Disorders In Depth
Hereditory Sensory and Autonomic Neuropathies (HSAN)
In HSAN, sensory (and variably autonomic) neurons and/or axons are affected. Motor neurons/axons are relatively or completely spared, except in HSAN1. With the likely exception of NGFB, the mutant genes are expressed by neurons are probably have cell autonomous effects. Diminished sensation of pain is common to all of these diseases, with the horrible consequences of delayed healing, Charcot arthopathies, infections, osteomyelitis, and amputations. Not all causes of altered pain sensation and/or autonomic function, however, are associated with neuropathy. Recessive mutations in SCN9A, which encodes the voltage-gated Na+ channel, Nav1.7, cause the absence of pain but not neuropathy (Congenital Indifference to Pain; OMIM 253000). Primary Erythermalgia (OMIM 133020, caused by dominant mutations in SCN9A), Paroxysmal Extreme Pain Disorder (OMIM 167400, caused by dominant mutations in SCN9A), Cold-Induced Sweating 1 (OMIM 272430, caused by recessive mutations in CRLF1), and Cold-Induced Sweating 2 (OMIM 610313, caused by recessive mutations in CLCF1), are not listed because an associated neuropathy is not adequately documented. HSAN associated with spastic paraplegia (OMIM 256840, caused by recessive mutations in CCT5), is not listed because it is a syndromic condition. Because only ~20% of affected patients have been found to mutations in thse genes, many causes that remain to be discovered (Rotthier et al., 2009). Altogether, HSAN is the rarest kind of hereditary neuropathy; HSAN1, 3, and 4 appear to be the most common..
HSAN1 (OMIM 162400)
Dominant mutations in SPTLC1 cause HSAN1 (Dawkins et al., 2001). SPTLC1 encodes serine palmitoyltransferase long chain subunit 1, the enzyme that catalyses the condensation of serine and palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramide. Mutants may allow other amino acids to be incorporated in place of serine (Eichler et al., 2009), but how this results in neuropathy remains to be determined.
According to Auer-Grumbach (Auer-Grumbach, 2008), “the main and consistent feature … is the reduction of sensation sense which is mainly distributed to the distal parts of the upper and lower limbs.” The onset varies between the second and fifth decades, with chronic progression. As the disease progresses, loss of pain sensation gives way to unheeded injuries, which can result in osteomyelitis and even amputation. Spontaneous fractures and Charcot joints further complicate matters. Length-dependent weakness caused by motor axon loss is a later feature. HSAN1 shares a similar clinical picture with CMT2B, except that some HSAN1 patients experience spontaneous pain. Electrophysiological studies document loss of sensory and motor axons in a length- and time-dependent manner; some patients have demyelinating features (Houlden et al., 2006). Nerve biopies confirm these electrophysiological findings, and autopsies show marked loss of sensory neurons.
HSAN2A (OMIM 201300)
Recessive mutations in WNK1 cause HSAN2. WNK1 is a member of the family of With No Lysine Kinases, and regulates the function of ion channels and transporters in a variety of cell types, and presumably in neurons/axons, too. Although a global deletion of WNK1 may be lethal, a neuronal-only loss of WNK function caused by mutations in one exon that is mainly expressed by PNS neurons causes HSAN2A (Shekarabi et al., 2008).
A progressive loss of sensation, including pain, begins in childhood, and may culminate in ulcers, osteomyelitis, and amputation. Overt autonomic dysfunction is not seen. Sensory responses are absent, whereas motor responses are normal, and sensory nerve biopsies show severe loss of myelinated and unmyelinated axons.
HSAN2B (OMIM 613115)
Recessive mutations in FAM134B cause HSAN2. FAM134B encodes a protein of the cis-Golgi, and is strongly expressed in sensory, autonomic, and CNS neurons (Kurth et al., 2009).
Impaired sensation, mutilating ulcers, and arthropathy begins in childhood. Nerve conductions and biopsies appear to show a loss of sensory axons in a length-dependent manner.
HSAN3/Familial Dysautonomia/Riley-Day Syndrome (OMIM 223900)
Recessive mutations in IKBKAP cause HSAN3. Most patients are homozygous for a mutation in a donor splice site; this causes a cell type specific reduction in the levels of IKBKAP protein. IKBKAP is a component of the elongator complex, which has diverse cellular functions, including the acetylation of microtubules (which increases their stability) and neuronal maturation (Creppe et al., 2009).
HSAN3 is almost exclusively found in individuals of Eastern European Jewish extraction, 1/30 are heterozygous for the donor splice site mutation (Axelrod and Gold-von Simson, 2007). HSAN3 can be recognized in infants, who have hypothermia, swallowing problems, lack of tearing, postural hypotension, lack of fungiform papilla, absent deep tendon reflexes, and absent flare response to intradermal histamine. Gastrointestinal dysmotility and aspiration are common, and episodes of vomiting or hypertension can be disabling. The loss of pain sensation is not as great as in other forms of HSAN; trophic ulcers, osteomyelitis and amputions appear to be less common, too, but Charcot arthropathies and unrecognized fractures are problems. Serial sensory testing indicates that sensory function of multiple modalities, including those subserved by large myelinated axons, diminishes with age. Scant electrophysiological data indicate that motor responses are normal, whereas sensory responses are diminished and likely disappear with age. Sensory nerve biopsies show a selective loss of unmyelinated axons, and autopsies demonstrate a loss of sensory and some kinds of autonomic neurons.
HSAN4/CIPA syndrome (OMIM 256800)
Recessive mutations in NTRK1 cause HSAN4. NTRK1 encodes TrkA, a receptor for nerve growth factor (NGF), but also neurotrophin-3. Based on the neurobiology of Ntrk1-null mice, autonomic and small sensory neurons likely die in utero, so that HSAN4 is really a congenital neuronopathy. These neurons, and the cholinergic neurons in the basal forebrain, express TrkA; the NGF is probably provided by other cells in their environment (Bibel and Barde, 1999).
The acronym CIPA stands for Congenital Insensitivity to Pain with Anhydrosis. In addition to these features, patients may develop unexplained high fevers, ulcers, osteomyelitis, and amputions. Patients have diminished intelligence, and often exhibit self-mutilating behavior. Sensory and nerve conductions are normal because large myelinated axons are not affected; sensory nerve biopsies show an absence of unmyelinated and small myelinated axons – these belong to the neurons that are known to depend on NGF for their survival during development.
HSAN5 (OMIM 162030)
Recessive mutations in NGFB cause HSAN5 in a single family. NGFB encodes NGF, the principle ligand for the TrkA receptor. Mature NGF is a dimer, produced by the proteolytic cleavage of pro-NGF. Most of the mutant protein remains as pro-NGF (Larsson et al., 2009), which is a ligand for the low-affinity neurotrophin receptor, p75, but not for TrkA. Like Ntrk1-null mice, the autonomic and small sensory neurons likely die in utero in Ngfb-null mice, so that HSAN5 is likely to be a congenital neuronopathy (Bibel and Barde, 1999).
Our knowledge of this disorder comes from a single family with a Arg211Trp missense mutation (Einarsdottir et al., 2004). Patients who are homozygous for this mutation develop Charcot arthropathy in childhood, but unlike patients who have HSAN4, they have a limited sense of pain, do sweat, and have normal intelligence; these discrepancies may owe to the preserved TrkA signalling mediated by the mutant protein or by an alternative ligand, neurotrophin-3, in nociceptive, sympathetic, and cholinergic neurons in the basal forebrain, respectively. Sensory and motor nerve conductions are normal; biopsies show a loss of unmyelinated and small myelinated axons – the very ones that are known to depend on NGF for their survival during development. Some adult patients who are heterozygous for this NGFB mutation develop Charcot arthropathies and variable symptoms of neuropathy, but a surprising number of unmyelinated and small myelinated axons are absent in sensory nerve biopsies (Minde et al., 2009). It remains to be determined whether the phenotype of heterozygous patients owes to haplotype insufficiency or a dominant effect of the mutant protein.
HSAN with cough and gastro-esophageal reflux (OMIM 608088)
HSAN with cough and gastro-esophageal reflux is an autosomal dominant disorder that maps to 3p22-p24 (Spring et al., 2005). Affected patients have a cough, likely due to severe reflux and not vocal cord paralysis, and a sensory neuropathy. Electrophysiological testing showed diminished sensory amplitudes, and sensory nerve biopsies showed loss of myelinated axons.
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Larsson E, Kuma R, Norberg A, Minde J, Holmberg M (2009) Nerve growth factor R221W responsible for insensitivity to pain is defectively processed and accumulates as proNGF. Neurobiol Disease 33:221-228.
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Spring PJ, Kok C, Nicholson GA, Ing AJ, Spies JM, Bassett ML, Cameron J, Kerlin P, Bowler S, Tuck R, Pollard JD (2005) Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24. Brain 128:2797-2810.