this remains to be proven, and the genes so controlled await identification.

Mendelian Causes of Painfulness

In recent years, major advances have been made in understanding the genetic basis for several inherited congenital and progressive painful disorders, which are described next.

Primary Erythromelalgia

Symptoms of primary erythromelalgia include mild-to-severe burning pain in the hands and feet (and occasionally in the nose and ears), increased skin temperature, edema, and erythema of affected areas (Bennett & Woods, 2014; Mitchell, 1878). Painful attacks are often triggered by warmth or moderate exercise, prolonged standing, and sometimes alcohol. Pain can be reduced by immersing the affected areas in ice-cold water, although this can cause skin ulceration. Analgesics such as opioids, anticonvulsants, and antidepressants are often prescribed but frequently with minimal positive effects on controlling symptoms. The sodium channel blocking drug mexiletine is sometimes helpful, as are topical lidocaine plasters applied to the soles of the feet. Primary erythromelalgia typically presents in early childhood, although cases with a later onset of symptoms have been reported (Cregg et al., 2013).

Primary erythromelalgia is an autosomal dominant disorder, and the first SCN9A mutations were reported in 2004 following linkage analysis and candidate gene sequencing in a Chinese kindred (Yang et al., 2004). Since then, numerous gain-of-function point mutations have been found in other patients (T. Z. Fischer & Waxman, 2010). Patch-clamping studies of the mutant NaV1.7 channels showed a hyperpolarizing shift in the voltage dependence of activation, slowed deactivation, and increased current response to slow depolarizations. The consequence of these altered electrophysiological properties of the NaV1.7 channels is enhanced excitability of the DRG neurons, with a lowered threshold observed for the generation of action potentials and a higher frequency of repetitive firing (Dib-Hajj et al., 2005). Further genetic causes of this disorder remain to be discovered, as even in the presence of a family history only 10% of primary erythromelalgia families are proven to have an SCN9A mutation (Goldberg et al., 2012).

Paroxysmal Extreme Pain Disorder

Formerly known as familial rectal pain syndrome, paroxysmal extreme pain disorder (PEPD) is characterized by paroxysmal episodes of severe perineal and rectal, ocular, and mandibular pain that typically presents at birth or in infancy (Hayden & Grossman, 1959). The pain attacks can also be accompanied by tonic nonepileptic seizures, syncopes, bradycardia, asystole, skin flushing, lacrimation, and rhinorrhea. Triggers for the painful symptoms in this autosomal dominant disorder include defecation, eating, and sometimes strong emotion (Bennett & Woods, 2014). In 2006, the first disease-causing mutations were mapped to SCN9A in 11 families and 2 sporadic cases (Fertleman et al., 2006). The gain-of-function mutations, like those for primary erythomelalgia, cause hyperexcitability of sensory neurons (Dib-Hajj et al., 2008). However, different biophysical properties of the PEPD-mutated sodium channels are observed with the voltage dependency of steady-state fast inactivation shifted in a depolarizing direction, which can make inactivation incomplete, resulting in a persistent current. The anticonvulsant carbamazepine can lower this persistent current and as such is effective at reducing the frequency and severity of painful attacks in most patients with PEPD.

Familial Episodic Pain Syndrome Types 1–3

Familial episodic pain syndrome (FEPS) is currently subdivided into three distinct disorders that differ in phenotype and causal gene. FEPS1 was described in a family from Columbia in which 15 individuals suffered from debilitating upper body pain, mainly affecting the thorax and arms (Kremeyer et al., 2010). The painful attacks are triggered by fasting, cold temperatures, or fatigue and typically last 60–90 minutes. The disorder presents in infancy, and affected individuals have a normal intraepidermal nerve fiber density. Linkage analysis and candidate gene sequencing led to the identification of a missense mutation in a transmembrane segment of TRPA1, the chemosensitive transient receptor potential channel. Patch clamping of the mutant channel showed a significant increase in inward current after activation at normal resting potentials, indicating a gain of function. Furthermore, patients with FEPS1 are hypersensitive to mustard oil, which is a TRPA1 agonist.

An adult-onset paroxysmal pain disorder, FEPS2 mainly affects the lower legs and feet (Faber, Lauria, et al., 2012). This autosomal dominant disorder has been described in a father–son pair and in an unrelated female. Skin biopsies showed a reduced intraepidermal nerve fiber density in the father, complete epidermal denervation in the son, and a normal nerve fiber count in the unrelated female. Different missense mutations were identified in SCN10A, which encodes the NaV1.8 voltage-gated sodium channel, with both mutations enhancing channel electrical activities and inducing hyperexcitability of DRG neurons.

Also an autosomal dominant disorder, FEPS3 was first reported in 2013 in two unrelated large Chinese families (X. Y. Zhang et al., 2013). Episodic pain is reported to manifest at the lower extremities and occasionally at the upper body, to appear late in the day, and to relapse every 2–5 days, with 10–20 recurrent pain episodes. Pain is triggered by fatigue or exercise and shows partial relief by oral administration of anti-inflammatory analgesic drugs. Pain episodes seem to improve with age in some cases. Whole-exome sequencing identified missense mutations in SCN11A, which encodes the NaV1.9 voltage-gated sodium channel. Electrophysiological analysis of the mutant channels in isolated DRG neurons showed an increase in peak current densities and enhanced action potential firing after current injection.

Small-Fiber Painful Neuropathy

Small-fiber neuropathy is typically an adult-onset disorder characterized by burning pain, often in the feet, together with autonomic symptoms such as orthostatic dizziness, palpitations, dry eyes, and a dry mouth. Small-diameter unmyelinated and thinly myelinated fibers are affected, with a skin biopsy showing reduced intraepidermal nerve fiber density. Large fibers are not affected, so deep-tendon reflexes and large-fiber sensory function are both normal. Gain-of-function mutations have been reported in patients with SFN in the sodium channel genes SCN9A, SCN10A and SCN11A (Faber, Hoeijmakers, et al., 2012; Faber, Lauria, et al., 2012; Huang et al., 2013, 2014). A number of variants reported in association with SFN are relatively common in the general population and are likely to be acting as risk factors rather than Mendelian pain disorder–causing mutations.

Conclusion

Mendelian pain disorders uniquely expose important aspects of human pain sensing. Each pain insensitivity disorder reveals a nonredundant pain pathway that cannot be controlled or ameliorated by other intrinsic pain mechanisms. The corollary of this is that surprisingly few genes can cause congenital insensitivity to pain (a handful, when compared to the more than 100 genes that cause either congenital blindness or congenital deafness), so there must be very considerable redundancy within pain-sensing circuitry, at least in humans. Conversely, Mendelian disorders of painfulness identify pain pathways that can be persistently overwhelmed despite no tissue-damaging event being present. Thus, Mendelian disorders of pain sensing identify pathways for analgesic targeting, which critically are nonredundant. So, while Mendelian disorders of pain sensing are extremely rare, their understanding has the potential to lead to novel analgesic classes with wide general applicability.

Acknowledgments

J. J. C. is supported by the Medical Research Council (MR/R011737/1) and the Wellcome Trust (200183/Z/15/Z). I. K. is supported by the Deutsche Forschungsgemeinschaft (KU1587/3-1, KU1587/4-1, KU1587/2-2). C. G. W. is supported by the Wellcome Trust (200183/Z/15/Z).

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