CRH – Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Limited genetic evidence supports a role for CRH in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In a single Italian family, two affected individuals carried a novel heterozygous missense variant c.89C>G (p.Pro30Arg), which cosegregated with disease in an autosomal dominant pattern (PMID:23593457). Conversely, linkage and mutational screening of CRH in three additional unrelated ADNFLE families (14 affected individuals) excluded CRH involvement, illustrating genetic heterogeneity (PMID:17324557).

Functional in vitro assays demonstrated that c.89C>G (p.Pro30Arg) leads to significantly reduced CRH secretion, consistent with a haploinsufficiency mechanism that could impair stress-response modulation and contribute to nocturnal frontal lobe seizures. However, this evidence is limited by the single kindred report and lack of replication cohorts, necessitating further studies to establish clinical validity and utility.

Key take-home: CRH variant c.89C>G (p.Pro30Arg) shows functional impact on hormone secretion and cosegregates in one ADNFLE family, but broader genetic and clinical confirmation is required before diagnostic implementation.

References

• PloS One • 2013 • Functional characterization of a CRH missense mutation identified in an ADNFLE family. PMID:23593457
• Epilepsy research • 2007 • Further evidence of genetic heterogeneity in families with autosomal dominant nocturnal frontal lobe epilepsy. PMID:17324557

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