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Received: 27 April 2022 Revised: 31 October 2022 Accepted: 6 November 2022
DOI: 10.1002/mus.27752

INVITED REVIEW

Expanding the genetic causes of small-fiber neuropathy:

SCN genes and beyond

Amanda C. Y. Chan FRCP 1,2 | Shivaram Kumar 2 | Grace Tan BSc (Hons) 2 |
3,4 1,2
Hiu Yi Wong MD, PhD | Jonathan J. Y. Ong MD |
1,2,5
Bharatendu Chandra MD | Hua Huang PhD 2 |
1,2 2,6
Vijay Kumar Sharma MD | Poh San Lai PhD

1
Division of Neurology, Department of
Medicine, National University Hospital, Abstract
Singapore, Singapore
Small-fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve
2
Yong Loo Ling School of Medicine, National
University of Singapore, Singapore, Singapore
fibers, sparing the large nerve fibers. Thinly myelinated Aδ-fibers and unmyelinated
3
Division of Life Science, State Key Laboratory C-fibers are damaged, leading to development of neuropathic pain, thermal dysfunc-
of Molecular Neuroscience, Hong Kong tion, sensory symptoms, and autonomic disturbances. Although many SFNs are sec-
University of Science and Technology,
Hong Kong, China ondary and due to immunological causes or metabolic disturbances, the etiology is
4
Hong Kong Center for Neurodegenerative unknown in up to half of the patients. Over the years, this proportion of “idiopathic
Diseases, Hong Kong Science Park, Hong
SFN” has decreased, as familial and genetic causes have been discovered, thus shifting
Kong, China
5
Division of Medical Genetics, University of a proportion of once “idiopathic” cases to the genetic category. After the discovery of
Iowa, Iowa City, Iowa, USA SCN9A-gene variants in 2012, SCN10A and SCN11A variants have been found to be
6
Adjunct Faculty, Genome Institute of
pathogenic in SFN. With improved accessibility of SFN diagnostic tools and genetic
Singapore, Singapore, Singapore
tests, many non-SCN variants and genetically inherited systemic diseases involving the
Correspondence
small nerve fibers have also been described, but only scattered throughout the litera-
Amanda C. Y. Chan, Division of Neurology,
Department of Medicine, 1 E Kent Ridge Road, ture. There are 80 SCN variants described as causing SFN, 8 genes causing hereditary
Level 10, NUHS Tower Block, Singapore
sensory autonomic neuropathies (HSAN) described with pure SFN, and at least 7 genes
119228, Singapore.
Email: acychan@nus.edu.sg involved in genetically inherited systemic diseases associated with SFN. This system-
atic review aims to consolidate and provide an updated overview on the genetic vari-
Funding information
National Medical Research Council, ants of SFN to date---SCN genes and beyond. Awareness of these genetic causes of
Grant/Award Number: MOH-000324-00
SFN is imperative for providing treatment directions, prognostication, and manage-
ment of expectations for patients and their health-care providers.

KEYWORDS
genetics, hereditary neuropathy, SCN genes, small-fiber neuropathy, sodium-channel mutations

Abbreviations: AIP, acute intermittent porphyria; cEDS, classic variant of Ehlers-Danlos syndrome; CIP, channelopathy-associated insensitivity to pain; DRG, dorsal root ganglion; EDS, Ehlers-
Danlos syndrome; EFNS, European Federation of Neurological Societies; FBLN5, fibulin-5; FGFR3, fibroblast-growth factor 3; FM, fibromyalgia; FMR1, fragile X mental retardation 1; FXTAS,
fragile X–associated tremor/ataxia syndrome; GAA, acid α-glucosidase; GLA, α-galactosidase A; GWAS, genome-wide association studies; HATTR, hereditary transthyretin amyloidosis; hEDS,
hypermobility variant of Ehlers-Danlos syndrome; HIV, human immunodeficiency virus; HMBS, hydroxymethylbilane synthase; HSAN, hereditary sensory autonomic neuropathy; IENFD,
intraepidermal nerve fiber density; IPD, infantile Pompe disease; iSFN, idiopathic small-fiber neuropathy; IVIg, intravenous immunoglobulin; LD-SFN, length-dependent small-fiber neuropathy;
LOPD, late-onset Pompe disease; MX1, interferon-induced GTP-binding protein; NCS, nerve conduction studies; NEURODIAB, Diabetic Neuropathy Study Group for the European Association
for the Study of Diabetes; NGF, nerve growth factor; NLD-SFN, non–length-dependent small-fiber neuropathy; PE, primary erythromelalgia; PEPD, paroxysmal extreme pain disorder; PNS,
Peripheral Nerve Society; QST, quantitative sensory test; SCN, sodium channel; SFN, small-fiber neuropathy; SIFT, sorting intolerant from tolerant; SLE, systemic lupus erythematosus; SNP,
single-nucleotide polymorphism; SPTLC1, serine palmitoyltransferase, long-chain base subunit 1; SPTLC2, serine palmitoyltransferase, long-chain base subunit 2; TRPA1, transient receptor
potential cation channel, subfamily a, member 1, also known as transient receptor potential ankyrin 1; TRPM3, transient receptor potential cation channel subfamily M member 3; TRPV3,
transient receptor potential cation channel, subfamily V, member 3; TS-HDS, trisulfated heparan disaccharide; TTR, transthyretin; vEDS, vascular variant of Ehlers-Danlos syndrome; VUS, variant
of unknown significance; WT, wild-type.

Muscle & Nerve. 2022;1–13. wileyonlinelibrary.com/journal/mus © 2022 Wiley Periodicals LLC. 1


2 CHAN ET AL.
1 | I N T RO DU CT I O N
Small-fiber neuropathy (SFN) is a disease that exclusively involves the
small nerve fibers, that is, Aδ and C fibers. Myelinated Aδ fibers are
responsible for cold temperature and sharp pain sensation, whereas
the unmyelinated C fibers are involved in warm sensation, heat pain,1
2,3
and autonomic function. Large nerve fibers and roots are excluded.
With increased availability of diagnostic tools, SFN is becoming
an increasingly recognized neurological syndrome. Its estimated mini-
mum prevalence was reported as 52.95 per 100 000 population in
4
2013 in The Netherlands, and calculated as 131.5 per 100 000 popu-
lation in 2021 in Switzerland.5 However, these are likely to be gross
underestimates due to diagnostic challenges and lack of awareness of
the disease.
Despite its impact and prevalence, the diagnostic criteria for SFN
are still evolving,6 with the highest diagnostic accuracy achieved
through a combination of skin biopsy for intraepidermal nerve fiber
density (IENFD),7,8 clinical findings, and functional tests.7 After con-
firming the diagnosis of SFN, the underlying etiologies, including met-
abolic, immunological, nutritional, toxic, neurodegenerative diseases,
9
genetics, etc, need to be determined. Novel genetic variants causing
SFN have emerged over the years, and a significant number of these
pathogenic variants involve the sodium-channel genes, which have
been found in up to 16.7%10 of SFN patients. A subsequent large
cohort study showed 11.6% of SFN patients harbor 73 potentially
pathogenic sodium-channel variants.11 Several other genetic variants
associated with hereditary sensory and autonomic neuropathies
(HSANs) as well as other genetic storage diseases have also been
12
implicated in SFN.
In this review we aim to provide an updated overview of the
underlying genetic variants associated with SFN.
2 | CLINICAL PRESENTATION
The clinical presentation of SFN is heterogeneous, and the two most
13
common clinical presentations of SFN are burning feet and neuro-
pathic pain, although symptoms can vary widely. Somatic symptoms
include constant or intermittent pain, electrical shocks or shooting, tin-
14
gling, hyperesthesia, allodynia, or dysesthesias. Simultaneously, SFN
can affect the autonomic nervous system, which further complicates
the clinical picture.15 Autonomic symptoms include postural dizziness,
syncope, palpitations, dry eyes and mouth, disturbances in perspiration,
constipation, urinary retention, and erectile dysfunction.14
The main patterns of presentation for SFN based on topography
are length-dependent SFN (LD-SFN) and non–length-dependent SFN
16,17
(NLD-SFN). In LD-SFN, the symptoms start at the toes and spread
18
upward. NLD-SFN presents in a diffuse patchy distribution that can
affect various parts of the body such as the face, tongue, scalp, upper
limb, and trunk before it involves the lower limbs.19 NLD-SFN patients
20
likely comprise about 20% to 25% of the total SFN population.
Childhood SFN may present differently, as most of these forms
are due to genetic mutations---gain-of-function or loss-of-function.
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The former presents with pain, itch, and autonomic lability, whereas
the latter presents with painless injuries, infections, and death.8 Epi-
sodic hand redness, pain, and hyperhidrosis can occur in early-onset
SFN, and adolescents may present with profound gastrointestinal
symptoms such as nausea, vomiting, and cachexia. Pupillary abnormal-
ities may also occur and neuropathic itch may be so severe that pain-
less foot ulcers may result from relentless scratching.8
3 | DI AGN OS I S
The first step in the diagnosis of SFN is exclusion of large nerve fiber
dysfunction or nerve root involvement, which needs to be investi-
gated with nerve conduction studies (NCS) and electromyography
(EMG). Commonly used electrodiagnostic tests include quantitative
sensory test (QST)21–24 and skin-punch biopsy.1 QST determines
cold-, warm-, and temperature-induced pain thresholds, and is nonin-
vasive, fast, and easy to perform, but lacks objectivity.25 Skin biopsy
and subsequent IENFD is often considered the definitive test in diag-
nosing definite SFN,9,26 and is still the most recommended confirma-
tory procedure that is reproducible,27 with sensitivity and specificity
rates as high as 90% and 97%, respectively.28 The limitations of skin
biopsy include its invasive nature and high cost compared with other
procedures.1 Other modalities of small-fiber functions can be assessed
by various autonomic function tests, including thermoregulatory
sweat test and quantitative sudomotor axon-reflex test29 that assess
sudomotor function, tilt table test with heart rate variability and Val-
salva ratio that test cardiovagal function,30 sympathetic skin response
and skin wrinkling tests24,31 that assess sympathetic function, and
contact heat-evoked potential (CHEP), which has been shown to cor-
relate with IENFD.32–34 Over the past decade, newer tests such as
laser evoked potentials (LEPs) and corneal confocal microscopy have
shown equally high sensitivity in diagnosing SFN.35,36 LEPs were
found to be strongly associated with pinprick sensory disturbances at
a sensitivity of 78% and specificity of 81% for the diagnosis of dia-
betic SFN,37 and superior in sensitivity compared with SSR, QST, and
electrochemical skin conductance for SFN.35 In vivo corneal confocal
microscopy visualizes the exclusive C-fiber innervation of the cornea,
is noninvasive and effective for longitudinal tracking.38 It identifies
SFN in patients with diabetes23 and Charcot-Marie-Tooth disease,39
but it is currently not yet available for routine use.
Diagnostic criteria for SFN have been proposed over the years.
The Besta criteria are based on the combination of at least 2 of the
following: (1) clinical signs of small-fiber impairment; (2) abnormal
warm or cold thresholds or both at the feet as assessed by QST; and
(3) reduced IENFD at the distal leg. Exclusion criteria were clinical
signs and NCS findings of large fiber impairment.3 In 2010, the
European Federation of Neurological Societies and the Peripheral
Nerve Society released a position paper recognizing skin biopsy as a
reliable and efficient procedure in the diagnosis of SFN.40 The second
set of criteria proposed by the Diabetic Neuropathy Study Group of
the European Association for the Study of Diabetes (NEURODIAB)
categorized patients according to their diagnostic certainty of SFN:

CHAN ET AL.
(1) possible---symptoms or clinical signs of small-fiber damage or
both; (2) probable---clinical signs of small-fiber damage with normal
NCS; and (3) definite---clinical signs of small-fiber damage, normal
sural NCS, and abnormal QST thresholds at the foot and/or reduced
IENFD at the ankle.2 Two proposed diagnostic criteria were recently
published. The first, by Devigili et al, for all causes of SFN, suggests a
combination of clinical symptoms and signs and functional and struc-
tural approaches should be employed to increase diagnostic accuracy
7
for clinical practice and research. The Analgesic, Anesthetic, and
Addiction Clinical Trial Translations, Innovations, Opportunities, and
Networks (ACTTION) diagnostic criteria, the most recent addition
proposing diagnostic criteria for idiopathic SFN, calls for at least one
small-fiber symptom and at least one small-fiber sign with abnormal
IENFD, normal sensory NCS, and absence of large-fiber symptoms
and signs. Absence of specific underlying etiologies need to be
excluded for an diagnosis of idiopathic SFN (Figure 2).41
4 | E T I O LO G I E S
SFN can be caused by many underlying disorders, some of which are
treatable.
4.1 | Acquired SFN
A large Dutch cohort of 921 SFN patients revealed that immunologi-
cal causes were found in 19%, vitamin B12 deficiency in 4.7%, and dia-
betes mellitus including glucose tolerance in 7.7%.10 Immunological
causes included systemic diseases, such as sarcoidosis and Sjögren
10 42
syndrome, paraneoplastic syndromes, and positive blood tests
10
such as antinuclear antibody. In some patients, SFN can develop
and present insidiously in patients with diabetes43 and, in others, SFN
can develop rapidly due to quick glycemic regulation in diabetic treat-
44
ment, known as treatment-induced neuropathy. Other metabolic
causes of SFN include hypothyroidism and uremia.19 Infectious
causes, such as hepatitis C virus, human immunodeficiency virus
(HIV), severe influenza, leprosy, and sepsis, form another group of
6
acquired SFNs. More recently, severe acute respiratory–syndrome
coronavirus-2 (SARS-CoV-2) causing a “long-haul” syndrome of
SFN,45,46 and possibly post–COVID-19 vaccine–associated SFN,47
have been described. Toxic exposure from industrial solvents,48 alco-
hol, and medications, such as chemotherapy, are also well known to
cause neuropathies.49
4.2 | Inherited SFN
Inherited forms of SFN have been increasingly described over the
years. Broadly, and for the purposes of characterization, they can be
characterized as genetic variants presenting with primary small-fiber
dysfunction, and genetically inherited diseases associated with SFN.
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3
This distinction is often unclear, and overlap presentations, such as
erythromelalgia-like symptoms, can occur in patients with pure SCN
mutations. The same SCN mutations may also be found in certain con-
ditions such as primary erythromelalgia. This was well illustrated in a
recent report of a patient with heterozygous variant c.554G>A in the
SCN9A gene who exhibited a clinical picture fulfilling all criteria of
inherited erythromelalgia (IEM), paroxysmal extreme pain disorder
(PEPD), and small-fiber neuropathy (SFN).50
4.3 | Idiopathic SFN
In 30% to 53% of SFN cases, the underlying cause remains
unknown,10,51 and these are referred to as idiopathic SFN (iSFN).
Considerable research has focused on iSFN, revealing novel autoanti-
bodies associated with iSFN, including anti-sulfatide antibodies,52
anti-trisulfated heparan disaccharide (TS-HDS),53 anti-fibroblast
growth factor-3,53 anti-plexin D1,54 and anti-interferon–induced
GTP-binding protein Mx1 (MX1).55
5 | METHODS
A literature review was performed with the search terms “small-fiber
neuropathy” and “genetics” or “genetic variants” or “genetic
mutations,” limited to human studies on PubMed/MEDLINE, Web of
Science, and EMBASE from 2010 to present. This year was chosen as
the cutoff as guidelines from the European Federation of Neurological
Societies/Peripheral Nerve Society were published on the use of skin
biopsy and normative values of IENFD for bright-field microscopy in
the diagnosis of SFN.40 A second check comparing reported muta-
tions in ClinVar, an open-source database of clinical variants, was car-
ried out. Thereafter, each manuscript was reviewed to ensure that
large nerve fiber involvement was excluded, complying with the first
set of diagnostic criteria in 2008.
6 | RE SU LT S
A total of 169 journal articles were found from PubMed/MEDLINE,
83 from EMBASE, and 37 from Web of Science. Further filtering for
duplicate entries yielded 79 journal articles. Manual review further
resulted in 63 journal articles addressing the management of geneti-
cally inherited SFN (Figure 1).
7 | T H E GE N E T I C S OF SF N
For this review, we focus on the inherited forms of SFN and dis-
cuss the underlying genetics of the condition, starting with the
variants that have been shown to cause pure SFN, followed by
inherited systemic diseases that may involve the small nerve fibers.
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4 CHAN ET AL.

F I G U R E 1 Search criteria employed for the literature search on the genetics of small-fiber neuropathy (SFN). Manuscript search was
performed on PubMed, MEDLINE, EMBASE, and Web of Science, using the terms “small fiber neuropathy” and “genetics” or “genetic mutations”
or “genetic variants,” from 2010 to 2022, limited to human studies and English language. This yielded 289 articles that were manually reviewed,
among which 180 were irrelevant, and duplicate journals were removed, resulting in 79 articles. An in-depth review of these 79 manuscripts
excluded 16 articles that were not purely SFN. Of the remaining 63 manuscripts, 25 were reports of novel variants, 35 were on systemic diseases
associated with SFN, and 3 that were related to the treatment of hereditary SFN.

7.1 | Sodium-channel genetic variants
7.1.1 | SCN9A
The frequency of SCN9A potentially pathogenic variants was
reported to be 5.1%.11 This SFN subgroup first emerged with the
discovery of a gain-of-function pathogenic variant in the SCN9A
gene encoding the Nav1.7 α-subunit. 56
Faber et al performed
genetic testing on 28 Dutch Caucasian, biopsy-confirmed iSFN
patients, of whom 8 were found to carry novel heterozygous mis-
56
sense mutations in SCN9A (Table S1). All patients presented with
pain that mainly started in the distal extremities, mostly aggravated
by warmth, with most having autonomic symptoms. Patients with
the R185H variant presented with less prominent autonomic symp-
56,57
toms. Patch-clamp tests showed all mutations carried gain-of-
function changes.56 In a subsequent study, Han et al studied
patch-clamping differences between R185H and I739V, showing
that, although R185H renders dorsal root ganglion neurons hyperex-
citable, it does not produce detectable changes within sympathetic
neurons. I739V, in comparison, renders dorsal root ganglion (DRG)
57
hyperexcitable, and sympathetic neurons hypoexcitable.
The I739V variant was described again in 2021 as associated with
a wide variety of phenotypes, ranging from congenital insensitivity to
pain to SFN. A father-daughter combination showed identical geno-
types, both carrying the I739V variant, but their phenotype varied
considerably. The index patient, a 55-year-old woman, complained of
muscle cramps and tightening for more than 10 years. Skin biopsy
confirmed SFN. Although this patient presented mainly with positive
symptoms, the patient's father, who was 80 years of age at the time
of diagnosis, had experienced decreased sensitivity to extremes of hot
or cold for decades, allowing him to walk without foot protection at
extreme temperatures. He refused neurophysiological tests, but had
been told in the past that he had a neuropathy. The authors concluded
that phenotypic variability exists in patients with this variant,58 which
was found to occur in approximately 1% of painful and nonpainful
peripheral neuropathy patients.59 The I739V variant was subse-
quently described in a family with paroxysmal itch,60 and associated
with the development of diabetes.61
The G856D variant was first described in 2012 in a 35-year-old
man with erythema, burning pain, and muscle cramps in the hands
since childhood that spread to the feet, cheeks, and ears. Dysautono-
mia symptoms were prominent. Physical examination showed small
hands and feet. The patient's father and brother experienced similar
symptoms and signs of acromesomelia and distal extremity redness
and pain. Genetic analysis of all three patients showed a missense
mutation (c.2567G>A) that was absent in unaffected family members.
Patch-clamp analysis showed that this variant led to hyperexcitability
in DRG neurons, and possibly contributed to distal limb underdevel-
opment.62 A similar set of siblings with the G856R variant was
described by Tanaka et al in 2017.63
Recently, a novel single-nucleotide polymorphism (SNP) of SCN9A
was described in two patients, leading to three amino-acid substitu-
tions that may determine immunotherapy responsiveness of SFN.
These variants of unknown significance (VUS) in SCN9A are located
on the chromosome 2q24 gene that encodes the α-subunit of the
NaV1.7 sodium channel. Both patients were treated with intravenous
immunoglobulin (IVIg) and responded well, with recurrence of symp-
toms during taper. Long-term treatment and follow-up revealed

CHAN ET AL.
improved symptoms, IENFD, and autonomic function tests.64 Whole-
exome sequencing of the first patient revealed a heterozygous rare
missense variant of SCN9A on exon 20 and the second patient
showed two heterozygous SCN9A variants at exons 17 and 18. This
codon should be Asn and not Asp, as reported by Kelley et al in 2020
(see Table S1). The first variant has low prevalence in European and
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5
American populations and was found to occur in a region of high
nucleotide and amino-acid conservation, with computational analysis
by sorting intolerant from tolerant (SIFT) predicting it to be
deleterious.64
In Germany, Egenolf et al performed a single-center study on
86 patients diagnosed with SFN, of whom 16% carried a genetic vari-
ant. Two of these patients had SCN9A pathogenic variants. Both were
males in their early 30s, presenting with burning feet sensation or a
generalized burning sensation. The patient presenting with burning
feet was found to carry a mutation of c.4942G>A, p.(Ala1648Thr),
whereas the patient with generalized burning carried a mutation of
c.3911T>C, p.(Ile1304Thr). Both variants occurred at a frequency of
1.16% among the SFN patients.65
7.1.2 | SCN10A
After the discovery of SCN9A, gain-of-function variants in SCN10A
encoding for NaV1.8 were described by the same author group. Faber
et al described three variants meeting the criteria for potential pathoge-
nicity in a series of 104 patients, where 9 of them harbored Nav1.8 vari-
ants.66 Two of the patients were a father-son combination. The father
was a 67-year-old man with burning and intense paroxysmal itch in the
feet for more than 10 years, whereas the son was a 39-year-old with
severe allodynia and hyperalgesia in the feet and legs. Seven variants
were identified; three satisfied the criteria for functional testing, of which
two variants demonstrated gain-of-function in SCN10A.66
The L554P channel variant was a missense mutation in exon
11 of the SCN10A gene, found in the father-son combination but not
in 325 healthy blood donors. Excitability of small DRG neurons
expressing L554P was increased, as suggested by the reduced cur-
rent threshold for action potential firing when compared with wild-
type (WT) neurons, yet the resting membrane potential was
unchanged.66
A mutation of c.3910G>A was found in a third patient described
by Faber et al. This variant was absent in 600 controls and not previ-
ously reported in the literature. This 69-year-old female patient pre-
sented with stabbing pain in the feet, lower legs, and hands for
4 years, associated with intolerance to bedsheets over her feet.
Symptoms were relieved by warmth, and she had noticed red
F I G U R E 2 Algorithm on the diagnostic approach to small-fiber
neuropathy (SFN). Patients who are suspected of having SFN based
on clinical features should undergo a nerve conduction study, which,
if normal, should be subjected to small-fiber quantitative and function
tests and skin biopsy to establish the diagnosis of SFN. Further
evaluation of underlying etiologies would include a systemic screen. If
patients are suspected of systemic hereditary diseases, and/or, if
malignancy and neurotoxicity investigations are negative, they should
be offered genetic testing for SFN-specific variants, or variants of
systemic hereditary diseases. Positive results will help to establish the
diagnosis of inherited SFN, whereas negative results will be classified
as Idiopathic SFN.

6 CHAN ET AL.
discoloration in her soles periodically.66 A1304T variants were also
found to alter Nav1.8 channel properties. A1304T channels were
found to be activated at a more hyperpolarized voltage when com-
pared with the WT. The A1304T mutation also led to increased
excitability of small DRG neurons with a more depolarized resting
membrane potential and reduced current threshold for action poten-
66
tial firing.
In 2013, Huang et al discovered a variant, I1706V (c.5116A>G), in
a 61-year-old patient who presented with burning and tingling sensa-
tions in both legs and feet, discoloration and episodic swelling of the
feet, and various autonomic dysfunction symptoms. The patient was
intolerant to shoes and bedsheets. Whole-cell patch-clamp analysis
showed that the I1706V variant resulted in hyperpolarized activation
and neuronal hyperexcitibility.67 Shortly thereafter, in 2014, Han et al
discovered the G1662S Nav1.8 variant that slowed channel inactiva-
tion with faster recovery from inactivation, leading to enhanced spon-
taneous firing in transfected DRG neurons. Two patients presented
with neuropathic pain in their legs, and to a lesser extent in their
hands. They both presented with variable autonomic symptoms. One
patient also had a significant family history of neuropathic pain in a
68
sibling and mother.
A rare variant of SCN10A, (c.G4915A, p.D1639N), was reported
in 2016. Interestingly, the 37-year-old patient presented with wide-
spread severe neuropathic pain for 2 years associated with gastropar-
esis, difficulties in swallowing, and heartburn sensation, resulting in
8-kg weight loss.69 This was one of the few loss-of-function muta-
tions involved in genetic SFN. In electrophysiological studies, this
mutation was later found to reduce current density without altering
the biophysical gating characteristics of Nav1.8.70 SCN10A variants
were shown to occur in 3.7% of SFN patients.11
7.1.3 | SCN11A
SCN11A has been reported to occur in 2.9% of SFN patients
(Table S1).11 Initial reports of pathogenic variants of the NaV1.9
α-subunit were described in 2014 by Huang et al, who screened
369 patients with pure SFN, for whom eight heterozygous SCN11A
variants were found in 12 patients. Most patients presented with tin-
gling and paresthesia in the distal extremities. There were seven mis-
sense variants in SCN11A, four of them located on exons 9, 12,
14, and 20, which substituted amino acids in membrane-spanning seg-
71
ments of the channel.
Voltage-clamp analysis of L1158P showed that the L1158P chan-
nel deactivates slower than the WT, yet the activation and inactiva-
tion profiles are not significantly altered. Current-clamp analysis
revealed a more positive resting potential of L1158P expressing DRG
71
neurons and lower current threshold for action potential firing.
the other hand, I381T variants led to increased window current and
defective channel deactivation when compared with WT channels.71
In the Egenolf et al study, three patients, 50 to 70 years of age,
were found to have SCN11A variants presenting with generalized
burning pain or burning pain in the feet.
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Variants of unknown significance (VUS), possibly or probably
pathogenic variants, had also been described by Eijkenboom et al in
2019 (Table S1).11
7.2 | Hereditary sensory autonomic neuropathy
Considerable phenotypic overlap exists between SCN variants and HSAN,
which are rare disorders. HSAN is commonly associated with neuropathic
symptoms and signs involving the large and small nerve fibers. The fol-
lowing subtypes have been described with pure SFN (Table S1).
7.2.1 | HSAN type I
HSAN type 1 is the most common form of HSAN,72 presenting in
adulthood with predominantly loss of pain and temperature sensation,
lancinating pain, and variable distal motor involvement, yet vibration
sense is preserved.72,73 Missense mutations in the SPTLC1 gene have
been associated with HSAN type 1.74,75 This gene encodes for serine
palmitoyltransferase, long-chain base subunit-1, which is involved in
the synthesis of sphingolipids. Mutations lead to accumulation of
deoxysphingolipid metabolites, which are neurotoxic. Egenolf et al
found the SPTLC1 variant in a 50-year-old SFN female patient with
severe generalized burning pain.65
SPTLC2 variants have also been found to cause a late-onset HSAN1.76
Among these variants, p.9Arg183Trp has been described as causing
biopsy-confirmed SFN in two families who had relatively mild progressive
distal sensory impairment at onset after 50 years of age. Small nerve fibers
were affected early in the course of the disease, progressing to develop-
ment of motor impairment without autonomic involvement.77
7.2.2 | HSAN type III
Familial dysautonomia, or Riley-Day syndrome or HSAN type III, is an
autosomal recessive disease almost exclusively affecting those of Ash-
kenazi Jewish ancestry. Patients present with variable autonomic dys-
function, decreased or absent deep tendon reflexes, absence of
overflow tears, and absence of fungiform papillae of the tongue, with
sensory loss.78 Unmyelinated and small myelinated neurons are
affected, resulting in decreased sensory, sympathetic, and parasympa-
thetic neurons. Mutations in the inhibitor of kappa light polypeptide
gene enhancer in B cells, kinase complex–associated protein (IKBKAP)
located on chromosome 9 (9q31), have been shown to cause HSAN,79
in which patients were confirmed to have SFN with a significantly
lower positive skin biopsy intraepidermal nerve fiber count.78
On
7.2.3 | HSAN type V
HSAN type V patients present with congenital insensitivity to pain,
severe loss of deep pain perception, painless fractures, joint

CHAN ET AL.
deformities, and normal intelligence.73 Most patients present at birth
or infancy. Nerve growth factor (NGF) missense mutations were origi-
nally discovered in a Swedish family with HSAN V, and confirmed in
80
mouse models to cause a selective peripheral sensory neuropathy.
7.3 | Miscellaneous
Egenolf et al identified various non-SCN genes in SFN patients, includ-
ing transient receptor potential ion-channel subfamilies (TRPA1,
TRPM3, and TRPV3) and fibulin-5 (FBLN5). Patients were mostly
middle-aged and presented with generalized moderate to severe
burning pain (Table S1).65
A point mutation (N855S) involving the S4 transmembrane seg-
ment of TRPA1 was first found to cause familial episodic pain syn-
81
drome in 2010. In that study, Kremeyer et al failed to show
abnormal morphology or reduced IENFD in the three subjects with
the N855S TRPA1 variant, but they did show that mutant channels
were more sensitive to both endogenous and exogenous ligands of
TRPA1 and cold temperature compared with WT in whole-cell patch
clamping. Although this specific point mutation has not been found in
definite SFN patients, it may suggest that the mutation of c.1678C>G,
p.(His560Asp), as described by Egenolf et al, may have a similar effect
of enhanced activity with TRPA1 variants.
In the same study, functional testing was not performed for the
TRPM3 and TRPV3 variants.65 Su et al and Mahar et al showed that
similar mutations of the respective channels in mouse models resulted
in differences in the perception of sensory modalities, albeit these
mutations differed from those described by Egenolf and
colleagues.82,83
FBLN5 variants have been found in Charcot-Marie-Tooth (CMT)
“plus” disease, which is an autosomal dominant form of CMT. Patients
present in their fourth to fifth decade with a mild to severe large-fiber
demyelinating neuropathy, skin hyperelasticity, and age-related macu-
lar degeneration. Fibulin expressed by FBLN5 in the extracellular matrix
plays an essential role in elastic fiber assembly.84–86 In 2021, Egenolf
et al provided the first description of FBLN5 in SFN patients.65
7.4 | Genetically inherited systemic diseases with
involvement of small nerve fibers
Many genetically inherited systemic diseases involve the nerve fibers.
Only the ones reported to be associated with a pure SFN are
described in what follows.
7.4.1 | Fabry disease
Fabry disease is a life-limiting glycolipid-storage disease that presents
in early childhood or adolescence. Patients present multisystemically---
typically with peripheral pain, angiokeratoma, and cornea verticillata.
Progression of the disease results from deficiency of lysosomal
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7
α-galactosidase A activity and accumulation of glycolipids in a variety
of cell types. In adulthood, patients may suffer from renal insufficiency
and cardiac and cerebrovascular complications.87
Fabry disease is transmitted in an X-linked manner, involving the
α-galactosidase A (GLA) gene. The first neurological symptoms of
Fabry disease may manifest as chronic, burning pain with superim-
posed acute attacks of neuropathic pain, and are present in 40% to
80% of patients. Autonomic symptoms are also common. Large nerve
fibers are generally spared in the early stages of Fabry disease, and
patients may present with a pure SFN.87
Despite early involvement of the small nerve fibers in Fabry dis-
ease, a recent study showed that 725 patients with isolated SFN and
no other symptoms of Fabry disease yielded no GLA mutations, thus
suggesting that genetic sequencing and protein-level assay should
only be done if other clinical features of Fabry disease are present.88
7.4.2 | Pompe disease
Pompe disease is rare and can be classified into infantile (IPD) and late-
onset (LOPD). IPD presents with cardiomyopathy, respiratory failure,
and proximal muscle weakness. Death occurs within the first 2 years of
life. LOPD has an emerging course and occurs when there is partial
deficiency of acid α-glucosidase (GAA). Neuropathy has rarely been
associated with IPD, but SFN was reported in LOPD in 2015. Hobson-
Webb et al described two patients, one of whom was an 11-year-old
Caucasian boy and the other a 49-year-old Caucasian woman, con-
firmed to have GAA mutations and biopsy-confirmed SFN. The authors
proceeded to screen 44 patients with the 21-item SFN screening list,
and found that half of the patients had a positive screen with a score of
≥11. Although skin biopsy was not performed for all 44 patients, the
findings are highly suggestive that SFN is prevalent in Pompe disease.89
7.4.3 | Porphyria
Porphyrias are a group of metabolic disorders arising from a defect in
the heme biosynthetic pathway. Clinical presentation is diverse and
neuropathy is common in acute intermittent porphyria (AIP). AIP is an
autosomal dominant disease due to a deficiency of hydroxymethylbi-
lane synthase (encoded by HMBS gene).90 Most, if not all, porphyric
neuropathies described have concomitant involvement of the large
nerve fibers, suggesting that it is not a pure SFN.91 However, auto-
nomic neuropathy is responsible for a variety of symptoms during the
acute attack and the majority of patients with AIP manifest with auto-
nomic dysfunction without large-fiber peripheral neuropathy or focal
central nervous system impairment.92
7.4.4 | Hereditary transthyretin amyloidosis
Hereditary transthyretin amyloidosis (HATTR) is a condition that
involves mutation of the transthyretin (TTR) gene. Affected adults

8 CHAN ET AL.
present with abnormalities in the peripheral nervous system, in the
heart, and to a lesser extent in other organs. The most frequent vari-
ant reported worldwide is Val30Met,93 and patients present at less
than 50 years of age in endemic areas like Portugal, Japan, and
Cyprus, but have later onset in other nonendemic areas. Other muta-
tions of the TTR gene usually lead to a late-onset phenotype.94
HATTR polyneuropathy occurs when TTR accumulates in the
peripheral nervous system, often causing an autonomic and/or axonal
length-dependent sensorimotor neuropathy. Without appropriate
treatment, and with progression of the disease to involve the large
nerve fibers, patients may have progressive difficulty walking, and
typically die within approximately 12 years of disease onset.94 Auto-
nomic dysfunction is a key component of HATTR, occurring more in
early-onset disease compared with later onset, and severity varies
95
according to the mutation.
Overall, the peripheral neuropathy of HATTR is a progressive axo-
nal and length-dependent sensorimotor and autonomic neuropathy,
but electrophysiological and clinical features will depend on the type
of HATTR and the time when neurophysiology tests are performed.94
7.4.5 | Ehlers-Danlos syndrome
Ehlers-Danlos syndrome (EDS)96 is a heritable soft connective tissue
disorder that is categorized into 13 variants according to their clinical
presentation.97 Patients present with generalized joint hypermobility,
skin texture abnormalities, and visceral and vascular fragility or dys-
function. Hypermobility (hEDS), classic (cEDS), and vascular (vEDS)
forms of EDS are the most common.96
Cazzato et al investigated 20 adults hEDS, 3 with vEDS, and
1 with cEDS in 2016. EDS was confirmed with genetic testing and
COL3A1 variants were found in three patients with vEDS, and the
COL5A1 variant was found in one patient with hEDS. All patients
except one had neuropathic pain that was moderate to severe in
intensity. Nerve conduction studies were normal in all patients, and
all of them had a reduction of IENFD that was consistent with
SFN.96
7.4.6 | Fragile X–associated tremor ataxia
syndrome
98
Fragile X–associated tremor/ataxia syndrome (FXTAS) is a move-
ment disorder characterized by tremor and/or ataxia, cognitive
involvement, neuropathy, and autonomic dysfunction. FXTAS patients
are carriers of the permutation the fragile X mental retardation
99
1 (FMR1) gene located at Xq27.3, which causes fragile X syndrome.
The association of SFN with FXTAS was first described by Chanson
et al in 2015, after excluding secondary causes of SFN.98 At least 80%
of FXTAS patients have peripheral neuropathy, although it is most
likely underrecognized. Numbness, neuropathic pain, and autonomic
dysfunction are common, and usually occur before motor
98
symptoms.
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8 | O T H E R CO N D I T I O N S A S S O C I A T E D
WITH S C N G E N ES
Sodium channels play a vital role in physiological mechanisms. They
transmit impulses throughout cells and their networks, thus enabling
coordination of higher processes like locomotion and cognition.100
Mutations in the sodium channels cause hypofunctioning or hyper-
functioning of the channels and lead to a variety of diseases
(Table S2).
Among the three SCN genes involved in SFN, SCN9A is perhaps
the most widely studied. SCN9A is known to cause a spectrum of
human genetic pain disorders and encodes Nav1.7, which is the
voltage-gated sodium-channel type IX α-subunit. Primary erythrome-
lalgia (PE),101–104 paroxysmal extreme pain disorder (PEPD),105 and
channelopathy-associated insensitivity to pain (CIP)106 are described
most frequently.
PE is a disease characterized by intermittent heat, redness, and
pain affecting the extremities. Exercise tends to aggravate the symp-
toms, and severe sudomotor impairment is present.107 Although there
is considerable overlap in patients with PE and SFN, it appears that a
reduced number of intraepidermal nerve fibers is seen in only 10% of
patients with PE,108 suggesting that the two conditions are distinct
from each other.
SCN9A loss-of-function mutations may lead to insensitivity to
pain. CIP is an extremely rare disease characterized by insensitivity
to all modalities of pain except neuropathic pain. Patients usually
present during the first decade of life with lack of pain sensation
and asymptomatic injuries. Mutations in CIP are transmitted as
autosomal recessive mode and lead to inactivation of the Nav1.7
channel. Most of these mutations were reported as nonsense
variants.109
Patients presenting with severe postoperative pain were found
to harbor SNPs in SCN9A, indicating that this may be used as a pre-
dictor of hypersensitivity to postoperative pain.110 The topic of
fibromyalgia (FM) is controversial and overlaps considerably with
SFN. FM is the most common cause of generalized musculoskeletal
pain and is accompanied by fatigue, cognitive disturbance, and psy-
chiatric and somatic symptoms.111 Patients may also present with
Raynaud phenomenon, dizziness, gastrointestinal and urological
symptoms, fatigue, and headache. Up to 50% of patients with FM
have an underlying SFN, suggesting that some patients with chronic
pain were mislabeled as FM when they had unrecognized SFN.112
Expectedly, SCN9A mutations have been found to be associated
with severe FM.113 In a study of 73 women with FM compared
with 48 age-matched controls, patients diagnosed with a severe
form of FM have been shown to harbor the rs6754031 SCN9A
SNP.113
Similarly, SCN10A mutations have been described in patients with
higher threshold for mechanical pain,114 rhythm disturbances of the
heart,115 and kidney stone disease.116 Although SCN11A mutations
have mainly resulted in multiple pain disorders, including familial epi-
sodic pain,117–119 alcohol-aggravated episodic pain,120 and increased
postoperative pain sensitivity121 (Table S2).

CHAN ET AL.
9 | T R E A T M E NT F O R G E N E T I C CA U S ES
OF SFN
The key strategy in treating SFN is to address the underlying cause.
Treating underlying genetic disorders, such as Fabry disease or heredi-
tary transthyretin amyloidosis, may indirectly help with the SFN symp-
toms and autonomic manifestations, but for other genetically
inherited SFNs we may need to await the development of gene ther-
apy. These strategies involve posttranscriptional silencing to suppress
gene expression by antisense oligonucleotides and RNA interference
technology, artificially increased expression with gene replacement
122
therapy, or gene modification with corrective gene therapy.
Neuropathic pain medications, such as gabapentinoids, sodium-
channel agents, and antidepressants, facilitate descending pain modu-
lation, whereas opioids and capsaicin inhibit ascending pain transmis-
sion. These agents are prescribed for symptomatic relief, but the
efficacy is poor. The number needed to treat (NNT) for 50% pain
intensity reduction ranged from 2.1 to 6.8 for antidepressants, 2.1 to
6.4 for anticonvulsants, and 2.1 to 5.1 for opioids. The number
needed to harm (NNH) ranged from 13.1 to 15.9, 6.3 to 32.5, and
13.3 to 17.1, respectively.123
The only clinical trial for patients with genetically inherited forms
of SFN was completed in 2019. Lacosamide was used for patients
with SCN9A mutations. Lacosamide is an anticonvulsant acting on
NaV1.3, NaV1.7, and NaV1.8, and was studied with the intent of asses-
sing symptomatic relief of neuropathic pain. The primary endpoint
was a 1-point average pain score reduction compared with baseline
on the pain intensity numerical rating scale. A statistically significant
improvement in pain score was seen in 58.3% of patients with lacosa-
mide compared with 21.7% in the placebo group.124
10 | DISCUSSION
Novel mutations in SFN may dictate treatment response of sub-phe-
notypes, and lead to future development of precise gene therapies.
Prognostication of sub-phenotypes may also allow for personalized
counseling and alignment of patient expectations. The epidemiology
of SFN has only been investigated in two studies so far, and both
studies calculated the minimum incidence and prevalence.4,5 Poten-
tially pathogenic sodium-channel variants alone were found in 11.6%
of patients with pure SFN,11 and the proportion of all genetic causes
of SFN is estimated to be considerably higher. Molecular screening
may uncover the true prevalence of hereditary SFN in the population,
thus guiding adequate direction of funds and planning of government
policies for this population of hereditary SFN patients.
Despite the many advantages of genetic testing, limitations are
exigent, especially with new high-throughput techniques that pick up
numerous new gene variants. Challenges in clinical interpretation
occur when encountering novel variants with unknown pathogenic
significance or when the identified variants are incidental or associ-
ated with a mismatching disease phenotype. There are also limitations
when analyzing pathogenicity of identified variants based on in-silico
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9
predictive algorithms when functional testing of novel variants is not
available. Scores of SCN9A variants associated with SFN and related
conditions have been reported with uncertain significance or conflict-
ing interpretations. The discovery of rare genetic variants in families
may not always imply pathogenicity and even a common allele can
confer risk for the disease phenotype. Even with in-vitro and in-vivo
analyses, it is possible that the functional effect is at the cellular level
alone, without any phenotypic manifestation, or may not even predict
the cellular response. The functional changes could also be complex
and the same variant can manifest as different phenotypes in different
patients due to variable expression or partial penetrance.125 Results
that are negative for mutations may not translate to an absent genetic
link, but rather that the genetic cause may not have been identified
due to other reasons. The disease could arise from disruptions not
identifiable through conventional clinical sequencing; for example,
deep intronic variants, large gene rearrangements, post-translational
processing, epigenetic modifications, mosaicism, etc. Nonetheless, the
importance of research genetic testing cannot be overemphasized,
and, if resources permit, clinicians should not stop at negative or inde-
terminate clinical genetic tests. Although erythromelalgia and warmth-
induced pain had been shown to have a significant relationship with
voltage-gated sodium-channel variants, researchers have suggested
genetic screening for these variants independent of clinical features
or underlying conditions.11 With the evolving number of variants and
improving availability of diagnostic tests, if a strong family history
exists, then clinicians should screen for novel mutations, with the limi-
tations and pitfalls of genetic testing in mind. The application of more
powerful genetic technologies, such as whole-genome sequencing
and genome-wide association studies (GWAS), can uncover new sub-
phenotypes and novel genes. Distinctions can thus be made between
acquired, hereditary, syndromic, and idiopathic SFN patients.
11 | C O N CL U S I O N
SFN is a heterogeneous disease with varied etiologies. Although the
Human Genome Project has identified and sequenced the full set of
human genes, as well as identified some alleles that cause disease when
mutated, novel genetic mutations are still being discovered. Clinicians'
awareness and vigilance of the evolving genetic causes of SFN are
required. Considering the increased availability and reduced costs,
genetic testing is an avenue that should be aggressively pursued, so that
new discoveries can be more easily made. New molecular tools like
whole-exome or genome sequencing may facilitate the identification of
novel genes, but understanding each test's strengths and limitations is
important. Further discoveries may enhance the development of preci-
sion treatments for patients with SFN and neuropathic pain.
AUTHOR CONTRIBU TIONS
Amanda Chee Yun Chan: Conceptualization; formal analysis; funding
acquisition; methodology; project administration; resources; visualiza-
tion; writing – original draft; writing – review and editing. Shivaram
S/O Kumar: Writing – original draft. Grace Tan: Data curation; formal
 10974598, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27752 by HINARI - ARGENTINA, Wiley Online Library on [02/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 CHAN ET AL.

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How to cite this article: Chan ACY, Kumar S, Tan G, et al.
Expanding the genetic causes of small-fiber neuropathy: SCN
genes and beyond. Muscle & Nerve. 2022;1‐13. doi:10.1002/
mus.27752