• PRRT2 Gene

  • Located on chromosome 16p11.2.
  • Consists of four exons.
  • Encodes a protein of 340 amino acids: proline-rich transmembrane protein 2. PRRT2 protein helps regulate signaling in the brain.
  • Composed of a proline-rich extracellular N-terminal domain and a membrane-bound C-terminal domain.

• PRRT2 Protein Interactions

  • Protein Interactions: The PRRT2 protein interacts with several proteins inside neurons that participate in neurotransmitter release.
  • Ion Channels: PRRT2 is thought to affect the function of several types of ion channels.
  • SNARE Complex: The PRRT2 protein impedes the formation of a group of proteins called the SNARE complex that helps vesicles fuse with the cell membrane.

• Mutation Types:

  • Mainly nonsense, missense, or deletion.
  • Frameshift mutation NM_145239 c.649dupC (p.Arg217Profs*8) is the most common.
  • Leads to a premature stop codon (reported in more than 75% of carriers, suggesting a mutational hotspot).
  • Causes a protein loss-of-function mechanism due to gene haploinsufficiency.
  • Evidence suggests that the c.649dupC-derived mRNA is degraded by nonsense-mediated decay and not translated into a protein
  • PRRT2 mutations are inherited in an autosomal dominant fashion, accounting for familial cases, but de novo mutations occur in about 5% of cases.

• Expression:

  • Highly expressed in the human brain, especially in the cerebral cortex, basal ganglia, and cerebellum
  • Matches expected locations based on phenotypes.
  • Animal model studies in mice show highest PRRT2 mRNA levels in the same brain areas
  • Mice basal ganglia and neocortex show relatively low mRNA and high protein levels.
  • Indicates that neocortex and basal ganglia might be targets of projections from areas rich in PRRT2-expressing neurons (e.g., cerebellum)

• Cellular Localization:

  • Localizes at the plasma membrane
  • Mainly expressed in glutamatergic neurons at the presynaptic level.
  • Interacts with 25 kDa Synaptosomal-Associated Protein (SNAP25), involved in Ca2+-mediated neurotransmitter release, synaptic endocytosis, and regulation of voltage-gated ion channels.
  • Also interacts with Vesicle Associated Membrane Protein 2 (VAMP2) and synaptotagmins Syt1 and 2.
  • Implicated in the Ca2+-sensing machinery involved in neurotransmitter release.

• Synaptic Function:

  • PRRT2-silenced neurons show impairment in synchronous, evoked neurotransmitter release in excitatory synapses, with no effect on asynchronous release.
  • Results in increased asynchronous/synchronous release ratio, suggesting a defect in coupling Ca2+ influx to exocytosis.
  • Short-term potentiation (STP) phenomena in response to short-duration, increasing frequency stimulation show opposite effects on excitatory (glutamatergic) and inhibitory (GABAergic) synapses.
  • Increased facilitation in excitatory transmission and increased depression in inhibitory transmission observed.
  • Suggests an excitation/inhibition imbalance underlying hyperexcitability/instability in neuronal networks expressing the mutant protein.

• Additional Physiologic Roles:

  • Negatively regulates voltage-gated Nav1.2 and Nav1.6 channels by modulating their voltage-dependent state of inactivation and recovery from inactivation
  • Induced pluripotent stem cell-derived neurons from homozygous patients and primary neurons from PRRT2 knockout mice show increased Na+ currents and spontaneous firing, fully reverted by reintroduction of wild-type PRRT2.
  • Suggests a mechanistic crossover between synapthopathies and channelopathies in paroxysmal neurological disorders.
  • Mutations in SCN8A (encoding Nav1.6) can also cause PxD with epilepsy.

• Brain Development:

  • PRRT2 highly expressed during early stages of development, involved in intense synaptogenesis.
  • PRRT2 silencing negatively affects synaptic connections, indicating a developmental effect.
  • In utero PRRT2 knockout in cortical neurons causes delay in neuronal migration and defects in synaptic development.
  • PRRT2 expression declines during adulthood, supporting age-related phenotype occurrence and self-limiting character.
  • Silencing PRRT2 in primary hippocampal neurons affects synaptic actin dynamics, leading to defects in dendritic spine density and maturation.
  • Interaction with cofilin, an actin-binding protein, affects synapse density, spine number, and morphology but not neurotransmitter release alterations.

PRRT2 Associated Disorders

• Paroxysmal Kinesigenic Dyskinesia
  • PRRT2 account for most cases of PKD.
  • Phenotype features:
    • Attacks of short duration (<1 min).
    • Consist of choreic, dystonic, and/or ballistic movements.
    • Triggered by sudden movements, intention to move, and/or acceleration (kinesigenic).
    • Interictal neurological examination is unrevealing in most cases.
  • Triggers:
    • Virtually all patients report a kinesigenic trigger.
    • About 40% have additional non-kinesigenic triggers:
      • Anxiety.
      • Startle.
      • Sleep deprivation.
      • Seldom, sustained exercise.
  • Clinical overlap:
    • Overlap with other PxD subtypes (PNKD and PED).
    • Clinical description should include:
      • Duration of the attacks.
      • Response to AED, especially carbamazepine (CBZ).
  • Response to CBZ:
    • PRRT2-PxD are brief in duration and respond well to CBZ.
    • Contrast with classic PNKD and PED.
  • Predictive factors for PRRT2 mutations:
    • Younger age at onset (around 9 years).
    • Familial clustering of PKD, epilepsy, and/or other rarer phenotypes.
    • Choreic phenomenology and bilateral distribution of attacks.
    • Preceding sensory aura not indicative.
• Paroxysmal Hypnogenic Dyskinesia (PHD)
  • Also described in isolated paroxysmal hypnogenic dyskinesia (PHD).
  • PHD attacks occur during sleep without identifiable triggers.
  • Evidence links PHD to autosomal dominant frontal lobe epilepsy (ADFLE).
  • Importance of PHD observation:
    • Re-inclusion of PHD as a PxD subtype alongside PKD, PNKD, and PED.
    • Clinical features (duration of attacks and response to CBZ) may predict genetic deficits.

• PKD condition and treatment:

  • PKD attacks might be violent.
  • Condition considered relatively benign with remission tendency during adulthood.
  • CBZ as first-line treatment (50–600 mg).
  • Alternative AEDs based on patient profile and side effects:
    • Zonisamide
    • Topiramate
    • Lamotrigine
    • Levetiracetam
• Epileptic Disorders
  • self-limited familial infantile epilepsy (benign familial infantile seizures, BFIS)
    • Autosomal-dominant epileptic disorder.
    • Non-febrile convulsions start in the first 12 months of life.
    • Good response to AED.
    • Favorable prognosis with remission before age two.
    • Seizure phenomenology:
      • Focal motor seizures start with:
        • Gaze staring.
        • Motor arrest.
        • Head deviation.
        • Hypertonia.
        • Cyanosis.
      • Usually occur in clusters and might have secondary generalization
    • Ictal EEG:
      • Often shows parieto-occipital epileptic activity.
      • May eventually generalize
  • Rare seizure types:
    • Bilateral tonic-clonic or absence seizures.
    • Benign myoclonus of infancy
  • Atypical infantile seizures:
    • PRRT2 mutations are not found in families with:
      • Later seizure onset or offset.
      • More severe seizures.
      • Multiple seizure types

  • PKD/IC Syndrome (Lee H-Y 2012):

    • Combination:
      • Infantile convulsion and paroxysmal kinesigenic dyskinesia in the same subject.
    • Formerly known as:
      • Infantile convulsions with choreoathetosis (ICCA) syndrome.
    • Characteristics:
      • Epileptic disorder presenting in the first year of life.
      • Usually remitting within 2 years of age.
      • Appearance of PKD later in life.

References

Landolfi A, Barone P, Erro R (2021) The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology. Front Neurol 12 ():629747. DOI: 10.3389/fneur.2021.629747 PMID: 33746883.

Lee H-Y, Huang Y, Bruneau N, Roll P, Roberson EDO, Hermann M, et al.. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. (2012) 1:2–12. 10.1016/j.celrep.2011.11.001 [PMC free article] [PubMed] [CrossRef] [Google Scholar]