European Journal of Medical Genetics 65 (2022) 104450

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European Journal of Medical Genetics

journal homepage: www.elsevier.com/locate/ejmg

Genetic paroxysmal neurological disorders featuring episodic ataxia

and epilepsy
Elisabetta Amadori a, b, 1, Giuditta Pellino c, d, 1, Lalit Bansal e, Serena Mazzone f,
Rikke S. Møller g, h, Guido Rubboli i, j, Pasquale Striano a, b, Angelo Russo k, *
a
Pediatric Neurology and Muscular Disease Unit, IRCCS G. Gaslini Institute, 16147, Genoa, Italy
b
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy
c
Pediatric Unit, Azienda USL Ferrara - Sant’Anna University Hospital of Ferrara, Ferrara, Italy
d
Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
e
Division of Neurology, Children’s Mercy Hospital, University of Missouri Kansas City, Missouri, United States
f
IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
g
Department for genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark
h
Institute for Regional Health Services Research, University of Southern Denmark, Odense, Denmark
i
Department of Neurology, Danish Epilepsy Center (Member of the European Reference Network EpiCARE), Dianalund, Denmark
j
University of Copenhagen, Copenhagen, Denmark
k
IRCCS, Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria dell’età pediatrica, Bologna, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: This review article focuses on clinical and genetic features of paroxysmal neurological disorders
Episodic ataxia featuring episodic ataxia (EA) and epilepsy and help clinicians recognize, diagnose, and treat patients with co-
Epilepsy existing EA and epilepsy. It also provides an overview of genes and molecular mechanisms underlying these
Paroxysmal neurological disorders
intriguing neurogenetic disorders.
Methods: Based on a literature review on Pubmed database, a list of genes linked to paroxysmal neurological
disorders featuring EA and epilepsy were compiled. Online Mendelian Inheritance in Man (OMIM) was used to
identify further reports relevant to each gene.
Results: Among the various forms of EAs, only EA1 (KCNA1), EA2 (CACNA1A), EA5 (CACNB4), EA6 (SLC1A3),
and EA9 (SCN2A) phenotypes with associated epilepsy have been described. Next-generation sequencing (NGS)
has helped in the identification of other genes (e.g.: KCNA2, ATP1A3, SLC2A1, PRRT2) which have shown an
overlapping phenotype with EA and epilepsy.
Conclusion: Overlapping clinical features between EA and epilepsy may hinder an accurate classification, and
complex genotype-phenotype correlation may often lead to misdiagnosis. NGS has increased the awareness of
common genetic etiologies for these conditions. In the future, extensive genetic and phenotypic characterizations
can help us to elucidate the boundaries of a wide phenotypic spectrum. These insights may help develop new
precision therapies in paroxysmal neurological disorders featuring EA and epilepsy.

1. Introduction regulators is implicated in co-existing paroxysmal/episodic neurologic

A paroxysmal neurological disorder is characterized by a rapid
recurrence or severity of symptoms as found in epilepsy and episodic
ataxia (EA). There is now an increased recognition of genetic causes of
epilepsy those at times overlap with other paroxysmal disorders. The
shared mechanism of abnormal ion channel function and synaptic
disorders (Erro et al., 2017).
Next-generation sequencing (NGS) technologies have advanced our
understanding of genetics for both common and rare neurological dis­
eases. These technologies have led to the identification of many new
genes and have helped target new treatment options. NGS of patient
cohorts with variable but correlated phenotypes has determined

* Corresponding author. Department of Paediatric Neurology, IRCCS – Institute of Neurological Sciences of Bologna, via Altura 3, Bologna, Italy.
E-mail address: russo.neuroped@gmail.com (A. Russo).
1
These authors contributed equally.

https://doi.org/10.1016/j.ejmg.2022.104450
Received 4 August 2021; Received in revised form 2 February 2022; Accepted 6 February 2022
Available online 24 February 2022
1769-7212/© 2022 Elsevier Masson SAS. All rights reserved.
E. Amadori et al.
phenotype expansions associated with different genes supporting
different pathogenic mechanisms and different phenotypic overlaps,
such as EA and epilepsy (Di Resta et al., 2018). Also, increased under­
standing of the genetic underpinnings has provided insights into the
shared mechanisms of EA and epilepsy, revealing the role of ion chan­
nels and proteins associated with the vesical synaptic cycle or involved
in energy metabolism (Erro et al., 2017).
Among the various forms of sporadic or familial autosomal dominant
EAs, EA1 (KCNA1) EA2 (CACNA1A), EA5 (CACNB4), and EA6 (SLC1A3)
have been associated with epilepsy. Other genes such as KCNA2, SCN2A,
ATP1A3, SLC2A1, and PRRT2 have shown an overlapping phenotype
with EA and epilepsy. In this paper, we provide an overview of the ge­
netic and clinical features underlying these neurogenetic disorders,
focusing on the coexistence of EA and epilepsy.
2. Methods
A bibliographic search was performed in PubMed for papers pub­
lished in English from 1975 to January 2021, using the key terms
“paroxysmal neurological disorders,” “episodic ataxia,” “paroxysmal
ataxia,” “epilepsy,” “developmental movement disorders,” “epileptic
encephalopathy,” “KCNA1,” “CACNA1A,” CACNB4,” “ATP1A3,”
“SCN2A,” “PRRT2,” “SCL2A1,” “GLUT1,” “SLC1A3,” “gene,” “genetic,”
“mutation,” and “phenotype-genotype” both individually and in com­
bination. According to their relevance for this review, both articles (e.g.,
case series, case reports, original research articles, and reviews) and
book chapters were selected for the final reference list. Online Mende­
lian Inheritance in Man (OMIM) was used to identify further reports
relevant to each gene.
Table 1 summarizes the electro-clinical and neuroimaging features of
each gene analyzed in this manuscript, while Table 2 summarizes gen­
otyping and epileptic features of some variants discussed.
3. Genetic and clinical overview
3.1. KCNA1: EA type 1 and epilepsy
Pathogenic variants in genes encoding potassium channels cause
several neurological diseases, including benign familial neonatal sei­
zures (KCNQ2, KCNQ3), neonatal epileptic encephalopathy (KCNQ2),
EA type 1 (KCNA1), and peripheral nerve hyperexcitability (KCNA1,
KCNQ2) (Charlier et al., 1998; Orhan et al., 2014; Browne et al., 1994).
Limbic encephalitis or neuromyotonia has also been identified second­
ary to antibodies to KV1.1 protein (KCNA1) or associated proteins such
as leucine-rich glioma inactivated 1 (LGI1) or contactin-associated
protein 2 (CASPR2) (Irani et al., 2010). Potassium channel genes thus
contribute importantly to neurodevelopmental disorders.
The KCNA1 gene encodes the ɑ-subunit of the Kv1.1 protein, a
voltage-gated delayed potassium channel with six transmembrane seg­
ments (S1–S6) that include the functionally critical voltage-sensing
(S1–S4) and pore domains (S5–S6). KCNA1 is widely expressed in the
hippocampus and cerebellum. Kv1.1 contributes to the regulation of
membrane potential and nerve signaling and prevents neuronal hyper­
excitability, which explains why pathogenic variants in KCNA1 are
responsible for a wide spectrum of paroxysmal neurological disorders
such as EA1 (Browne et al., 1994).
In rare instances, KCNA1 variants can cause hypomagnesemia, hy­
perthermia, paroxysmal dyskinesia, neuromyotonia, and cerebellar
dysfunction with or without cognitive/motor developmental delay
(Browne et al., 1994; D’Adamo et al., 2015). Furthermore, clinical
heterogeneity has been observed among patients with the same KCNA1
variant and has been observed even between identical twins (D’Adamo
et al., 2015). Therefore, genotype-phenotype correlations have been
difficult to establish.
EA1 is characterized by seconds to minutes-lasting attacks including
gait incoordination, limb ataxia, truncal instability, dysarthria,
2
European Journal of Medical Genetics 65 (2022) 104450
nystagmus and tremor, with constant interictal myokymia, typically
starting in early childhood (D’Adamo et al., 2015). Additional symptoms
may include distal weakness, tremors, muscle stiffness, spinning sensa­
tion, and cognitive dysfunction. One fifth of patients may develop per­
manent cerebellar symptoms and signs (Kipfer and Strupp, 2014).
EA1 patients are approximately 10 times more likely to develop
epilepsy than are healthy controls, implying that variants in KCNA1 may
be a pathogenic susceptibility factor for developing epilepsy (Smart
et al., 1998; Rho et al., 1999). In humans to date, only a few individuals
with a KCNA1 variant and epilepsy have been reported (Smart et al.,
1998; Rho et al., 1999).
Van Dyke et al. first described individuals belonging to an EA1 family
with the KCN1A missense variant p.Phe184Cys who presented with
generalized seizures (Van Dyke et al., 1975). KCNA1 variants Thr226Arg
and Ser243Ile were associated with EA and focal or generalized epilepsy
and the majority of patients have a favorable seizure outcome, with
either resolutions of seizures with age or in response to anti-seizure
medications (Zuberi et al., 1999). Other individuals with various epi­
lepsy phenotypes have subsequently been reported in combination with
EA1 (Tristán-Clavijo et al., 2016; Lee et al., 2004; Graves et al., 2010;
Rogers et al., 2018). Results of brain magnetic resonance imaging (MRI)
and neuropsychological evaluation were normal (Van Dyke et al., 1975;
Zuberi et al., 1999; Tristán-Clavijo et al., 2016; Lee et al., 2004; Graves
et al., 2010; Rogers et al., 2018; Russo et al., 2020). Electroencephalo­
graphic (EEG) abnormalities have been observed in these patients
regardless of the absence or presence of seizures. EA1 harboring the
KCNA1 missense variant p.Val174Phe has been identified in three sub­
jects with EEG abnormalities with no evidence of seizures (Van Dyke
et al., 1975).
Cognitive impairment with epilepsy and EA1 with KCNA1 mutation
was first reported associated in a patient with p.Val408Leu variant of the
KCNA1 gene, affecting in the Kv-specific Pro-Val-Pro (PVP) motif, a
critical domain for channel gating (Rogers et al., 2018).
Recently, a child with cognitive impairment related to electrical
status epilepticus during sleep due to a further de novo loss of function
(LOF) (Pro405Ser) KCNA1 variant in Kv-specific PVP motif has been
reported (Russo et al., 2020).
A review of KCNA1 pathogenic variants identified in previously
published patients highlighted the EA and epilepsy comorbidity (Paul­
hus et al., 2020). As expected, among these patients, EA1 was the most
common diagnosis resulting from a KCNA1 mutation, but many other
diseases, such as epilepsy, hypomagnesemia, and paroxysmal kinesi­
genic dyskinesia also resulted from the KCNA1 mutation (Paulhus et al.,
2020).
Variants of KCNA1 were partially examined by electrophysiological
functional studies that evidenced a loss-of-function (LOF) of Kv1,1 by
various mechanisms (Paulhus et al., 2020). Furthermore, the authors,
mapping the structural location of KCNA1 variants, showed a pattern of
genotype-phenotype correlation (Paulhus et al., 2020). Epilepsy or
seizure-related variants tend to cluster in the S1/S2 transmembrane
domains and the pore region of Kv1.1, whereas EA1-associated variants
can occur widely across the protein (Paulhus et al., 2020). Although
more cases need to be described, de novo variants in the PVP motif of
KCNA1 appear to confer specific risk of both cognitive impairment and
severe, early-onset epilepsy (Rogers et al., 2018; Russo et al., 2020).
Kcna1− /− mice models have been studied in detail. Their epileptic
phenotype is similar to limbic epilepsy seen in kainic acid-induced an­
imal models and human temporal lobe epilepsies with generalized tonic-
clonic seizures (Smart et al., 1998). Kcna1− /− mice have also been
implicated in clinically relevant animal models of SUDEP where respi­
ratory failure is considered the main driver of cardiac dysfunction dur­
ing seizures (Ren et al., 2019).
Genetic modifiers play an important role and adds to genotype-
phenotype complexity. If present, they can significantly alter Kcna1− /
−
phenotype. Modifiers such as CACNA1atg/tg, Mapt− /− and/or Bad− /−
have been identified and if present can reduce seizure frequency and
 Table 1

E. Amadori et al.
Electro-clinical and neuroimaging features of genes showing episodic ataxia and epilepsy.
Gene EA EA age Trigger Attack Other symptoms and Epilepsy (seizure Epilepsy EEG MRI Possible correlation Treatment
Subtype of onset (EA) duration related-disorders type) age of
onset

KCNA1 EA -1 3-5 y physical exertion, Brief myokymia, paroxysmal FSIA; Generalized variable, Normal or Normal Epilepsy - S1/S2 AZA
emotional stress, (minutes) dyskinesia, motor; neonatal to paroxysmal delta- transmembrane SCB (CBZ and
excitement associated hyperthermia, Photosensitive 21 y theta slowing, FS domain + Kv1.1 PHT)
with myokymia hypomagnesemia, GTCS, ESES Epilepsy + DD + ACTH
(face and hand muscles), neuromyotonia, tremors, encephalopathy –
elevated ambient and peripheral nerve Proline PVP motif
body temperature, hyperexcitability
caffeine/alcohol/diet,
sudden movement,
rest after exertion,
startle
CACNA1A EA-2 Later, physical exertion, Variable Ataxia, vertigo nausea, AS, Variable 3 Hz GSW, GSW, Cerebellar DEE, refractory AZA
4–18 y fatigue, (minutes to vomiting, oscillopia, GTCS, MAS, FS 15 m-18 y focal and atrophy seizures 4-
emotional distress, days) dysarthria, nystagmus, photosensitive LOF aminopyridine
excitement, dystonia discharges GOF
intercurrent illness
CACNB4 EA-5 Later, – Several hours Ataxia, Paroxysmal AS, JME, GTCS, 10-15 y 3 Hz GSW Unknown, likely AZA AZA
20–30 y dyskinesia, dysarthria Praxis-induced normal responsive
seizures C104F – neutral
polymorphism
SLC1A3 EA-6 Early, Febrile illness Prolonged absent myokymia, FSIA 9y MFS, FS Mild cerebellar Hemiplegic migraine, AZA
2–6 m (several nystagmus, tinnitus atrophy ppt with illness/stress
hours)
KCNA2 – Later exercise, Variable Mild ataxia DEE 7–15 m MFS, 2–3 Hz GSW Normal MRI to LOF – mild AZA
age, 17 fatigue, (Seconds to FSIA (motor), MS, mild cerebral GOF – severe (variable
3

m− 2y illness, menstruation, hours) AS atrophy or hypotonia response)

wheezing, Cerebellar
stress, hypoplasia
sudden movement
SCN2A – 10 m- minor head injuries, Variable Ataxia, hypermotor, BFNIS, DEE, <3 m PSW, MFS Normal or mild GOF mutation, AZA
14 y sleep deprivation, (minutes to hyperventilation, hypomotor, FS (remit by cerebellar increase persist Na (variable
alcohol ingestion, weeks) vomiting, slurred speech (Motor) 15 m) atrophy current or inc current response)
photostimulation, density, fav cognitive
sudden noise, body’s outcome
vibrations,
menstruation cycle
ATP1A3 – Later Febrile illness Variable Rapid onset Dystonia FS, GTCS. Drug Neonatal MFS Normal to MTS, – AZA

European Journal of Medical Genetics 65 (2022) 104450

onset (several Parkinsonism, EA resistant epilepsy -infancy thin CC, Profilaxys for
days) AHC progressive AHC:
cerebral and flunarizine,
cerebellar TPM, KD, BDZ
atrophy
SLC2A1 – <3 y fasting Intermediate Ataxia, dystonia, GTS, AS infancy 3Hz GSW Normal – KD,
(5–40 min) choreoathetosis, AHC Triheptanoin,
AZA
PRRT2 5y – Variable (min BIFS, ICCA, PED, PNKD, AS, febrile sz 3–7 m GSW Normal Homozygous mutation AZA
– days) HM, associated with ataxia SCB (for PKD)
Ataxia rare

AS – absence seizures, AHC – alternating hemiplegia of childhood, AZA – acetazolamide, BDZ – benzodiapepines, BIFS – benign familial infantile seizures, CBZ – carbamazepine, E-epilepsy, EA – episodic ataxia, ESES –
electrical status epilepticus of sleep, FS – focal seizures, FSIA – focal seizures with impaired awareness, GTS – generalized tonic seizures, GTCS – generalized tonic clonic seizures, GSW – generalized spike wave, HM -
hemiplegic migraine, ICCA - infantile convulsions and choreoathetosis, JME – juvenile myoclonic epilepsy, KD – ketogenic diet, MAS – myoclonic-atonic seizures, MFS – multifocal sharps, m - month, MS – myoclonic
seizures, PED - paroxysmal exercise-induced dyskinesia, PHT - phenytoin, PKD - paroxysmal kicnesigenic dyskinesia, PKND - paroxysmal non-kinesigenic dyskinesia, PSW - Polyspike and wave discharges, y – year, SCB -
Sodium Channel Blockers, TPM – topiramate.
§The attacks may occur spontaneously or may be triggered.
 E. Amadori et al.
Table 2
Genotyping and epileptic features of some variants discussed in this work.
Gene Nucleotide change Protein change Inheritance Status Effect Functional N. of Gender Age at Epileptic Origin References
domain individuals seizures phenotype
with EA and onset
seizures/
epilepsy

KCNA1 c.551T > G Phe184Cys Inherited HET Missense S1 3 F 21ys Generalized “Racially” Van Dyke DH et al.
motor seizures mixed (1975) (Van Dyke
F (2) _ Loss of et al., 1975)
consciousness
c.677C > G Thr226Arg Inherited HET Missense S2 2 M 7w Focal with Scottish family Zuberi SM et al.
impaired (1999) (Zuberi
awareness (i.a.) et al., 1999)
F 9ys Focal to
bilateral tonic-
clonic (tc)
c.971G > C Arg324Thr Inherited HET Missense S5 1 M _ Focal epilepsy Spanish family Tristán-Clavijo E.
et al. (2016) (
Tristán-Clavijo
et al., 2016)
c.1025G > T Ser342Ile Inherited HET Missense S5 3 M _ Generalized Family Lee H. et al.
motor during (not well (2014) (Lee et al.,
sleep specified - nws) 2004)
F (2) _ generalized
motor
c.1207C > T Pro403Ser De novo HET Missense S6 1 M 6 ms severe early- Twin boys Rogers A. et al.
(Pro-Val-Pro onset epilepsy (2018) (Rogers
motif) et al., 2018)
4

c.1222G > T Val408Leu De novo HET Missense S6 1 F neonatal nws Sporadic Demos M. et al.
Her son had M infancy nws Inherited (2006) (Russo
persistent et al., 2020)
ataxia
c.1241T > C Phe414Ser Inherited HET Missense S6 1 M 6 ms Focal with and Family Graves TD. et al.
without (nws) (2010) (Graves
evolution in tc et al., 2010)
c.1214C > T p.Val408Leu De novo HET Missense S6 1 F 2 ms myoclonic Sporadic Russo A. et al.
(Pro-Val-Pro seizures and (2021) (Russo
motif) ESES et al., 2020)
CACNA1A c.439G > A Glu147Lys Inherited HET Missense I S2 3 F 4ys Absences North American Imbrici P. et al.
M (2) Late family (2004) (Imbrici

European Journal of Medical Genetics 65 (2022) 104450

childhood et al., 2004)
c.5733C > T Arg1820stop De novo HET Nonsense IV S6 2 M 3ys Nocturnal Sporadic Jouvenceu A. et al.
generalized tc (2001) (
seizures (GTCS) Jouvenceau et al.,
Daytime 2001)
absences Strupp M. et al.
F 2ys Absences (2004) (Strupp
et al., 2004)
c.2131A > G Ile712Val De novo HET Missense II S6 1 F 15 ms status Sporadic Guerin AA et al.
epilepticus (2008) (Guerin
myoclonic et al., 2008)
seizures
2278-9delAG Change 681; stop Inherited HET – II S5–S6 3 _ _ Generalized Family Jen J. et al. (2004)
783 seizures (nws) (Jen et al., 2004)
Deletion ex 39-47 Truncation at _ HET – C-terminus 1 F 11ys Absences Sporadic (Irish)
residue 1917
(continued on next page)
 E. Amadori et al.
Table 2 (continued )
Gene Nucleotide change Protein change Inheritance Status Effect Functional N. of Gender Age at Epileptic Origin References
domain individuals seizures phenotype
with EA and onset
seizures/
epilepsy

Labrum RW et al.
(2009) (Labrum
et al., 2009)
IVS36-2A > G – Inherited HET Splice site C-terminus 3 M _ nws Finnish family Kaunisto MA et al.
acceptor (3′ ) F (2) (2004) (Kaunisto
et al., 2004)
Deletion ex 6 Premature stop Inherited HET Frameshift – 1 M Childhood nws Familial Riant F. et al.
codon (2010) (Riant
et al., 2010)
c.1618G > A Gly540Arg De novo HET Missense II 1 F 1-2 ys Febrile seizures Sporadic Rajakulendran S.
(FS) et al. (2010) (
4ys temporal focal Rajakulendran
epilepsy et al., 2010)
c.2763G > C Glu921Asp De novo HET Non- II-III 8 M (4) 8 ms - 14ys GTCS (6); Sporadic Rajakulendran S.
c.2978A > T Glu993Val synonymous F (4) absences (2); et al. (2010) (
polymorphism focal with i.a. Rajakulendran
(3) and without et al., 2010)
i.a. (1)
c.3313G > A Gly1105Ser De novo HET Non- II S5 1 M Childhood Absences Sporadic Rajakulendran S.
synonymous et al. (2010) (
polymorphism Rajakulendran
et al., 2010)
3679insATCCAATCC Ins.Ser,Asp,Pro De novo HET In-frame DII-DIII 1b M Juvenile focal with i.a. Sporadic Imbrici P. et al.
5

insertion (2005) (Imbrici

et al., 2005)
c.5396C > T Ser1799Leu _ HET Missense Pore of IV _ _ _ Epilepsy (not _ CITED IN:
well specified) Izquierdo-Serra M.
et al.
(2020) (
Izquierdo-Serra
et al., 2020)
c.3832C > T Arg1278Ter Inherited HET Nonsense III S1–S2 4 M 11 ms Drug-resistant Familial Damaj L. et al.
(DR) GTCS and (2015) (Damaj
absences et al., 2015)
Childhood Typical FS (3)

European Journal of Medical Genetics 65 (2022) 104450

c.2867_2869del Arg957fs Inherited HET Frameshift II-III 2 M 18 ms Absences Familial Damaj L. et al.
F 6 ms Atypical FS (2015) (Damaj
et al., 2015)
c.868+5G > A _ Inherited HET Splice site II S3 1 M 20 ms Typical FS Familial Damaj L. et al.
variant (2015) (Damaj
et al., 2015)
Del19p13.13 _ Inherited HET Deletion _ 1 M 8 ms Focal seizures; Familial Damaj L. et al.
GTCS (2015) (Damaj
et al., 2015)
CACNB4 c.311G > T Cys104Phe Inherited HET Missense Near 2 M _ Generalized German family Escayg A. et al.
N-terminus Not reported epilepsy; praxis- (2000) (Escayg
EA induced seizures et al., 2000)
5 M (2) Not Not reported French
F (3) reported Canadian family
SLC1A3 c.869C > G Pro290Arg De novo HET Missense Transmembrane 1 M 10ys Focal and Sporadic
domain (TMD) 5 generalized
(continued on next page)
 E. Amadori et al.
Table 2 (continued )
Gene Nucleotide change Protein change Inheritance Status Effect Functional N. of Gender Age at Epileptic Origin References
domain individuals seizures phenotype
with EA and onset
seizures/
epilepsy

subclinical Jen JC et al.

seizure activity (2005) (Jen et al.,
2005)
KCNA2 c.1214C > T Pro405Leu De novo HET Missense S6 5 M 9.5 ms–17 FS, hemiclonic, Sporadic Syrbe S. et al.
F (2) ms GTCS, status (2 German, (2015) (Hosford
epilepticus (SE) Spanish, et al., 1999)
F (2) 2 ms–14 Hemiclonic, Danish, Afro- Masnada S. et al.
ms GTCS, focal american) (2017) (Khan and
motor, SE, Jinnah, 2002)
absences,
myoclonic
c.890G > A Arg297Gln De novo HET Missense S4 (voltage 7 M 5 ms Febrile SE, Sporadic Syrbe S. et al.
sensor -vs) GTCS, absences (German, Latin (2015) (Hosford
(DR) American, et al., 1999)
M 15 ms FS, myoclonic, Danish, Franch- Corbett MA et al.
absences (DR) Spanish, Arabic, (2016)
M Byrth-1y Infantile ovodonation) Masnada S. et al.
F (4) spasms, FS, (2017) (Khan and
GTCS, Jinnah, 2002)
myoclonic,
absences
(typical and
atypical)
6

c.894G > T Leu298Phe De novo HET Missense S4 1 M 6 ms GTCS, atypical Sporadic Syrbe S.et al.
(vs) absences, (English) (2015) (Hosford
myoclonic (DR) et al., 1999)
c.869T > G Leu290Arg De novo HET Missense Vs domain 1 M 7ws Absences typical Sporadic Allen NM at al.
and atypical, (Irish) (2016) (Escayg
GTCS, et al., 2000)
(DR)
c.765_773del 255_257del Inherited HET In-frame S3, near the 5 F Infantile GTCS → Familial Corbett MA et al.
deletion S2–S3 linker → unclassified (7 affected (2016) (Pagani
region childhood individuals over et al., 2004)
M Infantile GTCS → 3 generations)
F (2) → generalized

European Journal of Medical Genetics 65 (2022) 104450

childhood genetic epilepsy
M 13ys Focal
c.469G > A Glu157Lys De novo HET Missense N-terminus 1 M 9 ms Febrile GTCS, Sporadic Masnada S. et al.
focal motor, (European- (2017) (Khan and
atypical American) Jinnah, 2002)
absences
c.878T > A Leu293His De novo HETa Missense S4 1 F 1m GTCS, Sporadic Masnada et al.
(vs) myoclonic, (Israelian) (2017) (Khan and
absences Jinnah, 2002)
c.982T > G Leu328Val De novo HET Missense S5 1 M 6 ms Febrile SE, GTCS Sporadic Masnada S. et al.
absences, atonic (German) (2017) (Khan and
Jinnah, 2002)
SCN2A c.2960G > T Ser987Ile De novo HET Missense Cytoplasmic loop 1 F 1st day (d) Hemiclonic, Sporadic Schwarz N. et al.
(II-III) apneas (2016) (Schwarz
et al., 2016)
c.4952T > G Phe1651Cys De novo HET Missense 1 F 5th d GTCS Sporadic
(continued on next page)
 E. Amadori et al.
Table 2 (continued )
Gene Nucleotide change Protein change Inheritance Status Effect Functional N. of Gender Age at Epileptic Origin References
domain individuals seizures phenotype
with EA and onset
seizures/
epilepsy

Cyt. loop (IV Schwarz N. et al.

S4–S5) (2016) (Schwarz
et al., 2016)
c.788C > T Ala263Val De novo (4) HET Missense I S5 7 M 1st d GTCS Sporadic and Liao Y. et al.
mutational hot spot Inherited F 3rd d generalized familial (2010) (Liao
(2) tonic; et al., 2010)
_ (1) focal with i.a. Johannesen KM
M 7th d Generalized et al. (2016) (
tonic → GTCS Johannesen et al.,
M 2nd d Generalized 2016)
tonic Schwarz N. et al.
F 2nd d – 2 GTCS, focal with (2016) (Schwarz
M (2) ms i.a., atypical et al., 2016)
absences Gorman KM et al.
(2017) (Gorman
and King, 2017)
Schwarz N. et al.
(2019) (Schwarz
et al., 2019)
c.3754A > G Ile1252Val De novo HET Missense III S2 1 M 6 ms focal with i.a. Sporadic Schwarz N. et al.
(2019) (Schwarz
et al., 2019)
c.3973G > A Val1325Ile Unknown HET Missense Cyt. loop (III 1 F 6ws Generalized Sporadic Schwarz N. et al.
7

S4–S5) tonic, GTCS (2019) (Schwarz

et al., 2019)
c.3973G > A Val1325Phe De novo HET Missense Cyt. loop (III 2 F 21 ms atonic Sporadic; Maksemous N.
inherited S4–S5) M 14ys familial et al. (2018) (
Maksemous et al.,
2018)
c.5311T > C Tyr1771His De novo HET Missense IV S5 1 M 18 ms Myoclonic; Sporadic Schwarz N. et al.
absences (2019) (Schwarz
et al., 2019)
c.1028A > G Asp343Gly De novo HET Missense Cyt. loop (I– II) 1 M 6 ms GTCS Sporadic Schwarz N. et al.
(2019) (Schwarz
et al., 2019)

European Journal of Medical Genetics 65 (2022) 104450

c.4565G > C Gly1522Ala Inherited HET Missense Cyt. loop (III-IV) 1 M 1m GTCS _ Schwarz N. et al.
(2016) (Schwarz
et al., 2016)
c.5644C > G Arg1882Gly De novo HET Missense Cyt. loop (IV 6 - 2 M 2nd d GTCS, Sporadic Schwarz N. et al.
C-terminus) F 1m desaturation (2016) (Schwarz
et al., 2016)
c.217G > A Gly1634Asp De novo HET Missense IV S4 1 M 11 ms GTCS Sporadic Leach EL et al.
(2016) (Corbett
et al., 2016)
ATP1A3 c.2267G > A Arg756His De novo HET Missense Cyt. loop (IV–V) _ _ _ Mainly focal Sporadic and Brashear A. et al.
and with i.a. famillial (2018) (Brashear
inherited et al., 2018)
Gasser M. et al.
(2020) (Gasser
et al., 2020)
SLC2A1 c.277C > T Arg93Trp De novo HET Missense TM helical3 1 M 11ys Sporadic
(continued on next page)
 E. Amadori et al.
Table 2 (continued )
Gene Nucleotide change Protein change Inheritance Status Effect Functional N. of Gender Age at Epileptic Origin References
domain individuals seizures phenotype
with EA and onset
seizures/
epilepsy

Atypical Joshi C. et al.

absences, (2008) (Joshi
myoclonic, et al., 2008)
atonic
c.497_499delTCG Val166del De novo HET Deletion – 1 F 3ys Generalized Sporadic Koy A. et al.
(nws) (2011) (Koy et al.,
2011)
c.938C > A Ser313Try De novo HET Missense TM helical8 1 F 10 ms GTCS, focal Sporadic Graham Jr JM
et al. (2012) (
Graham, 2012)
c.930_931ins- Ile311fs De novo HET Frameshift – 1 M 3ys Generalized Sporadic Ohshiro-Sasaki A.
GGATACC tonic et al.
(2014) (
Ohshiro-Sasaki
et al., 2014)
8

PRRT2 c.649dupC Arg217ProfsTer8 Inherited HOM Frameshift Exon2 3 M 3 ms BFIS, absences Familial Labate A. et al.
hotspot mutation F (2) 3 ms SE; focal (2012) (Labate
seizures et al., 2012)
Delcourt M. et al.
(2015) (Delcourt
et al., 2015)
c.913G > A Gly305Arg Inherited HOM Missense Cyt. domain 1 F 3 ms SE; focal Familial Delcourt M. et al.
seizures (2015) (Delcourt
et al., 2015)
c.649dupC/del Arg217ProfsTer8/ De novo Compound Duplication 1 M 6 ms SE Sporadic Delcourt M. et al.
whole deletion of HET and deletion (2015) (Delcourt
the gene et al., 2015)

European Journal of Medical Genetics 65 (2022) 104450

Abbreviations: N.:number; AD: autosomal dominant; d: day; DR: drug-resistant; EA: episodic ataxia; ESES: Encephalopathy related to Status Epilpesticus during slow Sleep. HET: heterozygous; F:female; FS: febrile
seizures; GTCS: generalized tonic-clonic seizure; i.a.: impaired awareness; M:male; ms: months; nws: not well specified; S: segment; SE: status epilepticus; tc: tonic-clonic; TM: transmembrane; TMD: transmembrane
domain; unk: unknown; vs: voltage-sensor; w: week; y: year.
—: Information not available.
a
Glu921Asp and Glu993Val are found to be located on the same allele; this two variants being in cis configuration have a combined functional impact on the P/Q channel [Rajakulendran et al. (2010)].
b
Late-onset ataxia.
E. Amadori et al.
improve ataxia and survival (Paulhus et al., 2020).
A recent systematic review on the therapeutic approach of KCNA1-
associated EA has shown a positive response to carbamazepine,
phenytoin (sodium channel blockers) and acetazolamide (AZA) (Laux­
mann et al., 2021). Similar remarkable positive effect on ataxia and
epilepsy have been reported with the use of ACTH (Russo et al., 2020).
Ketogenic diet treatment have also shown a decrease in seizure fre­
quency, hippocampal hyperexcitability, and improved survival (Ren
et al., 2019).
Several pharmacological attempts have been set out to modulate
Kv1.1 channel activity and expression, from small molecules research to
gene therapy and in silico approaches but they are still at a preclinical
stage of drug development (Lauxmann et al., 2021).
3.2. CACNA1A: EA type 2 and epilepsy
The CACNA1A gene encodes the pore-forming subunit (α1 subunit)
of the P/Q calcium channel, one of the principal channels supporting
neurotransmitter release in the mammalian central nervous system; this
gene is located at 19p13.13 and contains 47 exons (D’Adamo et al.,
2020). Most CACNA1A pathogenic variants are observed scattered along
the entire gene, though missense pathogenic variants usually involve
S5–S6 linkers that form the pore region of the channels (D’Adamo et al.,
2020; Westenbroek et al., 1995).
The calcium channels are multi-subunit complexes, which are
encoded by multiple genes. The largest subunit is an α1 subunit, which
encompasses approximately 2000 amino acid residues organized in four
homologous domains (I–IV) with six transmembrane segments (S1–S6)
in each. The S1–S4 segments serve as the voltage sensor module,
whereas the transmembrane segments S5 and S6 and the P loop between
them form the pore module, which contains the glutamate residue
required for calcium selectivity. Ca2+ channel α1 subunits are divided
into three subfamilies by sequence similarity. The CaV2 subfamily
members CaV2.1, CaV2.2, and CaV2.3 conduct P/Q-type, N-type, and R-
type Ca2+ currents, respectively. Cav2.1 channels (P/Q-type calcium
currents) are most important at synapses formed by neurons in the CNS
and are especially important in cerebellar networks (Westenbroek et al.,
1995; Catterall, 2000).
The wide spectrum of neurological disorders associated with het­
erozygous CACNA1A variants ranges from progressive or non-
progressive cerebellar syndrome to paroxysmal epileptic and non-
epileptic phenotypes and includes familial hemiplegic migraine type 1
(FHM1), early infantile EE (EIEE) type 42, congenital-ataxia, EA2, and
spinocerebellar ataxia type 6 (SCA6) (Catterall, 2000; Rajakulendran
et al., 2010; Travaglini et al., 2017). In general, phenotypes are
frequently overlapping and may co-exist.
EA2 is the most common and best-characterized EA syndrome. Onset
usually occurs in childhood or early adolescence (age range 2–32 years)
although late-onset cases (i.e., in the fifth or sixth decade) have been
reported (Choi and Choi, 2016). Intercurrent illness, physical stress,
exercise, or drinks (for instance, alcohol and coffee) can precipitate
ataxic episodes, and these episodes may last several hours or days (Choi
and Choi, 2016). Patients may experience random trunk and limb ataxia
with associated dizziness, dysarthria, migraine, nausea, vomiting,
diplopia, tinnitus, and generalized muscle weakness (Choi and Choi,
2016). These patients do not exhibit myokymia, which is typical of EA1
(Choi and Choi, 2016). Brain MRI in these patients can reveal cerebellar
or global atrophy (Travaglini et al., 2017; Choi and Choi, 2016).
The vast majority of variants of CACNA1A related to EA2 disease are
LOF, including small intragenic deletions or duplications and point
pathogenic variants (e.g., missense, nonsense, splice-site variants) (Choi
and Choi, 2016). However, specific CACNA1A pathogenic variants do
not strictly predict the EA2 phenotype (Choi and Choi, 2016).
Epilepsy syndrome is a frequent finding in EA2 patients, and the first
description dates back to 1999 (Singh et al., 1999). Subsequently,
several authors suggested that patients with genetically confirmed EA2
9
European Journal of Medical Genetics 65 (2022) 104450
have a sevenfold increased risk of epilepsy compared with the general
population, especially absence epilepsy with a 3 Hz spike-wave EEG
pattern, reported as the core symptom in several patients with LOF
pathogenic variants in CACNA1A (Jouvenceau et al., 2001; Damaj et al.,
2015).
Despite this first hypothesis of a strong association between absence
epilepsy and EA2 and high-profile genetic efforts, including genome-
wide association studies, a robust causal relationship between genetic
variants in ion channels and idiopathic generalized epilepsy has not
been established (Cavalleri et al., 2007). In addition to absences, the
epileptic phenotype associated with EA2 is more heterogeneous,
including focal and other generalized seizures and EE (Myers et al.,
2016; Jiang et al., 2019).
While LOF has been proposed as mechanism mainly underlying EA2
(Choi and Choi, 2016), both LOF (Gly230Val, Ile1357Ser) and gain of
function (GOF) (Ala713Thr, Val1396Met) are observed in epileptic
phenotypes (Jiang et al., 2019). The mechanisms by which GOF or LOF
pathogenic variants can both cause similar epilepsy phenotypes may lie
in the differential impact of these pathogenic variants in the different
components of neuronal circuits (Jiang et al., 2019).
Phenotypic presentation in some of the carriers of the CACNA1A
pathogenic variant is diverse. They may present with no symptoms, with
EA, or with major developmental delay due to EE. Modifier genes or
factors that could influence the pathogenicity of CACNA1A pathogenic
variants are yet unknown (Angelini et al., 2019). Of note,
spino-cerebellar ataxia type 6 (SCA6) is caused by CAG triplet expansion
in the same gene (Pradotto et al., 2016).
Acetazolamide is the treatment of choice for EA2. It may significantly
reduce to fully suppress EA episodes (Choi and Choi, 2016). Addition­
ally, 4-aminopyridine, a selective blocker for voltage-gated potassium
channels (KV1 family) and FDA/EMA approved for symptomatic treat­
ment of multiple sclerosis, has also been demonstrated to be effective in
patients with EA2 (Strupp et al., 2011).
Future large cohort studies are needed to identify clinical phenotypes
associated with LOF or GOF pathogenic variants. Also, therapeutic in­
terventions in patients with CACNA1A-associated developmental delay
and EE can be improved by identifying specific pathogenic variants and
their mechanism of function with CaV2.1 channels.
3.3. CACNB4: EA type 5 and epilepsy
P/Q-type channels are the principal presynaptic calcium channels
functioning in rapid neurotransmitter release (Randall and Tsien, 1995).
In the brain, they are largely composed of the pore-forming CaV2.1 α1
and the auxiliary α2δ-2 and β4 subunits (Randall and Tsien, 1995).
Pathogenic variants in genes encoding each of these subunits have been
associated with neurological disease (Pagani et al., 2004). The β4 sub­
unit, which encodes the gene CACNB4, is highly expressed in cerebellar
Purkinje and granule cells.46.
In mouse models, a β4 null mutation has been shown to cause an
autosomal recessive neurological disease with clinical phenotype such
as ataxia, paroxysmal dyskinesia, and absence seizures (Khan and Jin­
nah, 2002; Hosford et al., 1999).
In humans, EA5 presentation is similar to those observed in EA2
except for a later age of onset (Escayg et al., 2000). Heterozygous
pathogenic variants in CACNB4 on chromosome 2q23 have been asso­
ciated with different neurological phenotypes, presenting as EA5 from
childhood to adolescent onset (Sánchez et al., 2019). Acetazolamide has
been used successfully in these patients with good response (Kotagal,
2012).
The most described CACNB4 variant in heterozygous state is p.
Cys104Phe (Escayg et al., 2000; Sánchez et al., 2019). Of note, that same
variant has been reported to be associated with epilepsy, in particular
idiopathic generalized epilepsy, in the absence of EA (Escayg et al.,
2000). The observation that the Cys104Phe mutation is associated with
EA in some families and with epilepsy in others suggests either that it is a
E. Amadori et al.
neutral polymorphism or that the clinical effects of the mutation is
affected by genetic and environmental factors. Similar other heterozy­
gous variants in CACNB4 have been reported in different epileptic
phenotypes without ataxia such as p.(R482*) nonsense mutation, pre­
senting as juvenile myoclonic epilepsy (Escayg et al., 2000).
3.4. SLC1A3: EA type 6 and epilepsy
SLC1A3 encodes for excitatory amino acid transporter 1 (EAAT1), a
glial glutamate transporter. It is a trimeric complex; the predicted to­
pology of each subunit includes transmembrane domains 1–8 and re-
entrant hairpin loops (HP) 1–2 flanking transmembrane domain 7 (De
Vries et al., 2009). EAAT1 is present in glial cells in the cerebellum,
cerebral cortex, and brainstem, and it is responsible for glutamate up­
take in the synapses (De Vries et al., 2009). Thus, the SLC1A3 mutation
leads to excessive extracellular accumulation of glutamate and neuro­
toxic insults and may also lower the seizure threshold in epilepsy (Choi
and Choi, 2016). EAAT1 also functions as a glutamate-activated anion
channel (Jen et al., 2005).
SLC1A3 pathogenic variants have been found in patients with EA
type 6 (EA6), a rare disease, and only a few EA6-associated SLC1A3
pathogenic variants have been reported, with small numbers of affected
patients per family (Jen et al., 2005; Chivukula et al., 2020; Kovermann
et al., 2017).
In several cases, family members carrying the same SLC1A3 patho­
genic variants that were found in EA6 patients did not suffer from EA (De
Vries et al., 2009). SLC1A3 pathogenic variants have been found not
only in patients with EA6, but also in patients with migraine, Tourette
syndrome, attention deficit hyperactivity disorder (ADHD), and autism
(De Vries et al., 2009).
EA6 has shown strong association between paroxysmal cerebellar
ataxic episodes and epilepsy. It also differs from other EA forms as ep­
isodes are long-lasting and absent of myokymia, nystagmus, and
tinnitus. It also differs in the presence of epilepsy as a main clinical
feature and not as a possible symptom (Jen et al., 2005).
Currently, only seven missense pathogenic variants have been
discovered (p.Met128Arg, p.Cys186Ser, p.Pro290Arg, p.Thr318Ala, p.
Ala329Thr, p.Val393Ile, p.Arg399Gln). (Choi and Choi, 2016; Jen et al.,
2005; Chivukula et al., 2020; Kovermann et al., 2017).
The first variant described, p.Pro290Arg, is associated with a more
severe EA phenotype with epilepsy, migraine, and alternate hemiplegia
triggered by febrile illness during childhood (Jen et al., 2005). The
clinical severity of EA6 appears to be well correlated with the glutamate
reuptake capacity of the EAAT1 mutant. Proline-to-arginine replace­
ment in transmembrane domain 5 seems to determine a complete loss of
glutamate reuptake determining a severe EA phenotype with associated
epilepsy (Choi and Choi, 2016; Jen et al., 2005). Chivukula’s group
studied the functional consequences of the p.Pro290Arg mutation in
SLC1A3 (Chivukula et al., 2020). They found that p.Pro290Arg de­
creases glutamate transport rates, but increases the absolute open
probabilities of EAAT1 anion channels and thus decreases the anion
concentrations in Bergmann glia. They hypothesized that the resulting
increase in driving force of GABA transporters might reduce import of
GABA and thus inhibitory synaptic transmission in the EA6 patient.
However, the p.Pro290Arg knock in animals exhibited Bergmann glia
degeneration in the second postnatal week, presumably because of
enhanced Cl-efflux, cell shrinkage, and subsequent apoptosis (Chivukula
et al., 2020). Thus, p.Pro290Arg causes a dramatic reduction in cere­
bellar glutamate uptake and affects EAAT1 anion channel activity (Jen
et al., 2005).
The functional consequences of the remaining six known EA6-
associated, but not seizure-associated, SLC1A3 variants have also been
studied (Kovermann et al., 2017). The variants analyzed caused less
pronounced changes in transport functions than those observed for p.
Pro290Arg, and symptoms were milder than those for the p.Pro290Arg
patient (Kovermann et al., 2017).
10
European Journal of Medical Genetics 65 (2022) 104450
4. Other genes reported in EA associated with epilepsy
4.1. KCNA2
KCNA2 voltage-gated potassium (K+) channels are represented by
12 protein subfamilies, Kv1- Kv12. The Kv1 family channels are the most
expressed units, and Kv1.1, Kv1.2, and Kv1.4 are highly expressed
subunits in the CNS. KCNA2 encodes an α-subunit of the Kv1.2 channel
(Lai and Jan 2006).
Several studies of heterozygous pathogenic variants in KCNA2 have
reported a clinical phenotype characterized by ataxia in association with
epilepsy (Syrbe et al., 2015; Corbett et al., 2016; Masnada et al., 2017;
Allen et al., 2016). Only one of these studies has specified the ataxia as
episodic (Corbett et al., 2016). All the KCNA2 sequence alterations
detected were located in highly conserved and functionally important
protein regions and were predicted pathogenic. Arg297Gln, Thr374Ala,
Pro405Leu are the three most recurrent pathogenic variants and account
for two-thirds of the pathogenic variants (Masnada et al., 2017).
Clinically, patients with KCNA2-associated EA have reported a vague
warning before the start of an episode, maintain awareness during the
event, and experience dysarthria often preceding and persisting beyond
involvement of the limbs. No myokymia or nystagmus was reported.
Episodes often occurred in clusters, and the duration ranged from brief
attacks lasting 15 s to prolonged episodes lasting up to 12 h. The events
were triggered by exercise, fatigue, illness, menstruation, wheezing,
stress, and sudden movement. Most of the patients have responded to
acetazolamide and have reported reduction in episodes (Corbett et al.,
2016).
De novo KCNA2 pathogenic variants have been associated with mild
to severe EE and ataxia (Syrbe et al., 2015). The LOF pathogenic variants
(Pro405Leu, Ile263Thr, and Arg297Gln) are associated with early-onset
epilepsy (frequent febrile and afebrile focal motor and dyscognitive
seizures) and have a favorable outcome. EEG findings have shown
sleep-activated focal epileptiform discharges. Mild to moderate intel­
lectual disability (ID) is described in some cases with associated mild to
moderate ataxia and resting myoclonus. In contrast, GOF phenotypes
(Leu298Phe, Glu157Lys, and Arg297Gln variants) are associated with
more severe epilepsy, ataxia, and ID. They also have been shown to
differ electrographically and radiologically, with presence of general­
ized epileptic discharges on EEG and atrophy of the cerebellum or entire
brain, respectively. A few cases of mixed GOF/LOF phenotype
(Leu290Arg, Leu293His, Leu328Val, Thr374Ala) have also been re­
ported with more severe neonatal-onset epilepsy and developmental
impairment, as well as focal and generalized seizures, suggesting that
various pathological mechanisms underlie distinctive clinical symptoms
(Syrbe et al., 2015; Corbett et al., 2016; Masnada et al., 2017).
4.2. SCN2A
The SCN2A gene located on chromosome 2 (2q24.3) encodes the
α-subunit of the voltage-gated sodium channel NaV1.2, one of the major
neuronal sodium channels that play a role in the initiation and con­
duction of action potentials (Boiko et al., 2001). Pathogenic variants in
SCN2A are one of the most common causes of neurodevelopmental
disorders, accounting for 1% of all EE, with an estimated frequency of
approximately 1 in 78,608 births in the Danish population (Wolff et al.,
2017). Since the original description in families with benign familial
neonatal-infantile seizures (BFNIS), an autosomal dominant epilepsy
syndrome characterized by transient seizures in the first weeks or
months of life, the phenotype has expanded to include a spectrum of
developmental disorders: developmental and epileptic encephalopathies
(Ohtahara syndrome, epilepsy of infancy with migrating focal seizures,
infantile spasms, and Dravet syndrome), EA, schizophrenia, autism
spectrum disorder (ASD), and ID with and without seizures (Wolff et al.,
2017; Nakamura et al., 2013; Ben-Shalom et al., 2017).
The first report of a de novo SCN2A GOF pathogenic variant (p.
E. Amadori et al.
Ala263Val in the highly conserved transmembrane segment D1/S5) in a
patient with neonatal-onset seizures and subsequent EA was reported in
2010 (Liao et al., 2010). Since then, other patients with a de novo
missense SCN2A mutation showing superimposable clinical features
have been reported (Schwarz et al., 2016; Leach et al., 2016).
The clinical phenotype characterized by neonatal seizures and late
onset of EA is usually included under the heading of BFNIS. However,
this phenotype should be viewed as distinct. It is characterized by
epileptic seizures occurring primarily during the first 3 months of life
and by the onset of EA ranging from 10 months to 14 years of age. The
duration of each EA episode is heterogeneous between patients; while
most patients show episodes lasting minutes to several hours, in some
patients episodes may last for weeks (Schwarz et al., 2016, 2019;
Johannesen et al., 2016; Gorman and King, 2017; Maksemous et al.,
2018; Leach et al., 2016). Paroxysmal events can be triggered by
external factors such as minor head injuries, sleep deprivation, alcohol
ingestion, photostimulation, sudden noise and vibrations of the body,
and the menstruation cycle. The cognitive outcome is favorable in most
patients (80%), with normal or mildly impaired cognitive development.
Treatment responses in SCN2A-associated EA have been poor and in­
sights into SCN2A variant-related functional effects may offer a target
for novel specific therapies (Liao et al., 2010; Schwarz et al., 2016, 2019;
Johannesen et al., 2016; Gorman and King, 2017; Maksemous et al.,
2018; Leach et al., 2016). Acetazolamide has shown conflicting results,
and 4-aminopyridine has not been effective (Liao et al., 2010; Schwarz
et al., 2016, 2019; Johannesen et al., 2016; Gorman and King, 2017;
Maksemous et al., 2018; Leach et al., 2016).
4.3. ATP1A3
The protein encoded by the ATP1A3 gene belongs to the family of P-
type cation transport ATPases and the subfamily of Na+/K + -ATPases,
integral membrane proteins responsible for establishing and maintain­
ing the electrochemical gradients of Na and K ions across the plasma
membrane (Brashear et al., 2018). These gradients help induce
sodium-coupled transport of a variety of organic and inorganic mole­
cules, as well as electrical excitability of nerve and muscle. The Na+/K
+ -ATPase enzyme is composed of a large catalytic subunit (alpha) and a
smaller glycoprotein subunit (beta). The catalytic subunit is encoded by
multiple genes. ATP1A3 encodes alpha 3 subunit, expressed in the brain
exclusively in the GABAergic neurons of the basal ganglia and cere­
bellum (de Carvalho Aguiar et al., 2004).
ATP1A3-related neurologic disorders represent a clinical continuum.
ATP1A3-related rapid-onset dystonia-parkinsonism (RDP) (MIM
128235) was discovered in 2004 (de Carvalho Aguiar et al., 2004).
Other phenotypes were subsequently described related to other patho­
genic variants of this gene, some of which were characterized by EA and
epilepsy (not well specified), alternating hemiplegia of childhood (AHC)
(p.Glu815Lys, p.Asp801Asn, p.Leu371Pro), cerebellar ataxia, areflexia,
pes cavus, optic atrophy, sensorineural hearing loss syndrome (CAPOS)
(p.Glu818Lys), and a new relapsing encephalopathy with cerebellar
ataxia (RECA) phenotype (p.Arg756Cys). (Brashear et al., 2018).
The most common symptoms in patients with ATP1A3-related dis­
orders are paroxysmal episodic symptoms such as transient tonic or
flaccid hemiplegia, dystonia, tonic seizures, episodic cerebellar ataxia,
and abnormal ocular movements (Brashear et al., 2018). Most patients
present with persistent neurological deficits in intermittent periods be­
tween paroxysmal symptoms (Sasaki et al., 2021).
ATP1A3-related seizures are heterogenic, but some of the common
characteristics are early age of onset, drug-resistant seizure, and focal or
generalized tonic, tonic-clonic, myoclonic attacks, often triggered by
stress, excitement, extreme temperatures, water exposure, physical
exertion, and lighting changes (Gasser et al., 2020). EA in ATP1A3-re­
lated disorder is usually triggered by febrile illness, and episodes last
several days.73Acute phase treatment with acetazolamide has been tried
and has shown positive response with improvement in EA severity and
11
European Journal of Medical Genetics 65 (2022) 104450
duration (Gasser et al., 2020). Prophylactic treatment for AHC episodes
includes flunarizine, topiramate, ketogenic diet, niaprazine, and mela­
tonin. A trial of high-dose benzodiazepines may be considered in in­
dividuals with RDP and AHC. Triggers that lead to acute attacks should
be avoided (de Carvalho Aguiar et al., 2004).
4.4. SLC2A1
Glucose transporter 1 deficiency syndrome (GLUT1 DS) is a disorder
caused by pathogenic variants in the SLC2A1 gene, on chromosome
1p34, which encodes the membrane protein responsible for glucose
transport across the blood-brain barrier. Diagnosis of GLUT1 DS is made
by genetic testing and by cerebrospinal fluid (CSF) analysis showing
hypoglycorrhachia with concurrently normal blood glucose (De Vivo
et al., 1991).
There are reports of significant phenotypic variability among the
population having GLUT1 deficiency syndrome, with a wide spectrum of
heterozygous pathogenic variants, including nonsense, missense, inser­
tion, deletion, and splice site pathogenic variants. Most of the known
SLC2A1 gene variants are de novo, although autosomal dominant and
autosomal recessive inheritance can be found in affected families
(Klepper et al., 2009).
GLUT1 DS has two phenotypes: classic GLUT1 DS (~90% of affected
individuals) and non-classic GLUT1 DS (~10% of affected individuals)
(Wang et al., 2018). The classic phenotype is characterized by seizure
onset before 6 months, developmental delay, movement disorder, and
acquired microcephaly. Several seizure types are seen, such as gener­
alized tonic or clonic, focal, myoclonic, atypical absence, and atonic.
The frequency, severity, and type of seizures usually vary among
affected individuals. The movement disorders seen with classic GLUT1
DS are ataxia, dystonia, and chorea. These may occur in isolation or
combination and may be continuous or paroxysmal. Ataxia is one of the
most common associated movement disorders but is usually chronic
(Joshi et al., 2008; Koy et al., 2011; Graham, 2012; Ohshiro-Sasaki et al.,
2014).
The non-classic GLUT1 DS phenotype has expanded over the past few
years. In this group, EA or other paroxysmal movement abnormalities
are the most prominent clinical symptoms. The attack duration is in­
termediate (5–40 min) and could be isolated or combined with other
signs or symptoms (Wang et al., 2018). Unlike in the classic phenotype,
epilepsy is not a mandatory symptom, although atypical childhood
absence epilepsy and myoclonic astatic epilepsy have been described
(Tchapyjnikov and Mikati, 2018).
From a therapeutic standpoint, a positive response to acetazolamide
in a patient with EA has been reported but this should not delay testing
for GLUT1 DS or subsequent ketogenic diet initiation if the diagnosis is
confirmed (Tchapyjnikov and Mikati, 2018). Besides being effective to
treat ataxia, the ketogenic diet also reduces the frequency of seizures
(Wang et al., 2018). Increasing evidence suggests that it may improve
development and cognitive abilities in GLUT1 DS (Wang et al., 2018).
4.5. PRRT2
Proline-rich transmembrane protein 2 (PRRT2) is located on chro­
mosome 16p11.2 and encodes for a 340 amino acids protein (proline-
rich transmembrane protein 2) expressed highly in the cortex and the
cerebellum (Landolfi et al., 2021). This protein was first described to
interact with 25 kDa Synaptosomal-Associated Protein (SNAP25), a
t-SNARE protein that is involved in Ca2+-mediated neurotransmitter
release, in the synaptic endocytosis, and the regulation of voltage-gated
ion channels (Fruscione et al., 2018). It was recently described that
PRRT2 negatively also modulates the intrinsic neuronal excitability by
interacting with Nav1.2/1.6 (Landolfi et al., 2021; Fruscione et al.,
2018). This insight further explains the predominant paroxysmal char­
acter of PRRT2-associated pathology and the dramatic effectiveness of
sodium channel blockers, fulfilling the gap between synapthopathies
E. Amadori et al.
and channelopathies underlying paroxysmal neurological disorders
(Landolfi et al., 2021; Fruscione et al., 2018).
The vast majority of pathogenic variants are truncation (nonsense;
frame-shifting insertions or deletions) (Ebrahimi-Fakhari et al., 2015;
Chen et al., 2011; Meneret et al., 2013), leading to the rapid degradation
of the protein product and a state of haploinsufficiency consistent with a
LOF mechanism in PRRT2-related disorders. Frameshift insertion
c.649dupC (p.Arg217Profs*8) is the most common mutation, and ac­
counts for 78.5% of patients in the literature. It leads to a premature stop
codon, located in the nine-cytosine stretch, the mutational hotspot in the
PRRT2 gene (Gardiner et al., 2012).
PRRT2-associated neurological disorders share an autosomal domi­
nant inheritance, incomplete penetrance, and variable expressivity
(Fruscione et al., 2018; Ebrahimi-Fakhari et al., 2015). Pathogenic
variants in the PRRT2 gene have been associated with paroxysmal
kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis
(ICCA), BFIS, paroxysmal exercise-induced dyskinesia (PED), parox­
ysmal non-kinesigenic dyskinesia (PNKD), hemiplegic migraine (HM),
EA, childhood absence epilepsy (CAE), paroxysmal torticollis, and
febrile seizures (FS). (Meneret et al., 2013).
In heterozygous PRRT2 patients, EA is reported in less than 1% of the
patients (Chen et al., 2011); Gardiner et al. described a proband with p.
R217Pfs*8 pathogenic variants and a phenotype characterized by EA
and HM (Gardiner et al., 2012). Considerable variation in the phenotype
is seen both within and between families with the same pathogenic
PRRT2 variant for which no clear genotype-phenotype correlations are
established (Balagura et al., 2020).
Homozygous PRRT2 pathogenic variants (c.649dup; c.913G > A/p.
Gly305Arg; p.Arg217ProfsX8I) and compound heterozygous genotypes
(c.649dupC/p.Arg217ProfsX8 and whole deletion of PRRT2 gene) have
exhibited a complex phenotype including BIFC, PKD, CAE, EA, and
cognitive delay (Labate et al., 2012; Delcourt et al., 2015). EA is more
frequently described in individuals with a more severe phenotype, with
biallelic PRRT2 pathogenic variants and autosomal recessive inheritance
suggesting an additive effect of the double dose of the genetic mutation
(Labate et al., 2012; Delcourt et al., 2015).
EA in PRRT2 patients is observed as attacks of unsteadiness with
variable age of onset and varying duration. An episode may last from less
than 3 days to several days to 6 weeks (versus seconds to hours for the
most common EAs). These episodes are unique due to their long dura­
tion and severity and are often associated with vomiting. Ataxia attacks
often remit after treatment with acetazolamide (Labate et al., 2012;
Delcourt et al., 2015).
5. Conclusion
Genetic knowledge of paroxysmal neurological disorders has been
largely incremented with the advent of NGS methodologies. The wide
number of genes involved in the pathogenesis of paroxysmal neurolog­
ical disorders reflects a high complexity of molecular bases of neuro­
transmission in central nervous system.
The similarities between epilepsy and EA are striking, particularly
their episodic nature, triggering factors, and therapeutic response to the
same drugs. Increased knowledge on the genetic background of epilepsy
syndromes and EAs has provided insights into the shared pathogenic
mechanisms of these two conditions, revealing the role of ion channels
and proteins associated with the vescicles synaptic cycle or involved in
energy metabolism (Erro et al., 2017).
It is difficult to explain how the same variant in certain genes can
have phenotypic heterogeneity such as presence of both epilepsy and EA
either in a given patient or family or in separate families. These clinical
heterogeneities could sometimes be explained by a remarkable pleiot­
ropy and by a temporal expression pattern of the affected gene. In the
future, extensive genetic and phenotypic characterizations will help
elucidate the boundaries of a wide phenotypic spectrum.
A revolution in the management of genetic neurological disorders
12
European Journal of Medical Genetics 65 (2022) 104450
has occurred in recent years, and has allowed us to move from an
empirical therapy to a precision therapy. The advent of high-throughput
genomic sequencing and related tools in molecular diagnosis further
offers the possibility of developing specific therapies by directly tar­
geting the pathophysiological mechanisms that produce the outspread
effects of these disorders.
Funding
The authors received no financial support for the research, author­
ship, and/or publication of this article.
Declaration of competing interest
The authors declared no potential conflicts of interest to the research,
authorship, and/or publication of this article.
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