A 32-year-old on valproate for bipolar disorder becomes pregnant. Apart from neural tube defects, the teratogenic concern specifically linked to valproate's inhibition of histone deacetylase (HDAC) relates to:

• A Impaired cardiac septation due to misregulation of GATA transcription factors
• B Increased risk of autism spectrum disorder and cognitive impairment in offspring via epigenetic disruption of neurodevelopmental gene expression ✓
• C Limb reduction defects due to inhibition of Wnt/beta-catenin signaling in limb bud mesenchyme
• D Cleft palate secondary to reduced bone morphogenetic protein signaling in palatal shelves

Explanation

Valproate inhibits HDAC enzymes, which regulate chromatin structure by removing acetyl groups from histone lysine residues. During fetal neurodevelopment, valproate-induced HDAC inhibition leads to persistent hyperacetylation of histones, disrupting normal gene expression patterns in the developing brain. Epidemiological studies (EUROCAT, MONEAD) have established a ~3-fold increased risk of autism spectrum disorder and significant cognitive deficits in children exposed to valproate in utero, even independent of the neural tube defect risk (which is folic acid-related). This is now a black-box warning.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.