Neurological Sciences

https://doi.org/10.1007/s10072-021-05493-8

REVIEW ARTICLE

Advances in hyperekplexia and other startle syndromes

Fei‑xia Zhan1   · Shi‑Ge Wang1   · Li Cao1 

Received: 13 May 2021 / Accepted: 14 July 2021

© Fondazione Società Italiana di Neurologia 2021

Abstract
Startle, a basic alerting reaction common to all mammals, is described as a sudden involuntary movement of the body evoked
by all kinds of sudden and unexpected stimulus. Startle syndromes are heterogeneous groups of disorders with abnormal
and exaggerated responses to startling events, including hyperekplexia, stimulus-induced disorders, and neuropsychiatric
startle syndromes. Hyperekplexia can be attributed to a genetic, idiopathic, or symptomatic cause. Excluding secondary fac-
tors, hereditary hyperekplexia, a rare neurogenetic disorder with highly genetic heterogeneity, is characterized by neonatal
hypertonia, exaggerated startle response provoked by the sudden external stimuli, and followed by a short period of general
stiffness. It mainly arises from defects of inhibitory glycinergic neurotransmission. GLRA1 is the major pathogenic gene of
hereditary hyperekplexia, along with many other genes involved in the function of glycinergic inhibitory synapses. While
about 40% of patients remain negative genetic findings. Clonazepam, which can specifically upgrade the GABARA1 chloride
channels, is the main and most effective administration for hereditary hyperekplexia patients. In this review, with the aim at
enhancing the recognition and prompting potential treatment for hyperekplexia, we focused on discussing the advances in
hereditary hyperekplexia genetics and the expound progress in pathogenic mechanisms of the glycinergic-synapse-related
pathway and then followed by a brief overview of other common startle syndromes.

Keywords  Startle syndromes · Hereditary hyperekplexia · Genetics · Inhibitory glycinergic synapse · Glycine receptor ·
Clonazepam · Dr. Zhan and Dr. Wang contributed in manuscript preparation by performing the literature review and
writing the first draft. Prof. Cao critically revised the work

Introduction [2]. When abnormal and exaggerated, it is called startle

The term “startle” refers to a sudden, involuntary, jerky
movement of the body response to a sudden and intense
stimulus, such as auditory, tactile, and visual stimuli [1].
The normal startle reflex is a bilaterally synchronous flex-
ion response, most marked in the face and upper half of
the body that follows an unexpected stimulus in all healthy
individuals from six weeks of age and lasts for life, which is
considered to be a protective reaction against stress or injury
* Li Cao
caoli2000@yeah.net
Fei‑xia Zhan
zhanfx@rjlab.cn
Shi‑Ge Wang
wangsg@rjlab.cn
1
Department of Neurology, Shanghai Jiao Tong University
Affiliated Sixth People’s Hospital, 600 Yi Shan Road,
Shanghai 200233, China
syndrome. The startle syndromes consist of heterogeneous
groups of disorders: hyperekplexia, stimulus-induced dis-
orders, and neuropsychiatric startle syndromes [3]. Hyper-
ekplexia is characterized by exaggerated startle response
and associated severe generalized or intermittent muscle
stiffness, which can be genetic (hereditary hyperekplexia),
idiopathic (sporadic hyperekplexia), or an acquired (symp-
tomatic hyperekplexia) cause [2, 4]. Clinically, a generalized
stiffness is always noted early after birth, which may lead
to apnea attacks and sudden infant death syndrome. While
excessive startling  may last throughout life and can occa-
sionally cause serious traumatic injuries and impaired social
interactions in older children [1]. Genetically, mutations in
five genes including GLRA1, SLC6A5, GLRB, GPHN, and
ARHGEF9 have been identified as causative for hereditary
hyperekplexia, which is related to the glycinergic neuro-
transmission system [5, 6]. Moreover, other glycinergic-
neurotransmission-related genes, such as CTNNB1, SLC6A9,
SLC32A1, SLC6A17, SLC7A10, DPYSL5, and SDCBP, are

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also taken into consideration as the candidate genes [2, 7–9].
It is confirmed that hyperekplexia has relatively a good prog-
nosis with clonazepam to effectively control the startle epi-
sodes [10]. However, the actual “hyperekplexia” group of
diseases is rare and often could be misdiagnosed and missed
the prompt and appropriate treatment due to limited under-
standing of the disease. Besides, the pathogenic mechanism
of the disease is still not fully understood. To deepen the
understanding, bring up new thoughts on pathogenesis, and
promote the therapy breakthrough for the disease, in this
review, we discuss more detail in the advances in current
genetics of hereditary hyperekplexia and the potential patho-
genesis in the glycinergic-synapse-related pathway, followed
by a brief overview of other common startle syndromes.
Hyperekplexia
Hyperekplexia, or startle disease, was first described in
1958 by Kirstein and Silfverskiold. They reported a family
in which affected members suffered sudden falls precipitated
by “emotional” stimuli [11]. In 1966, Suhren and colleagues
investigated similar symptoms and firstly named the disorder
“hyperekplexia” [12]. The other terms used in the past to
describe the same condition included congenital stiff-man
syndrome and hereditary stiff-baby syndrome, which were
probably responsible for sudden infant death syndrome in
some severe cases [13]. To date, hyperekplexia is prone to
be genetic, sporadic, or symptomatic. The detailed descrip-
tion of the three disease entities are summarized in Table 1.
We focused on the review of hereditary hyperekplexia as
follows.
Clinical phenotype and management
of hyperekplexia
Though the exact prevalence remains unknown, more than
200 hyperekplexia cases were reported worldwide. Most
patients present their symptoms from birth or even in utero
during the last three months of prenatal period, while few
have the onset later into the childhood [1]. The core clini-
cal pictures are exaggerated startle response followed by a
shortly generalized stiffness provoked by unexpected exter-
nal stimuli. The precipitating factors are mostly sudden
auditory, visual, and tactile, but sometimes daily care like
feeding and changing diapers could also be a trigger [1, 14].
The major form has been associated with (1) a generalized
stiffness immediately after birth; (2) excessive startle reflex
to unexpected stimuli present from birth; and (3) a period
of generalized stiffness after the startle response. Neonatal
generalized hypertonia aggravates by handling but allayed
during sleep while in some severe cases may cause recur-
rent neonatal apnea attack and even sudden infant death [15,
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Neurological Sciences
16]. Exaggerated startle response with following generalized
stiffness and neonatal hypertonia might improve during the
first year of life, but falls of startle reflex can sustain until
adulthood [12, 17]. Consequently, patients are likely to get
head injuries or bone fractures, and walk with a wide-based
and stiff gait due to the fear of falling [14, 18, 19]. The minor
form is usually sporadic and is limited to excessive hyp-
nic jerks and abnormal startle response without a general-
ized stiffness [2]. Newly discovered clinical manifestations
include weird laughing and delayed development [20]. Intel-
lectual growth is normal in most cases, but delays in gross
motor and speech acquisition are reported [21]. Patients
sometimes avoid social interactions as they feel inferiority,
timidity, or anxiety when they are teased for startle reflex in
unfamiliar or loud environment [22, 23]. Other associated
symptoms include congenital dislocation of the hip; periodic
limb movements in sleep; hypnagogic myoclonus; epilepsy;
and inguinal, umbilical, or epigastric hernia [2, 10, 23].
During physical examinations, exaggerated head-retrac-
tion reflex (HRR) could be observed in most infant patients.
When tapped on the tip of nose, patients present head exten-
sion and excessive flexor spasms of limbs and neck mus-
cles [23]. Therefore, HRR test is considered a preliminary
judgement. Most laboratory tests, radiological examination
and electromyography of individual with hyperekplexia
reveal no abnormalities. During the interictal period, elec-
troencephalogram (EEG) is normal or shows non-specific
pathological changes [24, 25]. In startle and tonic spasm,
fast spikes followed by slow background activity and flat-
tening can be observed on EEG without epileptic discharges
[22, 26]. Synchronous poly-electromyography can help with
differential diagnosis as the brain wave on EEG can be cov-
ered by plenty electromyography artifact [16]. In general,
hyperekplexia patients have a comparatively good progno-
sis. Clonazepam, a GABAAR agonist, is the main and most
effective treatment for hyperekplexia [10]. It can specifically
upgrade GABAAR chloride channels, increasing the inward
chloride current of GABAergic neurotransmission, and thus
lowers the excitability of neurons and compensate for the
loss of functional glycine transmission caused by all genetic
forms [1, 10]. The treatment is recommended to start with
a dose of 0.5 mg daily, adjust dosage based on effects, up to
6 mg daily if necessary [2]. The effect of other antiepileptic
drugs, like carbamazepine or phenobarbital, is still in debate.
For psychological problems like social anxiety, timidity,
and self-basement, psychotherapy and family support are
crucial for personality development and alleviating mental
problems. For infant cases, once acute hypertonia and apnea
episodes occur, a simple intervention called the Vigevano
action (flexing of the head and limbs toward the trunk) can
relieve the event [27]. Here in Fig. 1, we summarized key
points of diagnosing and managing hyperekplexia.
 Neurological Sciences

Table 1  The detailed description of the three disease entities of hyperekplexia

Hereditary hyperekplexia Sporadic hyperekplexia Symptomatic hyperekplexia

Clinical The major form: generalized stiffness immediately after The excessive startle is not associated with any positive The majority of these cases manifest later in life, behave
features birth, excessive startle reflex to unexpected stimuli family history, a clear genetic basis, or an established as minor forms, and have associated other neurological
from birth, and a period of generalized stiffness after neurological cause signs and symptoms
the startle response. The minor form is limited to It mainly resembles the major form of hyperekplexia.
abnormal startle response without a generalized stiff- The minor form is mild, heterogeneous, and late-onset
ness. Other associated symptoms include congenital without other neurological signs
dislocation of the hip, periodic limb movements in
sleep, hypnagogic myoclonus, epilepsy, and inguinal,
umbilical or epigastric hernia
Pathophysiolog It is a neurogenetic disorder with highly genetic hetero- Unclear, may be correlated with genetic mechanism It is associated with an underlying cerebral or brainstem
geneity. The genetic basis involves genes that affect damage or neurodegenerative disorders
glycine neurotransmission
Genetics Causative genes: Have no clearly defined genetic basis No
GLRA1, SLC6A5, GLRB,
GPHN, ARHGEF9
So far candidate genes:
CTNNB1, SLC6A9, SLC32A1,
SLC6A17, SLC7A10, DPYSL5, SDCBP
Treatment Emergency interventions:
Vigevano action: flexing of the head and limbs toward the trunk
Long-term treatment:
(1) Drugs:
Clonazepam (0.01 to 0.1 mg/kg/d for infants and children and 0.8 mg/kg/d for adults)
Combination benzodiazepine therapy
Clobazam (0.1–0.2 mg/kg/day in divided doses, maximum up to 2 mg/kg/day)
Other drugs: diazepam, carbamazepine, phenytoin, valproate, levetiracetam, phenobarbital, fluoxetine
(2) Physical, cognitive therapy, and psychotherapy

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Fig. 1  Flow chart of diagnosing and managing of hyperekplexia. HRR, head-retraction reflex; PLMS, periodic limb movements in sleep; EEG,
electroencephalograph; ACMG, American college of medical genetics and genomics
Hyperekplexia and glycinergic inhibitory synapses
Besides anti-inflammation, immunoregulation, and cytopro-
tection, glycine works mainly as an inhibitory neurotrans-
mitter in adult central nervous system (CNS), regulating
muscle tone. Several recent studies elucidated that synaptic
release of both glycine and GABA has been shown to play a
determinative role in the proper development of many motor
and sensory pathways, including those necessary for audi-
tion, vision, respiration, and nociception [28]. Disruption
of glycinergic transmission during neural development has
been shown to cause hyperekplexia. Glycinergic inhibitory
synapse has a wide distribution in the CNS and is composed
of the presynaptic terminal, glycine-filled vesicles; synap-
tic cleft; glycine transporters (GlyTs); and glycine receptors
(GlyRs) [29, 30] (Fig. 2). Presynaptic glycinergic terminals
contain glycine-filled vesicles. A sufficient pool of glycine
to release and immediate clearance of glycine in the synaptic
cleft rely on synthesis enzyme, GlyTs, and vesicular inhibi-
tory amino acid transporter (VIAAT). Isoenzyme serine
hydroxymethyltransferase catalyzes serine into CNS glycine,
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Neurological Sciences
while GlyTs uptakes released glycine, and then VIAAT
transports glycine into synaptic vesicles. GlyT1 and GlyT2
both belong to the superfamily of N ­ a+/Cl−dependent neu-
rotransmitter transporters. GlyT1 is mainly found in astro-
cytes, catalyzing the removal of glycine from the synaptic
cleft into the nearby glial cells by its stoichiometry of ­2Na+/
Cl−/glycine [31]. In astrocytes, glycine cleavage system, a
multi-enzyme mitochondrial complex with high activity,
is responsible for glycine catabolism. In addition, GlyT1
relates to N-methyl D-aspartate receptor (NMDAR) function
by regulating glycine concentration, which is the co-agonist
for excitatory synapses containing glutamatergic NMDARs.
In contrast, GlyT2 expression is confined to glycinergic
transmission, predominantly detected in axon terminals of
glycinergic neurons, reuptaking glycine into presynaptic
terminal by its stoichiometry of ­3Na+/Cl−/glycine. Syn-
aptobrevin is responsible for synaptic vesicles fusing with
the presynaptic membrane when an action potential arrives
at the presynaptic axon terminal [32]. Thereby, glycine is
released to the synaptic cleft with a width of 10–20 nm and
conducts inhibitory signaling.
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GlyRs are pentamentric ­Cl−-selective channel protein,
belonging to the superfamily of Cys-loop ligand-gated
ion channel, mediating the inhibitory action of glycine
by improving the transmembrane influx of C ­ l − and
hyperpolarization [29]. GlyRs consist of five subunits
of glycosylated membrane proteins, arranged as a sym-
metrical ring around an ion conducting pore in the center
[33]. Each subunit contains an extracellular N-terminal
domain forming the ligand binding site and a transmem-
brane domain (TMD) constituted by four α-helices termed
TM1–TM4, TM2 domains of which forming the wall of
ion channel pore [5]. α subunits (Mw: 48 kDa) are the
binding site of glycine, while β subunits (Mw: 58 kDa)
help with anchor. Four kinds of α subunits termed α1–α4
and one kind of β have been described in human [30].
GlyRs can be either α/β heteromers or α homomers, but
only α/β heteromers are predominantly present in syn-
apses [34, 35]. Most α/β heteromeric GlyRs have a stoi-
chiometry of 3:2 or 2:3 [33, 36]. Only α1 and β subunits
are expressed in inhibitory glycinergic synapses of motor
reflex pathway in the spinal cord of adults, and α1 subu-
nit is the main target potently activated by glycine [37].
Gephyrin and collybistin are also detected at the cyto-
plasmic face of postsynaptic membrane [38]. Gephyrin
is the cytoplasmic anchor protein essential for the post-
synaptic localization of GlyRs, connecting receptors to
cytoskeleton [39, 40]. Collybistin is the brain-specific
GDP-GP exchange factor and regulates dendritic migra-
tion of gephyrin during postsynaptic membrane forma-
tion. Thus, it helps with the development and plasticity
of GlyRs clusters [41]. A proper functional ion channel
state and sensitivity to released glycine are essential for
inhibitory glycinergic synapse function. After glycine
is released, GlyRs reaches its maximum gating effi-
cacy as three binding sites are bound with glycine [42].
Then, each extracellular domain rotates relatively to the
transmembrane domain and tilts TM2 domain top out-
ward, opening the ion channel pore and increasing the
­Cl− influx. This process leads to postsynaptic membrane
hyperpolarization and inhibits the conductance of excita-
tory neural signal. Thus, disruptions in the functioning
of inhibitory glycinergic synapses in neuromotor path-
ways would increase the general level of excitability of
motor neurons [43]. Recently, dehydroxylcannabidiol, a
synthetic non-psychoactive cannabinoid, has been shown
to selectively rescue impaired presynaptic GlyRs activ-
ity and the functions of GABAAR in animal models of
hyperekplexia [44]. Moreover, the FDA-approved com-
pound 4-phenylbutyrate crosses the blood–brain barrier
and restores both membrane expression and glycine trans-
port in GlyT2 transporters, thus holding a therapeutic
potential [45].
Molecular genetics of hyperekplexia
So far, pathogenic variants in 5 genes relating to the gly-
cinergic neurotransmission system have been identified in
hyperekplexia, most of which are related to the glycinergic
inhibitory synapse, inherited in different patterns. In 1993,
Shiang first identified mutations in the GLRA1 gene as the
causative factor for hyperekplexia, which is marked hyper-
ekplexia the first hereditary synaptopathy resulting from
the defective neurotransmitter receptor [46]. Other reported
disease-causing genes include SLC6A5, GLRB, GPHN, and
ARHGEF9. However, approximately 40% of patients remain
negative during genetic testing [2]. The genetic spectrum of
hyperekplexia is still expanding. Other genes involved in
glycine signaling are expected to reveal the hidden patho-
genic factors for “gene-negative” patients. The brief infor-
mation of pathogenic and candidate pathogenic genes of
hyperekplexia are summarized in Table 2.
GLRA1 gene and hyperekplexia
GLRA1 is the most common one, which demonstrated both
dominant and recessive inheritance. The encoding pro-
tein α1 subunit of GlyRs contains an extracellular domain
(ECD) that harbors the neurotransmitter binding site and a
TMD that comprises 4 α-helices, termed TM1–TM4. Nor-
mal GlyRs desensitize slowly with rate of 0.5–5 s, which
relies on intracellular loops of α subunits interacting with
another [5, 47]. So far, about 77 mutations have been iden-
tified, including 64 missense/nonsense mutations, 7 small
deletions, 5 gross deletions, and 1 gross insertion [25].
The mutations are distributed in all domains, clustering in
ECD, TM1, TM2 domains, and Loop2. Dominant muta-
tions are mainly located in and around TM2 domain and
Loop2, while the recessive or compound variants are scat-
tering in all the domains. To date, there is no evidence for a
correlation between clinical traits and inheritance mode of
GLRA1 mutations. Studies indicated that dominant muta-
tions could compromise glycine ligand binding, decrease
the glycine sensitivity by disrupting the hydrogen bond,
or cause chloride conductance defects [48]. Localized at
the extracellular end of TM2 domain, R299 is the most
frequent mutant locus, which can decrease the sensitivity
of glycine by disrupting the hydrogen bond between R299
and Q254 that is essential for stabilizing open state and
reduce the conductance of one channel by erasing the posi-
tive charge on R299 that enables the pore to cluster ­Cl− in
its channel [5]. Additionally, a few dominant mutations
which are located in the ECD, TM1, and TM2 domain
could cause fast desensitization to limit chloride flux [47,
49]. For many recessive mutations, reduced expression or
a deficiency of cell surface targeting of GlyRs might be
implicated, in which the related glycine-activated currents
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◂Fig. 2  Schematic overview of normal and hyperekplexia-causing
inhibitory glycinergic synapse. A Normal glycinergic inhibitory
synapse structure. B The pathogenic mechanisms of GLRA1 loss-
of-function are the impaired ligand-gated ion channel gating or
increased desensitization rate or reduced cell surface expression
or the loss of zinc potentiation. C The pathogenic mechanisms of
GLRA1 gain-of-function are caused by inducing spontaneous activa-
tion of GlyRs and tonic Cl- influx. D The pathogenesis of SLC6A5
mutation is caused by the destruction of the GlyT2 structure and the
process of reuptake glycine. E The pathogenesis of GLRB loss-of-
function is caused by eliminating functional GlyRs expression and
reducing glycine sensitivity (left) or the potential chloride leak cur-
rent (right). F The pathogenesis of ARHGEF9 is caused by affecting
postsynaptic targeting of GlyRs through disrupting dendritic traffick-
ing of collybistin. G The pathogenesis of GPHN is caused by affect-
ing the localization of GlyRs through destructing bindings between
gephyrin and microtube
could be observed when co-expressed with α1 and/or β
wild-type subunits [47, 48]. Moreover, zinc is known to
have a potentiating effect on glycinergic currents upon
neuronal stimulation [50]. Upon stimuli, presynaptic ter-
minals in the spinal cord can release Z ­ n2+ in the synaptic
cleft and enhance postsynaptic GlyRs [51]. Three residues,
Asp-222, His-243, and Glu-220, are considered to be the
­ n2+; studies showed that the mutant resi-
binding sites for Z
dues which are to be the binding sites for ­Zn2+ may involve
in the loss of zinc potentiation [5, 52]. It was reported
that W198S mutation can diminish the enhancing effect
of zinc and results in hyperekplexia [53]. Except for the
loss-of-function mechanism above, some gain-of-function
mutations can also cause hyperekplexia. To date, several
dominant mutations have been demonstrated to induce
spontaneous GlyRs activation and decelerate glycinergic
inhibitory post-synaptic currents (IPSCs) decaying, which
result in enhanced sodium and calcium influx rates and
directly contribute to the reduction in the glycine-induced
current amplitude [47, 48, 54]. Based on the affected posi-
tions of Q254E and V308M mutations, it is deduced that
mutations may create a constitutively open channel state
by tilting related TM domain and thereby induce tonic
­Cl− influx and change C ­ l− equilibrium potential to more
positive values [5]. Hypothetically, this will eventually
lower the efficacy of inhibitory glycinergic neurotransmis-
sion or lead to a chronic depolarization. An experiment
conducted by Vuilleumier revealed that hyperekplexia
patients have increased pain sensitivity and damaged cen-
tral pain modulation, which might support this hypoth-
esis, as glycinergic synapses regulate nociceptive signal-
ing transduction in spinal dorsal horn [55]. However, drug
tests of tropisetron, a 5-HT3 receptor antagonist prolong-
ing IPSCs decay, do not induce hyperekplexia symptoms,
which disapprove such mechanism [56]. Another hypoth-
esis raised by Yan is that increased ­Cl− concentration dur-
ing late stage of formation of glycinergic synapses will
decrease the postsynaptic clustering of α1/β GlyRs and
later the efficacy of glycinergic neurotransmission [57].
In summary, the exact mechanism still remains unknown
and requires more investigation.
SLC6A5 gene and hyperekplexia
SLC6A5 gene encodes presynaptic GlyT2, which belongs
to solute carrier family 6 and contains twelve transmem-
brane domains. GlyT2 is a glycine transporter critical for
maintaining a plentiful presynaptic pool of neurotransmitter
at glycinergic synapses. Findings about SLC6A5 mutations
marks hyperekplexia the first neurological disorder related to
mutations of a ­Na+/Cl−dependent transporter for a classical
fast transmitter [58]. Phenotypes analysis showed that cases
with SLC6A5 mutations have higher prevalence of recur-
rent neonatal apneas and delays in development than cases
with GLRA1 mutations but also respond well to clonazepam
treatment [45, 59]. Several reports have shown that muta-
tions in SLC6A5 gene are the second major gene of effect
in hereditary hyperekplexia [59, 60]. Mostly, mutations in
GlyT2 identified so far are recessive ranging from missense
mutations, frameshift mutations, and nonsense or splice site
mutations [45]. In addition to recessive mutants, two domi-
nant negative mutations, Y705C and S512R, were described
associated with impaired transporter trafficking and trap-
ping of mutated GlyT2 [61, 62]. Most GlyT2 mutations are
loss-of-function, resulting in hereditary hyperekplexia by
influencing subcellular GlyT2 localization or glycine uptake
(Fig. 2). It was found that frameshift and nonsense muta-
tions could truncate the transporters and cause retention of
the misfolded inactive protein in the endoplasmic reticu-
lum. Others are missense mutations affecting residues with
crucial roles for the catalytic transport activity such as the
sodium binding sites, the Cl- site, or the glycine site [45, 59].
GLRB gene and hyperekplexia
GlyRs β subunit is encoded by GLRB gene, contains four
transmembrane domains, and is essential components of
heteromeric ligand-gated chloride channels by involving
in forming the channel pore and binding with gephyrin for
proper synaptic localization. The first hyperekplexia case
caused by GLRB mutation was reported in 2002 [63]. After-
wards, at least 18 GLRB mutations causing hyperekplexia
have been identified, making GLRB gene the third major
causative gene in hyperekplexia, accounting for almost
12–14% of the patient population [21, 64]. GLRB mutations
are mainly inherited by autosomal recessive pattern. Most
patients with GLRB mutations respond well to clonazepam
treatment. But like hyperekplexia cases with SLC6A5 muta-
tions, genotype–phenotype analysis shows that patients with
GLRB mutations are more severe, as they are more likely to
have delays in development of gross motor and language
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Table 2  Information of pathogenic and candidate genes of hyperekplexia

Gene Location OMIM Exons Encoding protein Gene function

GLRA1 5q33.1 138,491 9 α1 subunit of GlyRs Providing binding sites for glycine on GlyRs
SLC6A5 11p15.1 604,159 16 GlyT2 Removing glycine from the synaptic cleft to the presynaptic bodies
GLRB 4q32.1 138,492 10 β subunit of GlyRs Providing binding sites for Gephyrin on GlyRs
GPHN 14q23.3 603,930 23 Gephyrin Anchoring GlyRs to the postsynaptic cytoskeleton
ARHGEF9 Xq11.1 300,429 10 Collybistin Regulating the localization of gephyrin
CTNNB1* 3p22.1 116,806 19 β-catenim Regulating gene expression in the canonical Wnt signaling pathway
SLC6A9* 1p43.1 601,019 18 GlyT1 Terminating glycine signaling by clearing glycine from inhibitory glycinergic
synapses
SLC32A1* 20q11.23 616,440 2 VIAAT​ Uptaking glycine into the synaptic vesicles
SLC6A17* 1p13.3 6,102,995 13 Rxt1 Uptaking glycine into the synaptic vesicles
SLC7A10* 19q3.11 607,959 11 Asc-1 Regulating NMDAR activity at glutamatergic synapses by mobilizing
D-serine
DPYSL5* 2p23.3 608,383 16 ULIP6 Interacting with GlyT2 and regulating endocytosis and recycling of GlyT2
SDCBP* 8q12.1 602,217 10 Syntenin-1 Interacting with GlyT2 and regulating localization of GlyT2

GlyRs glycine receptors, GlyT glycine transporter, VIAAT​ vesicular inhibitory amino acid transporter, Rxt1 the orphan transporter NTT4, Asc-1
the astrocytic transporter SLC7A10, NMDAR N-methyl D-aspartate receptor
Genes with * are candidate genes

acquisition, repeated attack of neonatal apneas, and learn-
ing difficulties [21]. Therefore, prenatal consultation and
qualified newborn baby care for patients with GLRB muta-
tions are fairly recommended. GLRB mutations mainly cause
hyperekplexia through loss-of-function pathogenic mecha-
nisms. The main type is reduced functional GlyRs β subunit
expression, which either reduce cell surface expression of
functional heteromeric GlyRs or cause modest reductions in
glycine sensitivity and thus functional GlyRs declines and
glycinergic transmission dysfunctions [5] (Fig. 2). In addi-
tion, it has been reported that one de novo mutation, L285R,
replacing leucines located in pore-lining TM2 domain with
polar or charged residues defecting the closed pore confor-
mation, is reported to cause hyperekplexia through a sig-
nificant, potentially damaging, chloride leak current [65].
GPHN gene and hyperekplexia
GPHN gene encodes gephyrin, regulating the efficiency of
inhibitory synaptic function by not only binding GlyRs to
the cytoskeleton but also affecting the clustering, recruit-
ment and stability of the receptors [66] (Fig. 2). A mis-
sense GPHN mutation (p.N10Y) has been reported to cause
hyperekplexia. The male infant patient with GPHN muta-
tion has infant-onset startle reflex and neonatal hypertonia,
and a short recovery showed up at the age of 4. Functional
study revealed that the mutation p.N10Y disrupts neither the
binding of GlyRs and gephyrin nor the collybistin-regulated
clustering of GlyRs on the postsynaptic membrane, but it
may lower the efficiency of glycinergic inhibitory synapses
in other ways such as damaging the binding to the cytoskel-
eton [67].
ARHGEF9 gene and hyperekplexia
ARHGEF9 gene encodes Rho guanine-nucleotide exchange
factor 9, also known as collybistin. Collybistin is in charge
of regulating postsynaptic localization of gephyrin and by
association, the clustering and localization of GlyRs, which
is essential for inhibitory glycinergic synapses development
[68, 69]. One mutation, a missense mutation p.G55A, in
the ARHGEF9 gene has been reported causative for hyper-
ekplexia. The patient presented with neonatal cyanosis,
hypertonia, and stare once born. Afterwards, he suffered
from tonic seizures resulted from both hyperekplexia and
epilepsy, but clonazepam or even multi-drug treatment did
not work effectively. Eventually, he died at the age of four.
Functional analysis revealed that the mutation p.G55A
causes phenotype of both hyperekplexia and epilepsy by
failure on collybistin dendritic transportation and bindings
with gephyrin, and thus lowering the postsynaptic recruit-
ment of both gephyrin and GlyRs [68] (Fig. 2).
Candidate genes in hyperekplexia
Despite five identified pathogenic genes, there are still
about 40% patients with hyperekplexia that show no patho-
genic variants in glycine pathway-associated genes. They
might be authentic hyperekplexia patients with mutations
in genes not identified yet or in known causative genes but
not detected. The uncertainty urges clinicians and geneti-
cist to find more potential candidate genes for reasonable
explanations, thereby implicating candidate genes for other
subunits; receptor clustering; and presynaptic transporters

13
Neurological Sciences
such as CTNNB1, SLC6A9, SLC32A1, SLC6A17, SLC7A10,
DPYSL5, and SDCBP.
CTNNB1 gene encodes β-catenim, which belongs to
the armadillo family of proteins and is a key downstream
component of canonical Wnt signaling pathway regulating
expression of proteins involved in neuron excitability [70].
CTNNB1 mutations have been identified to relate to several
neurodevelopmental disorders including microcephaly, spas-
tic paraplegia, and disabilities of intelligence; speech; and
movement [71]. A case report described a patient with a de
novo nonsense mutation in exon 3 of CTNNB1; other than
CTNNB1-related syndrome, he also presented with early-
onset atypical syndromic hyperekplexia, development delay,
and apraxia of upward gaze, suggesting that CTNBB1 should
be considered a candidate causative gene for hyperekplexia
[7].
SLC6A9 gene encodes GlyT1, predominantly expressed
in glial cells and well distributed in the cell membrane.
GlyT1 terminates glycinergic transmission and regulates
glycine concentration in the glycinergic inhibitory synapse
during infancy stage [72]. Experimental SLC6A9-knockout
mice show that GlyT1 could be necessary for the develop-
ment of normal respiratory rhythm and muscular tone [30].
Though only one case due to SLC6A9 mutation causing gly-
cine encephalopathy was reported, it is possible that gain-
of-function mutations in SLC6A9 could clear glycine from
the synaptic cleft faster than normal [73].
SLC32A1 gene encodes VIAAT, which is expressed
in both glycinergic and GABAergic neurons, crucial for
loading glycine presynaptic vesicles. It has been proven
that increased cytosolic availability of glycine in VIAAT-
containing terminals was crucial for the emergence of gly-
cinergic transmission in vertebrates [74]. Besides, it was
suggested that certain mutations in VIAAT could lead to
the specific loss of glycine (but not GABA) loading into
synaptic vesicles, thus resulting in hyperekplexia [8].
The orphan transporter NTT4 (also known as Rxt1),
encoded by SLC6A17 gene, has recently been implicated as
a vesicular transporter for glycine, proline, leucine, and ala-
­ a+-dependent vesicular transporter
nine [75]. It is another N
for glycine in glutamatergic and GABAergic neurons, which
is highly expressed in several brain regions. Mutations in
SLC6A17 might result in hyperekplexia by disrupting the
sufficient storage of presynaptic glycine [75].
Asc-1 encoded by SLC7A10 gene is a N ­ a+-independent
amino acid transporter for small neutral amino acids with
high affinity, regulating excitatory glutamatergic signaling
by mobilizing D-serine. Recent study shows that SLC7A10
expression is enriched in astrocytes of the brainstem and
spinal cord as well as inhibitory glycinergic synapses [76].
SLC7A10-null mice show remarkable glycinergic sponta-
neous IPSCs decline in spinal cord motor neurons, along
with hyperekplexia-like symptoms including tremors,
ataxia, rigidity, and sustained myoclonus, and are relieved
by replenishing glycine [9], suggesting that SLC7A10 might
play a role in supplementing and recycling of glycine from
astrocytes to glycinergic neurons.
ULIP6 encoded by DPYSL5 gene and Syntenin-1 encoded
by SDCBP gene are both interacting protein of GlyT2 as
they can both affect the expression of GlyT2 in glyciner-
gic neurons [8]. ULIP6 belongs to the ULIP/Collapsing
response mediator protein family but expressed in brain only.
Since ULIP6 has been implicated in GlyT2 endocytosis and
recycling [77], it is plausible that mutations in ULIP6 could
cause hyperekplexia by altering levels of presynaptic GlyT2.
By contrast, mutations in SDCBP can lead to mislocation of
presynaptic GlyT2 since Syntenin-1 is thought to regulate
the trafficking or presynaptic localization of GlyT2 in gly-
cinergic neurons as it contains PDZ binding domains and
work as the binding partner of GlyT2 [78]. However, due to
the wide range of proteins interacting with syntenin-1, it is
unlikely that defects in syntenin-1 will give rise to classical
hereditary hyperekplexia.
Stimulus‑induced disorders
The stimulus-induced disorder is a broad group of rare dis-
orders where the startle itself is not excessive, but it evokes
another prominent and characteristic clinical feature. These
startle-triggered disorders include startle epilepsy, reflex
myoclonus, startle-induced stiffness, and other rare diseases
[2]. Startle epilepsy is featured by a startle response fol-
lowed by an epileptic seizure, which can be a myoclonic,
tonic–clonic, absence, or atonic seizure. It was classified as
a type of reflex epilepsy by the International League Against
Epilepsy [79]. Startle epilepsy typically begins in early life,
and patients always have a history of perinatal asphyxia or
structural brain malformation. Interictal discharges can be
localized by EEG. Prevention of injury during the seizures
and anti-epileptic drugs are the main management [18, 80].
Although the reflex myoclonus resembles the startle reflex, it
also shows differences. In cortical myoclonus, the stimulus-
sensitive myoclonus is usually distally located and focal and
shows increased sensitivity to tactile stimuli [18]. Electro-
physiological studies can reveal specific features, such as
giant somatosensory evoked potentials, enhanced long-loop
reflexes, and premovement cortical spikes [1]. Brainstem
or reticular myoclonus is marked by a more generalized,
synchronized muscle activation pattern that is axially local-
ized, which can be distinguished from startle syndromes by
shorter intervals between bursts [18]. Stiff-person syndrome
(SPS) is characterized by progressive axial stiffness and
intermittent spasms, which are provoked by sudden stim-
uli. SPS can be classified base on the clinical presentation
into classic SPS and SPS variants: focal or segmental-SPS,
13

jerking-SPS, and progressive encephalomyelitis with rigid-
ity and myoclonus. Most patients with SPS have antibodies
directed against the glutamic acid decarboxylase, ­GABAA
receptor-associated protein, or the glycine-α1 receptor [13,
81]. Different from hyperekplexia, the stiffness is nearly con-
tinuous; electromyography of the long back muscles also
shows continuous muscle activity [1]. Treatment of SPS
with drugs that increase the GABAergic tone combined with
immunotherapy can be symptomatic relief and modulation
of the autoimmune process. Although the disease is asso-
ciated with autoimmunity, its role in pathogenesis is still
unclear. In a word, the phenomenology and pathophysiol-
ogy of stimulus-induced disorders are diverse. Therefore, a
detailed history, video recording, and, if necessary, electro-
physiological testing are needed to make a comprehensive
consideration.
Neuropsychiatric startle syndromes
Neuropsychiatric startle syndromes are a group of non-
habituating, excessive startle responses, which are followed
by a prominent, secondary orientating psychiatric, and/
or behavioral response, which are partially suppressible.
Disorders include startle-induced tics, culture-specific syn-
dromes, hysterical jumps or functional startle syndromes,
anxiety disorders, and Gilles de la Tourette syndrome [2,
18]. Different from the normal startle reflex, the intensity
of this startle response is positively correlated with the fre-
quency of stimulation and often causes injuries [3]. Owing
to the lack of big and detailed neurophysiologic data, it is
unclear if these individuals develop the syndrome because
of a neurophysiologic or psychopathologic vulnerability.
The gold standard treatment is multimodal, combining psy-
chotherapy, rehabilitation, physical therapy, hypnosis, and
antidepressants.
Conclusions
Startle syndromes, a group of heterogeneous disorders
characterized by an abnormal startle reflex to various sud-
den stimuli, encompass three main types including hyper-
ekplexia, stimulus-induced, and neuropsychiatric startles.
Importance should be attached to any newborns or infants
with generalized or episodic stiffness, recurrent apnea, stim-
ulus-sensitive behavioral states, or sudden infant death syn-
drome. Comprehensive investigations should be considered
to assess the underline causes. Hereditary hyperekplexia is
a rare neurogenetic disorder with highly genetic heterogene-
ity; clonazepam is the drug of choice. Early awareness of the
disease is crucial to prompt and proper administration. Iden-
tifying the genotype–phenotype correlations helps to clarify
13
Neurological Sciences
the pathogenic mechanism. Hereditary hyperekplexia is also
a glycinergic synaptopathy, and gene mutations related to the
function of glycinergic inhibitory synapses can be causa-
tive through different mechanisms. For suspicious patients,
next-generation sequencing is more recommended for diag-
nosing to avoid serious adverse events and advantageous
to genetic counseling. Moreover, studies on the candidate
genes involved in inhibitory synapses can help design a new
target enrichment system kit, establish new genetic diagnosis
thoughts for possible patients, and shed light on the break-
through of the therapy of hyperekplexia.
Author contribution  Dr. Zhan and Dr. Wang contributed in manuscript
preparation by performing the literature review and writing the first
draft. Prof. Cao critically revised the work.
Funding  Prof. Cao is in charge of National Natural Science Foundation
of China (No.81870889 and 82071258).
Declarations 
Conflict of interest  The authors declare no competing interests.
Ethical approval None.
Informed consent  We declare that all authors and contributors have
participated sufficiently in this work and approved the final version of
the manuscript. No conflict of interest exists in the submission of this
manuscript, and the manuscript is approved by all authors for publica-
tion.
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