PPFIA4 mutation: A second hit in POLG related disease?

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Epilepsy is often linked to mutations in the DNA polymerase gamma (POLG) gene, typically requiring two mutated copies (biallelic recessive).
• Monoallelic POLG mutations have been observed in patients with seizures, but a second genetic factor was often presumed but unidentified.
• Understanding the genetic basis of epilepsy is crucial for tailoring treatment strategies, such as avoiding hepatotoxic drugs like valproic acid (VPA) in POLG-related epilepsy.

Observation:

• A 12-year-old boy presented with drug-resistant focal onset epilepsy, mild developmental delay, and behavioral issues.
• Genetic analysis revealed potential pathogenic variants in the POLG gene inherited from his asymptomatic mother.
• He also carried a potential pathogenic variant in the liprin-alpha-4 (PPFIA4) gene, inherited from his asymptomatic father.

Findings:

• The PPFIA4 gene has no prior association with neurological disorders, but its product interacts with genes involved in neurotransmission and epileptogenesis.
• The patient's phenotype is hypothesized to result from the combined detrimental effects of variants in both POLG and PPFIA4 on neurons.
• The possibility of an undetected second POLG mutation cannot be excluded.

Implications:

• This case highlights the potential for oligogenic inheritance (multiple genes contributing to a disorder) in unexplained neurological conditions.
• It expands the genetic landscape of epilepsy beyond monogenic causes.
• Future genetic research should consider complex inheritance patterns for neurological diseases.