Topic review

Paroxysmal Movement Disorders and Episodic Ataxias

Submitted by: Francesco Nicita

Abstract

Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.

Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements[1]. The term “paroxysmal” indicates a well-defined onset and termination of clinical manifestations. Two main categories of PMDs are recognized based on phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs)[2]. From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are recognized. Some aspects of clinical history may help to distinguish primary from secondary PMDs: Most primary forms occur as sporadic or familial cases with autosomal dominant inheritance, and most often onset of manifestations is set in childhood or adolescence (Figure 1), and interictal neurological examination is unremarkable; secondary forms occur sporadically, more usually begin after the second decade of life (Figure 1), and clinical examination is frequently abnormal also outside of attacks.

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Figure 1. Onset of different paroxysmal movement disorders (PMDs) according with age. BNSM: benign neonatal sleep myoclonus; BMEI: benign myoclonus of early infancy; BPTI: Benign paroxysmal torticollis of infancy; PEM: paroxysmal eye movements; PED: paroxysmal exercise-induced dyskinesia; PKD: paroxysmal kynesigenic dyskinesia; PNKD: paroxysmal non-kynesigenic dyskinesia.

A further category that may manifest as PMDs are functional (psychogenic) movement disorders (FMDs). Patients with FMDs may show tremor, dystonia, myoclonus, parkinsonism, speech and gait disturbances, or other movement disorders whose patterns are usually incongruent with that observed in organic diseases, although sometimes diagnosis may be challenging. Diagnosis of FMDs is based on positive clinical features (e.g., variability, inconsistency, suggestibility, distractibility, and suppressibility) during physical examination and should be considered in presence of some clues such as intra-individual variability of phenomenology, duration and frequency of attacks, and/or precipitation of the disorder by physical or emotional life events. Other supporting information can be helpful (i.e., neurophysiologic and imaging studies)[3].

Recognition and diagnosis of PMDs are based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology (possibly including video-recording of at least one attack), brain magnetic resonance imaging (MRI), and genetic analysis. Neurophysiological (i.e., standard electroencephalogram or long-term monitoring) or laboratory tests are reserved for cases in which an epileptic origin of the attack cannot be excluded, or brain MRI reveals alterations that are compatible with genetic-metabolic or secondary causes. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies, which allowed to increase both molecular diagnosis and identification of ultra-rare or new genes. The wide number of genes involved in the pathogenesis of PMDs (Table 1) reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits (Figures 2–4). This comprehensive review is focused on clinical and genetic features of PMDs according to current nosology (Table 2). As this review is mainly targeted on genetic causes of PMDs, functional PMDs will not be discussed further.

 

Table 1. Main genetic causes of paroxysmal movement disorders. A question mark follows treatment options that: have been proposed basing on pathophysiological assumptions, are under investigation or have been shown to be beneficial only in single-case reports.

Gene

OMIM

Inheritance

Age at onset

PMDs subtype

Attack duration

Isolated versus
combined

Allelic disorders

Other possible features

MRI

Treatment

PRRT2

614386

AD

<18 years

PKD

Very brief (<1
min)

I/C

BFIS, ICCA,
FHM, EA

 

Normal

CBZ (PKD) ACZM (EA)

PNKD

609023

AD

<18 years

PNKD

Long (>1
hour)

I

Migraine
(rare), PKD

 

 

BDZ (Attacks relief)

SLC2A1 (GLUT-1)

138140

AD

Variable

PED, EA, HA, PEM

Intermediate
(5–40 min)

I/C

Classic GLUT1-DS, HSP,

Anaemia,
hypotonia,
spasticity, seizures, Developmental delay/ID, dystonia, ataxia

 

Ketogenic diet,

triheptanoin

PDH complex (PDHA1/PDHX

/DLAT)

300502/608769/608770

AR

Infancy

PED/PNKD

Variable

I/C

Leigh
syndrome

Developmantal delay/ID, Seizures, progressive dystonia

Pallidal hyperintensities, Callosal agenesis

Ketogenic diet

ECHS1

602292

AR

Infancy

PED

Variable

I/C

 

Leigh
syndrome

From Pallidal hyperintensities to Leigh-like abnormalities

Valine-restricted diet? detoxifying drugs?

HIBCH

610690

AR

Infancy

PED

Variable

I/C

Leigh
syndrome

ID, Seizures, progressive dystonia

From Pallidal hyperintensities to Leigh-like abnormalities

Valine-restricted diet? detoxifying drugs?

ATP1A3

182350

AD

Variable

PNKD ([hemi]dystonic attacks), HA, PEM

Variable

C

EIEE, AHC, CAPOS, RECA, RDP

Seizures, dysautonomic paroxysms, nonparoxysmal
dystonia, ataxia, parkinsonism

 

Flunarizine (HA prophylaxis), BDZ (HA relief)

ADCY5

600293

AD

Variable

PKD/PNKD/PED/PND

Brief
(minutes)

C

PNKD

Axial
hypotonia,
nonparoxysmal
dystonia and
chorea

 

Caffeine?

TBC1D24

613577

AR

Childhood

PED

Variable

C

Deafness,

DOORS syndrome, Rolandic Epilepsy,

EIEE16, Myoclonic epilepsy

Sizures, Developmental delay/ID, myoclonus, ataxia, extraneurological abnormalities

 

 

SLC16A2 (MCT8)

300095

X linked

<1–2 months

PKD (triggered by passive movements)

Very brief
(seconds to
minutes)

C

 

Mental
retardation

 

TRIAC?

SCN8A

600702

AD

Infancy

PKD

Brief

C

Epilepsy

Mental
retardation

 

CBZ, oxcarbazepine

KCNMA1

600150

AD

Childhood

PNKD

Long (>1
hour)

C

 

epilepsy, developmental delay, progressive HSP, ataxia

 

 

GCH1

600225

AD

<18 years

PED

Variable

I/C

DRD

Non paroxysmal dystonia and parkinsonism

 

L-DOPA

PDE10A

610652

AR/AD

Childhood

PNKD

NR

C

Chorea without paroxysms

Dystonia, Parkinsonism, marked fluctuations

Striatal hyperintensities (in AD cases)

 

KCNA1

176260

AD

Childhood (2–15)

EA1

Minutes

I

EIEE, PKD, EDE (AR)

interictal Myokymia; progressive ataxia (20%), epilepsy (10%)

Normal ore cerebellar atrophy (10%)

CBZ, PHT, ACZM

CACNA1A

601011

AD

Childhood (0–20)

EA2/PTU/BPT

Variable
(minutes to
days)

I/C

FHM1, SCA6, CA

progressive ataxia, Developmental delay

Normal or cerebellar atrophy

ACZM, 4-APD, LEV

CACNB4

601949

AD

Young-adult onset

EA5

several hours

I

JME, IGE, CND (AR)

Epilepsy, permanent ataxia

Normal

ACZM

SLC1A3 (EAAT1)

600111

AD

infancy or childhood (rarely adulthood)

EA6

several hours

I

Adult-onset progressive ataxia

Seizures (rare)
HA

Nornmal; rarely cerebellar atrophy

ACZM

UBR4

609890

AD

around age 2 years

EA8

minutes to hours

I

 

nystagmus, myokymia, tremor

 

Clonazepam

FGF14

601515

AD

late-childhood to early adulthood

EA9

minutes

I/C

SCA27, CA

progressive ataxia, nystagmus, postural upper limb tremor, ID

 

 

BCKD Complex

608348/248611

AR

Variable

EA/PNKD

Minutes to hours

C

Classic MSUD

developmental delay, progressive psychomotor retardation, seizures, ataxia,

T2 hypersignal in in the brainstem, globus pallidus, thalami, and dentate nuclei

BCAA restricted diet

KCNA2

176262

AD

Infancy or childhood

EA

Seconds to hours

C

EIEE32, SCA, PME

Epilepsy

 

ACZM (variable)

SCN2A

182390

AD

infancy or childhood

EA

minutes to days

C

EIEE11, BFIS3

Seizures +/- encephalopathy, developmental delay/ID

Normal or cerebellar atrophy

ACZM (variable)

4-APD: 4-amynopiridine; ACZM: acetazolamide; AHC: alternating hemiplegia of childhood; AR: autosomic recessive; AD autosomic dominant; BDZ: benzodiazepines; BFIS: benign familial infantile seizures; BPTI: Benign paroxysmal torticollis of infancy; C. Combined; CA: congenital ataxia; CAPOS: cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss; CBZ: carbamazepine; CND: complex neurodevelopmental disorder; DOORS: deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures; DRD: Dopa-Responsive Dystonia EA: episodic ataxia; EDE: epileptic dyskinetic encephalopathy; EIEE: early infantile epileptic encephalopathy; FHM: familiar hemiplegic migraine; HA: hemiplegic attacks; I: Isolated; ID: Intellectual disability; JME: juvenile myoclonic epilepsy; LEV: levetiracetam; MSUD: maple syrup urine disease; PED: paroxysmal exercise-induced dyskinesia; PEM: paroxysmal eye movements; PHT: phenytoin; PKD: paroxysmal kynesigenic dyskinesia; PNKD: paroxysmal non-kynesigenic dyskinesia; PME: progressive myoclonic epilepsy; PTU: paroxysmal tonic upgaze, RECA: recurrent encephalopathy with cerebellar ataxia; RDP: rapid onset dystonia-parkinsonism; SCA: spinocerebellar ataxia; VPA: Valproic Acid.

References

  1. Roberto Erro; Kailash P. Bhatia; Unravelling of the paroxysmal dyskinesias. Journal of Neurology, Neurosurgery & Psychiatry 2018, 90, 227-234, 10.1136/jnnp-2018-318932.
  2. Aurélie Méneret Md; E. Roze; Paroxysmal movement disorders: An update. Revue Neurologique 2016, 172, 433-445, 10.1016/j.neurol.2016.07.005.
  3. Mary Ann Thenganatt; Joseph Jankovic; Psychogenic (Functional) Movement Disorders. CONTINUUM: Lifelong Learning in Neurology 2019, 25, 1121-1140, 10.1212/con.0000000000000755.

Keywords

hyperkinetic movement disorders dyskinesia ataxia cerebellum basal ganglia therapy acetazolamide epilepsy whole exome sequencing functional movement disorders