PRRT2 encodes for proline-rich transmembrane protein 2 involved in synaptic vesicle fusion and presynaptic neurotransmitter release. Mutations in human PRRT2 have been related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with choreoathetosis, benign familial infantile epilepsies, and hemiplegic migraine. PRRT2 mutations cause neuronal hyperexcitability, which could be related to basal ganglia or cortical circuits dysfunction, leading to paroxysmal disorders. PRRT2 is expressed in the cerebral cortex, basal ganglia, and cerebellum. Approximately, 90% of pathogenic variants are inherited and 10% are de novo. Paroxysmal attacks in PKD are characterized by dystonia, choreoathetosis, and ballismus. In the benign familial infantile epilepsy (BFIE), seizures are usually focal with or without generalization, usually begin between 3 and 12 months of age and remit by 2 years of age. In 30% of cases of PRRT2-associated PKD, there is an association with BFIE, and this entity is referred to as PKD with infantile convulsions (PKD/IC). PRRT2 mutations are the cause of benign family childhood epilepsy and PKD/IC. On the other hand, PRRT2 mutations do not seem to correlate with other types of epilepsy. The increasing incidence of hemiplegic migraine in families with PRRT2-associated PKD or PKD/IC suggests a common disease pathway, and it is possible to assert that BFIE, paroxysmal kinesigenic dyskinesia, and PKD with IC belong to a continuous disease spectrum of PRRT2-associated diseases.

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AbstractAicardi–Goutières syndrome (AGS) is a rare disorder characterized by acquired microcephaly, cerebral calcifications, leukodystrophy, cerebral atrophy, chronic lymphocytosis, and increased interferon-α in cerebrospinal fluid. We report on two children affected by AGS type 2, caused by mutations in RNASEH2B. The first child had the mutation c.529G > A (p.A177T) and presented with an atypical and mild phenotype, with delayed psychomotor development, calcifications of the brain white matter and basal ganglia, and interferon signature positivity. The disease course was stable. The second child presented the mutation c.554T > G (p.V185G) and showed a later onset (15 months) and a more progressive clinical course with functional inability in the upper limbs, steppage gait, and irritability. Despite immunoglobulin therapy, she developed to progressive tetraparesis and severe hypotonia. This case report highlights that RNASEH2B mutation cannot fully predict the phenotype of AGS type 2 when a mutation c.529G > A occurs. Moreover, an earlier symptomatology may be not related to a more severe prognosis or to a partial or absent response to treatment.

Glutamate is the most relevant excitatory neurotransmitter of the central nervous system; it binds with several receptors, including N-methyl-D-aspartate receptors (NMDARs), a subtype of ionotropic glutamate receptor that displays voltage-dependent block by Mg2+ and a high permeability to Ca2+. GRIN2A and GRIN2B genes encode the GluN2A and GluN2B subunits of the NMDARs, which play important roles in synaptogenesis, synaptic transmission, and synaptic plasticity, as well as contributing to neuronal loss and dysfunction in several neurological disorders. Recently, individuals with a range of childhood-onset drug-resistant epilepsies, such as Landau–Kleffner or Lennox–Gastaut syndrome, intellectual disability (ID), and other neurodevelopmental abnormalities have been found to carry mutations in GRIN2A and GRIN2B, with high variable expressivity in phenotype. The first one is found mainly in epilepsy-aphasia syndromes, while the second one mainly in autism, schizophrenia, and ID, such as autism spectrum disorders. Brain magnetic resonance imaging alterations are found in some patients, even if without a clear clinical correlation. At the same time, increasing data on genotype–phenotype correlation have been found, but this is still not fully demonstrated. There are no specific therapies for the treatment of correlated NMDARs epilepsy, although some evidence with memantine, an antagonist of glutamate receptor, is reported in the literature in selected cases with mutation determining a gain of function.