Table of Contents

    Topic review

    Paroxysmal Movement Disorders

    Submitted by: Francesco Nicita

    Definition

    Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements.

    1. Introduction

    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.

    2. Main Categories 

    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.

    Ijms 21 03603 g001 550

    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].

    3. Recognition and Diagnosis

    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.

    The entry is from 10.3390/ijms21103603

    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.
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