Paroxysmal Movement Disorders Update

Home , Choreoathetosis, Generalized epilepsy, Paroxysmal dyskinesia, PNKD, PRRT2

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Available online at ScienceDirect www.sciencedirect.com

Movement disorders

Paroxysmal movement disorders: An update

a,b a,b,

A. Me´neret , E. Roze *

Inserm U 1127, CNRS UMR 7225, Sorbonne University Group, UPMC University Paris 06 UMR S 1127,

Brain and Spine Institute, ICM, 75013 Paris, France

AP–HP, Pitie´-Salpeˆtrie`re Hospital, Department of Neurology, 75013 Paris, France

i n f o a r t i c l e a b s t r a c t

Article history: Paroxysmal movement disorders comprise both paroxysmal dyskinesia, characterized by

Received 28 February 2016 attacks of dystonic and/or choreic movements, and episodic ataxia, deﬁned by attacks of

Received in revised form cerebellar ataxia. They may be primary (familial or sporadic) or secondary to an underlying

10 April 2016 cause. They can be classiﬁed according to their phenomenology (kinesigenic, non-kinesi-

Accepted 8 July 2016 genic or exercise-induced) or their genetic cause. The main genes involved in primary

Available online xxx paroxysmal movement disorders include PRRT2, PNKD, SLC2A1, ATP1A3, GCH1, PARK2,

ADCY5, CACNA1A and KCNA1. Many cases remain genetically undiagnosed, thereby sug-

Keywords: gesting that additional culprit genes remain to be discovered. The present report is a general

Paroxysmal overview that aims to help clinicians diagnose and treat patients with paroxysmal move-

Movement disorders ment disorders.

Genetics

Paroxysmal neurological disorders are characterized by genetic origin) or secondary to underlying causes, such as

episodes of neurological dysfunction that are either isolated lesions of the central nervous system or metabolic disorders.

or part of a more complex disorder with interictal manifesta- Primary PxDs may be familial or sporadic, with onset in either

tions. They encompass apparently heterogeneous disorders childhood or adolescence.

such as migraine, epilepsy, periodic paralysis and paroxysmal A new classiﬁcation is emerging, based on both clinical and

movement disorders. They are, however, all linked by a genetic characteristics [1]. Indeed, recent genetic advances are

common pathophysiological feature, namely neuronal hyper- rendering the historical, clinically based classiﬁcation obso-

excitability, and by overlapping genetic causes. lete: a given paroxysmal movement disorder can be caused by

Paroxysmal movement disorders are rare disorders that mutations in various genes, while mutations in a given gene

can be divided into paroxysmal dyskinesias (PxDs) and can give rise to various paroxysmal disorders. The present

episodic ataxias (EAs). PxDs are characterized by attacks of review provides an update on the clinical characteristics,

dystonic and/or choreic movements, whereas EAs are deﬁned genetic causes and pathophysiology of paroxysmal movement

by attacks of cerebellar ataxia. They may be primary (mostly of disorders.

* Corresponding author. Department of Neurology, Pitie´-Salpeˆtrie`re Hospital, 47-83, boulevard de l’Hoˆ pital, 75651 Paris cedex 13, France.

E-mail address: ﬂ[email protected] (E. Roze).

http://dx.doi.org/10.1016/j.neurol.2016.07.005

Please cite this article in press as: Me´neret A, Roze E. Paroxysmal movement disorders: An update. Revue neurologique (2016), http://dx.doi.org/ 10.1016/j.neurol.2016.07.005 © 2018 Elsevier Masson SAS. Tous droits réservés. - Document téléchargé le 02/02/2018 par VIDAILHET MARIE (885771). Il est interdit et illégal de diffuser ce document.

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patients may have paroxysmal movement disorders that do

1. Clinical characteristics and

not fall into any of the proposed categories, and paroxysmal

phenomenological classiﬁcation

events corresponding to more than one category may be

present in a given case.

The ﬁrst step in the diagnostic process is to determine

whether the disorder is likely to be primary or secondary. 1.1. Paroxysmal kinesigenic dyskinesia

Signs of an underlying cause include onset in adulthood, the

absence of a family history, variable duration of attacks and Paroxysmal kinesigenic dyskinesia (PKD) is characterized by

triggering factors, abnormal interictal clinical status, and attacks of dystonia and/or chorea triggered by sudden

abnormal laboratory or magnetic resonance imaging (MRI) voluntary movement and lasting from a few seconds to a

ﬁndings. Clinical classiﬁcation is based on the phenomeno- minute (see Box 1) [2]. PKD is the most frequent form of PxD,

logy, triggering factors and duration of attacks; a diagnostic albeit with an estimated prevalence of only 1:150,000 [3]. Onset

algorithm can provide some guidance (Fig. 1). However, some is usually in childhood or adolescence, with a reported range

Fig. 1 – Diagnostic algorithm for paroxysmal movement disorders. MD: movement disorders; PKD: paroxysmal

kinesigenic dyskinesia; PNKD: paroxysmal non-kinesigenic dyskinesia; PED: paroxysmal exercise-induced dyskinesia;

EA: episodic ataxia.

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Box 1. Diagnostic criteria for PKD Box 2. Diagnostic criteria for PNKD

Attacks of dystonia and/or chorea Attacks of dystonia and/or chorea

Age of onset between 1 and 20 years Onset in childhood

Kinesigenic triggering factor No clear triggering factor, but coffee, alcohol and stress

Duration of attacks < 1 min are precipitating factors

No pain or loss of consciousness during attacks Duration of attacks: from 10 min to 4 h

Response to antiepileptic drugs No loss of consciousness during attacks

No clear response to antiepileptic drugs other than ben-

zodiazepines

of 6 months to 33 years [4]. There is a male predominance in

sporadic cases (gender ratio of 3–4 to 1), but not in familial

cases [4]. valproate or levetiracetam [32–34]. Deep brain stimulation can

Attacks may be triggered by sudden initiation of move- also be helpful in severe or refractory PNKD [35,36].

ment, such as getting up from a seated position, or by The main causative gene in PNKD is PNKD (formerly MR-1)

modiﬁcation of an ongoing movement, such as breaking into [37,38], although it is occasionally due to mutations in PRRT2,

a run while walking. These attacks are favored by stress, and sometimes in association with PKD [15,39]. As part of a more

may also be induced by startle and sound or light stimulation. complex phenotype, PNKD can be associated with mutations

Most patients experience auras such as tingling sensations or in SLC2A1 [40–45], ATP1A3 [46–49], ADCY5 [27], KCNMA1 [50,51]

general unease, which may sometimes allow them to control or in genes encoding the branched-chain a-ketoacid dehy-

the attacks [2,4,5]. The attacks may be focal, multifocal or drogenase complex (maple syrup urine disease) [52,53].

generalized, and can involve the limbs, trunk and/or speech

(through orofacial involvement). There is no pain or loss of 1.3. Paroxysmal exercise-induced dyskinesia

consciousness during attacks. The frequency of attacks is

variable, ranging from < 1 per month to up to 100 per day. Paroxysmal exercise-induced dyskinesia (PED) is characteri-

They usually wane or even abate during adulthood. In zed by attacks of dystonia and/or chorea triggered by

primary pure PKD, interictal examination is normal. Migraine prolonged exercise, typically lasting for 5 to 30 min [4] (see

or epilepsy may be present, especially benign infantile Box 3). The attacks often start in the body part involved in the

epilepsy, forming part of the infantile convulsions and exercise. The frequency of attacks is variable, depending on

choreoathetosis (ICCA) syndrome [6]. Treatment with low the routine level of physical exercise. Symptomatic treatment

doses of antiepileptic drugs, especially those that modulate with antiepileptics, levodopa or acetazolamide is sometimes

voltage-gated sodium channels, can suppress or dramatically effective, but usually disappointing [4]. Speciﬁc treatment of

reduce attacks. an underlying disorder may be beneﬁcial.

Mutations in the PRRT2 gene are the main cause of isolated Mutations in SLC2A1 are the main cause of PED, which can

PKD [7–11], accounting for 27% to 65% of cases [11–20]. The be isolated or part of a more complex phenotype [41,43,44,54–

existence of at least a second culprit gene is suspected in 58]. Mutations in GCH1, PARK2 (encoding parkin) or other

primary PKD [21–24]. The ICCA syndrome might also be due to genes involved in recessive juvenile Parkinson’s disease can

a mutation in SCN8A [25], although the typical SCN8A-mutated occasionally cause PED [4,59–66]. Rare genetic causes include

phenotype is one of severe epileptic encephalopathy [26]. mutations in PRRT2 [15,67,68], ATP1A3 [46–48], ADCY5 [27],

ADCY5 mutations cause PKD associated with other PxDs and PDHA1 and PDHX (pyruvate dehydrogenase deﬁciency) [69,70].

interictal manifestations [27]. Mutations in the SLC16A2

(MCT8) gene, which codes for a thyroid hormone transporter, 1.4. Paroxysmal hypnogenic dyskinesia

may also cause PKD as part of a complex phenotype

associating cognitive disability and motor disorders [28,29]. Paroxysmal hypnogenic dyskinesia (PHD) is characterized by

violent attacks of dystonic and tonic movements that occur

1.2. Paroxysmal non-kinesigenic dyskinesia during sleep and last for around 45 sec. In fact, PHD is almost

always a form of frontal lobe epilepsy called ‘autosomal-

Paroxysmal non-kinesigenic dyskinesia (PNKD) is characteri- dominant nocturnal frontal lobe epilepsy’ (ADNFLE) [71].

zed by attacks of dystonia and/or chorea with no clear Mutations have been found in CHRNA4, CHRNA2 and CHRNB2,

immediate trigger, lasting for a few minutes to a few hours (see

Box 2) [30]. Precipitating factors include coffee, alcohol and

stress, whereas attacks may be alleviated by sleep. The attacks

Box 3. Diagnostic criteria for PED

are infrequent (rarely > 1 per day), and attack-free intervals

may last for months. As in PKD, the attacks tend to diminish

Attacks of dystonia and/or chorea

with advancing age. Auras resembling those seen in PKD may

Onset in childhood

occur. In primary pure PNKD, interictal examination is

Triggered by exercise

normal. PNKD can occasionally be severe or even fatal in

Duration of attacks: 5–30 min

cases of laryngeal dystonia causing respiratory failure [31].

No loss of consciousness during attacks

Antiepileptic drugs, except for benzodiazepines, are usually

No clear response to antiepileptic drugs

ineffective. Some patients have improved with acetazolamide,

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which code for acetylcholine receptor subunits [72]. Anti- [7–11,88]. They can also occasionally cause PNKD, PED, EAs,

epileptic drugs are effective. hemiplegic migraine and other headache disorders, paroxys-

mal torticollis and various forms of epilepsy [24]. PKD, ICCA or

1.5. Episodic ataxias BFIE was diagnosed in 94.7% of 1444 PRRT2-mutated patients,

leaving only 5.3% of patients with other diagnoses [39].

EAs are characterized by attacks of cerebellar ataxia that can Inheritance is autosomal dominant with incomplete pene-

last from a few seconds to several days, depending on the trance. Biallelic PPRT2 mutations have been reported to cause a

underlying cause (Box 4). Attacks may be accompanied by severe phenotype that can include various kinds of PxD,

dysarthria, tremor, vertigo, nausea, diplopia, dystonia, prolonged episodes of ataxia and cognitive disability

hemiplegia, headache, and tinnitus [73–75]. Triggering fac- [86,89,90].

tors include physical and psychological stress, startle, sudden PRRT2 normally interacts with synaptosomal-associated

movements, fatigue, caffeine, alcohol, fever and heat [75]. protein 25 kDa (SNAP25), a presynaptic protein involved in

Interictal examination may be normal, or show nystagmus, calcium-dependent neuronal exocytosis [91], but this inter-

cerebellar ataxia, myokymia or dystonia. Cognitive disability action is perturbed by PRRT2 mutations [92]. PRRT2 is also

and psychiatric disorders may also be present. Onset is part of AMPA-type glutamate receptor complexes, in

usually in childhood or adolescence, and the frequency of which it is associated with the GRIA1 subunit [93].

attacks ranges from a few per year to several per day. PRRT2 likely inhibits glutamate release and hinders GRIA1

Acetazolamide can reduce the severity and frequency of trafﬁcking to the cell membrane. PRRT2 loss of function

attacks in some patients. Brain MRI can be normal or show mutations may lead to increased glutamate release and

cerebellar atrophy. glutamate receptor activity, thereby inducing neuronal

The two most common types of EA are caused by hyperexcitability.

mutations in the KCNA1 (EA1) and CACNA1A (EA2) genes.

Other genetic causes of EAs include mutations in CACNB4 2.2. The PNKD gene

(EA5) [76] and SLC1A3 (EA6) [77]. However, the genes

corresponding to the EA3, EA4, EA7 and EA8 loci are still Mutations in the PNKD gene (formerly MR-1) are the main

unknown [78–82]. Rare causes of EAs include mutations in cause of primary PNKD. Inheritance is autosomal dominant

SCN2A [83], FGF14 [84,85], PRRT2 [21,86], SLC2A1 [44,45,87], with near-complete penetrance [30]. Three different muta-

ATP1A3 [49], PDHA1, PDHX [69] and genes encoding the tions of the gene have been found in unrelated families of

branched-chain a-ketoacid dehydrogenase complex (maple different ethnicities [34,94]. The phenotype is one of pure

syrup urine disease) [52]. PNKD with normal interictal examination, and is very

homogeneous in PNKD-mutated patients [3,34,67,95,96].

PNKD codes for a synaptic protein that modulates neuro-

2. Genetic characteristics and

transmitter release [97,98]. Its mutations may induce abnor-

pathophysiology

mal dopamine release in response to precipitating factors

such as stress, caffeine and alcohol, through a gain-of-

Most primary paroxysmal movement disorders are of genetic function mechanism [97,98].

origin even in cases without a family history, as de novo

mutations are not uncommon. The main genetic defects are 2.3. The SLC2A1 gene

summarized in Table 1, along with the principal characte-

ristics of the corresponding disorders. The ﬁrst genes to SLC2A1 codes for glucose transporter 1 (GLUT1), a membrane

consider in paroxysmal dyskinesia are PRRT2, PNKD and protein that mediates glucose transport across the blood–

SLC2A1, respectively responsible for most PKD, PNKD and PED brain barrier. Mutations in SLC2A1 cause GLUT1 deﬁciency, a

cases. It should also be noted that PRRT2 and PNKD mutations treatable disease characterized by reduced availability of

induce pure phenotypes of PxD, whereas mutations in other brain glucose causing a cerebral energy deﬁcit. Sporadic

genes are generally responsible for more complex phenotypes. cases, due to de novo mutations, are most common, although

The main causative genes of EAs are KCNA1 and CACNA1A. familial cases with autosomal dominant inheritance also

occur. Rare cases of recessive inheritance have also been

2.1. The PRRT2 gene reported [99]. The phenotypic spectrum is very wide, ranging

from pure PED to severe encephalopathy. Manifestations can

Mutations in the PRRT2 gene are the main cause of PKD, ICCA include cognitive disability, acquired microcephaly, dysto-

syndrome and benign familial infantile epilepsy (BFIE) nia, chorea, ataxia, spasticity and paroxysmal manifesta-

tions, including seizures and PxDs [44,45,54,55,100–102].

There are no ﬁrm genotype–phenotype correlations, although

Box 4. Diagnostic criteria for EAs

milder forms are often associated with missense mutations

resulting in 50–75% residual GLUT1 function, whereas severe

Attacks of cerebellar ataxia

forms are usually due to mutations resulting in a 50% loss of

Onset in childhood or adolescence

GLUT1 [55,102].

Duration of attacks: a few seconds to several days

Mutations in SLC2A1 are likely to be the main cause of PED

No loss of consciousness during attacks

[54,56,103], but can also be responsible for PNKD and EAs

Possible response to acetazolamide

[44,45,87]. Attacks are most often precipitated by exercise or

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Table 1 – Main genetic defects causing primary paroxysmal movement disorders (MD) and characteristics of the

corresponding diseases.

Gene Paroxysmal Age of onset Attack duration Other Interictal abnormalities MD paroxysmal

disorders

PRRT2 PKD Childhood–adolescence < 1 min BFIS None (heterozygous mutations)

ICCA HM Cognitive deﬁciency

PNKD FS (homozygous mutations) PED CAE

PNKD PNKD Childhood–adolescence Minutes to hours – None

SLC2A1 PED Infancy–childhood Minutes to hours Epilepsy Microcephaly PNKD Migraine Hypotonia EA Paroxysmal Dystonia/chorea drowsiness, Spasticity

weakness, Ataxia

dysphoria, pain Cognitive deﬁciency

Sleep disturbances

ATP1A3 PNKD Infancy Minutes to days Plegic attacks Cognitive deﬁciency PED Epilepsy Dystonia/chorea

EA Paroxysmal eye Hypotonia movements Parkinsonism Paroxysmal Ataxia dysautonomy Psychosis

Migraine

ADCY5 PKD Infancy–childhood Minutes to hours Dystonia/chorea/ PNKD myoclonus/tremor

PED Axial hypotonia

Nocturnal Orofacial myoclonus

PxD Fluctuations

GCH1 PED Infancy–childhood Minutes to hours Oculogyric crises Generalized dystonia

Restless legs syndrome Postural tremor, parkinsonism

Axial hypotonia, cerebellar features,

spastic paraparesis

PARK2 PED Adolescence–adulthood Minutes Parkinsonism

PDHA1, PED Infancy–childhood Minutes to days Epilepsy Lactic acidosis

PDHX, EA Episodic weakness Hypotonia

DLAT Signs of brainstem involvement

Microcephaly, psychomotor delay

Neuropathy, optic atrophy

Oculocephalic asynergy

with nystagmus

KCNA1 EA Childhood–adolescence Seconds to minutes Epilepsy Myokymia

Paroxysmal dyspnea Mild cerebellar syndrome

Cataplexy

CACNA1A EA Childhood–adolescence Hours to days Migraine Mild cerebellar syndrome

Paroxysmal Absence epilepsy Nystagmus

torticollis Fluctuating weakness Dystonia

Paroxysmal HM Learning disability

tonic upgaze

CACNB4 EA Childhood–adolescence Hours to days Juvenile myoclonic Nystagmus

epilepsy Mild cerebellar syndrome

Generalized epilepsy

SLC1A3 EA Childhood–adolescence Hours to days Epilepsy Mild cerebellar syndrome

Migraine Pyramidal signs

Plegic attacks

SCN2A EA Childhood Minutes to hours Neonatal epilepsy None

Paroxysmal pain

FGF14 EA Childhood–adulthood Minutes to days Paroxysmal dystonia Mild cerebellar syndrome

Headaches Nystagmus

KCNMA1 PNKD Childhood Seconds to minutes Epilepsy None

SLC16A2 PKD Infancy < 1 min Epilepsy Cognitive disability (MCT8) Hypotonia Weakness Dystonia

Pyramidal signs

Pectus excavatum, scoliosis

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Table 1 (Continued )

Gene Paroxysmal Age of onset Attack duration Other Interictal abnormalities MD paroxysmal

disorders

SCN8A PKD Infancy–childhood < 1 min Epilepsy Cognitive disability Hypotonia

Pyramidal signs Dystonia Chorea

Ataxia

Italicized symptoms are those rarely associated with mutations in the corresponding gene. PKD: paroxysmal kinesigenic dyskinesia; ICCA:

infantile convulsions and choreoathetosis; PNKD: paroxysmal non-kinesigenic dyskinesia; PED: paroxysmal exercise-induced dyskinesia; EA:

episodic ataxia; BFIS: benign familial infantile seizures; HM: hemiplegic migraine; FS: febrile seizures; CAE: childhood absence epilepsy.

fasting, whereas carbohydrate intake and rest are alleviating 2.5. The GCH1 gene

factors. The diagnosis is suggested by a low cerebrospinal ﬂuid

(CSF)/serum glucose ratio (< 0.60) and conﬁrmed by genetic Heterozygous mutations in the GTP-cyclohydroxylase-1

analysis. Treatment consists of providing alternative energy (GCH1) gene cause dopa-responsive dystonia (DRD, or

supplies to the brain. A ketogenic diet, inducing a switch from DYT5). They also occasionally cause PED, either in isolation

glucose to ketone body metabolism, is currently the standard or as part of a more complex phenotype [59]. DRD usually

treatment. Adherence is a problem, however, and alternative manifests as childhood-onset dystonia with motor ﬂuctua-

treatments are therefore needed. Acetazolamide is a possible tions. Accurate diagnosis is important, as treatment with low-

option, as it was reportedly effective in one case [40]. A dose levodopa greatly alleviates symptoms; thus, although

dramatic improvement in PxD was recently noted in an open- DRD is probably a rare cause of PED, it is essential to consider a

label pilot trial of triheptanoin, which provides energy levodopa trial in PED patients.

substrates to the brain [104], although this needs to be GCH1 codes for GTP-cyclohydroxylase 1, an enzyme that

conﬁrmed in a larger controlled study. catalyzes the ﬁrst step in the synthesis of tetrahydrobiopterin,

which is essential for dopamine synthesis. GCH1 mutations

2.4. The ATP1A3 gene result in haploinsufﬁciency with reduced striatal dopamine

levels. No genotype–phenotype correlations have been esta-

Mutations in ATP1A3, which encodes the a3-subunit of the blished [111].

+ +

Na /K -ATPase pump, cause rapid-onset dystonia-parkinso-

nism (RDP), alternating hemiplegia of childhood (AHC), the 2.6. The ADCY5 gene

cerebellar ataxia, areﬂexia, pes cavus, optic atrophy and

sensorineural hearing loss (CAPOS) syndrome [49,105], early Mutations in ADCY5 cause a childhood-onset mixed hyper-

infantile epileptic encephalopathy [106] and the relapsing kinetic movement disorder, typically without ataxia, marked

encephalopathy with cerebellar ataxia (RECA) syndrome cognitive disability or seizures [112]. The disorder is either

[107]. AHC is characterized by episodic hemiplegia, dystonic stable or progresses very slowly. Diagnostic clues include axial

or tonic attacks, cognitive disability and permanent move- hypotonia, orofacial myoclonus and marked ﬂuctuations. In

ment disorders. RDP is characterized by rapid onset of addition to baseline movement disorders, many patients have

dystonia (hours to weeks) and parkinsonism. Paroxysmal PxDs manifesting as various PxD subtypes, including non-

dystonia (PNKD and/or PED) is reported in most AHC patients, epileptic nocturnal paroxysmal dyskinesia [27]. The presence

and also in a few RDP patients, either as part of a complex of various types of PxD and/or nocturnal non-epileptic PxD in a

phenotype or as the main symptom [46,48,49,108,109]. The given patient points strongly to an ADCY5-related disorder.

phenotypes overlap, implying that ATP1A3-related disorders ADCY5 codes for adenylate cyclase type 5, which is strongly

may rather be seen as a continuous phenotypic spectrum expressed in the striatum. This protein interacts with Gaolf,

[107]. ATP1A3 mutation analysis should be considered when a which is encoded by GNAL, a gene involved in primary

patient presents with paroxysmal episodes of ataxia, hemidystonia [113]. ADCY5 integrates signals from multiple

plegia or dystonia, with or without interictal manifestations receptors, including adenosine A2A and D1 and D2 dopamine

[49]. receptors [114]. The pathophysiology likely involves increased

+ +

The Na/K-ATPase pump exchanges Na for K through adenylate cyclase activity, thereby affecting signal transduc-

ATP hydrolysis and is therefore a major determinant of tion within the striatum [112].

resting membrane potentials. In the brain, the a3-subunit

(encoded by ATP1A3) is exclusively expressed in neurons, 2.7. The KCNA1 gene

particularly GABAergic neurons of the basal ganglia and

cerebellum [110]. Nevertheless, the pathophysiology Mutations in KCNA1 cause episodic ataxia type 1 (EA1) [115].

remains poorly understood, and the observed phenotypic Inheritance is autosomal dominant with incomplete pene-

variability is not fully explained by genotype–phenotype trance. Onset usually occurs in childhood or early adoles-

correlations [49]. cence. The attacks are brief (seconds to minutes), with a

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Table 2 – Causes of secondary paroxysmal movement disorders (MD).

Cause Paroxysmal Clinical clues Laboratory ﬁndings MRI ﬁndings

Multiple sclerosis & other PKD, PNKD, EA Onset in adulthood CSF oligoclonal bands, CNS demyelinating

demyelinating diseases Baseline neurological defects anti-NMO antibodies lesions

Stroke (including moyamoya PKD, PNKD, EA Onset in adulthood NA Basal ganglia, thalamus,

disease) Baseline neurological defects subcortical white-matter

History of stroke or midbrain infarction

Seizures, headaches (moyamoya)

Transient cerebral ischemia PNKD Onset in adulthood NA Arterial stenosis

Cardiovascular risk factors

Basal ganglia calciﬁcations PKD, PNKD Onset in adulthood None, or hypocalcemia, Symmetrical T2

Baseline neurological defects hyperphosphoremia and hypointensity & T1

Response to calcium abnormal PTH levels hyperintensity in basal

supplementation if ganglia

hypocalcemic

Hypo-/hyperglycemia PNKD Onset in adulthood Hypoglycemia or NA

History of diabetes hyperglycemia

Systemic autoimmune PKD, PNKD, EA Onset in adulthood Autoantibodies White-matter & basal

disorders (lupus Baseline neurological defects ganglia T2

erythematosus/ Systemic involvement hyperintensities antiphospholipid syndrome/Behc¸et’s

disease)

Autoimmune PKD Onset in adulthood Autoantibodies Normal or basal ganglia

encephalopathy Cognitive impairment T2 hyperintensities

(VGKC, Hashimoto) Seizures

Poststreptococcal disorder PNKD Recent upper respiratory tract Antistreptolysin O, NA

infection streptococci in throat

Behavioral changes culture

Paraneoplastic limbic EA Onset in adulthood Paraneoplastic Temporal lobe T2 encephalitis Seizures antibodies hyperintensity

Behavioral changes

Celiac disease PNKD Gastrointestinal disorder Autoantibodies NA

Migraine PNKD Other aura symptoms NA NA

Attacks followed by migraine

Response to migraine treatment

Perinatal brain injury PKD, PNKD Baseline neurological defects NA NA

(hypoxic encephalopathy/ History of perinatal hypoxic

kernicterus) encephalopathy or kernicterus

CNS infections (HIV, CMV, PKD, PNKD Onset in adulthood CSF abnormalities, low Normal or white-matter

H1N1, syphilis) Baseline neurological defects CD4 count, virus abnormalities

detection, positive

TPHA/VDRL test

Thyrotoxicosis PKD Onset in adulthood Abnormal TSH, NA

Weight loss, muscle weakness, T4 levels

heat intolerance, anxiety

Medullary lesion PKD Baseline neurological defects NA Medullary lesion or

(syringomyelia) or malformation

malformation (Chiari)

Head or peripheral trauma PKD, PNKD Baseline neurological defects NA Variable traumatic

History of trauma sequelae

Progressive supranuclear PKD Late onset NA NA

palsy Baseline neurological defects

Methylphenidate treatment PKD Onset shortly after treatment NA NA

initiation

Parasagittal meningioma PNKD Baseline neurological defects NA Parasagittal meningioma

Neuroacanthosis PKD Baseline neurological defects Acanthocytes NA

Lesch–Nyhan disease PKD Baseline neurological defects Hyperuricemia Normal or cerebral

atrophy

Psychogenic PKD, PNKD Psychological context NA NA

Inconsistent manifestations &

clinical ﬁndings

MRI: magnetic resonance imaging; PKD: paroxysmal kinesigenic dyskinesia; PNKD: paroxysmal non-kinesigenic dyskinesia; PED: paroxysmal

exercise-induced dyskinesia; EA: episodic ataxia; CSF: cerebrospinal ﬂuid; NMO: neuromyelitis optica; CNS: central nervous system; NA: not

available; PTH: parathyroid hormone; VGKC: voltage-gated potassium channel; HIV: human immunodeﬁciency virus; CMV: cytomegalovirus;

TPHA: Treponema pallidum hemagglutination; VDRL: Venereal Disease Research Laboratory; TSH: thyroid-stimulating hormone.

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frequency ranging from once a month to several per day. onset; (ii) paroxysmal tremor; (iii) highly variable phenome-

Precipitating factors include sudden movement, startle res- nology, with variable duration and frequency of attacks and

ponse and stress. Interictal examination reveals myokymias triggering factors; (iv) altered consciousness during attacks;

of the limbs and face. Affected individuals may also display and (v) atypical associated symptoms [169]. Multidisciplinary

delayed motor development, cognitive disability, epilepsy, therapeutic approaches combining physiotherapy, cognitive

choreoathetosis, neuromyotonia (muscle cramps and stiff- behavioral therapy and/or hypnotherapy are helpful in some

ness) and permanent cerebellar ataxia [75,116]. Acetazolamide patients [32,169]. Other causes include encephalopathy,

and antiepileptic drugs can reduce the frequency and severity metabolic disorders (hypocalcemia, hypo- or hyperglycemia),

of attacks in some patients. central nervous system infections, head trauma and peri-

KCNA1 codes for the voltage-gated potassium channel pheral trauma, as well as other rare deﬁnite or possible causes

Kv1.1, which is strongly expressed in the cerebellum, (Table 2) [32,128,133,143,170–210]. Treatment is mainly focu-

hippocampus and motor axons [74]. Most KCNA1 defects are sed on the underlying cause, especially when it is reversible.

missense mutations that impair channel dynamics, probably Antiepileptic drugs, benzodiazepines and botulinum toxin

causing increased neuronal excitability [73]. There are no clear injections may also be beneﬁcial.

genotype–phenotype correlations [116].

3. Conclusion

2.8. The CACNA1A gene

Mutations in CACNA1A cause episodic ataxia type 2 (EA2) New sequencing methods have enabled numerous culprit

[117]. Inheritance is autosomal dominant with an estimated genes to be identiﬁed in patients with paroxysmal movement

penetrance of 80–90% [118]. Onset is often in childhood or early disorders, and more are likely to be discovered in the near

adolescence. Attacks last longer than in EA1, from hours to future. These genetic advances have led to greater diagnostic

days, but are less frequent, ranging from a few episodes per certainty, improved genetic counseling, and targeted thera-

year to no more than several per week. Vertigo and nausea are peutics. However, genetic diagnosis is sometimes hindered by a

frequently present. Triggering factors include stress, exercise lack of reliable genotype–phenotype correlations, as a given

and caffeine or alcohol intake [119]. While interictal examina- phenotype may be caused by mutations in various genes.

tion may be normal early on, patients typically develop Multigene diagnostic panels should further improve the

permanent interictal cerebellar ataxia and nystagmus. They diagnosis of these rare but probably underdiagnosed disorders.

may also have epilepsy, migraine, dystonia, ﬂuctuating

weakness and cognitive disability [73,120]. Acetazolamide is

Disclosure of interest

effective for paroxysmal episodes in two-thirds of patients

[121,122]. The potassium channel blocker 4-aminopyridine

can also help to control attacks [123]. The authors declare that they have no competing interest.

CACNA1A encodes the pore-forming subunit of a voltage-

dependent P/Q-type calcium channel that is strongly expres-

r e f e r e n c e s

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