PRRT2 mutations and paroxysmal disorders.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Mutations in the Piankurtin-related protein 2 (PRRT2) gene have recently been linked to paroxysmal disorders.
• The clinical spectrum and underlying pathophysiology of PRRT2 mutation-associated disorders require further elucidation.

Purpose of the Study:

• To comprehensively review the literature on PRRT2 mutation-associated disorders.
• To describe the broad clinical spectrum of these conditions.
• To present current hypotheses regarding the pathophysiology of PRRT2-related disorders.

Main Methods:

• Literature review of studies reporting PRRT2 mutations and associated clinical phenotypes.
• Analysis of reported clinical syndromes, including paroxysmal dyskinesias, seizures, and other neurological manifestations.
• Synthesis of current hypotheses on the molecular mechanisms and pathogenetic pathways.

Main Results:

• PRRT2 mutations are associated with a diverse range of clinical syndromes, encompassing various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, and episodic ataxia.
• Homozygous PRRT2 mutations have been linked to intellectual disability.
• The PRRT2 protein interacts with SNAP-25, suggesting a role in synaptic regulation within the cortex and basal ganglia, potentially leading to neuronal hyperexcitability via loss of function.

Conclusions:

• The clinical spectrum associated with PRRT2 mutations is broad and extends beyond typical paroxysmal disorders.
• PRRT2 loss of function is a proposed mechanism causing synaptic deregulation and neuronal hyperexcitability.
• Phenotypic variability likely results from interactions with environmental factors, modifier genes, and age-dependent expression, highlighting the need for further research into molecular pathways for improved diagnosis and treatment.